JPS63170316A - Percutaneously absorbable pharmaceutical of nifedipine for external use - Google Patents
Percutaneously absorbable pharmaceutical of nifedipine for external useInfo
- Publication number
- JPS63170316A JPS63170316A JP31178286A JP31178286A JPS63170316A JP S63170316 A JPS63170316 A JP S63170316A JP 31178286 A JP31178286 A JP 31178286A JP 31178286 A JP31178286 A JP 31178286A JP S63170316 A JPS63170316 A JP S63170316A
- Authority
- JP
- Japan
- Prior art keywords
- nifedipine
- absorption
- oleic acid
- mixture
- methyl
- 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
- 229960001597 nifedipine Drugs 0.000 title claims abstract description 45
- 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 title claims abstract description 44
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 26
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims abstract description 20
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000005642 Oleic acid Substances 0.000 claims abstract description 20
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims abstract description 20
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 238000010521 absorption reaction Methods 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000003623 enhancer Substances 0.000 claims description 7
- 230000000699 topical effect Effects 0.000 claims description 6
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 5
- 239000002075 main ingredient Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 239000003655 absorption accelerator Substances 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 abstract 1
- 230000002459 sustained effect Effects 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 208000019300 CLIPPERS Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 2
- 229940031578 diisopropyl adipate Drugs 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 241000252233 Cyprinus carpio Species 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 229950004580 benzyl nicotinate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 description 1
- 229960004027 molsidomine Drugs 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N nicotinic acid benzyl ester Natural products C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006298 saran Polymers 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、ニフェジピンを経皮的に吸収せしめる外用製
剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an external preparation that allows nifedipine to be absorbed transdermally.
（従来技術との関係）
ニフェジピンは狭心症及び高血圧症などの治療にａ効な
カル／ラム拮抗剤であるが、従来専ら、経口剤としてし
か使用されていない。(Relationship with Prior Art) Nifedipine is an effective Cal/Ram antagonist for the treatment of angina pectoris, hypertension, etc., but has conventionally been used exclusively as an oral preparation.
一方、狭心症の治療薬ニトログリセリンや鎖酸イソソル
ビドは既に経皮吸収外用製剤として使用され、それら製
剤の持つ投与の容易さ、効果の持続性、副作用の軽減、
過剰段を手の場合の処理の容易さ等の利点はよく知られ
ている。On the other hand, nitroglycerin and chain acid isosorbide, which are therapeutic for angina pectoris, have already been used as transdermal topical preparations, and these preparations have advantages such as ease of administration, long-lasting effects, and reduced side effects.
The advantages of using excess stages, such as ease of handling, are well known.
それ故、ニフェジピンについても、既に、そのものの経
皮吸収外用製剤を製造するための試みは行われており、
特開昭５８−１７７９１６ではニフェジピンの経皮吸収
を促進する薬剤としてのＮ−メチル−２−ピロリドンの
使用が、また、特開昭５８−１７７９１６や特開昭６０
−１７４７１６にはアジピン酸ジイソプロピルの使用が
提案されている。しかし乍ら、それら化合物のニフェジ
ピン吸収促進作用は、後でも明らかにするように、決し
て十分なものでなく、ニフェジピンの経皮吸収外用製剤
は、それ故、未だ、市販されるに到っていない。Therefore, attempts have already been made to produce a transdermal topical formulation of nifedipine.
In JP-A-58-177916, the use of N-methyl-2-pyrrolidone as a drug to promote transdermal absorption of nifedipine was also reported.
-174716 proposes the use of diisopropyl adipate. However, as will be revealed later, the effects of these compounds on promoting nifedipine absorption are by no means sufficient, and therefore, transdermal topical formulations of nifedipine have not yet been commercially available. .
