JPH0345043B2 - - Google Patents
Info
- Publication number
- JPH0345043B2 JPH0345043B2 JP56014574A JP1457481A JPH0345043B2 JP H0345043 B2 JPH0345043 B2 JP H0345043B2 JP 56014574 A JP56014574 A JP 56014574A JP 1457481 A JP1457481 A JP 1457481A JP H0345043 B2 JPH0345043 B2 JP H0345043B2
- Authority
- JP
- Japan
- Prior art keywords
- indomethacin
- ethanol
- water
- experiment
- weight
- 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
- 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 claims description 78
- 229960000905 indomethacin Drugs 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 150000001298 alcohols Chemical class 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 10
- 239000000194 fatty acid Substances 0.000 claims description 10
- 229930195729 fatty acid Natural products 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000001361 adipic acid Substances 0.000 claims description 4
- 235000011037 adipic acid Nutrition 0.000 claims description 4
- 238000010586 diagram Methods 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 claims description 2
- 235000021360 Myristic acid Nutrition 0.000 claims description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 2
- 238000002474 experimental method Methods 0.000 description 14
- 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 9
- 229940031578 diisopropyl adipate Drugs 0.000 description 9
- -1 fatty acid esters Chemical class 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 229940100613 topical solution Drugs 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 230000037374 absorbed through the skin Effects 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- IFQSXNOEEPCSLW-DKWTVANSSA-N L-cysteine hydrochloride Chemical compound Cl.SC[C@H](N)C(O)=O IFQSXNOEEPCSLW-DKWTVANSSA-N 0.000 description 1
- 206010050031 Muscle strain Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007774 longterm Effects 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
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical group CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は安定なインドメタシンの外用液剤に関
する。
インドメタシンは優れた非ステロイド性抗炎症
剤として知られており、現在臨床において広く使
用されているものである。
インドメタシンの通常行われている投与方法は
経口投与あるいは坐剤投与であるが、これらの場
合には胃腸障害、食欲不振、嘔吐、腹痛等の副作
用を惹起するとともに、その効果を発揮させるた
めには大量の投与が必要であるという欠点があつ
た。
そこで、本発明者は、斯かる欠点を解消せんと
研究を行い、先にインドメタシンをゲル状軟膏剤
の形態として局所に直接投与する外用剤を開発
し、特許出願した（特開昭53−81616号）。
本発明者は、更にインドメタシンの投与方法の
拡大を目的として鋭意研究を行つた結果、安定な
インドメタシン外用液剤を得ることに成功した。
従来、インドメタシンの液状製剤としては、
エタノールにジメチルアセトアミドを配合した基
剤にインドメタシンを溶解して日焼けの処置に使
用した報告〔J.Invest.Dermatol、64、322〜325
（1975）〕及びインドメタシンを脂肪酸エステル
類を含む基剤に溶解したもの（西ドイツ特許第
1617653号）がある。
しかしながら、のものは皮膚からの吸収が悪
いので、皮膚表面の治療には有効であるが、深部
の炎症には殆んど効果を奏さない。また、のも
のはインドメタシンを経口投与と同レベルの血中
濃度を得るように皮膚から吸収させることを目的
としているものであり、その結果多量のインドメ
タシンを配合している。従つて、その製剤は不安
定であり、しかも皮膚に対する刺激が強く、実用
に供せられないものである。
そこで、本発明者は、長期間の保存においても
安定で、皮膚からの吸収がよく、しかも皮膚に対
する刺激が少ないインドメタシンを提供すべく研
究を行つた。
インドメタシンは水に殆んど溶けないため、外
用液剤の調製に一般に使用されている水−アルコ
ール系液剤ベースを用いても、結晶の析出、分
解、変色等が生起して目的は達成されない。しか
し、多くの実験の結果次の新知見を得た。
実験１に示す如く、アルコール類と脂肪酸エ
ステル類を一定の比率で混合した系におけるイ
ンドメタシンの溶解度は、それ単独の場合の３
〜４倍となる。
実験２に示す如く、水−アルコール類の系に
インドメタシンを溶解し、これに脂肪酸エステ
ル類を添加すると、その添加量とインドメタシ
ンの経皮吸収率の間には特殊な相関関係があ
