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Lecithin organogels as matrix for the transdermal transport of drugs
Vol.
177,
No.
June
28,
1991
3, 1991
BIOCHEMICAL
AND
BIOPHYSICAL
RESEARCH
COMMUNICATIONS
Pages
897-900
LECITHIN ORGANOGELS AS MATRIX FOR THE TRANSDERMAL TRANSPORT OF DRUGS Hong-Li Willimann
and Pier Luigi Luisi
Institute of Polymers, ETH-Ziirich Received
May
8,
, Switzerland
1991
Summary. The stable, transparent, thermoreversible organogels which are prepared by adding a minute amount of water to a solution of lecithin in isopropylpalmitate are studied as matrices for promoting the transdermal transport of drugs throughout the skin. In this work we study this process by using two model drug substances, scopolamine (already well known as a transdermally active substance) and broxaterol, a new drug against asthma. It is found that the transport of scopolamine is much more effective in gel than in aqueous solution and that the transport of broxaterol is also proceeding well. Since the same can be observed with a variety of substances differing in the chemical structure, we speculate on the application of lecithin gels as general matrices for the transdermal transport. B 1991Academic Press,Inc.
It has been shown in our laboratory that solutions of natural and synthetic lecithin in organic solvents display a surprising property: upon addition of minute amount of water, the solution is converted into a gel which can have a remarkably high macroscopic viscosity- up to a few thousand poise (1). A large series of organic solvents is capable of forming gels in this way, for example linear and cyclic hydrocarbons, esters of fatty acids, as well as certain amines (1). For each solvent, there is a characteristic ratio water to lecithin ( w,= [H’O]/[LEC])
at which the
maximal viscosity is observed. The structure and the rheological properties of these organogels have been in the meantime investigated (2,3). It has also been observed that these gels are capable of solubilizing hydrophilic,
hydrophobic and amphophilic compounds (1,4). These gels
are transparent, thermoreversible, isotropic, and lend themselves to spectroscopic studies (4) and also to studies of enzyme activity in the gel phase (5).
897
0006-291X/91 $1.50 Copyright 0 1991 by Acudemic Press, Inc. All rights of reproduction in any form reserved.
Vol.
177,
No.
BIOCHEMICAL
3, 1991
In this communication,
AND
we describe how
used as agents for the transdermal be of potential
use to facilitate
transport
As is well known,
been investigated
as one important
with
O,gel= 3, with
a smaller
the skin. In the studies
lecithin
i.e. how
concentration,
substance,
scopolamine,
transport-
actually
study, which
being described
they can
from the skin into
transport
is currently
route to the more classic organogels
must be one which
forms a gel with
of 200 mM.
is
the viscosity
lecithin
is however
smaller.
we have used two drugs: one reference has been already used in transdermal
sickness(8);
as Scopoderm,
and broxatherol,
which
as an effective bronchodilatatory
scopolamine
as has
agent and
being used against asthma (9). The chemical structure
is shown
below.
broxaterol
These two chemicals
have been solubilized
concentration
of 40 mg/ml
for scopolamine
by dissolving
them first in the IPP-lecithin
in the gel up to a
and 75 mg/ml solution
for broxaterol
to which
then water
has been added used to induce gelation. For the transdermal
experiment,
been used. This is provided
with
a Franz diffusion
a donor compartment,
gel with
the drug, and an acceptor compartment
aqueous
solution.
A sample of skin (0.64 cm2)separates drawing
drug throughout
the skin into the acceptor compartment
surgery
The skin samples department
cell (10) has containing
consisting
compartment-see
HPLC.
the
of a buffered
the two
in the insert of Fig.1. The rate of flux of the
were kindly
Prof.Frei)
at a
Gels can be formed
in this form it is on the market
active drug against motion
can be
we will describe here, we will
(IPP), which
a lecithin concentration
In this preliminary
recently
transdermal
e.g. the organic solvent
make use of isopropylpalmitate W
of drugs,
alternative
COMMUNICATIONS
lecithin organogels
drugs (67). For such an application,
must be biocompatible, compatible
RESEARCH
the passage of drugs
the blood vessels.
routes for delivering
BIOPHYSICAL
provided
of the University 898
is measured
by
to us by the plastic Hospital
in Zurich.
The
at
Vol.
177,
No.
