JPH07112928A - Method for improving solubility of slightly-soluble medicine and granule medicine obtained by the same - Google Patents
Method for improving solubility of slightly-soluble medicine and granule medicine obtained by the sameInfo
- Publication number
- JPH07112928A JPH07112928A JP25830893A JP25830893A JPH07112928A JP H07112928 A JPH07112928 A JP H07112928A JP 25830893 A JP25830893 A JP 25830893A JP 25830893 A JP25830893 A JP 25830893A JP H07112928 A JPH07112928 A JP H07112928A
- Authority
- JP
- Japan
- Prior art keywords
- hydrophilic substance
- medicine
- solubility
- nozzle
- solution
- 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 51
- 238000000034 method Methods 0.000 title claims abstract description 38
- 239000008187 granular material Substances 0.000 title abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 23
- 239000000843 powder Substances 0.000 claims abstract description 18
- 239000002245 particle Substances 0.000 claims abstract description 13
- 238000005469 granulation Methods 0.000 claims abstract description 11
- 230000003179 granulation Effects 0.000 claims abstract description 11
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000011248 coating agent Substances 0.000 claims abstract description 8
- 238000000576 coating method Methods 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims description 37
- 239000000725 suspension Substances 0.000 claims description 3
- 238000005507 spraying Methods 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 238000003756 stirring Methods 0.000 abstract description 2
- 239000006185 dispersion Substances 0.000 abstract 3
- 238000005096 rolling process Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 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 description 10
- 229960001597 nifedipine Drugs 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- 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 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 8
- 239000008101 lactose Substances 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 229940032147 starch Drugs 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 3
- 229960003464 mefenamic acid Drugs 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000006104 solid solution Substances 0.000 description 3
- 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 2
- 229920002488 Hemicellulose Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- 238000005280 amorphization Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- CJDRUOGAGYHKKD-RQBLFBSQSA-N 1pon08459r Chemical compound CN([C@H]1[C@@]2(C[C@@]3([H])[C@@H]([C@@H](O)N42)CC)[H])C2=CC=CC=C2[C@]11C[C@@]4([H])[C@H]3[C@H]1O CJDRUOGAGYHKKD-RQBLFBSQSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 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 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- CJDRUOGAGYHKKD-UHFFFAOYSA-N Iso-ajmalin Natural products CN1C2=CC=CC=C2C2(C(C34)O)C1C1CC3C(CC)C(O)N1C4C2 CJDRUOGAGYHKKD-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 244000061121 Rauvolfia serpentina Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 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 description 1
- 230000009471 action Effects 0.000 description 1
- 229960004332 ajmaline Drugs 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 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
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- -1 for example Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000012052 hydrophilic carrier Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000003232 water-soluble binding agent Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、水に難溶性の結晶性薬
物の溶解性を改善する方法およびそれにより得られる溶
解性の改善された薬剤組成物に関するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for improving the solubility of a poorly water-soluble crystalline drug and a pharmaceutical composition having improved solubility obtained thereby.
【０００２】[0002]
【従来の技術】通常、人（ひと）が内服する医薬は、消
化器内で溶解され、溶液の状態で体内に吸収されるた
め、溶解度の小さい医薬や溶解速度の遅い医薬（以下、
これらを難溶性医薬という）は、そのまま服用しても全
量が吸収されることはなく、一部が未溶解のまま体外に
排泄されてしまう。2. Description of the Related Art Usually, a medicine taken by a person is dissolved in the digestive tract and absorbed in the body in a solution state. Therefore, a medicine having a low solubility or a medicine having a slow dissolution rate (hereinafter
These are referred to as sparingly soluble drugs), but even if they are taken as they are, the whole amount is not absorbed, and some are excreted outside the body in an undissolved state.
【０００３】しかし、これでは医薬が無駄になるばかり
でなく、医薬の吸収量が各個人によって異なったり、消
化器内の状態によって変動したりするために、適正な内
服量を決めることが出来なくなってしまう。However, this not only wastes the medicine, but also the absorption amount of the medicine varies from individual to individual and varies depending on the state of the digestive system, so that it is impossible to determine an appropriate internal dose. Will end up.
