JPH0328404B2 - - Google Patents
Info
- Publication number
- JPH0328404B2 JPH0328404B2 JP56177323A JP17732381A JPH0328404B2 JP H0328404 B2 JPH0328404 B2 JP H0328404B2 JP 56177323 A JP56177323 A JP 56177323A JP 17732381 A JP17732381 A JP 17732381A JP H0328404 B2 JPH0328404 B2 JP H0328404B2
- Authority
- JP
- Japan
- Prior art keywords
- nifedipine
- formulation
- solid solution
- preparation
- present
- 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 - Lifetime
Links
- 239000000203 mixture Substances 0.000 claims description 80
- 239000006104 solid solution Substances 0.000 claims description 61
- 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 description 58
- 229960001597 nifedipine Drugs 0.000 claims description 58
- 238000002360 preparation method Methods 0.000 claims description 46
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 32
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 32
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 29
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 29
- 239000010419 fine particle Substances 0.000 claims description 19
- 238000000576 coating method Methods 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000004503 fine granule Substances 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 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 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000003232 water-soluble binding agent Substances 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 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 3
- 235000001727 glucose Nutrition 0.000 claims 1
- 238000009472 formulation Methods 0.000 description 77
- 230000000052 comparative effect Effects 0.000 description 29
- 238000004090 dissolution Methods 0.000 description 16
- 239000000843 powder Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005469 granulation Methods 0.000 description 7
- 230000003179 granulation Effects 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000007922 dissolution test Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 235000021189 garnishes Nutrition 0.000 description 2
- 229940031702 hydroxypropyl methylcellulose 2208 Drugs 0.000 description 2
- 238000005096 rolling process Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は安定な易吸収性ニフエジピン製剤の製
法に係り、更に詳しくは、水溶性の医薬添加物を
造粒して得られる細粒担体をニフエジピンとヒド
ロキシプロピルメチルセルロース（以下HPMC
という）またはメチルセルロース（以下MCとい
う）よりなる固溶体でコーテイングすることを特
徴とする易溶出性ないし易吸収性であり、かつ安
定なニフエジピン製剤の製法に関する。
ニフエジピンは冠血管拡張作用を有し狭心症発
作の優れた治療剤であるが、狭心症発作の治療の
ためにはその製剤は服用が容易であり服用後急速
に体内へ吸収されるものでなければならない。
しかし、ニフエジピンは水に難溶な結晶であつ
て、その粉末を通常の製剤としても体内への吸収
性が悪く狭心症発作に対する上記要求に応じ難
い。
そこでニフエジピンの吸収不良性を改善する手
段の１つとして、ニフエジピンとポリビニルピロ
リドン（以下PVPという）を有機溶媒に溶解し、
その溶液から有機溶媒を留去し、ここに得られる
ニフエジピンとPVPよりなる固溶体を散剤また
は顆粒剤〔以下この種の製剤をPVP固溶体紛末
製剤（比較製剤イ）という〕とする方法が提案さ
れている（特開昭54−2316号公報）。このPVP固
溶体粉末製剤（比較製剤イ）の溶出性ないし吸収
性は、単なるニフエジピンの粉末製剤に比し改善
されているが、しかし未だ充分とはいい難い。
一方、本発明者等は、より改良されたニフエジ