他方、特開昭Ｅ３０−１９９８３４や特開昭Ｅ３０−１
９９８２２には、モルシドミンやある種のポリペプチド
の経皮吸収外用製剤の吸収促進剤として、オレイン酸が
使用されているが、このものはニフェジピンについては
、経皮吸収外用製剤における吸収促進効果を全く佇しな
い。その際、ニフェジピンをポリエチレングリコール４
００、アンピン酸ジイソプロピル、ベンノルアルコール
、ニコチン酸ベンジル、安息香酸ベンジル、セパチン酸
ンエチル、ポリオキンエチレン−２−オレイルエーテル
等ニ溶解し、これにオレイン酸を加えることによりニフ
ェジピンをオレイン酸に溶解せしめても、期侍せられた
オレイン酸の吸収促進効果は発現しなかった。On the other hand, Japanese Patent Application Publication No. Sho E30-199834 and Japanese Patent Application Publication No. Sho E30-1
99822 uses oleic acid as an absorption enhancer in transdermal topical formulations of molsidomine and certain polypeptides, but this product has no absorption promoting effect in transdermal topical formulations of nifedipine. Don't stand still. At that time, nifedipine was added to polyethylene glycol 4
00, diisopropyl ampic acid, benol alcohol, benzyl nicotinate, benzyl benzoate, ethyl cepatate, polyoxine ethylene-2-oleyl ether, etc., and by adding oleic acid thereto, nifedipine was dissolved in oleic acid. However, the expected absorption promoting effect of oleic acid did not occur.
今、Ｎ−メチル−２−ピロリドンとオレイン酸との混合
物を吸収促進剤して使用するとき、ニフェジピンの経皮
吸収が、顕著に促進せられることが見出された。It has now been found that the transdermal absorption of nifedipine is significantly promoted when a mixture of N-methyl-2-pyrrolidone and oleic acid is used as an absorption enhancer.
このことは、Ｎ−メチル−２−ピロリドンが単独ではニ
フェジピンの経皮吸収を極めて僅かしか促進せず、また
、オレイン酸はニフェジピンの溶鯉剤と併用しても、同
様、そのニフェジピンの経皮吸収効果が極めて僅少であ
るに過ぎない事実を考慮するとき、誠に驚嘆すべきこと
であった。This indicates that N-methyl-2-pyrrolidone alone promotes the transdermal absorption of nifedipine very little, and that oleic acid also promotes the transdermal absorption of nifedipine in a similar manner even when used in combination with nifedipine's molten carp. This is truly surprising when considering the fact that the absorption effect is extremely small.
（発明の目的）
従って、本発明の目的はニフェジピンを主剤とし、Ｎ−
メチル−２−ピロリドンとオレイン酸との混合物を吸収
促進剤して含佇する経皮吸収外用製剤に関する。(Object of the invention) Therefore, the object of the present invention is to use nifedipine as the main agent,
The present invention relates to a percutaneous absorption external preparation containing a mixture of methyl-2-pyrrolidone and oleic acid as an absorption enhancer.
（発明の詳細な説明）
本発明でニフェジピンの吸収促進剤として使用されるＮ
−メチル−２−ピロリドンとオレイン酸との混合物の混
合割合は、凡そ、９：１ないし１：４であり、好ましく
は、約１＝１であるまた、主剤たるニフェジピンに対す
る本発明の混合物の使用割合は混合物がニフェジピンを
完全に溶解する量であれば差し支えはな（、別に限定が
ないが、通常、重量比で１０ないし１００倍量である。(Detailed Description of the Invention) N used as an absorption enhancer of nifedipine in the present invention
- The mixing ratio of the mixture of methyl-2-pyrrolidone and oleic acid is approximately 9:1 to 1:4, preferably about 1=1.Also, the use of the mixture of the present invention for nifedipine as the base agent There is no problem with the ratio as long as the mixture completely dissolves nifedipine (although there is no particular limitation, it is usually 10 to 100 times the amount by weight).
ニフェジピンの本発明の経皮吸収外用製剤中の配合量は
１回（−・、す１４の製剤中、通常、１０ないし１００
ｍｇ になるように選ばれる。The amount of nifedipine incorporated in the transdermal absorption topical preparation of the present invention is usually 10 to 100 in the 14 preparations.
mg.
本究明のニフェジピンの経皮吸収外用製剤は、そのまま
皮膚に適用することが出来る。The percutaneous absorption external preparation of nifedipine of the present study can be applied to the skin as is.
し力化ながら、日本薬局方に記載の親水性試剤、油性基
剤を用い軟・ａとして皮膚に適用できる。It can be applied to the skin in a soft form using a hydrophilic agent and an oily base as described in the Japanese Pharmacopoeia.
また、ヒドロキシプロピルセルローズおよび／またはメ
チルセルローズなどを用いてゲル軟膏として皮膚に投与
できる。It can also be administered to the skin as a gel ointment using hydroxypropyl cellulose and/or methyl cellulose.