3, 1991
BIOCHEMICAL
AND
20
BIOPHYSICAL
RESEARCH
40 Time
COMMUNICATIONS
60
2
(h)
Fig.. Transdermal transport of Scopolamine and Broxaterol throughout human skin in vitro. Curve (3) is a reference system obtained with an aqueous solution of 39.8 mg/ml scopolamine in the donor compartment
and curve (2) is scopolamine at the same concentration in an isopropylpalmitate lecithin gel (200 mM lecithin W,=3). The concentration of Broxaterol in the same gel was 75 mg/ml (curve 1) and all at room temperature.
studies described here were performed
with breast skin from female
patients in the range 35-40 years of age. Typical
results are reported in Fig.1. In particular,
flux rate of scopolamine
as obtained
with the lecithin
IPP-gel is compared
with the flux rate obtained when an aqueous solution with the same concentration
the transdermal
of scopolamine
is used in the donor compartment.
same figure, also the transport
rate of broxaterol
In the
is given.
One can see that the flux obtained with the gel is considerably higher than that obtained with the aqueous solution. considerably preparation
higher than the flux obtained with a commercial (data not shown).
it is not always advantageous simply
It is also
Of course, from the clinical point of view, to have a high flux rate- here the point is
to show that the lecithin gels facilitate the transport
throughout
Scopoderm
of the drug
the skin.
In this sense, the data for the new drug broxaterol flux corresponds to 47 ug/cm’/hr
are interesting.
when a concentration
The
of 75mg/ml
broxaterol
is used in the gel. Notice the relatively
beginning,
and the tendency to reach a plateau at longer times. The lag
phase is also present in the experiments
long lag phase at the
with scopolamine.
Vol.
177,
No.
BIOCHEMICAL
3, 1991
We are now involved understanding
AND
BIOPHYSICAL
RESEARCH
in a systematic investigation,
COMMUNICATIONS
aimed at
the most basic feature of this transport phenomena.
Preliminary
data show that lecithin
gels also permit
the transport of
aminoacids
and peptides, as well as of substances such as estradiol. We
can then , even at this early stage, conclude that lecithin transdermal
gels enable the
transport of a large variety of chemical structures.
The fact that the transport is not so specific regarding structure poses some restrictions
on the mechanism
throughout
that the stratum
the skin. Recognizing
the chemical
of the transport corneum contains also
layers of lipids arranged in a regular structure (ll), one may argue that they are capable of interacting
with the phospholipids
of the gel matrix:
the disorganization
of the skin lipidic
drug permeability.
Studies are in progress in our group to test this
mechanism
structure may be the cause of the
and to clarify the range of applicability
of the procedure.
Acknowledgments We thank helping us with Stroppolo of the with samples of chemical.
Dr. Peter Walde for fruitful discussion, Dr. Bruckner for the samples of human skin, Dr. Gazzaniga and Dr. Company Inpharzam (Campesino, CH) for providing us broxaterol and corresponding discussion over this
References 1) Scartazzini R. and Luizi P.L. (1988)J.Phys.Chem.,a829-833. 2) Luisi P.L., Scartazzini R., Haering G. and Schurtenberger P. (1990) Colloid.Polym.Sci. 268356-374. 3) Schurtenberger P., Scartazzini R. and Luisi P.L. (1989) Rheol. Acta, X5-372-381. 4) Nastruzzi C, Colombo L., Willimann H. and Luisi P.L. in preparation. 5) Scartazzini R. and Luisi J?.L (1990) Biocatalysis&377-380. 6) Chien Y.W. (editor) Transdermal Controlled Svstemic Medications, Marcel Dekker, Inc., New York, 1987. 7) Johnson P. and Lloyd-Jones J.G. (editors) Drug Delivery Systems: Fundamentals and Techniaues,Ellis Horwood Ltd., Chichester,l987. 8) Brandau R. and Lippold B.H. (editors) Dermal and Transdermal Absorotion, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1982. 9) Chiarino D., Fantucci M., Carenzi A., Della Bella D., Frigeni V. and Sala R. (1986) II Farmaco-Ed. SC., & 440453. 10) Kydonieus A.F. and Bemer B. (Editors) Transdermal Deliverv of DrugsYol I-III, CRC Press, Inc., Boca Raton, Florida, 1987. 11) P.M. Elias, B. E. Brown, J. Invest. Dermatol. a(1979) 339.