ピン製剤を得るために種々検討した結果、ニフエ
ジピンとPVPを有機溶媒に溶解し、この溶液を
結晶乳糖に噴霧乾燥してニフエジピンとPVPよ
りなる固溶体で均一にコーテイングされた細粒製
剤〔以下この種の製剤をPVP固溶体コーテイン
グ製剤（比較製剤ロ）という〕を提案した（ケミ
カル・フアルマシユウテイカル・ブレテイン、29
巻、1715〜1723頁、1981年）。このPVP固溶体コ
ーテイング製剤（比較製剤ロ）は、前記のPVP
固溶体粉末製剤（比較製剤イ）に比し遥かに易溶
出性ないし易吸収性であつて、狭心症発作の治療
により適している。しかしながら、この製剤は、
高湿度下に放置すると、該製剤から水へのニフエ
ジピンの溶出性が低下するという現象が見られ
（試験例３、第６図参照）、かかる現象の故に該製
剤の保存のみならずその製造工程においても防湿
処置が要求されることになる。
本発明等は、上記のPVP固溶体コーテイング
製剤（比較製剤ロ）の難点を改良するために検討
した結果、PVPの代りにHPMCまたはMCを採
用し、水溶性の医薬添加物を造粒して得られる細
粒担体をニフエジピンとHPMCとの固溶体、ま
たはニフエジピンとMCとの固溶体で均一にコー
テイングする方法を発明した。
本発明の方法によつて製造したニフエジピンと
HPMCとの固溶体でコーテイングした細粒製剤
（以下HPMC固溶体コーテイング製剤という）お
よびニフエジピンとMCとの固溶体でコーテイン
グした細粒製剤（以下MC固溶体コーテイング製
剤という）は、ニフエジピンの水への溶出性ない
し体内への吸収性はPVP固溶体コーテイング製
剤（比較製剤ロ）のそれに匹敵し、しかもその
上、湿気に対して安定である。
本発明の方法は、水溶性の医薬添加物よりなる
細粒担体を調製する工程、ニフエジピンと
HPMCの有機溶媒溶液またはニフエジピンとMC
を調製する工程、該ニフエジピン固溶体溶液を用
いて細粒担体を均一にコーテイングする工程より
なる。以下各工程について説明する。
まず、本発明における細粒担体の調製工程にお
ける細粒および最終製剤における細粒とは、共に
日本薬局方製剤総則に定義されている粒度範囲の
ものをいう。
本発明の細粒担体は、水溶性の医薬添加物、例
えば乳糖、白糖、グルコース等に水溶性の結合
剤、例えばヒドロキシプロピルセルロース，
HPMC，PVP，ポリビニールアルコール，アラ
ビアゴム，ゼラチン等を配合し、さらに好ましく
はアルキル硫酸エステル，ジアルキルスルホサク
シネート等の界面活性剤を配合し、常法に従つて
造粒される。この造粒法としては、湿式造粒法、
乾式造粒法、流動層造粒法、転動造粒法など通常
用いられるもののいずれを適用してもよいが、流
動層造粒法または、転動造粒法が最も好ましい。
賦形剤と結合剤の使用量は、通常の場合と同様
でよいが、さらに界面活性剤を配合する場合には
全仕込量の２〜５％程度とするのがよい。
次にニフエジピン固溶体溶液は、ニフエジピン
とHPMCまたはニフエジピンとMCを有機溶媒好
ましくはエタノールージクロルメタン（１：
1w／ｗ）に溶解して調製される。ここに用いら
れるHPMCとしては第十改正日本薬局方の「ヒ
ドロキシプロピルメチルセルロース2208」、「同
2906」「同2910」が挙げられ、MCとしては同薬
局方の「メチルセルロース」が挙げられる。
ニフエジピンに対するHPMCおよびMCの使用
割合は、共に１：１〜１：７好ましくは１：２〜
１：５（重量比）である。
ニフエジピンに対するHPMCまたはMCの使用
割合が上記範囲の下限以下の場合（比較製剤ハお
よび比較製剤ニ）は、次の工程であるコーテイン
グ工程で細粒担体の表面にニフエジピン結晶が析
出し、薬剤からのニフエジピンの水への溶出性が
低下する（第２図、第３図参照）。一方、HPMC
またはMCを前記範囲の上限以上に使用しても、
徒らに剤形が大きくなるばかりであつて、それに
よつてニフエジピンの溶出性をより向上させるこ
とはできない。
次にニフエジピン固溶体溶液に使用するエタノ
ール−ジクロルメタン（１：1w／ｗ）の使用量
は、ニフエジピンとHPMCまたはニフエジピン
とMCを室温で完溶するに要する量の1.2〜1.5倍
量が適当である。
最後に、本発明においては、細粒担体はニフエ
ジピン固溶体によつて正確にかつ均一にコーテイ
ングされなければならない。
従つて、コーテイング工程においては、細粒担
体を常に流動状態に保持しつつ、これに所定量の
ニフエジピン固溶体溶液を均一に添加し乾燥する
のが望ましい。具体的には、通常の頚粒や細粒の
製造に用いられる流動層造粒機、転動造粒機内で
噴霧コーテイング操作を施すのが好便である。
この場合の諸条件例えば単位時間当りの噴霧量
処理温度、細粒担体の流動度等は、通常の頚粒や
細粒を製造する場合の諸条件を準用することがで
きる。
かかるコーテイング法の採用によつて原料の細
粒担体の破砕および相互結合を防止しつつ、所定
の量のニフエジピン固溶体で正確均一にコーテイ
ングすることができ、しかもその操作は容易で作
業効率も良好である。
上述のようにして得られる本発明の製剤は品質
的に極めて優れている。
まず、経口投与した場合の生体内へのニフエジ
ピンの吸収性においては、本発明のHPMC固溶
体コーテイング製剤（本発明製剤Ａ−２）および
MC固溶体コーテイング製剤（本発明製剤Ｂ−
２）は、PVP固溶体粉末製剤（比較製剤イ）よ
り著るしく優れており、PVP固溶体コーテイン
グ製剤（比較製剤ロ）と略同等に易吸収性である
（試験例１、第１図参照）。
次に、本発明の製剤は、PVP固溶体コーテイ
ング製剤（比較製剤ロ）の如く湿気に対して不安
定ではない。PVP固溶体コーテイング製剤（比
較製剤ロ）は、低湿度条件下では安定であるが、
高湿度条件下例えば相対湿度75％，40℃に放置す
ると、ニフエジピンの溶出性が著るしく阻害され
る（試験例３、第６図参照）。これに対し、本発
明のHPMC固溶体コーテイング製剤（本発明製
剤Ａ−２）およびMC固溶体コーテイング製剤
（本発明製剤Ｂ−２）は、上記湿度条件下に放置
しても、共にニフエジピンの溶出性の低下が見ら
れない（試験例３、第４図、第５図参照）。
本発明の製剤の湿気に対する安定性は、製剤の保
存保管上は勿論のこと、製剤工程上においても極
めて有益である。
以下に実施例を挙げて説明する。
参考例 １
PVP固溶体粉末製剤（比較製剤イ）の製造乳
糖940gに、ヒドロキシプロピルセルロース20g、
PVP30gおよびニフエジピン10gを温エタノール
300mlに溶解して加え、万能混合攪拌機（品川工
業所、8DMV−Ｒ型）にて練合後、0.5mmのスク
リーンを用いて押し出し造粒し、61℃で棚乾燥し