さらに、粘若テープ、シートまたはパッチ伏の製品に加
工して皮膚に投与することもできる。Furthermore, it can be processed into a sticky tape, sheet or patch product and administered to the skin.
本究明のニフェジピンの経皮吸収外用製剤が、その他適
当な剤形で外用製剤に製造し使用できることは言うまで
もない。It goes without saying that the transdermal absorption topical preparation of nifedipine of the present invention can be manufactured and used in other appropriate dosage forms as external preparations.
（究明の効果）
Ｎ−メチル−２−ピロリドンとオレイン酸との混合物を
吸収促進剤として使用することにより、従来知られてい
ない優れた吸収性を以って、ニフェジピンを吸収せしめ
ることの出来る経皮吸収外用製剤を製造することが可能
となった。(Effect of the research) By using a mixture of N-methyl-2-pyrrolidone and oleic acid as an absorption enhancer, nifedipine can be absorbed through an oral route with previously unknown excellent absorption properties. It has become possible to produce skin-absorbable external preparations.
その結果、経口的な投与に伴う欠陥不利を解消すること
ができた。そうして、本発明の経皮吸収外用製剤による
とき、投与は極めて容易であり、効果は持続的であり、
コンプライアンスは良好であり、消化器官における副作
用は解消し過剰投与の処７／はｌ１ｌｉ′ｉ易であるな
ど、その効果は枚挙できないほどである。As a result, the disadvantages associated with oral administration could be overcome. Thus, when using the transdermal absorption topical preparation of the present invention, administration is extremely easy, the effect is long-lasting,
Compliance is good, side effects in the gastrointestinal tract are eliminated, and overdosing is easy, and the effects are too numerous to list.
（実施例）
以ド、実施例により、本究明を説明するが、本発明がそ
れら実施例により限定されるものでないことはいうまで
もないことである。(Examples) Hereinafter, the present invention will be explained with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.
実施例に
フェジピン０．２ｇをＮ−メチル−２−ピロリドン９．
９ｇとオレイン酸９．９ｇとの混合物に溶解する。In an example, 0.2 g of fedipine was added to 9.9 g of N-methyl-2-pyrrolidone.
9 g of oleic acid and 9.9 g of oleic acid.
対照例１−１の製造法
ニフェジピン０．２ｇをＮ−メチル−２−ピロリドン１
９．８ｇに溶かす。Manufacturing method of Control Example 1-1 0.2 g of nifedipine was added to 1 part of N-methyl-2-pyrrolidone.
Dissolve in 9.8g.
対照例１−２の製造法
ニフェジピン０．２ｇをオレイン酸１９．８ｇに加え乳
鉢中でよ（混ぜる。Manufacturing method for Control Example 1-2 Add 0.2 g of nifedipine to 19.8 g of oleic acid and mix in a mortar.
対ｊｌ、ｒ１例１−３の製造法
二フェノビン０．２ｇをアノピン酸ジイソプロピル９６
９ｇとオレイン酸９．９ｇとの混合物に溶解する。vs. jl, r1 Example 1-3 manufacturing method 0.2 g of diphenobine was added to diisopropyl anopate 96
9 g of oleic acid and 9.9 g of oleic acid.
対照例１−４の製造法
二フェノピア０．２ｇをアノピン酸ジイソプロピル１９
．８ｇに溶解する。Manufacturing method of Control Example 1-4 0.2 g of difenopia was added to diisopropyl anopate 19
．． Dissolve in 8g.
実施例１および対照例１−１ないし１−４のニフェジピ
ン２０ｍｇ相当量に就いて、ウサギを用いて経皮吸収試
験を行った。A transdermal absorption test was conducted using rabbits for 20 mg equivalent of nifedipine in Example 1 and Control Examples 1-1 to 1-4.
即ち、？均体ｆｆ１３Ｋｇ のウサギ （雄性 ニュ
ージンランド 本ワイド ！３羽を使用し、電気バリ
カンで除毛した腹部に内径６ｃ腸（面積：２８．３平方
センチメートル）のロートの広い部分をアロンアルファ
ーで接召した。ロートの細 い部分から試料を入れ、バ
ラフィルムで包み、更にアルミホイルで包んで遮光した
。試料適用の後、それぞれ１時間、２時間、４時間、８
時間口にウサギの耳介動脈から各々３１ずつ採血した。In other words,? Using 3 rabbits (male, New Zealand, 13 kg), the wide part of the funnel with an internal diameter of 6 cm (area: 28.3 square centimeters) was placed on the abdomen, which had been removed with electric clippers, using Aron Alpha. .The sample was put into the narrow part of the funnel, wrapped in rose film, and then wrapped in aluminum foil to protect it from light.After applying the sample, the tube was heated for 1 hour, 2 hours, 4 hours, and 8 hours, respectively.
