CN1151866A - 用于皮炎的外用治疗组合物 - Google Patents
用于皮炎的外用治疗组合物 Download PDFInfo
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- CN1151866A CN1151866A CN96105337A CN96105337A CN1151866A CN 1151866 A CN1151866 A CN 1151866A CN 96105337 A CN96105337 A CN 96105337A CN 96105337 A CN96105337 A CN 96105337A CN 1151866 A CN1151866 A CN 1151866A
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- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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Abstract
本发明提供由包含有效治疗量的肾上腺皮质甾类化合物、环糊精、多糖和载体例如水的水溶液构成的用于皮炎的外用治疗组合物及其制备方法:使用匀浆机在环糊精中笼合肾上腺皮质甾类化合物形成笼形包合物,将该包合物加至多糖水溶液中,同时均匀搅拌,使包合物溶于该水溶液中。本发明还提供用于治疗哺乳类动物皮炎的方法,它包括给与所述患者有效治疗量的上述用于皮炎的外用治疗组合物。按照本发明的用于皮炎的外用治疗组合物是极为安全的,可治愈诸如特应性皮炎等皮炎而无副作用。
Description
本发明涉及用于皮炎的外用治疗组合物,它对于特应性皮炎、皮脂溢性皮炎、湿疹等有极好的疗效,且非常安全。
迄今为止,含具有很强的抗炎作用的肾上腺皮质甾类化合物的甾类化合物制剂主要用于治疗诸如特应性皮炎等皮炎。这类甾类化合物制剂通常是霜剂,根据使用的目的不同,它可含凡士林、甲基纤维素、表面活性剂、合成树脂乳剂、粉料(powders)等。在某些情况下,它可以是含表面活性剂的液体。
此外,还有一种外用组合物,它是安全的,其用途包括(1)对皮肤具消毒作用;(2)膜作用;(3)通过防止皮肤上水分蒸发的促润湿作用等。在该类外用组合物中,使用诸如氯化钠等无机盐(美国专利第3,574,854号)、诸如葡萄糖等天然糖(美国专利第3,859,436号)或等离子体(Plasma)(美国专利第3,777,597号)作为配合剂。
此外,本发明人曾提出一种用于皮肤和/或头发的水溶性化妆品组合物,它是安全的,并由于在多糖中含有葡萄糖和氯化钠,可在皮肤表面形成与皮肤细胞间液相同的环境,维持正常电解质平衡和渗透压平衡并促进皮肤表面的病害细胞恢复正常,以便激活皮肤细胞和治疗由于降低了皮肤细胞功能所引起的疾病(日本专利第1,597,430号)。
肾上腺皮质甾类化合物具有优良的药效如抑制成纤维细胞生长、抗炎作用等,而它对治疗特应性皮炎等的作用很差。尽管造成肾上腺皮质甾类化合物作用差异的原因是不明确的,可以假设用于配制软膏剂或霜剂的油性成分溶解了皮肤角质层,并阻滞正常皮肤的再生。此外,可以观察到对垂体-肾上腺皮质功能的抑制作用以及例如由于大量使用肾上腺皮质甾类化合物所引起的眼和其他器官的功能性疾病的副作用。为了避免以上所述缺点,需要降低甾类化合物的剂量,而保持其作为抗炎剂的药效。
另一种使用氯化钠等的安全的外用组合物,尽管它能使皮肤消毒作用和保护作用如缓和皮肤、使皮肤健康、使皮肤平滑等作用加强,但从治疗皮炎如特应性皮炎的作用的角度来看未被接受。
另一方面,以本发明人曾提出的用于治疗皮肤和头发的化妆品组合物水溶液形式,已证明该化妆品水溶液能激活皮肤、鼻粘膜等的细胞并对例如脱发、色素沉着、口炎、枯草热等病症具有优良的作用。