た。これを32メツシユの飾で整粒した。
参考例 ２
PVP固溶体コーテイング製剤（比較製剤ロ）
の製造後記の実施例１の細粒担体960gを用い、
これをニフエジピン10gとPVP30gをエタノール
−ジクロルメタン（１：1w／ｗ）300mlに溶解し
た溶液を用いて実施例１と同様に噴霧コーテイン
グした。
実施例 １
HPMC固溶体コーテイング製剤（本発明の製
剤Ａ−１、Ａ−２、Ａ−３、Ａ−４）の製造
(1) 細粒担体の製造
流動層造粒乾燥機〔Glatt Okawara WSG−
１型〕に乳糖930部を入れ、これにヒドロキシプ
ロピルセルロース20部を水500部に溶かした溶液
を噴霧し、造粒、乾燥した後32メツの飾で整粒し
細粒担体を得る。
(2) コーテイング
以下の処方と方法によつて本発明のHPMC固
溶体コーテイング製剤（本発明製剤Ａ−１、Ａ−
２、Ａ−３、Ａ−４）および比較製剤ハを製造し
た。
The present invention relates to a method for producing a stable and easily absorbable nifedipine preparation, and more specifically, the present invention relates to a method for producing a stable and easily absorbable nifedipine preparation.
The present invention relates to a method for producing a stable nifedipine preparation that is easily dissolvable or absorbable, and is coated with a solid solution consisting of methylcellulose (hereinafter referred to as MC) or methyl cellulose (hereinafter referred to as MC). Nifedipine has a coronary vasodilatory effect and is an excellent therapeutic agent for angina attacks, but for the treatment of angina pectoris attacks, it is necessary to use a preparation that is easy to take and is rapidly absorbed into the body after taking it. Must. However, nifedipine is a crystal that is sparingly soluble in water, and even if its powder is used as a normal formulation, it is poorly absorbed into the body and cannot meet the above-mentioned requirements for angina pectoris attacks. Therefore, one way to improve the malabsorption properties of nifedipine is to dissolve nifedipine and polyvinylpyrrolidone (hereinafter referred to as PVP) in an organic solvent.
A method has been proposed in which the organic solvent is distilled off from the solution and the resulting solid solution of nifedipine and PVP is made into a powder or granules [hereinafter, this type of preparation is referred to as a PVP solid solution powder preparation (comparative preparation A)]. (Japanese Unexamined Patent Publication No. 54-2316). Although the dissolution and absorption properties of this PVP solid solution powder preparation (comparative preparation A) are improved compared to a simple powder preparation of nifedipine, they are still not sufficient. On the other hand, as a result of various studies to obtain a more improved nifedipine preparation, the present inventors dissolved nifedipine and PVP in an organic solvent and spray-dried this solution onto crystalline lactose to form a solid solution consisting of nifedipine and PVP. We proposed a uniformly coated fine granule preparation [hereinafter this type of preparation will be referred to as PVP solid solution coated preparation (comparative preparation B)] (Chemical Pharmaceutical Bulletin, 29).
Vol., pp. 1715-1723, 1981). This PVP solid solution coated formulation (comparative formulation B) is the PVP solid solution coated formulation described above.