At the same time, 31 blood samples were taken from each rabbit's auricular artery.
採血の後、１１！ｆちに遮光し、遠心分離して血清を分
取した。After blood collection, 11! After that, the tube was protected from light and centrifuged to collect the serum.
ニフェジピンの血清中の濃度の測定方法血清０．５鵬ｌ
に内部標準としてジエチル−２，６−ノメチルー４（
２−二トロフェニル）−３，５−ピリノンカルホキフレ
ート水溶液（１００ｎｇ／ｍ１）１００）１１を加え、
１％亜硝酸ナトリウム水溶液０．３■ｌ及び０．ＩＮ塩
酸２１を加えて５０＠Ｃ水浴中で酸化し、冷徹ベンゼン
４１を加えて抽出し、ベンゼン層３１をとり留去した。Method for measuring the concentration of nifedipine in serum Serum 0.5 Peng l
diethyl-2,6-nomethyl-4 (
2-nitrophenyl)-3,5-pyrinone carboxyflate aqueous solution (100 ng/ml) 100) 11 was added,
0.3 μl of 1% sodium nitrite aqueous solution and 0.3 μl of 1% sodium nitrite aqueous solution. IN hydrochloric acid 21 was added and oxidized in a 50@C water bath, cold benzene 41 was added and extracted, and the benzene layer 31 was removed and distilled off.
残さに２００ｐｌの酢エチを加え溶解し、その３Ｐ１を
ガスクロマトグラフィー（ＥＣＤ）に注入して測定した
。カラムは１６ＡＯＶ−１７を用いた。その結果を第１
表及び第１図に示す。200 pl of ethyl acetate was added to the residue to dissolve it, and the resulting 3P1 was measured by injecting it into a gas chromatography (ECD). A 16AOV-17 column was used. The result is the first
It is shown in the table and Figure 1.
経皮吸収性の評価方法
二フェノビンの経皮吸収性の評価は、血中濃度と時間と
の関係をＡＵＧ （０−８）値（８時間までのニフェジ
ピンの血ｔｎｌｌｆ５度一時間曲線下の面積）で表して
評価した。また、経皮吸収持続性の評価はニフェジピン
のウサギでの血清中？Ｈ度が１１００ｎ／ｍ１以上を維
持する時間によって行った。その結果は、第２表に示さ
れている。Evaluation method of percutaneous absorption The percutaneous absorption of Nifenovine is evaluated by evaluating the relationship between blood concentration and time using the AUG (0-8) value (area under the blood tnllf5 degree 1 hour curve of nifedipine up to 8 hours). ) and evaluated. Also, is the persistence of percutaneous absorption evaluated in serum of nifedipine in rabbits? The test was carried out for a period of time during which the H degree was maintained at 1100 n/ml or higher. The results are shown in Table 2.
、（ｌＩ ｒ＜−ニフェジピン血１ｖ中濃度（ｎｇ／ｍ
ｌ） Ｉｌ［移、Ｓ；７ｋ 実施例１及び対照例１の
経皮吸収実験結果第４表及び第１図に明らかなように、
本発明の実施例に示す本発明の経皮吸収外用製剤は、対
照例１−１ないし例１−４のいずれに対比しても顕１に
高い血中濃度を示している。, (lI r<-nifedipine blood 1v concentration (ng/m
l) Il [transfer, S; 7k As is clear from Table 4 and Figure 1 of the transdermal absorption experiment results of Example 1 and Control Example 1,
The transdermal absorption external preparations of the present invention shown in Examples of the present invention exhibit significantly higher blood concentrations than any of Control Examples 1-1 to 1-4.
また、第２表に明らかなように、実施例１の本発明の経
皮吸収外用製剤のＡＵＧ （０−８）値は４７９７ｎｇ
＊ ｈｒ／ｍｌで俸めて高い吸収値を示し、１１００
ｎ／■！以上の血清中ニフェジピン、・口度の維持時間
は７時間で持続性が高い。Furthermore, as is clear from Table 2, the AUG (0-8) value of the transdermal absorption topical preparation of the present invention in Example 1 was 4797 ng.