引起各种皮炎如湿疹,过敏性皮炎、特应性皮炎等的因素有很多,但是主要原因还不清楚。然而,当只考虑细胞水平的变化时,皮炎的成因在于细胞膜和线粒体(胞内细胞器之一)膜失去功能。换句话说,在发炎皮肤中,因为线粒体膜异常,降低了细胞的能源ATP(三磷酸腺苷)生成,所以,抑制了细胞内呼吸。由于缺乏ATP,使细胞膜的活性输送功能降低,导致在细胞和细胞间液间输送物质的能力降低。这引起细胞内营养物质如葡萄糖等缺乏,伴随ATP生成下降。如此形成恶性循环。
所以,在考虑以上因素后,本发明人致力于使用含多糖的水性基质替代通常用在含肾上腺皮质甾类化合物的治疗用外用组合物中的油性成分(表面活性剂),因为与肾上腺皮质甾类化合物合用制备软膏剂或霜剂的油性成分可能会通过使线粒体膜功能丧失而引起细胞内呼吸抑制。
本发明的目的是通过使肾上腺皮质甾类化合物(略溶于水)溶在水溶液中提供一种极为安全的治疗皮炎的外用制剂,皮炎例如特应性皮炎等可被完全治愈,无副作用。
本发明的目的是提供由包含有效治疗量的肾上腺皮质甾类化合物、环糊精、多糖和载体的水溶液构成的用于皮炎的外用治疗组合物。
本发明的另一个目的是提供治疗哺乳动物皮炎的方法,它包括给与所述患者有效治疗量的由包含有效治疗量的肾上腺皮质甾类化合物、环糊精、多糖和载体的水溶液构成的治疗皮炎外用组合物。
按照本发明,由包含有效治疗量的肾上腺皮质甾类化合物、环糊精、多糖和载体水的水溶液构成的治疗皮炎的外用组合物是依下法制备的:即通过使用匀浆机在环糊精中笼合肾上腺皮质甾类化合物形成笼形包合物,并将该包合物加至多糖水液中,同时均匀搅拌,使该包合物溶于该水溶液中。
在本发明中,为了将仅微溶于水的肾上腺皮质甾类化合物溶于水溶液中,预先将该肾上腺皮质甾类化合物笼合在所述环糊精中。
可提及的肾上腺皮质甾类化合物包括二氟松(diflorazones)、氢化可的松、甲基氢化***、***、倍他米松等。肾上腺皮质甾类化合物含量可为按照本发明的外用治疗组合物总重量的0.025%~0.5%(重量)。用于笼合肾上腺皮质甾类化合物的环糊精的含量可为按照本发明的外用治疗组合物总重量的0.2%~30%(重量)。
用于溶解肾上腺皮质甾类化合物的水溶液中所含的多糖可以提及葡聚糖、支链淀粉等。它们的含量可为按照本发明的外用治疗组合物总重量的0.5%~55%(重量)。
此外,用于溶解肾上腺皮质甾类化合物的水溶液除了多糖外还可含葡萄糖、mutan、蘑菇多糖、氯化钠、氯化钙和氯化钾。
利用这类水溶液,可在皮肤表面提供与细胞间液相同的环境,促进细胞的正常活性。这样可获得生物体自身具有的天然愈合能力与肾上腺皮质甾类化合物间的协同效应。
下面将参照制剂实施例和实施例药学实验详细解释按照本发明的用于皮炎的外用治疗剂。
制剂实施例1
葡聚糖 10g
葡萄糖 10g
麦芽糖 5g
甘露醇 15g
氯化钠 0.2g
倍他米松 0.06g
环糊精 15g
净化水 44.74g
总量 100.0g
按照制剂实施例1的制剂依下法制备:用部分净化水制备环糊精的10%水溶液,加入倍他米松到该水溶液中,同时搅拌,加入剩余的净化水、盐和糖类。
制剂实施例1的效果如下所示。
表1
疾病 受试者 效用 有效率
数目 (分数) (%)
特应性皮炎(1) 25 48 96
特应性皮炎(2) 10 19 95
特应性皮炎(3) 25 46 92
特应性皮炎(4) 25 49 98
皮脂溢性皮炎(1) 25 48 96
皮脂溢性皮炎(2) 100 198 99
皮脂溢性皮炎(3) 10 19 95
牛皮癣 5 9 90
湿疹 25 48 96
痤疮 50 99 99
表1显示关于制剂实施例1的药学实验结果。在表1中“效用”是通过按照如下评价的总分数来表示:评价:0分 使用制剂实施例1后无变化1分 使用制剂实施例1后观察到治疗变化2分 使用制剂实施例1后确证了治疗效果表1中“有效率”是依据如下数学表达式计算而得:有效率={(总分数)/(受试者数目)×2}×100
表1中有关特应性皮炎的数据基于来自位于日本Nagareyama(千叶县)、Sendai(Miyagi县)、Oomiya(Saitama县)和Kichijyoji(东京)的诊所所完成的药学实验结果,表1中除了特应性皮炎外有关其它疾病的数据基于在Nagareyama的诊所所完成的药学实验结果。