It is far more easily dissolvable and absorbable than the solid solution powder preparation (comparative preparation A), and is more suitable for the treatment of angina pectoris attacks. However, this formulation
When left under high humidity, a phenomenon was observed in which the dissolution of nifedipine from the formulation into water decreased (see Test Example 3, Figure 6), and due to this phenomenon, not only the storage of the formulation but also its manufacturing process was observed. Moisture-proofing measures will also be required. As a result of studies to improve the drawbacks of the above-mentioned PVP solid solution coated preparation (comparative preparation B), the present invention adopts HPMC or MC instead of PVP and granulates water-soluble pharmaceutical additives. We have invented a method for uniformly coating a fine particle carrier with a solid solution of nifedipine and HPMC or a solid solution of nifedipine and MC. Nifedipine produced by the method of the present invention and
Fine granule preparations coated with a solid solution of HPMC (hereinafter referred to as HPMC solid solution coated preparations) and fine granule preparations coated with a solid solution of nifedipine and MC (hereinafter referred to as MC solid solution coated preparations) are characterized by the ability of nifedipine to dissolve into water or in the body. The absorbency of this product is comparable to that of the PVP solid solution coated formulation (comparative formulation B), and moreover, it is stable against moisture. The method of the present invention includes a step of preparing a fine particle carrier consisting of a water-soluble pharmaceutical additive, nifedipine and
Organic solvent solution of HPMC or nifedipine and MC
and uniformly coating a fine particle carrier with the nifedipine solid solution solution. Each step will be explained below. First, in the present invention, the fine particles in the fine particle carrier preparation process and the fine particles in the final preparation both refer to particles within the particle size range defined in the Japanese Pharmacopoeia General Rules for Preparations. The fine particle carrier of the present invention comprises a water-soluble pharmaceutical additive such as lactose, sucrose, glucose, etc., a water-soluble binder such as hydroxypropylcellulose, etc.
HPMC, PVP, polyvinyl alcohol, gum arabic, gelatin, etc. are blended, and more preferably, a surfactant such as alkyl sulfate or dialkyl sulfosuccinate is blended, and the mixture is granulated according to a conventional method. This granulation method includes wet granulation method,
Any commonly used method such as dry granulation, fluidized bed granulation, or rolling granulation may be applied, but fluidized bed granulation or rolling granulation is most preferred. The amounts of excipients and binders used may be the same as in the usual case, but when a surfactant is further added, it is preferably about 2 to 5% of the total amount charged. Next, the nifedipine solid solution solution is prepared by combining nifedipine and HPMC or nifedipine and MC in an organic solvent, preferably ethanol-dichloromethane (1:
1w/w). The HPMC used here is "Hydroxypropyl methylcellulose 2208" and "Hydroxypropyl methylcellulose 2208" of the 10th revised Japanese Pharmacopoeia.
2906" and "2910", and MC includes "methylcellulose" in the same pharmacopoeia. The ratio of HPMC and MC to nifedipine is both 1:1 to 1:7, preferably 1:2 to
The ratio is 1:5 (weight ratio). If the usage ratio of HPMC or MC to nifedipine is below the lower limit of the above range (comparative formulation C and comparative formulation D), nifedipine crystals will precipitate on the surface of the fine particle carrier in the next coating process, and the drug will be removed. The solubility of nifedipine in water is reduced (see Figures 2 and 3). On the other hand, HPMC
Or even if MC is used above the upper limit of the above range,
The size of the dosage form is unnecessarily increased, and the dissolution of nifedipine cannot thereby be further improved. Next, the amount of ethanol-dichloromethane (1:1 w/w) used in the nifedipine solid solution solution is suitably 1.2 to 1.5 times the amount required to completely dissolve nifedipine and HPMC or nifedipine and MC at room temperature. Finally, in the present invention, the fine particle carrier must be accurately and uniformly coated with the nifedipine solid solution. Therefore, in the coating step, it is desirable to uniformly add a predetermined amount of nifedipine solid solution solution to the fine particle carrier while keeping it in a fluid state, and then dry the