り、例えばインドメタシン0.05％含有の40％ア
ルコール類水溶液においては、脂肪酸エステル
類の約５〜７％添加で吸収が極大となる。
実験３に示す如く、アルコール類−水−脂肪
酸エステル類の３成分は、第３図の斜線部分の
混合比において均一系となる。
実験４に示す如く、上記３成分の均一系にお
けるインドメタシンの溶解度は第４図のとおり
であり、最大は約７％である。
以上の実験から、安定な均一系で、しかも経皮
吸収のよいインドメタシン溶液が得られる水、
アルコール類及び脂肪酸１価アルコール類
の混合比は、第５図の三角図表上の次の各点、Ａ
（＝11.44、＝28.56、＝60）、Ｂ（＝12、
＝28、＝60）、Ｃ（＝50、＝40、＝10）、
Ｄ（＝50、＝49、＝１）、Ｅ（＝29、＝
70、＝１）、及びＦ（＝11.44、＝70、＝
18.56）を結んでできる範囲内（第５図の黒点示
部分）であることを見出し、本発明を完成した。
すなわち、本発明は、水11.44〜50重量％、
エタノール及びイソプロパノールから選ばれる
アルコール類10〜70重量％及びアジピン酸、セ
バチン酸及びミリスチン酸の炭素数１〜５の１価
アルコールエステルから選ばれる脂肪酸１価アル
コールエステル類１〜60重量％よりなり、その３
成分の混合比が第５図の三角図表上のＡ，Ｂ，
Ｃ，Ｄ，Ｅ及びＦを結んでできる範囲内にある基
剤にインドメタシンを含有せしめたことを特徴と
するインドメタシン外用液剤を提供するものであ
る。
本発明において、アルコール類としては、エタ
ノール、プロパノール、イソプロパノール等の１
価アルコール；ポリエチレングリコール、プロピ
レングリコール、ブチレングリコール等の多価ア
ルコールが挙げられ、これらは単独又は組合せて
使用することができる。また、脂肪酸エステル類
としては、炭素数４〜14のモノカルボン酸の炭素
数１〜５のアルコールエステル又は炭素数４〜10
のジカルボン酸の炭素数１〜５のアルコールエス
テルが使用され、就中アジピン酸、セバチン酸、
ミリスチン酸のエステルが好ましい。
本発明のインドメタシン外用液剤は、インドメ
タシンを0.01〜５重量％になるように上記基剤に
溶解することによつて調製されるが、更にBHT
（ブチルヒドロキシトルエン）、BHA（ブチルヒド
ロキシアニソール）、亜硫酸ナトリウム、Ｌ−シ
ステイン塩酸塩等の抗酸化剤；EDTA−ナトリ
ウム等の安定化剤；トリエタノールアミン、水酸
化ナトリウム、水酸化カリウム塩のPH調整剤；メ
チルセルロース、ヒドロキシプロピルセルロース
等の粘性付与剤等を添加することもできる。
叙上の如くして得られた本発明のインドメタシ
ン外用液剤は、後述の実験例に示すごとく、長期
間安定で、皮膚からの吸収が優れており、しかも
皮膚に対する刺激が少ないので、関節炎、肩関節
周囲炎、筋肉痛、捻挫、腱鞘炎等の整形外科領域
あるいは皮膚炎、乾癬、褥瘡等の皮膚科領域の疾
患の治療に優れた効果を示す。
次に実験例及び本発明の実施例を挙げて説明す
る。
実験 １
エタノールとアジピン酸ジイソプロピルを種々
の割合で混合し、これに対するインドメタシンの
25℃における溶解度を測定した。その結果は第１
図のとおりである。
実験 ２
インドメタシン0.05％を含有する40％エタノー
ル水溶液にアジピン酸ジイソプロピルを種々の濃
度で添加して試験液を調製し、これをモルモツト
背部の剪毛した部分に装着したセル（10cm2）内に
２mlずつ入れ、５時間後のインドメタシンの残存
量から吸収率を測定した。尚アジピン酸ジイソプ
ロピルを約７％以上添加した系は不均一となつ
た。その結果は第２図のとおりである。
実験 ３
アルコール類、水及び脂肪酸エステル類の親和
性をエタノール、アジピン酸ジイソプロピルを用
いて調べた。その結果は第３図のとおりであり、
図中斜線部分は均一系を、それ以外は不均一系を
示す。
実験 ４
実験３で得た均一系におけるインドメタシンの
溶解度を調べた。その結果は第４図のとおりであ
る。図中の記号ａ〜ｆはインドメタシンの溶解度
が次のものであることを示す。
ａ：７％以上、ｂ：５〜７％、ｃ：３〜５％、
ｄ：１〜３％、ｅ：0.5〜１％、ｆ：0.5％以下
実験 ５
本発明のインドメタシン外用液剤及びゲル状軟
膏（特開昭53−81616号に従つて調製した）を、
40℃で60日間保存し、その安定性を調べた。その
結果は第１表のとおりである。
The present invention relates to a stable topical solution of indomethacin. Indomethacin is known as an excellent non-steroidal anti-inflammatory agent and is currently widely used in clinical practice. The usual administration method for indomethacin is oral administration or suppository administration, but these cases cause side effects such as gastrointestinal disorders, anorexia, vomiting, and abdominal pain, and it takes a lot of effort to achieve its effectiveness. The drawback was that large doses were required. Therefore, the present inventor conducted research to eliminate such drawbacks, and first developed a topical preparation for local administration of indomethacin in the form of a gel ointment, and filed a patent application (Japanese Patent Application Laid-Open No. 53-81616). issue). The present inventor further conducted intensive research with the aim of expanding the administration method of indomethacin, and as a result, succeeded in obtaining a stable topical solution of indomethacin. Conventionally, liquid formulations of indomethacin include:
A report on the use of indomethacin dissolved in a base containing dimethylacetamide in ethanol for the treatment of sunburn [J.Invest.Dermatol, 64 , 322-325