应注意到在上述300个病例中未观察到任何副作用。此外,按照本发明的外用治疗性组合物在治疗非常难以治愈的皮炎病如特应性皮炎或皮脂溢性皮炎方面显效。此外,在治疗皮脂溢性皮炎或痤疮方面可获得99%的有效率。
按照本发明用于皮炎的外用治疗组合物对于表1中所示所有疾病显示不低于90%的有效率。部分患者在大约7~30天后,不需要本发明的外用治疗组合物。此外,将除溶于水中的肾上腺皮质甾类化合物含多糖的水溶液(日本专利第1597430号)涂于患部,将该疾病完全治愈。
制剂实施例2
葡聚糖 10g
葡萄糖 5g
麦芽糖 10g
甘露醇 5g
氯化钠 0.1g
氯化钾 0.2g
倍他米松磷酸钠 0.06g
环糊精 10g
净化水 59.58g
总量 100.0g
制剂实施例3
支链淀粉 10g
Betain 15g
麦芽糖 10g
氯化钠 0.1g
*** 0.06g
环糊精 15g
净化水 49.84g
总量 100.0g
制剂实施例4
葡聚糖 5g
Betain 20g
麦芽糖 5g
氯化钠 0.1g
***磷酸钠 0.05g
环糊精 15g
净化水 54.85g
总量 100.0g
制剂实施例5
葡聚糖 10g
羟乙基纤维素 2g
Betain 10g
甘露醇 10g
氯化钙 0.1g
氯化钠 0.1g
糊精 7g
***磷酸钠 0.1g
环糊精 10g
净化水 50.7g
总量 100.0g
制剂实施例6
支链淀粉 15g
羟乙基纤维素 10g
Betain 15g
甘露醇 5g
氯化钙 0.1g
氯化钠 0.1g
糊精 7g
*** 0.05g
环糊精 15g
净化水 32.75g
总量 100.0g
已观察到制剂实施例2~6的效果与制剂实施例1的相似。可按照皮炎病情选用这些制剂。
对比制剂及其药效如下:
对比制剂实例1
戊酸倍他米松 0.12g
对羟基苯甲酸甲酯 0.15g
白凡士林 99.73g
总量 100.0g
对比制剂实例2
戊酸倍他米松 0.12g
对羟基苯甲酸甲酯 0.15g
表面活性剂 30g
白凡士林 69.73g
总量 100.0g
对比制剂实例1的效果见下表2。
表2
疾病 受试者 效用 有效率
数目 (分数) (%)
特应性皮炎(1) 10 2 10
特应性皮炎(2) 50 5 5
特应性皮炎(3) 25 5 10
特应性皮炎(4) 50 7 7
皮脂溢性皮炎(3) 50 5 5
湿疹 100 18 9
表2显示有关对比制剂实例1的药学实验结果。在表2中,“效用”、“有效率”和完成药学实验的诊所与制剂实施例1的相同。
根据有关采用油性基质的对比制剂实例1的药学实验结果,该对比制剂与本发明制剂的治愈效果相差甚远,且引起副反应,即在一些病例中,由于使用对比制剂实例1而加重病情,结果停止其使用。此外,通常观察到该对比制剂的有效率与用药天数成负相关。
从以上观察可得出结论:因为根据对比制剂实例1的对比制剂其中的油性基质抑制角质化这一皮肤的生理功能,使得皮炎难于治愈。在某些病例中,油性基质实际上使病情加重。
另一方面,在根据本发明的外用治疗组合物的制剂实施例1中,水性基质对皮肤生理功能无任何抑制作用。此外,加至水性基质中的成分能在皮肤表面产生与细胞间液相同的环境,促进细胞的正常化。所以,按照本发明的组合物可作为抗炎肾上腺皮质甾类化合物药物产生很强的药效。
正如上述所表明的本发明可达到预定的目标。换句话说,按照本发明,通过将经在环糊精中笼合的有效治疗量的肾上腺皮质甾类化合物溶于含多糖的水溶液中不会产生因常规基质中的油性成分溶解皮肤的角质层因而抑制正常皮肤再生的缺点。
此外,通过使用0.025%~0.5%(重量)的肾上腺皮质甾类化合物、0.2%~30%(重量)的环糊精和0.5%~55%(重量)的多糖例如葡聚糖、支链淀粉等以及含葡萄糖、mutan、蘑菇多糖、氯化钠、氯化钙等的多糖水溶液,根据本发明的外用治疗组合物可防止由于线粒体膜功能丧失所引起的细胞内呼吸抑制和防止作为细胞活性源的ATP(三磷酸腺苷)生成减少。此外,按照本发明的外用治疗组合物能维持电解质平衡和渗透压平衡并能产生肾上腺皮质甾类化合物的药效。