carrier. Specifically, it is convenient to carry out the spray coating operation in a fluidized bed granulator or a tumbling granulator that is commonly used for producing neck granules and fine granules. Conditions in this case, such as the amount of spray per unit time, the processing temperature, the fluidity of the fine particle carrier, etc., can be the same as those for producing ordinary neck particles or fine particles. By adopting such a coating method, it is possible to accurately and uniformly coat with a predetermined amount of nifedipine solid solution while preventing the fine particle carriers of the raw material from being crushed and mutually bonded. Moreover, the operation is easy and the work efficiency is good. be. The preparation of the present invention obtained as described above is extremely excellent in quality. First, regarding the absorption of nifedipine into the body when administered orally, the HPMC solid solution coated preparation of the present invention (preparation of the present invention A-2) and
MC solid solution coating preparation (Preparation B-
2) is significantly superior to the PVP solid solution powder formulation (comparative formulation A), and has approximately the same absorbability as the PVP solid solution coated formulation (comparative formulation B) (see Test Example 1, Figure 1). Next, the formulation of the present invention is not unstable to moisture like the PVP solid solution coated formulation (comparative formulation B). PVP solid solution coated formulation (comparative formulation B) is stable under low humidity conditions;
When left under high humidity conditions, for example at 75% relative humidity and 40°C, the dissolution of nifedipine is significantly inhibited (see Test Example 3, Figure 6). On the other hand, the HPMC solid solution coated preparation of the present invention (the present invention preparation A-2) and the MC solid solution coated preparation (the present invention preparation B-2) both show no dissolution of nifedipine even when left under the above humidity conditions. No decrease was observed (see Test Example 3, Figures 4 and 5). The stability of the formulation of the present invention against moisture is extremely beneficial not only in storage of the formulation but also in the formulation process. Examples will be described below. Reference Example 1 Production of PVP solid solution powder formulation (comparative formulation A) 940g of lactose, 20g of hydroxypropylcellulose,
Add 30g of PVP and 10g of nifedipine to warm ethanol.
The mixture was dissolved in 300 ml and added, kneaded using a universal mixer (Shinagawa Kogyosho, Model 8DMV-R), extruded into granules using a 0.5 mm screen, and dried on a shelf at 61°C. This was sized with 32 mesh decorations. Reference example 2 PVP solid solution coating formulation (comparative formulation B)
Using 960 g of the fine particle carrier of Example 1 described below,
This was spray coated in the same manner as in Example 1 using a solution of 10 g of nifedipine and 30 g of PVP dissolved in 300 ml of ethanol-dichloromethane (1:1 w/w). Example 1 Manufacture of HPMC solid solution coated preparations (formulations A-1, A-2, A-3, A-4 of the present invention) (1) Manufacture of fine particle carrier Fluidized bed granulation dryer [Glatt Okawara WSG-
930 parts of lactose was added to Type 1], and a solution of 20 parts of hydroxypropyl cellulose dissolved in 500 parts of water was sprayed thereon, granulated, dried, and then sized with a 32-metre garnish to obtain a fine granule carrier. (2) Coating The HPMC solid solution coating preparations of the present invention (preparations of the present invention A-1, A-
2, A-3, A-4) and comparative formulation C were manufactured.
【表】
所定量のニフエジピンとHPMCを300mlのエタ
ノール−ジクロルメタン（１：１）に溶解し、前
記流動層造粒乾燥機（60℃）中で(1)で得た細粒担
体の所定量にこの溶液を噴霧（噴霧速度100ml／
mm）、乾燥し、32メツシユの飾で整粒した。
実施例 ２
MC固溶体コーテイング製剤（本発明の製剤Ｂ
−１、Ｂ−２、Ｂ−３、Ｂ−４）の製造
(1) 細粒担体
実施例１の(1)で得た細粒担体を使用した。
(2) コーテイング
実施例１のHPMCの代りにMCを用い、以下の
処方に従い、実施例１の方法と同様にコーテイン
グした。[Table] A predetermined amount of nifedipine and HPMC were dissolved in 300 ml of ethanol-dichloromethane (1:1), and added to the predetermined amount of the fine granule carrier obtained in (1) in the fluidized bed granulation dryer (60°C). Spray this solution (spray rate 100ml/
mm), dried and sized with a 32-mesh garnish. Example 2 MC solid solution coated formulation (formulation B of the present invention)
-1, B-2, B-3, B-4) (1) Fine particle carrier The fine particle carrier obtained in Example 1 (1) was used. (2) Coating Coating was carried out in the same manner as in Example 1, using MC instead of HPMC in Example 1 and following the recipe below.