【０００４】そこで、従来より、消化器内における難溶
性医薬の溶解度を大きくしたり、溶解速度を速めたりす
る方法が数多く提案されているが、それらの中でも実用
性のある方法としては、微細化、非晶質化、包接
化にほぼ限られる。Therefore, many methods have been proposed in the past for increasing the solubility of a poorly soluble drug in the digestive tract or for increasing the dissolution rate. Among them, as a practical method, micronization is used. It is almost limited to amorphization and inclusion.
【０００５】[0005]
【発明が解決しようとする課題】しかし、上記の方法
〜のうち、例えばシクロデキストリンを用いる包接化
方法は、シクロデキストリンの孔径が包接される難溶性
薬物に適した大きさであることが必要とされ、おそらく
このために溶解性の改善効果は、シクロデキストリンの
種類と難溶性薬物の組み合わせとによって甚だしい差異
が生じる。従って、特定の薬物に対して適当な孔径のシ
クロデキストリンが見い出せない場合や、見い出せたと
しても極めて高価な品種であったりする場合が少なくな
く、汎用性のある方法とは言い難い。However, among the above-mentioned methods, the inclusion method using cyclodextrin, for example, may have a pore size of cyclodextrin which is suitable for a poorly soluble drug to be included. The solubility improvement effect that is required, and perhaps because of this, makes a huge difference depending on the type of cyclodextrin and the combination of poorly soluble drugs. Therefore, there are many cases where a cyclodextrin having an appropriate pore size cannot be found for a specific drug, or even if found, it is an extremely expensive variety, and it cannot be said to be a versatile method.
【０００６】また、固溶体を形成して非晶質化する方法
は古くから知られているが、その溶解性改善効果は十分
ではないことが指摘されていて、これを改善する手法が
提案されている（特公平３−１２８８号公報、特公平３
−２８４０４号公報）。これは、乳糖などをヒドロキシ
プロピルセルロースのような水溶性バインダーで造粒し
た細粒上に、難溶性薬物の一種であるニフェジピンと、
ポリビニルピロリドン、ヒドロキシプロピルメチルセル
ロース、メチルセルロースなどの有機溶媒液とを噴霧、
乾燥して固溶体コーティングを施すものである。Further, although a method of forming a solid solution to make it amorphous has been known for a long time, it has been pointed out that its effect of improving the solubility is not sufficient, and a method for improving this has been proposed. (Japanese Patent Publication No. 3-1288, Japanese Patent Publication No. 3)
-28404 publication). This is because nifedipine, a kind of poorly soluble drug, is added to fine granules obtained by granulating lactose with a water-soluble binder such as hydroxypropyl cellulose.
Spray with an organic solvent liquid such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylcellulose,
It is dried to apply a solid solution coating.
【０００７】また、デンプングリコール酸ナトリウム
（ＣＭＳ）と、難溶性薬物の１つであるメフェナム酸と
を自動乳鉢で摩砕して機械的にＣＭＳ粉末上にメフェナ
ム酸を付着させることにより非晶質化し、溶解性を改善
する提案（桜井ら、薬剤学52，NO.2、86(1992)）がなさ
れている。また、その際の剥落による効果の低下を防止
するために、この粒子をさらにポリエチレングリコール
と摩砕してポリエチレングリコールでコーティングする
方法（桜井ら、ｉbid.，93(1992)）もある。Further, sodium starch glycolate (CMS) and mefenamic acid, which is one of the poorly soluble drugs, are ground in an automatic mortar and mechanically attached to the CMS powder to form amorphous. Has been proposed (Sakurai et al., Pharmaceutical Science 52 , NO.2, 86 (1992)). There is also a method of further grinding the particles with polyethylene glycol and coating with polyethylene glycol in order to prevent the reduction of the effect due to peeling at that time (Sakurai et al., Ibid., 93 (1992)).
【０００８】しかし、非晶質は、もともと不安定な状態
であり、光、熱、湿度などのような外界の刺激により、
あるいは経時的に安定形である結晶状態に変化し易いた
め、確実な手法ではない。[0008] However, amorphous is an unstable state by nature, and it is exposed to external stimuli such as light, heat, and humidity.
Alternatively, it is not a reliable method because it easily changes to a stable crystalline state over time.