因为该组合物中的水性基质不抑制皮肤的生理功能,所以,可获得生物体自身的自然愈合能力和肾上腺皮质甾类化合物药物间的协同作用。所以,按照本发明的外用治疗组合物在治疗采用常规油性基质治疗作用较差的特应性皮炎、湿疹等方面产生很强的治疗作用。
此外,因为达到完全治愈所用的肾上腺皮质甾类化合物的总量降低,所以看不到对垂体-肾上腺皮质功能的抑制作用以及诸如由于使用大量肾上腺皮质甾类化合物引起的眼和其它器官的功能性疾病等的副作用。
如上所述,按照本发明的用于皮炎的外用治疗组合物与常规的皮炎外用组合物相比能显著提高有效率,尤其对难于治愈的疾病如特应性皮炎、皮脂溢性皮炎等具有疗效。所以,由于按照本发明的用于皮炎的外用治疗组合物可替代常规皮炎外用组合物,因而,从治愈率和安全性角度出发,有效性有很大的提高,即观察到很小的副作用。可以期待按照本发明的外用组合物将被许多患有难治性皮炎的患者所使用。
Claims (12)
1.由包含有效治疗量的肾上腺皮质甾类化合物、环糊精、多糖和载体的水溶液构成的用于皮炎的外用治疗组合物。
2.按照权利要求1的外用治疗组合物,其中所述肾上腺皮质甾类化合物被笼合在所述环糊精中。
3.按照权利要求1的外用治疗组合物,其中所述水溶液含有肾上腺皮质甾类化合物的环糊精笼形包合物,溶在多糖的水溶液中。
4.按照权利要求1的外用治疗组合物,含有0.025%~0.5%(重量)的肾上腺皮质甾类化合物、0.2%~30%(重量)的环糊精和0.5%~55%(重量)的多糖。
5.按照权利要求1的外用治疗组合物,其中所述多糖包括葡聚糖或支链淀粉。
6.按照权利要求3的外用治疗组合物,其中所述多糖水溶液还含有葡萄糖、mutan、蘑菇多糖、氯化钠、氯化钙和氯化钾。
7.治疗哺乳动物皮炎的方法,它包括给与所述患者有效治疗量的由包含有效治疗量的肾上腺皮质甾类化合物、环糊精、多糖和载体的水溶液构成的用于皮炎的外用治疗组合物。
8.按照权利要求7的方法,其中所述肾上腺皮质甾类化合物被笼合在所述环糊精中。
9.按照权利要求7的方法,其中所述水溶液含有肾上腺皮质甾类化合物的环糊精笼形包合物,溶在多糖的水溶液中。
10.按照权利要求7的方法,包含0.025%~0.5%(重量)的肾上腺皮质甾类化合物、0.2%~30%(重量)的环糊精和0.5%~55%(重量)的多糖。
11.按照权利要求7的方法,其中所述多糖包括葡聚糖或支链淀粉。
12.按照权利要求9的方法,其中所述多糖水溶液还含有葡萄糖、mutan、蘑菇多糖、氯化钠、氯化钙和氯化钾。
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JP2681527B2 (ja) * | 1990-02-15 | 1997-11-26 | ジャパンファインケミカル株式会社 | 細胞活性促進外用剤 |
GB9012663D0 (en) * | 1990-06-07 | 1990-08-01 | Erba Carlo Spa | Galenic formulations containing cyclodextrins |
JP2578048B2 (ja) * | 1992-05-22 | 1997-02-05 | 株式会社 シーエーシー | 循環瀘過装置 |
US5324718A (en) * | 1992-07-14 | 1994-06-28 | Thorsteinn Loftsson | Cyclodextrin/drug complexation |
JP3535883B2 (ja) * | 1993-06-25 | 2004-06-07 | 井関農機株式会社 | 作業機連結装置 |
JPH0756417A (ja) * | 1993-08-09 | 1995-03-03 | Ricoh Co Ltd | 回転型現像装置 |
JP2772619B2 (ja) * | 1994-06-28 | 1998-07-02 | 株式会社シーエーシー | 多糖類水溶液用循環風呂 |
-
1995
- 1995-12-11 JP JP7346006A patent/JP2920611B2/ja not_active Expired - Lifetime