(1975)] and indomethacin dissolved in a base containing fatty acid esters (West German Patent No.
1617653). However, these drugs are poorly absorbed through the skin, so while they are effective for treating the skin surface, they have little effect on deep inflammation. In addition, the purpose of this drug is to allow indomethacin to be absorbed through the skin to achieve the same level of blood concentration as when administered orally, and as a result, it contains a large amount of indomethacin. Therefore, the preparation is unstable and highly irritating to the skin, making it impractical. Therefore, the present inventor conducted research to provide indomethacin, which is stable even during long-term storage, has good absorption through the skin, and is less irritating to the skin. Indomethacin is almost insoluble in water, so even if a water-alcohol base, which is commonly used for preparing topical solutions, is used, crystal precipitation, decomposition, discoloration, etc. will occur, and the objective will not be achieved. However, as a result of many experiments, we obtained the following new findings. As shown in Experiment 1, the solubility of indomethacin in a system in which alcohols and fatty acid esters are mixed at a certain ratio is 3
~4 times. As shown in Experiment 2, when indomethacin is dissolved in a water-alcohol system and fatty acid esters are added thereto, there is a special correlation between the amount added and the transdermal absorption rate of indomethacin. In a 40% alcohol aqueous solution containing 0.05%, absorption reaches a maximum when about 5 to 7% of fatty acid esters are added. As shown in Experiment 3, the three components of alcohols, water, and fatty acid esters form a homogeneous system at the mixing ratio shown in the shaded area in FIG. As shown in Experiment 4, the solubility of indomethacin in a homogeneous system of the above three components is as shown in Figure 4, and the maximum is about 7%. From the above experiments, we found that water, which is a stable, homogeneous solution with good transdermal absorption, can be obtained.
The mixing ratio of alcohols and fatty acid monohydric alcohols is determined by the following points on the triangular diagram in Figure 5, A
(=11.44, =28.56, =60), B (=12,
=28, =60), C(=50, =40, =10),
D(=50,=49,=1),E(=29,=
70, = 1), and F (= 11.44, = 70, =
18.56), and completed the present invention. That is, the present invention contains 11.44 to 50% by weight of water,
Consisting of 10 to 70% by weight of alcohols selected from ethanol and isopropanol and 1 to 60% by weight of fatty acid monohydric alcohol esters selected from monohydric alcohol esters having 1 to 5 carbon atoms of adipic acid, sebacic acid and myristic acid, Part 3
The mixing ratio of the components is A, B, on the triangular diagram in Figure 5,
The present invention provides a liquid preparation for external use of indomethacin, which is characterized in that indomethacin is contained in a base within the range formed by connecting C, D, E, and F. In the present invention, alcohols include ethanol, propanol, isopropanol, etc.