【０００９】本発明者らは、先にデンプン上に、ヒドロ
キシプロピルセルロースのエタノール溶液に難溶の薬物
であるインドメタシンを一部溶解したスラリー状で（粉
体工学誌27，750(1990) ）、あるいはメフェナム酸を溶
液として（第８回 製剤と粒子設計、要旨集、P.11(199
1)）加えた液を噴霧して溶解性を改善する方法を提案し
た。この方法は、溶解時に難溶性薬物の実効表面積を広
くし、かつデンプンやヒドロキシプロピルセルロースの
作用で溶解性を上げるものとされるが、一部固溶化の作
用が加わっているものと考えられ、また溶解性の向上も
不十分であった。The present inventors previously prepared a slurry in which indomethacin, which is a poorly soluble drug in an ethanol solution of hydroxypropylcellulose, was partially dissolved on starch (Powder Engineering Journal 27 , 750 (1990)). Or mefenamic acid as a solution (8th Preparation and Particle Design, Abstracts, P. 11 (199
1)) We proposed a method to improve the solubility by spraying the added liquid. This method is to increase the effective surface area of the poorly soluble drug at the time of dissolution, and increase the solubility by the action of starch or hydroxypropyl cellulose, but it is considered that a part of the solution is added. Further, the improvement in solubility was insufficient.
【００１０】本発明の目的は、難溶性薬物の溶解性を大
幅に改善することのできる新規な技術を提供することに
ある。An object of the present invention is to provide a new technique capable of greatly improving the solubility of a poorly soluble drug.
【００１１】[0011]
【課題を解決するための手段】本発明者らは、前述した
デンプンのような親水性担体上に難溶性薬物を湿式で付
着させて溶解性を改善する方法についてさらに研究を行
った結果、固溶体による非晶質化を伴うことなく、難溶
性薬物を著しい過飽和溶液として安定に維持することが
できる溶解性改善方法を確立することに成功し、本発明
を完成した。Means for Solving the Problems The present inventors further conducted research on a method for wet-adhering a poorly soluble drug on a hydrophilic carrier such as the above-mentioned starch to improve solubility, and as a result, a solid solution was obtained. The inventors have succeeded in establishing a solubility improving method capable of stably maintaining a sparingly soluble drug as a significantly supersaturated solution without causing amorphization due to, and have completed the present invention.
【００１２】すなわち、本発明は、難溶性薬物を担持せ
しめた親水性物質の微粉末を水溶性高分子をバインダー
として造粒することを特徴とするものである。That is, the present invention is characterized in that a fine powder of a hydrophilic substance carrying a poorly soluble drug is granulated using a water-soluble polymer as a binder.
【００１３】本発明において、難溶性薬物とは水に難溶
性の薬物を意味し、例えばイブプロフェン、インドメタ
シン、メフェナム酸、フェニトイン、アジマリン、硝酸
イソソルビド、ニフェジピン、ノスカピン、エピネフリ
ン、プレドニゾロン、プロスタグランジンＥ1 およびＥ
2 などを挙げることができるが、勿論これらに限定され
るものではなく、日本薬局方の規定で「水にほとんど溶
けない」または「水に極めて溶けにくい」とされる薬物
は全て本発明の適用対象となる。In the present invention, the poorly soluble drug means a drug which is poorly soluble in water, for example, ibuprofen, indomethacin, mefenamic acid, phenytoin, ajmaline, isosorbide nitrate, nifedipine, noscapine, epinephrine, prednisolone, prostaglandin E 1 And E
2, etc., but of course the present invention is not limited to these, and all drugs that are “poorly soluble in water” or “extremely insoluble in water” according to the Japanese Pharmacopoeia are applicable to the present invention. Be the target.