900
177,
No.
June
28,
1991
3, 1991
BIOCHEMICAL
AND
BIOPHYSICAL
RESEARCH
COMMUNICATIONS
Pages
897-900
LECITHIN ORGANOGELS AS MATRIX FOR THE TRANSDERMAL TRANSPORT OF DRUGS Hong-Li Willimann
and Pier Luigi Luisi
Institute of Polymers, ETH-Ziirich Received
May
8,
, Switzerland
1991
Summary. The stable, transparent, thermoreversible organogels which are prepared by adding a minute amount of water to a solution of lecithin in isopropylpalmitate are studied as matrices for promoting the transdermal transport of drugs throughout the skin. In this work we study this process by using two model drug substances, scopolamine (already well known as a transdermally active substance) and broxaterol, a new drug against asthma. It is found that the transport of scopolamine is much more effective in gel than in aqueous solution and that the transport of broxaterol is also proceeding well. Since the same can be observed with a variety of substances differing in the chemical structure, we speculate on the application of lecithin gels as general matrices for the transdermal transport. B 1991Academic Press,Inc.
It has been shown in our laboratory that solutions of natural and synthetic lecithin in organic solvents display a surprising property: upon addition of minute amount of water, the solution is converted into a gel which can have a remarkably high macroscopic viscosity- up to a few thousand poise (1). A large series of organic solvents is capable of forming gels in this way, for example linear and cyclic hydrocarbons, esters of fatty acids, as well as certain amines (1). For each solvent, there is a characteristic ratio water to lecithin ( w,= [H’O]/[LEC])
at which the
maximal viscosity is observed. The structure and the rheological properties of these organogels have been in the meantime investigated (2,3). It has also been observed that these gels are capable of solubilizing hydrophilic,
hydrophobic and amphophilic compounds (1,4). These gels
are transparent, thermoreversible, isotropic, and lend themselves to spectroscopic studies (4) and also to studies of enzyme activity in the gel phase (5).
897
0006-291X/91 $1.50 Copyright 0 1991 by Acudemic Press, Inc. All rights of reproduction in any form reserved.
Vol.
177,
No.
BIOCHEMICAL
3, 1991
In this communication,
AND
we describe how
used as agents for the transdermal be of potential
use to facilitate
transport
As is well known,
been investigated
as one important
with
O,gel= 3, with
a smaller
the skin. In the studies
lecithin
i.e. how
concentration,
substance,
scopolamine,
transport-
actually
study, which
being described
they can
from the skin into
transport
is currently
route to the more classic organogels
must be one which
forms a gel with
of 200 mM.
is
the viscosity
lecithin
is however
smaller.
we have used two drugs: one reference has been already used in transdermal
sickness(8);
as Scopoderm,
and broxatherol,
which
as an effective bronchodilatatory
scopolamine
as has
agent and
being used against asthma (9). The chemical structure
is shown
below.
broxaterol
These two chemicals
have been solubilized
concentration
of 40 mg/ml
for scopolamine
by dissolving
them first in the IPP-lecithin
in the gel up to a
and 75 mg/ml solution
for broxaterol
to which
then water
has been added used to induce gelation. For the transdermal
experiment,
been used. This is provided
with
a Franz diffusion
a donor compartment,
gel with
the drug, and an acceptor compartment
aqueous
solution.
A sample of skin (0.64 cm2)separates drawing
drug throughout
the skin into the acceptor compartment
surgery
The skin samples department
cell (10) has containing
consisting
compartment-see
HPLC.
the
of a buffered
the two
in the insert of Fig.1. The rate of flux of the
were kindly
Prof.Frei)
at a
Gels can be formed
in this form it is on the market
active drug against motion
can be
we will describe here, we will
(IPP), which
a lecithin concentration
In this preliminary
recently
transdermal
e.g. the organic solvent
make use of isopropylpalmitate W
of drugs,
alternative
COMMUNICATIONS
lecithin organogels
drugs (67). For such an application,
must be biocompatible, compatible
RESEARCH
the passage of drugs
the blood vessels.
routes for delivering
BIOPHYSICAL
provided
of the University 898
is measured
by
to us by the plastic Hospital
in Zurich.
The
at
Vol.
177,
No.