-
1996
- 1996-03-20 TW TW085103373A patent/TW431889B/zh not_active IP Right Cessation
- 1996-04-03 CA CA002173403A patent/CA2173403C/en not_active Expired - Lifetime
- 1996-04-03 US US08/626,963 patent/US5885978A/en not_active Expired - Lifetime
- 1996-04-04 AU AU50560/96A patent/AU705996B2/en not_active Expired
- 1996-04-10 EP EP96302509A patent/EP0780129B1/en not_active Expired - Lifetime
- 1996-04-10 AT AT96302509T patent/ATE290883T1/de active
- 1996-04-10 ES ES96302509T patent/ES2240987T3/es not_active Expired - Lifetime
- 1996-04-10 DK DK96302509T patent/DK0780129T3/da active
- 1996-04-10 DE DE69634472T patent/DE69634472T2/de not_active Expired - Lifetime
- 1996-06-03 CN CNB961053372A patent/CN1153571C/zh not_active Expired - Lifetime
- 1996-06-07 KR KR1019960020250A patent/KR0181763B1/ko not_active IP Right Cessation
- 1996-06-29 SG SG1996010182A patent/SG48460A1/en unknown
-
1998
- 1998-05-13 HK HK98104115A patent/HK1004979A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
EP0780129A2 (en) | 1997-06-25 |
KR0181763B1 (ko) | 1999-05-01 |
CA2173403A1 (en) | 1997-06-12 |
AU5056096A (en) | 1997-06-19 |
EP0780129B1 (en) | 2005-03-16 |
JP2920611B2 (ja) | 1999-07-19 |
DE69634472T2 (de) | 2006-02-16 |
TW431889B (en) | 2001-05-01 |
HK1004979A1 (en) | 1998-12-18 |
CN1153571C (zh) | 2004-06-16 |
ATE290883T1 (de) | 2005-04-15 |
SG48460A1 (en) | 1998-04-17 |
DE69634472D1 (de) | 2005-04-21 |
CA2173403C (en) | 2000-05-16 |
KR970032871A (ko) | 1997-07-22 |
US5885978A (en) | 1999-03-23 |
ES2240987T3 (es) | 2005-10-16 |
JPH09157171A (ja) | 1997-06-17 |
AU705996B2 (en) | 1999-06-03 |
EP0780129A3 (en) | 2000-07-19 |
DK0780129T3 (da) | 2005-06-20 |
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