Hydrolic alcohols include polyhydric alcohols such as polyethylene glycol, propylene glycol, butylene glycol, and these can be used alone or in combination. In addition, as fatty acid esters, alcohol esters having 1 to 5 carbon atoms of monocarboxylic acids having 4 to 14 carbon atoms, or alcohol esters having 4 to 10 carbon atoms
Alcohol esters having 1 to 5 carbon atoms of dicarboxylic acids are used, especially adipic acid, sebacic acid,
Esters of myristic acid are preferred. The indomethacin topical solution of the present invention is prepared by dissolving indomethacin in the above base to a concentration of 0.01 to 5% by weight, and further includes BHT.
Antioxidants such as (butylated hydroxytoluene), BHA (butylated hydroxyanisole), sodium sulfite, L-cysteine hydrochloride; Stabilizers such as EDTA-sodium; PH of triethanolamine, sodium hydroxide, potassium hydroxide salt Regulators; viscosity-imparting agents such as methyl cellulose and hydroxypropyl cellulose can also be added. The indomethacin topical solution of the present invention obtained as described above is stable for a long period of time, has excellent absorption through the skin, and is less irritating to the skin, as shown in the experimental examples below. It is highly effective in treating orthopedic diseases such as periarthritis, muscle pain, sprains, and tendonitis, and dermatological diseases such as dermatitis, psoriasis, and bedsores. Next, an explanation will be given with reference to experimental examples and examples of the present invention. Experiment 1 Ethanol and diisopropyl adipate were mixed in various proportions, and indomethacin was
Solubility at 25°C was measured. The result is the first
As shown in the figure. Experiment 2 A test solution was prepared by adding diisopropyl adipate at various concentrations to a 40% aqueous ethanol solution containing 0.05% indomethacin, and 2 ml of this was placed in a cell (10 cm 2 ) attached to the shaved part of the back of a guinea pig. The absorption rate was measured from the remaining amount of indomethacin after 5 hours. The system in which about 7% or more of diisopropyl adipate was added became non-uniform. The results are shown in Figure 2. Experiment 3 The affinity of alcohols, water and fatty acid esters was investigated using ethanol and diisopropyl adipate. The results are shown in Figure 3.
In the figure, the shaded area indicates a homogeneous system, and the other areas indicate a non-uniform system. Experiment 4 The solubility of indomethacin in the homogeneous system obtained in Experiment 3 was investigated. The results are shown in Figure 4. Symbols a to f in the figure indicate that the solubility of indomethacin is as follows. a: 7% or more, b: 5-7%, c: 3-5%,
d: 1 to 3%, e: 0.5 to 1%, f: 0.5% or less Experiment 5 Indomethacin topical liquid preparation and gel ointment of the present invention (prepared according to JP-A-53-81616),
It was stored at 40°C for 60 days and its stability was investigated. The results are shown in Table 1.
【表】
実験 ６
次の３成分からなる混合系に対するインドメタ
シンの溶解度は第２表のとおりである。[Table] Experiment 6 The solubility of indomethacin in a mixed system consisting of the following three components is shown in Table 2.
【表】
実験 ７
体重約190ｇのウイスター系雄性ラツト腹部の
皮膚を剪毛し、面積２cm2のプラスチツクカツプを
皮膚上に接着した。カツプ内に、第３表に示す組
成のインドメタシン外用液剤0.5mlを入れ、２時
間後に血液を採取した。血液を遠心分離して血漿
を得、血漿中のインドメタシン濃度をHPLC法で
測定した。その結果は第３表のとおりである。[Table] Experiment 7 The abdominal skin of a male Wistar rat weighing approximately 190 g was shaved, and a plastic cup with an area of 2 cm 2 was glued onto the skin. 0.5 ml of indomethacin topical solution having the composition shown in Table 3 was placed in the cup, and blood was collected 2 hours later. Blood was centrifuged to obtain plasma, and the concentration of indomethacin in the plasma was measured by HPLC method. The results are shown in Table 3.
【表】
実施例 １
インドメタシン 3.0（％）
エタノール 50.0
アジピン酸ジイソプロピル 30.0
ヒドロキシプロピルセルロース 1.5
水 15.5
〜の混合溶液にを加えて撹拌分散させ、
これにを加え、均一になるまで撹拌した。
実施例 ２
インドメタシン 0.1（％）
イソプロパノール 50.0
イソプロピルミリステート 1.0
トリエタノールアミン 0.023
水 48.877
〜の混合溶液に、をにとかした溶液を
撹拌しながら混合し、均一になるまで撹拌した。[Table] Example 1 Indomethacin 3.0 (%) Ethanol 50.0 Diisopropyl adipate 30.0 Hydroxypropyl cellulose 1.5 Water 15.5 were added to a mixed solution of ~ and stirred and dispersed.