【表】
試験例 １
ニフエジピン血中濃度の測定
一夜絶食したビーグル犬（体重８〜12Kg）４頭
に前記の本発明製剤Ａ−２、本発明製剤Ｂ−２、
PVP固溶体粉末製剤（比較製剤イ）、PVP固溶体
コーテイング製剤（比較製剤ロ）のそれぞれニフ
エジピン10mg相当量を経口投与した。投与後20，
40，60，120，240分の各時点でそれぞれ採血し、
血漿中のニフエジピン濃度をECDガスクロマト
グラフイーによつて求め第１図の結果を得た。
第１図に示されるようにHPMC固溶体コーテ
イング製剤（本発明製剤Ａ−２）およびMC固溶
体コーテイング製剤（本発明製剤Ｂ−２）の生体
内への吸収性は、PVP固溶体粉末製剤（比較製
剤イ）に比し遥かに優れており、PVP固溶体コ
ーテイング製剤（比較製剤ロ）のそれに匹敵す
る。
試験例 ２
ニフエジピン溶出試験
USPX1X溶出試検装置（富山産業製）と、二波
長分光光度計（日立製作所製）にとりつけたフロ
ーセルとをチユーブで連結し、溶出液をポンプで
連続的に還流する方法を用いた。
溶出液としては蒸留水500mlを用い、これを37
±0.5℃に保ちつつ４枚羽根の攪拌プロペラにて
150rpmの速度で攪拌した。
この溶出液中に、ニフエジピン50mgに相当する
試料を投入し、325nmと500nmの差吸光度を経時
的に測定して溶出量を求めた。
HPMC固溶体コーテイング製剤（本発明製剤
Ａ−１，Ａ−２，Ａ−３，１−４）および比較製
剤ハのニフエジピン溶出試験の結果を第２図に示
し、MC固溶体コーテイング製剤（本発明製剤Ｂ
−１，Ｂ−２，Ｂ−３，Ｂ−４）および比較製剤
二の二フエジピン溶出試験の結果を第３図に示
す。
第２図および第３図から判るように、ニフエジ
ピンに対するHPMCまたはMCの使用量はニフエ
ジピン１重量部に対して１重量部以上が必要であ
り、２〜５倍重量部が好ましい。
試験例 ３
湿気に対する安定性の検討
デシケーターに飽和食塩水を入れ40℃に保つと
相対湿度は約75％となる。これに下記の各製剤を
保存し、各製剤の水に対する溶出性を調べた。第
４図はHPMC固溶体コーテイング製剤（本発明
製剤Ａ−２）の溶出性を、第５図はMC固溶体コ
ーテイング製剤（本発明製剤Ｂ−２）の溶出性
を、第６図はPVP固溶体コーテイング製剤（比
較製剤ロ）の溶出性を示し、各図において曲線ａ
は初期溶出性を、曲線ｂは１ヶ月保存後の溶出性
を、曲線ｃは３ヶ月保存後の溶出性を示す。
第６図の示すとうり、PVP固溶体コーテイン
グ製剤（比較製剤ロ）においては、保存１ヶ月以
内にニフエジピンの溶出性が著るしく低下する。
これに対し、第４図および第５図の示すとう
り、HPMC固溶体コーテイング製剤（本発明製
剤Ａ−２）およびMC固溶体コーテイング製剤
（本発明製剤Ｂ−２）においては、共に保存３ヶ
月後においてもニフエジピンの溶出性に変化は見
られない。[Table] Test Example 1 Measurement of Nifedipine Blood Concentration Four beagle dogs (weight 8-12 kg) that had been fasted overnight were given the above-mentioned formulation A-2 of the present invention, formulation B-2 of the present invention,
A dose equivalent to 10 mg of nifedipine was orally administered to each of the PVP solid solution powder formulation (comparative formulation A) and the PVP solid solution coated formulation (comparative formulation B). 20 days after administration
Blood was collected at 40, 60, 120, and 240 minutes, respectively.
The concentration of nifedipine in plasma was determined by ECD gas chromatography, and the results shown in Figure 1 were obtained. As shown in Figure 1, the in vivo absorption of the HPMC solid solution coated formulation (the present invention formulation A-2) and the MC solid solution coated formulation (the present invention formulation B-2) is different from that of the PVP solid solution powder formulation (the comparative formulation). ), and comparable to that of the PVP solid solution coated formulation (comparative formulation B). Test example 2 Nifedipine dissolution test A method in which a USPX1X dissolution testing device (manufactured by Toyama Sangyo) and a flow cell attached to a dual-wavelength spectrophotometer (manufactured by Hitachi, Ltd.) are connected via a tube, and the eluate is continuously refluxed using a pump. was used. Use 500 ml of distilled water as the eluent, and add 37
Using a 4-blade stirring propeller while maintaining the temperature at ±0.5℃
Stirred at a speed of 150 rpm. A sample equivalent to 50 mg of nifedipine was added to this eluate, and the difference in absorbance between 325 nm and 500 nm was measured over time to determine the elution amount. The results of the nifedipine dissolution test for HPMC solid solution coated formulations (present invention formulations A-1, A-2, A-3, 1-4) and comparative formulation C are shown in Figure 2, and the MC solid solution coated formulations (present invention formulation B
-1, B-2, B-3, B-4) and comparative formulation II-2-fedipine dissolution test results are shown in FIG. As can be seen from FIGS. 2 and 3, the amount of HPMC or MC used relative to nifedipin is required to be 1 part by weight or more, preferably 2 to 5 parts by weight, per 1 part by weight of nifedipin. Test Example 3 Examination of stability against humidity When saturated saline is placed in a desiccator and maintained at 40°C, the relative humidity will be approximately 75%. Each of the following formulations was stored in this, and the dissolution of each formulation in water was examined. Figure 4 shows the dissolution properties of the HPMC solid solution coated formulation (invention formulation A-2), Figure 5 shows the dissolution properties of the MC solid solution coated formulation (invention formulation B-2), and Figure 6 shows the dissolution properties of the PVP solid solution coated formulation. (Comparative formulation B) is shown, and in each figure, curve a
curve b shows the dissolution property after 1 month of storage, and curve c shows the dissolution property after 3 months of storage. As shown in FIG. 6, in the PVP solid solution coated preparation (comparative preparation B), the dissolution of nifedipine significantly decreases within one month of storage. On the other hand, as shown in FIGS. 4 and 5, both the HPMC solid solution coated formulation (present invention formulation A-2) and the MC solid solution coated formulation (present invention formulation B-2) However, no change was observed in the dissolution properties of nifedipine.
