CN1201385A - 用于通过皮肤而经皮施用活性物质的治疗制剂 - Google Patents

用于通过皮肤而经皮施用活性物质的治疗制剂 Download PDF

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CN1201385A
CN1201385A CN96198113A CN96198113A CN1201385A CN 1201385 A CN1201385 A CN 1201385A CN 96198113 A CN96198113 A CN 96198113A CN 96198113 A CN96198113 A CN 96198113A CN 1201385 A CN1201385 A CN 1201385A
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博杜·阿斯马森
安德烈亚斯·科克
鲁道夫·马杜施
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LTS Lohmann Therapie Systeme AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

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Abstract

本发明所提出的制剂含有使活性物质被更迅速地吸收的添加剂,该活性物质通常仅能通过皮肤不充分地吸收。该制剂的特征在于该添加剂是β－羟基－β－甲基戊二酸单酰辅酶A还原酶抑制剂。

Description

用于通过皮肤而经皮施用 活性物质的治疗制剂
本发明涉及一种用于通过皮肤而经皮施用活性物质的治疗制剂，其含有使通常仅能经皮不充分地吸收的活性物质的吸收速率增加的添加剂。
含可经皮吸收的活性物质的给药形式，例如经皮治疗系统的一个主要问题是克服皮肤的天然穿透屏障。它行使着皮肤的表皮保护功能，由表皮的胞间隙中的宽的成层脂双层构成，是抵御任何试图经皮吸收的屏障。
为解决这一问题，现在向用于活性物质的经皮使用的治疗制剂中加入所谓常规增强剂的促渗透添加剂已有一段时间了。这些增强剂在更长的一段时间内增加亲脂或亲水药用物质的经皮吸收速率。但是，结果是一些活性物质还是经皮吸收速率不够。经皮治疗制剂的面积偶尔被扩大到能达到有疗效的活性物质经过皮肤流至器官中。但这也导致了一些缺点；另一方面，就成本和生产来说，这样的贴片不必要地变得昂贵，并且另一方面，病人发现大的经皮贴片让人讨厌。在覆盖更大的皮肤面积时，通过肌肉运动或身体的其他运动，容易发生贴片的部分剥离，这就大大减小了可控的活性物质流量。
对常规增强剂的作用方式还未作彻底研究。但将当今常规使用的增强剂归因于理化作用机制；例如，通过改变活性物质在表皮脂双层中的分布系数，增加脂溶性，或者由于通过增强剂和透皮脂质之间的位阻效应和极性相互作用，透皮脂质的液-晶状态下的熵值减少，降低扩散系数。
此外，了解到还可以通过生物化学的再生过程中的直接介入，如在表皮中影响皮肤的渗透屏障，来改变皮肤结构。如Proksch(J.Hautarzt，1955，46卷，第2期，76-80页)的著作描述了局部施用β-羟基-β-甲基戊二酸单酰辅酶A(HMG-CoA)的特异抑制剂洛伐他汀导致了皮肤中的胆固醇水平的下降，同时水的经表皮损失增加且表皮中的DNA合成增加；这就干扰了皮肤的天然渗透屏障。
在DE 3634016中提到了降脂物质在经皮治疗系统中的用途。但对与其他活性物质组合的降脂物质的详细说明只是为了治疗的目的；它不是用来增加通常只能被不充分地经皮吸收的活性物质的经皮吸收速率。
本发明的目的是研制权利要求1的前叙部分提到的那种治疗制剂，并以这样的方式改进它以使其以这样的程度改变皮肤结构，以使由于皮肤(尤其是表皮)的扩散阻力减小而达到药剂的吸收增加，如此使得即便是通常仅能不充分地吸收的活性物质也有大大增加的扩散速率。
为达到这一目的，本发明建议增加制剂的经皮吸收的添加剂应该是HMG-CoA还原酶抑制剂。
因而，Prosch的著作中所提到的效果(即干扰皮肤的天然渗透屏障-根据此文章仅仅是通过将降脂物质和其他活性物质结合而用于治疗目的)可通过将最少0.1重量而最大20％重量的HMG-CoA-还原酶抑制剂用作促渗透添加剂而选择地用来在更长的时间内增加亲脂或亲水药剂的经皮吸收速率。
与常规的增强剂相反，就意外地达到增加渗透而论，本发明是基于作用的生物化学成份。随着表皮渗透屏障被干扰，该成份在更长的时间内形成一个“窗口”，而那些药剂由于其理化性质(例如，分子量大于400道尔顿，熔点高、水中溶解度低或水/油分配系数低)而产生问题的药剂确实能通过它而以增加的力量经皮通过皮肤通道。
由HMG-CoA还原酶抑制剂引起的表皮生物脂合成的抑制也阻止恢复被干扰的渗透屏障的表皮天然修复机制，这在使用有脂溶性的增强剂时是常见的，没有成功。由于这个原因，该促进渗透效果，渗透屏障中的所谓“窗口”，持续时间更长，因而在药物的经皮治疗中也有实际意义。
对妨碍很多强的增强剂的并且尤其是也适合于HMG-CoA-还原酶抑制剂(如洛伐他汀)的实际应用的刺激皮肤的副作用的问题，根据本发明通过在经皮施用系统(TTS，软膏或糊剂)中使用最多20％重量的可降脂的药物的事实进行了解决。
将通过示于图1和图2的测量结果来说明本发明。
通常，吸收不充分的活性物质的例子除吗啡外还包括：茶碱，L-甲状腺素，麦角胺，D，L-醉椒素，D，L-苄丙酮香豆素。
图1示降脂物质洛伐他汀对吗啡碱的渗透速率的影响，使用的是切下的豚鼠皮肤。(于T＝37℃下，在0.9％盐溶液中释放，n＝3，+/-SD)。
该实施例证明即使以少量(2％重量)加入降脂物质洛伐他汀，在24小时后也能使渗透速率加倍。
甚至在这段时间之后(长至48小时)，也能保持增加大约80％。
图2示降脂物质洛伐他汀对D，L-醉椒素的渗透速率的影响，使用的是切下的豚鼠皮肤(在T＝37℃下于等张的pH7.4的磷酸缓冲液中释放，n＝3，+/-SD)。
该实施例证明即使少量(2％重量)加入降脂物质洛伐他汀，也能在24小时后达到增加经皮吸收不好的活性物质的渗透速率70％。甚至在这段时间之后(长至52小时)，还能维持增加50％。注：洛伐他汀：lovastatin
西伐他停：simvastatin
美伐他汀：mevastatin
普伐他汀：provastatin