【００１４】また、本発明においては、難溶性薬物を担
持する親水性物質として、例えばグルコース、フラクト
ース、蔗糖、乳糖、デキストリン、デンプン、プルラ
ン、カルボキシメチルセルロースおよびその塩、カルボ
キシメチルスターチおよびその塩、セルロース、ポリビ
ニルアルコール、ヘミセルロースなどが使用されるが、
これらに限定されるものではない。また、親水性物質は
微粉末であることを要し、特に粒径５〜１００μｍのも
のが好適とされる。Further, in the present invention, as the hydrophilic substance carrying the poorly soluble drug, for example, glucose, fructose, sucrose, lactose, dextrin, starch, pullulan, carboxymethyl cellulose and its salt, carboxymethyl starch and its salt, cellulose. , Polyvinyl alcohol, hemicellulose, etc. are used,
It is not limited to these. Further, the hydrophilic substance is required to be a fine powder, and the one having a particle size of 5 to 100 μm is particularly suitable.
【００１５】難溶性薬物を親水性物質に担持させる方法
については、難溶性薬物の有機溶媒液に親水性物質を浸
漬する方法、親水性物質を攪拌、転動あるいは流動させ
つつ難溶性薬物の有機溶媒溶液および／または懸濁液を
噴霧する方法など任意であるが、なかでも親水性物質を
ノズルから噴射し、このノズルと一体化されたノズルま
たは別ノズルから難溶性薬物の有機溶媒溶液および／ま
たは懸濁液を噴霧して親水性物質にコーティングするジ
ェットコーティングシステム（特開平３−１３５４３０
号公報、特願平３−２７０５９８号明細書、フロイント
産業株式会社製「コートマイザー」）によるのが有利で
ある。なお、本発明では、難溶性薬物を親水性物質に担
持させる際にバインダーなどを添加する必要はない。Regarding the method of supporting the poorly soluble drug on the hydrophilic substance, the hydrophilic substance is immersed in an organic solvent solution of the poorly soluble drug, or the organic substance of the poorly soluble drug is agitated, tumbled or flowed while the organic substance of the poorly soluble drug is stirred. Any method such as spraying a solvent solution and / or suspension may be used. Among them, a hydrophilic substance is sprayed from a nozzle, and an organic solvent solution of a poorly soluble drug and / or a nozzle integrated with this nozzle or a separate nozzle Alternatively, a jet coating system in which a suspension is sprayed to coat a hydrophilic substance (JP-A-3-135430).
JP-A No. 3-270598, Freund Sangyo Co., Ltd. "Coatmizer"). In the present invention, it is not necessary to add a binder or the like when the poorly soluble drug is loaded on the hydrophilic substance.
【００１６】次に、このようにして得られた難溶性薬物
担持親水性物質の微粉末を水溶性高分子をバインダーと
して造粒する。水溶性高分子としては、ヒドロキシプロ
ピルセルロース、ヒドロキシプロピルメチルセルロー
ス、ヒドロキシエチルセルロース、カルボキシメチルセ
ルロースのナトリウム塩、ポリビニルピロリドン、プル
ラン、ポリビニルアルコール、ポリアクリル酸またはそ
の塩、アラビアガム、ヘミセルロースなどが例示され
る。なお、造粒の際には、水溶性高分子は水溶液とする
のが好ましいが、有機溶媒溶液あるいは含水有機溶媒溶
液でもよい。Next, the fine powder of the hardly-soluble drug-carrying hydrophilic substance thus obtained is granulated using a water-soluble polymer as a binder. Examples of the water-soluble polymer include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, sodium salt of carboxymethyl cellulose, polyvinylpyrrolidone, pullulan, polyvinyl alcohol, polyacrylic acid or a salt thereof, gum arabic, hemicellulose and the like. The water-soluble polymer is preferably an aqueous solution at the time of granulation, but an organic solvent solution or a water-containing organic solvent solution may be used.
【００１７】また、造粒によって得られる粒子の大きさ
や形状には特に制限はなく、細粒、顆粒、球形顆粒など
とすることができる。さらに、この造粒物は打錠した
り、カプセルに充填したりして用いることもできる。造
粒方法は、得ようとする造粒物の性状により流動層造
粒、攪拌造粒、転動造粒、押出し造粒などが適宜選択さ
れるが、なかでも流動層造粒が好適である。The size and shape of the particles obtained by granulation are not particularly limited, and fine particles, granules, spherical granules and the like can be used. Further, this granulated product can be used by tableting or filling a capsule. The granulation method is appropriately selected from fluidized bed granulation, stirring granulation, tumbling granulation, extrusion granulation and the like depending on the properties of the granulated product to be obtained, and among them, fluidized bed granulation is preferred. .