第１図は、下記のニフエジピン製剤を犬に経口
投与した時のニフエジピンの血中濃度測定結果を
示す。HPMC固溶体コーテイング製剤（本発明
製剤Ａ−２）、MC固溶体コーテイング製剤（本
発明製剤Ｂ−２）、PVP固溶体粉末製剤（比較製
剤イ）、PVP固溶体コーテイング製剤（比較製剤
ロ）、第１図において、縦軸は血中ニフエジピン
濃度（ng／ml）を示し、横軸は経口与時から採
血時までの経過時間（分）を示す。
第２図および第３図は、それぞれHPMC固溶
体コーテイング製剤（本発明製剤Ａ−１，Ａ−
２，Ａ−３，Ａ−４）、MC固溶体コーテイング
製剤（本発明製剤Ｂ−１，Ｂ−２，Ｂ−３，Ｂ−
４）および比較製剤ハ、比較製剤ニのニフエジピ
ン溶出試験の結果を示す。第４図、第５図、第６
図は、それぞれHPMC固溶体コーテイング製剤
（本発明製剤Ａ−２）、MC固溶体コーテイング製
剤（本発明製剤Ｂ−２）、PVP固溶体コーテイン
グ製剤（比較製剤ロ）を相対湿度約75％、40℃に
保存した場合のニフエジピンの溶出試験結果を示
す。各図中において曲線ａは初期溶出性を、曲線
ｂは保存１ヶ月後の溶出性を、曲線ｃは保存３ヶ
月後の溶出性を示す。以上第２図〜第６図におい
て縦軸はニフエジピンの水への溶出量（mg／500
ml）を示し、横軸は溶出時間（分）を示す。
FIG. 1 shows the results of measuring the blood concentration of nifedipine when the following nifedipine preparation was orally administered to dogs. HPMC solid solution coated formulation (present invention formulation A-2), MC solid solution coated formulation (present invention formulation B-2), PVP solid solution powder formulation (comparative formulation A), PVP solid solution coated formulation (comparative formulation B), FIG. The vertical axis shows the blood nifedipine concentration (ng/ml), and the horizontal axis shows the elapsed time (minutes) from the time of oral administration to the time of blood collection. Figures 2 and 3 show HPMC solid solution coated formulations (preparations of the present invention A-1 and A-1, respectively).
2, A-3, A-4), MC solid solution coating preparation (Preparation of the present invention B-1, B-2, B-3, B-
4) and the results of the nifedipine dissolution test for Comparative Preparation C and Comparative Preparation D are shown. Figure 4, Figure 5, Figure 6
The figure shows HPMC solid solution coated formulation (present invention formulation A-2), MC solid solution coated formulation (present invention formulation B-2), and PVP solid solution coated formulation (comparative formulation B) stored at 40°C at a relative humidity of approximately 75%. The results of the dissolution test of nifedipine are shown below. In each figure, curve a shows the initial dissolution property, curve b shows the dissolution property after one month of storage, and curve c shows the dissolution property after three months of storage. In Figures 2 to 6 above, the vertical axis is the amount of nifedipine dissolved in water (mg/500
ml), and the horizontal axis shows elution time (min).