Claims (4)

1.一种用于通过皮肤而经皮施用活性物质的治疗制剂，其含有使那些通常只能被不充分地经皮吸收的活性物质的经皮吸收速率增加的添加剂，其特征在于该添加剂为β-羟基-β-甲基戊二酸单酰辅酶A还原酶抑制剂。
2.如权利要求1的制剂，其特征在于该添加剂为洛伐他汀，西伐他停，美伐他汀和普伐他汀。
3.如权利要求1的制剂，其特征在于β-羟基-β-甲基戊二酸单酰辅酶A还原酶抑制剂部分占至少0.1且至多20％重量。
4.如权利要求1-3中一项或几项的制剂，其特征在于它是一种软膏剂或糊剂。
CN96198113A 1995-11-06 1996-09-21 用于通过皮肤而经皮施用活性物质的治疗制剂 Pending CN1201385A (zh)

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DE19541260.5 1995-11-06
DE19541260A DE19541260A1 (de) 1995-11-06 1995-11-06 Therapeutische Zubereitung zur transdermalen Applikation von Wirkstoffen durch die Haut

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AU (1) AU716896B2 (zh)
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MY132407A (en) 2007-10-31
CZ136698A3 (cs) 1998-07-15
WO1997017061A1 (de) 1997-05-15
MX9803563A (es) 1998-09-30
EP0859595B1 (de) 1999-11-03
GR3032523T3 (en) 2000-05-31
PT859595E (pt) 2000-04-28
KR19990067320A (ko) 1999-08-16
SK281405B6 (sk) 2001-03-12
KR100445940B1 (ko) 2005-09-30
ATE186209T1 (de) 1999-11-15
EP0859595A1 (de) 1998-08-26
IL124279A (en) 2003-07-06
NZ318783A (en) 1999-04-29
NO982006D0 (no) 1998-05-04
AU716896B2 (en) 2000-03-09
DE19541260A1 (de) 1997-05-07
ZA969271B (en) 1997-06-03
US6379696B1 (en) 2002-04-30
ES2141534T3 (es) 2000-03-16
JP2001507331A (ja) 2001-06-05
NO982006L (no) 1998-05-04
CZ289143B6 (cs) 2001-11-14
AU7085996A (en) 1997-05-29
DE59603597D1 (de) 1999-12-09
SK55898A3 (en) 1998-11-04

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