* Shows high absorption value in terms of hr/ml, 1100
n/■! Nifedipine in serum has a high persistence time of 7 hours.
これに対して、既にニフェジピンの吸収促進剤として提
案されているＮ−メチル−２−ピロリドン及びアジピン
酸ジイソプロピルについては吸収促進の効果は認められ
るが、この効果はＡＵＶ （０−８）値で比較すると本
発明の実施例１のものに対比して、それぞれ、約１／２
０ないし１／１７に過ぎない。またニフェジピンの血中
濃度はいずれの時間においても、１１００ｎ／履１を越
えることがない。On the other hand, N-methyl-2-pyrrolidone and diisopropyl adipate, which have already been proposed as absorption enhancers for nifedipine, have an absorption promoting effect, but this effect is compared by AUV (0-8) value. Then, compared to the one of Example 1 of the present invention, each is about 1/2
It is only 0 to 1/17. Furthermore, the blood concentration of nifedipine never exceeded 1100 n/l at any time.
また、アノピン酸ジイソプロピルとオレイン酸との混合
物も、全く吸収をしないか、吸収するとしても、極めて
軽微なものだあった。そして、ニフェジピンの血中１０
度は、いずれの時間でも、ｌｏｏｎｇ／■ｌを越えるこ
とがなかった。Also, a mixture of diisopropyl anopate and oleic acid did not absorb at all, or if it did absorb it, it was only very slight. And nifedipine blood 10
The temperature did not exceed loong/l at any time.
実施例２
ニフェジピン０．２ｇをＮ−メチル−２−ピロリドン２
ｇとオレイン酸２ｇの混合溶液に溶かし、これを日本薬
局方の「白色軟膏Ｊ １５．８ｇに加えて、均一に混ぜ
て、軟膏剤をＩ！ＩＩ！した。この試料のニフェジピン
２０■ｇ 相当量につき、平均３Ｋｇのウサギ（雄性ニ
ューシーラントホワイト種）３羽を使用し、電気バリカ
ンで除毛した腹部（面積：５ｃｍＸ５ｃ層 ＝２５Ｃ躊
２２に塗布し、サランラップで覆い、アルミホイルで遮
光した。Ｊとは実施例１と同様に操作した。Example 2 0.2 g of nifedipine was mixed with N-methyl-2-pyrrolidone 2
g and 2 g of oleic acid, and added this to 15.8 g of "White Ointment J" from the Japanese Pharmacopoeia, mixed uniformly, and made an ointment.This sample was equivalent to 20 g of nifedipine. Three rabbits (male New Sealant White) weighing an average of 3 kg were used, and the product was applied to the abdomen (area: 5 cm x 5 c layer = 25 C) which had been dehaired with electric clippers, covered with Saran wrap, and shielded from light with aluminum foil. J was operated in the same manner as in Example 1.
この試料のニフェジピン血中ｒＨ度推移は第３表及び第
２図のρりである。また、ＡＵＧ （０−８）値は２６
６８ｎｇ ｅ ｈｒ／ｍｌ −ｔｌ ００＋ｇ／ｍ１以
上の血清中ニフェジピン濃度保持の時間は７Ｂ間以上で
あった。The changes in nifedipine blood rH level of this sample are shown in Table 3 and Figure 2. Also, the AUG (0-8) value is 26
The time period for which the serum nifedipine concentration was maintained at 68 ng e hr/ml -tl 00+g/ml or more was 7B or more.
直 、 ニフ ノピン ｎ 爾ＩDirect, Nif Nopin
第１図及び第２図は、本発明の詳細な説明するための説
明図−ある。1 and 2 are explanatory diagrams for explaining the present invention in detail.
Claims (3)
リドンとオレイン酸との混合物を吸収促進剤として含有
する経皮吸収外用製剤(1) Transdermal absorption external preparation containing nifedipine as the main ingredient and a mixture of N-methyl-2-pyrrolidone and oleic acid as an absorption enhancer.