【００１８】[0018]
【実施例】以下、本発明の実施例を詳細に説明する。EXAMPLES Examples of the present invention will be described in detail below.
【００１９】（実施例１）難溶性薬物としてニフェジピ
ン（平均粒径２０μｍ）を用い、これをエタノールに溶
解して２重量％の溶液とした。この溶液を図１に示す構
造のジェットコーティング装置（フロイント産業株式会
社製、ＣＭ−ＭＩＮＩ）を使用し、下記の表１に示す条
件で平均粒径３２μｍの乳糖微粉末に噴霧して担持させ
ることにより粉末ａを得た。乳糖とニフェジピンとの割
合は、乳糖１００重量部に対してニフェジピン２重量部
とした。Example 1 Nifedipine (average particle size 20 μm) was used as a poorly soluble drug, which was dissolved in ethanol to give a 2% by weight solution. Using a jet coating device (CM-MINI manufactured by Freund Sangyo Co., Ltd.) having a structure shown in FIG. 1, this solution is sprayed and carried on lactose fine powder having an average particle diameter of 32 μm under the conditions shown in Table 1 below. Thus, powder a was obtained. The ratio of lactose and nifedipine was 2 parts by weight of nifedipine per 100 parts by weight of lactose.
【００２０】図１において、１は処理室、２はサイクロ
ン、３は空気導入部、４はフィルタ、５はヒータ、６は
ブロアである。処理室１内の底部に設置された３流体ノ
ズル７には、外部から薬物粒子８、水溶性高分子溶液９
および圧縮空気１０がそれぞれ供給される。図２に拡大
して示すように、３流体ノズル７には、粒子導入路８
ａ、溶液導入路９ａおよび２系統の空気導入路１０ａ、
１０ｂが設けられ、この３流体ノズル７から上方に向か
ってスプレーされる薬品粒子８と水溶性高分子溶液９と
がジェット気流によって接触される。In FIG. 1, 1 is a processing chamber, 2 is a cyclone, 3 is an air inlet, 4 is a filter, 5 is a heater, and 6 is a blower. A drug particle 8 and a water-soluble polymer solution 9 are externally applied to a three-fluid nozzle 7 installed at the bottom of the processing chamber 1.
And compressed air 10 are respectively supplied. As shown in an enlarged scale in FIG. 2, the three-fluid nozzle 7 has a particle introduction passage 8
a, solution introducing passage 9a and two systems of air introducing passage 10a,
10b is provided, and the chemical particles 8 sprayed upward from the three-fluid nozzle 7 and the water-soluble polymer solution 9 are brought into contact with each other by a jet stream.
【００２１】 表１ 吸気温度 ： ５０℃ 排気風量 ： 1.０ｍ3 ／ｍｉｎ フィーダー空気圧 ： 3.０ｋｇ／ｃｍ2 Ｇ スプレー空気圧 ： 1.０ｋｇ／ｃｍ2 Ｇ 粉体供給量 ： ５ｇ／ｍｉｎ 液体供給量 ： ５ｇ／ｍｉｎ 表２ 仕込量 ： ２００ｇ 吸気温度 ： ６０℃ スプレー空気圧 ： 1.０ｋｇ／ｃｍ2 Ｇ 液体供給量 ： 5.４ｇ／ｍｉｎ 次に、上記粉末ａを流動層造粒装置（フロイント産業株
式会社製、ＦＬ−ＭＩＮＩ）を使用し、ヒドロキシプロ
ピルセルロースの５重量％水溶液を用いて上記の表２に
示す条件で顆粒状に造粒し、0.３５〜0.７ｍｍ径に整粒
して顆粒Ａを得た。ヒドロキシプロピルセルロースは、
乳糖１００重量部に対して1.５重量部とした。Table 1 Intake temperature: 50 ° C. Exhaust air volume: 1.0 m 3 / min Feeder air pressure: 3.0 kg / cm 2 G Spray air pressure: 1.0 kg / cm 2 G Powder supply amount: 5 g / min Liquid supply amount : 5 g / min Table 2 Charge amount: 200 g Intake temperature: 60 ° C. Spray air pressure: 1.0 kg / cm 2 G Liquid supply amount: 5.4 g / min Next, the above powder a is granulated with a fluidized bed granulator (Freund Industrial Co., Ltd.). FL-MINI) (manufactured by the company) and granulated into granules using a 5% by weight aqueous solution of hydroxypropyl cellulose under the conditions shown in Table 2 above, and then sized to a diameter of 0.35-0.7 mm. Granule A was obtained. Hydroxypropyl cellulose is
The amount was 1.5 parts by weight based on 100 parts by weight of lactose.