3, 1991
BIOCHEMICAL
AND
20
BIOPHYSICAL
RESEARCH
40 Time
COMMUNICATIONS
60
2
(h)
Fig.. Transdermal transport of Scopolamine and Broxaterol throughout human skin in vitro. Curve (3) is a reference system obtained with an aqueous solution of 39.8 mg/ml scopolamine in the donor compartment
and curve (2) is scopolamine at the same concentration in an isopropylpalmitate lecithin gel (200 mM lecithin W,=3). The concentration of Broxaterol in the same gel was 75 mg/ml (curve 1) and all at room temperature.
studies described here were performed
with breast skin from female
patients in the range 35-40 years of age. Typical
results are reported in Fig.1. In particular,
flux rate of scopolamine
as obtained
with the lecithin
IPP-gel is compared
with the flux rate obtained when an aqueous solution with the same concentration
the transdermal
of scopolamine
is used in the donor compartment.
same figure, also the transport
rate of broxaterol
In the
is given.
One can see that the flux obtained with the gel is considerably higher than that obtained with the aqueous solution. considerably preparation
higher than the flux obtained with a commercial (data not shown).
it is not always advantageous simply
It is also
Of course, from the clinical point of view, to have a high flux rate- here the point is
to show that the lecithin gels facilitate the transport
throughout
Scopoderm
of the drug
the skin.
In this sense, the data for the new drug broxaterol flux corresponds to 47 ug/cm’/hr
are interesting.
when a concentration
The
of 75mg/ml
broxaterol
is used in the gel. Notice the relatively
beginning,
and the tendency to reach a plateau at longer times. The lag
phase is also present in the experiments
long lag phase at the
with scopolamine.
Vol.
177,
No.
BIOCHEMICAL
3, 1991
We are now involved understanding
AND
BIOPHYSICAL
RESEARCH
in a systematic investigation,
COMMUNICATIONS
aimed at
the most basic feature of this transport phenomena.
Preliminary
data show that lecithin
gels also permit
the transport of
aminoacids
and peptides, as well as of substances such as estradiol. We
can then , even at this early stage, conclude that lecithin transdermal
gels enable the
transport of a large variety of chemical structures.
The fact that the transport is not so specific regarding structure poses some restrictions
on the mechanism
throughout
that the stratum
the skin. Recognizing
the chemical
of the transport corneum contains also
layers of lipids arranged in a regular structure (ll), one may argue that they are capable of interacting
with the phospholipids
of the gel matrix:
the disorganization
of the skin lipidic
drug permeability.
Studies are in progress in our group to test this
mechanism
structure may be the cause of the
and to clarify the range of applicability
of the procedure.
Acknowledgments We thank helping us with Stroppolo of the with samples of chemical.
Dr. Peter Walde for fruitful discussion, Dr. Bruckner for the samples of human skin, Dr. Gazzaniga and Dr. Company Inpharzam (Campesino, CH) for providing us broxaterol and corresponding discussion over this
References 1) Scartazzini R. and Luizi P.L. (1988)J.Phys.Chem.,a829-833. 2) Luisi P.L., Scartazzini R., Haering G. and Schurtenberger P. (1990) Colloid.Polym.Sci. 268356-374. 3) Schurtenberger P., Scartazzini R. and Luisi P.L. (1989) Rheol. Acta, X5-372-381. 4) Nastruzzi C, Colombo L., Willimann H. and Luisi P.L. in preparation. 5) Scartazzini R. and Luisi J?.L (1990) Biocatalysis&377-380. 6) Chien Y.W. (editor) Transdermal Controlled Svstemic Medications, Marcel Dekker, Inc., New York, 1987. 7) Johnson P. and Lloyd-Jones J.G. (editors) Drug Delivery Systems: Fundamentals and Techniaues,Ellis Horwood Ltd., Chichester,l987. 8) Brandau R. and Lippold B.H. (editors) Dermal and Transdermal Absorotion, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1982. 9) Chiarino D., Fantucci M., Carenzi A., Della Bella D., Frigeni V. and Sala R. (1986) II Farmaco-Ed. SC., & 440453. 10) Kydonieus A.F. and Bemer B. (Editors) Transdermal Deliverv of DrugsYol I-III, CRC Press, Inc., Boca Raton, Florida, 1987. 11) P.M. Elias, B. E. Brown, J. Invest. Dermatol. a(1979) 339.
900