合割合が、凡そ、９：１ないし１：４であり、好ましく
は、約１：１である特許請求の範囲１によるニフェジピ
ンの経皮吸収外用製剤(2) The transdermal administration of nifedipine according to claim 1, wherein the mixing ratio of N-methyl-2-pyrrolidone and oleic acid is approximately 9:1 to 1:4, preferably about 1:1. Absorption topical preparation
比の混合物を使用する特許請求の範囲２によるニフェジ
ピンの経皮吸収外用製剤(3) A transdermal absorption topical formulation of nifedipine according to claim 2, which uses a mixture in a weight ratio of 10 to 100 to nifedipine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31178286A JPS63170316A (en) | 1986-12-30 | 1986-12-30 | Percutaneously absorbable pharmaceutical of nifedipine for external use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31178286A JPS63170316A (en) | 1986-12-30 | 1986-12-30 | Percutaneously absorbable pharmaceutical of nifedipine for external use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63170316A true JPS63170316A (en) | 1988-07-14 |
Family
ID=18021405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP31178286A Pending JPS63170316A (en) | 1986-12-30 | 1986-12-30 | Percutaneously absorbable pharmaceutical of nifedipine for external use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63170316A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990006120A1 (en) * | 1988-12-01 | 1990-06-14 | Schering Corporation | Compositions for transdermal delivery of estradiol |
| EP0417496A2 (en) * | 1989-08-17 | 1991-03-20 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
| FR2722988A1 (en) * | 1994-07-26 | 1996-02-02 | Egyt Gyogyszervegyeszeti Gyar | PHARMACEUTICAL COMPOSITION FOR LOWERING BLOOD PRESSURE AND PROCESS FOR PREPARING THE SAME |
| EP1250927A2 (en) | 1997-02-24 | 2002-10-23 | S.L.A. Pharma AG | Pharmaceutical composition for topical application comprising nifedipine |
-
1986
- 1986-12-30 JP JP31178286A patent/JPS63170316A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990006120A1 (en) * | 1988-12-01 | 1990-06-14 | Schering Corporation | Compositions for transdermal delivery of estradiol |
| EP0417496A2 (en) * | 1989-08-17 | 1991-03-20 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
| FR2722988A1 (en) * | 1994-07-26 | 1996-02-02 | Egyt Gyogyszervegyeszeti Gyar | PHARMACEUTICAL COMPOSITION FOR LOWERING BLOOD PRESSURE AND PROCESS FOR PREPARING THE SAME |
| BE1011413A4 (en) * | 1994-07-26 | 1999-09-07 | Egyt Gyogyszervegyeszeti Gyar | Pharmaceutical composition for lowering blood pressure and method of preparation. |
| EP1250927A2 (en) | 1997-02-24 | 2002-10-23 | S.L.A. Pharma AG | Pharmaceutical composition for topical application comprising nifedipine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2418135C (en) | Novel composition for transdermal and/or transmucosal administration of active compounds that ensures adequate therapeutic levels | |
| RU2110261C1 (en) | Transdermal delivery system | |
| ISHIDA et al. | Highly viscous gel ointment containing carbopol for application to the oral mucosa | |
| US20070098747A1 (en) | Topical pharmaceutical composition for the treatment of inflammatory dermatoses | |
| AU2001282064A1 (en) | Novel composition for transdermal and/or transmucosal administration of active compounds that ensures adequate therapeutic levels | |
| JP2002518434A (en) | Matrix-type transdermal drug delivery systems that deliver steroid hormones at high rates and their use in hormone replacement therapy | |
| JPH08501529A (en) | Use of glycerin to alleviate skin-penetrating drug administration | |
| PT1510213E (en) | Penetration enhancing and irritation reducing systems comprising testosterone | |
| US6943197B2 (en) | Topical administration of pharmacologically active bases in the treatment of inflammatory dermatoses | |
| JPS63170316A (en) | Percutaneously absorbable pharmaceutical of nifedipine for external use | |
| JP2002516879A (en) | Composition for transdermal administration of non-steroidal anti-inflammatory analgesic | |
| JPS63170317A (en) | Percutaneously absorbable pharmaceutical of nifedipine for external use | |
| JPH0371409B2 (en) | ||
| JPS58177916A (en) | External drug | |
| AU618976B2 (en) | Transdermal absorptive drug formulation | |
| KR20210133821A (en) | Percutaneous absorption system comprising piroxicam | |
| JPS62187415A (en) | Composition for promoting transcutaneous absorption | |
| CN115813889A (en) | Vitamin D 3 Transdermal patch and preparation method thereof | |
| JPH0311014A (en) | Gel preparation for external use | |
| JPH0193542A (en) | External preparation of drug |