Claims (1)
は２種以上よりなる水溶性医薬添加物とヒドロキ
シプロピルセルロース，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から選ばれ
る１種または２種以上よりなる水溶性結合剤とを
用いて水溶性細粒を製造する、 （第２工程） ニフエジピンの１重量部とヒドロキシプロピル
メチルセルロースまたはメチルセルロースの１〜
７重量部をエタノールまたはジクロルメタン、ま
たは両者の混液に溶解し溶液を製造する、 （第３工程） 第２工程で得られる溶液を第１工程で得られる
水溶性細粒に噴霧乾燥し、該細粒の表面をニフエ
ジピンとヒドロキシプロピルメチルセルロースと
の固溶体、またはメチルセルロースとの固溶体で
コーテイングする、 ことを特徴とする湿気に安定な易吸収性ニフエジ
ピン細粒製剤の製造方法。[Claims] 1 The following steps: (First step) A water-soluble pharmaceutical additive consisting of one or more selected from lactose, sucrose, and glucose, and hydroxypropylcellulose, polyvinylpyrrolidone,
Producing water-soluble fine particles using a water-soluble binder consisting of one or more selected from hydroxypropyl methyl cellulose (Second step) 1 part by weight of nifedipine and 1 to 1 part of hydroxypropyl methyl cellulose or methyl cellulose
Dissolve 7 parts by weight in ethanol or dichloromethane, or a mixture of both to produce a solution. (Third step) The solution obtained in the second step is spray-dried onto the water-soluble fine particles obtained in the first step. A method for producing a moisture-stable and easily absorbable nifedipine fine granule preparation, which comprises coating the surface of the particles with a solid solution of nifedipine and hydroxypropyl methylcellulose or a solid solution of methylcellulose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17732381A JPS5877811A (en) | 1981-11-04 | 1981-11-04 | Preparation of stable and easily absorbable pharmaceutical preparation of nifedipine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17732381A JPS5877811A (en) | 1981-11-04 | 1981-11-04 | Preparation of stable and easily absorbable pharmaceutical preparation of nifedipine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5877811A JPS5877811A (en) | 1983-05-11 |
| JPH0328404B2 true JPH0328404B2 (en) | 1991-04-19 |
Family
ID=16028964
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17732381A Granted JPS5877811A (en) | 1981-11-04 | 1981-11-04 | Preparation of stable and easily absorbable pharmaceutical preparation of nifedipine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5877811A (en) |
Cited By (2)
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|---|---|---|---|---|
| US7432392B2 (en) | 2003-08-29 | 2008-10-07 | Japan Tobacco Inc. | Ester derivatives and medical use thereof |
| WO2010137888A2 (en) | 2009-05-27 | 2010-12-02 | 주식회사 삼양사 | Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3318649A1 (en) * | 1983-05-21 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | TWO-PHASE FORMULATION |
| JPS6038322A (en) * | 1983-08-11 | 1985-02-27 | Fujisawa Pharmaceut Co Ltd | Easily soluble solid preparation containing dihydropyridine-a substance |
| SE457326B (en) * | 1986-02-14 | 1988-12-19 | Lejus Medical Ab | PROCEDURES FOR PREPARING A QUICK SUBSTANTIAL CANDLES CONTAINING BLA MICROCRISTALLIN CELLULOSA |
| KR100525275B1 (en) | 1998-04-10 | 2005-11-02 | 미쓰비시 가가꾸 가부시키가이샤 | Solid Dispersion Containing Sialic Acid Derivative |
| JP2002138034A (en) * | 2000-10-27 | 2002-05-14 | Kyoto Pharmaceutical Industries Ltd | Bitter taste masked chewable tablet and preparation method of the same |
| JP4644397B2 (en) | 2001-09-05 | 2011-03-02 | 信越化学工業株式会社 | Method for producing pharmaceutical solid preparation containing poorly soluble drug |
| JP6838446B2 (en) * | 2017-03-22 | 2021-03-03 | ニプロ株式会社 | Tolvaptan preparation and its manufacturing method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS542316A (en) * | 1977-06-07 | 1979-01-09 | Yamanouchi Pharmaceut Co Ltd | Solid pharmaceutical composition containing nifedipene |
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1981
- 1981-11-04 JP JP17732381A patent/JPS5877811A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS542316A (en) * | 1977-06-07 | 1979-01-09 | Yamanouchi Pharmaceut Co Ltd | Solid pharmaceutical composition containing nifedipene |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7432392B2 (en) | 2003-08-29 | 2008-10-07 | Japan Tobacco Inc. | Ester derivatives and medical use thereof |
| WO2010137888A2 (en) | 2009-05-27 | 2010-12-02 | 주식회사 삼양사 | Microspheres with improved bioavailability containing poorly water-soluble drugs, and method for preparing same |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5877811A (en) | 1983-05-11 |
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