This was added and stirred until uniform. Example 2 Indomethacin 0.1 (%) Isopropanol 50.0 Isopropyl myristate 1.0 Triethanolamine 0.023 Water 48.877 A solution of .
第１図はエタノールをアジピン酸ジイソプロピ
ルの混合割合とインドメタシンの溶解度との関係
を、第２図はアジピン酸ジイソプロピルの添加量
とインドメタシンの吸収率の関係を、第３図はエ
タノール、水及びアジピン酸ジイソプロピルの親
和性を、第４図はエタノール、水及びアジピン酸
ジイソプロピルの均一系に対するインドメタシン
の溶解度を、第５図は本発明で使用できる基剤の
水、アルコール類及び脂肪酸１価アルコールエス
テル類の混合比を示す。
Figure 1 shows the relationship between the mixing ratio of ethanol and diisopropyl adipate and the solubility of indomethacin, Figure 2 shows the relationship between the amount of diisopropyl adipate added and the absorption rate of indomethacin, and Figure 3 shows the relationship between ethanol, water and adipic acid. Figure 4 shows the solubility of indomethacin in a homogeneous system of ethanol, water and diisopropyl adipate, and Figure 5 shows the solubility of indomethacin in a homogeneous system of ethanol, water and diisopropyl adipate. Indicates the mixing ratio.
Claims (1)
ソプロパノールから選ばれるアルコール類10〜70
重量％及びアジピン酸、セバチン酸及びミリス
チン酸の炭素数１〜５の１価アルコールエステル
から選ばれる脂肪酸１価アルコールエステル類１
〜60重量％よりなり、その３成分の混合比が第５
図の三角図表上のＡ，Ｂ，Ｃ，Ｄ，Ｅ及びＦを結
んでできる範囲内にある基剤にインドメタシンを
含有せしめたことを特徴とするインドメタシン外
用液剤。1 Water 11.44-50% by weight, alcohol selected from ethanol and isopropanol 10-70%
Weight% and fatty acid monohydric alcohol esters selected from monohydric alcohol esters having 1 to 5 carbon atoms of adipic acid, sebacic acid and myristic acid 1
~60% by weight, and the mixing ratio of the three components is the fifth
1. A liquid preparation for external use of indomethacin, characterized in that indomethacin is contained in a base within the range formed by connecting A, B, C, D, E, and F on the triangular diagram in the figure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1457481A JPS57128623A (en) | 1981-02-03 | 1981-02-03 | External solution of indomethacin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1457481A JPS57128623A (en) | 1981-02-03 | 1981-02-03 | External solution of indomethacin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57128623A JPS57128623A (en) | 1982-08-10 |
| JPH0345043B2 true JPH0345043B2 (en) | 1991-07-09 |
Family
ID=11864925
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1457481A Granted JPS57128623A (en) | 1981-02-03 | 1981-02-03 | External solution of indomethacin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57128623A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5988419A (en) * | 1982-11-12 | 1984-05-22 | Sumitomo Chem Co Ltd | Stable medicinal pharmaceutical |
| JPS5995212A (en) * | 1982-11-23 | 1984-06-01 | Nitto Electric Ind Co Ltd | Base composition and pharmaceutical composition for external use |
| JPH04217925A (en) * | 1990-03-27 | 1992-08-07 | Nippon Saafuakutanto Kogyo Kk | New antipyretic, antiphlogistic and analgesic agent composition |
| JP2945140B2 (en) * | 1991-05-02 | 1999-09-06 | 久光製薬株式会社 | Transdermal administration absorption promoting composition and transdermal administration external composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5381616A (en) * | 1976-12-27 | 1978-07-19 | Kowa Co | Production of antiinflammatory and anodyne ointment |
-
1981
- 1981-02-03 JP JP1457481A patent/JPS57128623A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5381616A (en) * | 1976-12-27 | 1978-07-19 | Kowa Co | Production of antiinflammatory and anodyne ointment |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57128623A (en) | 1982-08-10 |
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