【００２２】（実施例２）ニフェジピンのエタノール溶
液に、ニフェジピンと同量のヒドロキシプロピルセルロ
ースを加えた他は、実施例１と同様に操作して粉末ｂお
よび顆粒Ｂを得た。Example 2 Powder b and granule B were obtained in the same manner as in Example 1 except that the same amount of hydroxypropylcellulose as nifedipine was added to the ethanol solution of nifedipine.
【００２３】（比較例１）乳糖１００重量部とニフェジ
ピン２重量部とを均一に混合して粉末ｃを得た。Comparative Example 1 100 parts by weight of lactose and 2 parts by weight of nifedipine were uniformly mixed to obtain powder c.
【００２４】（比較例２）粉末ａに乳糖１００重量部に
対して２重量部のヒドロキシプロピルセルロースを均一
に混合して粉末ｄを得た。Comparative Example 2 Powder d was obtained by uniformly mixing powder a with 2 parts by weight of hydroxypropyl cellulose per 100 parts by weight of lactose.
【００２５】上記各粉末および顆粒からのニフェジピン
の溶出は、日局１２溶出試験法第２法（パドル法）に準
拠し、日局１２崩壊試験法第１液（ｐＨ約1.２）を用い
て自動溶出試験器（日本分光工業株式会社、ＤＴ−６１
０）で評価した。結果を図３に示す。The elution of nifedipine from each of the above powders and granules is based on the Japanese Pharmacopoeia 12 dissolution test method No. 2 (paddle method), and the Japanese Pharmacopoeia 12 disintegration test method No. 1 liquid (pH about 1.2) is used. Automatic Dissolution Tester (JASCO Corporation, DT-61
It was evaluated by 0). The results are shown in Fig. 3.
【００２６】図３から明らかなように、本発明による顆
粒はニフェジピンの飽和溶解度の５倍の過飽和溶液を与
え、かつそれが経時的に減少することなく過飽和濃度を
維持することができる。As can be seen from FIG. 3, the granules according to the invention give a supersaturated solution with 5 times the saturated solubility of nifedipine and can maintain the supersaturated concentration without it decreasing over time.
【００２７】[0027]
【発明の効果】難溶性薬物を担持させた親水性物質の微
粉末を水溶性高分子をバインダーとして造粒する本発明
によれば、水に難溶性の薬物の溶解性を改善することが
できるという優れた効果が得られる。Industrial Applicability According to the present invention in which a fine powder of a hydrophilic substance carrying a poorly soluble drug is granulated using a water-soluble polymer as a binder, the solubility of a poorly water-soluble drug can be improved. That is an excellent effect.
【図１】造粒工程で用いたジェットコーティング装置の
全体構成図である。FIG. 1 is an overall configuration diagram of a jet coating apparatus used in a granulation process.
【図２】図１に示すジェットコーティング装置の３流体
ノズルを拡大して示す断面図である。FIG. 2 is an enlarged sectional view showing a three-fluid nozzle of the jet coating apparatus shown in FIG.
【図３】実施例の顆粒および比較例の粉末の溶出曲線を
示す図である。FIG. 3 is a diagram showing elution curves of granules of Examples and powders of Comparative Examples.
