Preparation with an acrylic-based, adhesive copolymeric matrix f

Details Preparation with an acrylic-based, adhesive copolymeric matrix f Preparation with an acrylic-based, adhesive copolymeric matrix f

1994-07-15

2000-12-05

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

424449, A61F 1302

Patent

active

061563358

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to pharmaceutical delivery systems and more particularly to preparations for transdermal administration of estradiol.
2. Brief Description of Related Art
Introduction
Ovarian secretion of 17.beta.-estradiol is lacking in postmenopausal women. In many women this physiological phenomenon induces progressive hypotrophy of the urogenital system as well as characteristic vasomotor symptoms, often followed by osteoporosis affecting particularly the vertebral column.
These climacteric symptoms can be prevented by an exogenous estrogen-based hormone replacement therapy. However, the oral administration of 17.beta.-estradiol (hereinafter referred to as "estradiol") has problems, since the hormone is modified in the intestine and in the liver and produces high blood levels of its metabolites, such as estradiol sulfate, estrone and estrone sulfate which may accumulate in the organism, if the administration is prolonged. One of the undesired effects of the oral administration of estradiol is the increased synthesis by the liver of proteins, including the substrate of renin, with a possible consequent increase in arterial pressure.
The oral route can be bypassed by the transdermal administration of estradiol, which delivers the active ingredient directly into the systemic circulation. However, the diffusion of estradiol through the skin is difficult. To improve it, a special transdermal systems must be developed that can enhance the absorption of estradiol, such as an especially designed, estradiol containing, pressure sensitive adhesive patch, i.e. an Estradiol Transdermal Patch (hereinafter referred to as "OTP").
The OTP represents a considerable therapeutic progress, over the conventional oral administration, since it avoids the "first pass effect" and delivers estradiol directly into the systemic circulation in quantities comparable to those which are physiologically produced by the ovaries.
A widely used OTP is represented by a reservoir in which estradiol is dissolved in ethanol gelatinised with, for example, hydroxypropyl cellulose. The reservoir is contained by a membrane, through which estradiol diffuses to the skin. In this system the membrane becomes the diffusion-rate limiting component of the OTP, as it is the case of an OTP already on the market.
Various patents have been applied for in connection with OTPs provided with diffusion-rate limiting membranes and the use of solvents such as ethanol, alone or in mixture, for dissolving or dispersing estradiol in the drug reservoir, and for improving its absorption through the skin. Thus, for example, GB patent 2158 355 describes the use of a combination of propylene glycol and glycerol in variable ratios; U.S. Pat. No. 4,658,343 described the use of polyethylene glycol monolaurate as agent for improving the skin-penetration of estradiol ("enhancer"), and EP patent 0 147 146 describes the use of methanol for the same purpose.
The transdermal systems based on a diffusion-rate limiting membranes involve various problems. For instance any small hole in the membrane causes inevitably the breakdown of the whole transdermal system.
These systems often require the use of absorption enhancers, which ultimately act by disrupting the intercellular connections of the superficial layers of the skin. This effect increase the permeability of the skin to the active ingredient but often causes skin irritation or sensitisation. The absorption enhancers may also be absorbed through the skin causing unwanted systemic side effects.
In general the systems with diffusion-rate limiting membranes do not allow to achieve constant release rates of the active ingredient, which is disadvantageous since usually the therapeutic treatments require that the active ingredient is released over a prolonged period of time.
Another possible structure of transdermal systems is that of the so-called "monolithic" systems. In these systems the active ingredient is dissolved or dispersed in a "matrix", which becomes the drug re

REFERENCES:
patent: 4906475 (1990-03-01), Kim
patent: 4994267 (1991-02-01), Sablotsky

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