１ 処理室 ２ サイクロン ３ 空気導入部 ４ フィルタ ５ ヒータ ６ ブロア ７ ３流体ノズル７ ８ 薬物粒子 ８ａ 粒子導入路 ９ 水溶性高分子溶液 ９ａ 溶液導入路 １０ 圧縮空気 １０ａ 空気導入路 １０ｂ 空気導入路 1 Processing chamber 2 Cyclone 3 Air introduction part 4 Filter 5 Heater 6 Blower 7 3 Fluid nozzle 7 8 Drug particle 8a Particle introduction path 9 Water-soluble polymer solution 9a Solution introduction path 10 Compressed air 10a Air introduction path 10b Air introduction path
─────────────────────────────────────────────────────
─────────────────────────────────────────────────── ───
【手続補正書】[Procedure amendment]
【提出日】平成５年１０月１９日[Submission date] October 19, 1993
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】図面[Document name to be corrected] Drawing
【補正対象項目名】図３[Name of item to be corrected] Figure 3
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【図３】 [Figure 3]
Claims (5)
粉末を水溶性高分子をバインダーとして造粒することを
特徴とする難溶性薬物の溶解性改善方法。1. A method for improving solubility of a poorly soluble drug, which comprises granulating a fine powder of a hydrophilic substance carrying a poorly soluble drug with a water-soluble polymer as a binder.
００μｍであることを特徴とする請求項１記載の難溶性
薬物の溶解性改善方法。2. The particle size of the fine powder of the hydrophilic substance is 5 to 1
The method for improving solubility of a poorly soluble drug according to claim 1, wherein the method has a solubility of 00 μm.
のノズルと一体化されたノズルまたは別ノズルから前記
難溶性薬物の有機溶媒溶液および／または懸濁液を噴霧
して前記親水性物質にコーティングすることにより、前
記難溶性薬物を前記親水性物質に担持させることを特徴
とする請求項１記載の難溶性薬物の溶解性改善方法。3. The hydrophilic substance is sprayed from a nozzle, and an organic solvent solution and / or suspension of the sparingly soluble drug is sprayed from a nozzle integrated with this nozzle or another nozzle to the hydrophilic substance. The method for improving solubility of a poorly soluble drug according to claim 1, wherein the hydrophilic substance is caused to support the poorly soluble drug by coating.
特徴とする請求項１記載の難溶性薬物の溶解性改善方
法。4. The method for improving the solubility of a poorly soluble drug according to claim 1, wherein granulation is performed using a fluidized bed granulator.
られた粒状薬剤。5. A granular drug obtained by the method for improving solubility according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25830893A JPH07112928A (en) | 1993-10-15 | 1993-10-15 | Method for improving solubility of slightly-soluble medicine and granule medicine obtained by the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25830893A JPH07112928A (en) | 1993-10-15 | 1993-10-15 | Method for improving solubility of slightly-soluble medicine and granule medicine obtained by the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07112928A true JPH07112928A (en) | 1995-05-02 |
Family
ID=17318451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25830893A Pending JPH07112928A (en) | 1993-10-15 | 1993-10-15 | Method for improving solubility of slightly-soluble medicine and granule medicine obtained by the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07112928A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003073261A (en) * | 2001-09-05 | 2003-03-12 | Shin Etsu Chem Co Ltd | Method for producing pharmaceutical solid preparation containing poorly soluble drug |
| US7081255B2 (en) * | 1996-05-20 | 2006-07-25 | Janssen Pharmaceutica, N.V. | Antifungal compositions with improved bioavailability |
| JP2009120615A (en) * | 2000-01-18 | 2009-06-04 | Bayer Schering Pharma Ag | Drospirenone for hormone replacement therapy |
-
1993
- 1993-10-15 JP JP25830893A patent/JPH07112928A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7081255B2 (en) * | 1996-05-20 | 2006-07-25 | Janssen Pharmaceutica, N.V. | Antifungal compositions with improved bioavailability |
| US8591948B2 (en) * | 1996-05-20 | 2013-11-26 | Janssen Pharmaceutica N.V. | Antifungal compositions with improved bioavailability |
| US9642806B2 (en) | 1996-05-20 | 2017-05-09 | Janssen Pharmaceutica Nv | Antifungal compositions with improved bioavailability |
| JP2009120615A (en) * | 2000-01-18 | 2009-06-04 | Bayer Schering Pharma Ag | Drospirenone for hormone replacement therapy |
| JP2003073261A (en) * | 2001-09-05 | 2003-03-12 | Shin Etsu Chem Co Ltd | Method for producing pharmaceutical solid preparation containing poorly soluble drug |
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