Drug interactions with a gel crystalline (L) phase of hydrated stratum
corneum lipids
A. Mundstock, G. Lee
Friedrich-Alexander-University Erlangen, Division of Pharmaceutics, Cauerstr. 4, 91058 Erlangen, Tel.: +499131-8529551, Fax: +49-9131-8529545, email: mundstock@pharmtech.uni-erlangen.de
INTRODUCTION
According to the ‘thermodynamic activity’ concept
of membrane permeation the flux, J = m/t, is not
determined by the donor phase concentration, cd,
alone. It is the degree of saturation in the donor
phase, ad = cd/cd*, that controls the value of J, since
this implicitly includes the partitioning behaviour at
the donor/membrane interface. This concept predicts
that a reduction in cd* combined with a fixed value
of cd should lead to higher J. This relation must,
however, have a lower limit for cd*. If the partition
coefficient, Km/d = cm*/cd*, is a constant, then this
lower limit must be given by, or at least closely
related to, cm*, the saturation solubility of the
permeant (drug) in the membrane. The objective of
the current work is to determine the solubility of
selected drugs in the lipid fraction of skin by using a
gel crystalline L phase composed of stratum
corneum lipids. In this first report we show how
liquid nicotine has a strong effect on the L phase at
concentrations predicted to exist on application of a
TTS.
MATERIALS AND METHODS
Materials
Stearic, palmitic, oleic, linoleic, palmitoleic, myristic
acids and nicotine were all purchased by Sigma
Aldrich (Steinheim Germany) with a minimum
content of 99%. Water was used in double distilled
quality. Sodium hydroxide pellets were obtained
from Merck (Darmstadt, Germany).
Preparation of the Lipid Matrix
The SC lipid matrices were composed of stearic acid
9.35mol%, palmitic acid 38.72mol%, myristic acid
4.49mol%, oleic acid 31.63mol%, linoleic acid
12,04mol% and palmitoleic acid 3,77mol% with
41mol% NaOH. Water content was at 32% (w/w).
Nicotine was added in different percentages of 0%,
0.5%, 1%, 3% and 5% (all w/w). All contents were
weighted into centrifuge tubes which were
constricted to 7mm. Matrices were centrifuged 30
times through the capillary until homogeneous.
Small Angle X-Ray Diffraction (SAXD)
SAXD measurements were performed with an XPert X-ray diffractometer (Phillips, Kassel,
Germany) with 40kV at =0.1542nm in a 2mm
aluminium pan. Unloaded matrix was measured
from 25°C to 75°C in increments of 10°C. Loaded
samples were measured at 25°C as well as at 55°C.
RESULTS
If the stratum corneum is represented as a single
homogeneous compartment, then the drug
concentration during application of a nicotine plaster
delivering 290 µg/h can be approximated using
infusion kinetics. For a first order clearance, Cl, of
15.6 mL/min for nicotine, a steady-state drug
concentration in the stratum corneum of 0.03 % w/v
is calculated. This does not account for any depot
formation. If the volume fraction of lipid phase in
the stratum corneum, l, is taken as 0.1 and the drug
is located exclusively within the lipid phase, then a
nicotine concentration of max. 0.3 % w/v is
obtained.
The presence of 0.5 % w/v nicotine in the lipid
matrix changes the microscopic appearance greatly:
Figure 1: unloaded SC lipid matrix
Polarized light microscopy (PLM)
Matrices were observed with an Olympus
microscope IMT-2 using crossed polarizers at room
temperature. Pictures were taken with a Pixelink PLA662 camera.
Differential Scanning Calorimetry (DSC)
Drug-loaded and unloaded matrices were sealed in
aluminium pans. After equilibration at 25°C it was
measured from -100°C to 80°C with 4°C/min using
a Mettler Toledo DSC 822e. As reference an empty
aluminium pan was used.
Figure 2: SC lipid matrix loaded with 0.5% nicotine.
No signs of crystallinity are apparent in Fig.2.
Increase up to 3 % w/v nicotine results, however, in
the presence of crystallinity, and with % 5 w/v
These shift to larger distances and lower intensity for
higher temperatures; at 65°C and 75°C no peaks are
existent. Both the unloaded matrix and matrices with
3% or 5% nicotine show an interference ratio of
1:2:3:4. (Figs. 6-9) The inter-lamellar distance
calculated from the Bragg Equation is 4.18nm for
both the unloaded and 50% nicotine matrices, and
4.14nm for the 3% nicotine matrix.
Figure 3: SC lipid matrix loaded with 3.0% nicotine,
small crystalline domains are visible.
Figure 7: Diffractogram of SC lipid matrix loaded
with 0.5% nicotine, nearly complete disappearance
of peaks
Figure 4: SC lipid matrix loaded with 5.0% nicotine,
droplets and crystalline domains can be distinguished.
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droplets can be observed (Fig. 4). In the DSCmeasurements a phase transition temperature (PTT)
between at onset of 40 and 50°C is revealed. the peak
between -10°C and 0°C is derived from ice melting in
the sample. No signs of nicotine solidifying/melting
are seen around -90°C.
Figure 8: Diffractogram of SC lipid matrix loaded
with 3.0% nicotine,
Figure 9: Diffractogram of SC lipid matrix loaded
with 5% nicotine
Figure 5: DSC of matrices with different nicotine
content
The diffractograms of the unloaded lipid matrix show
reflections at 25°C at 2.11° (4.184nm), 4.13°
(2.138nm), 6.15° (1.436nm) and 8.15° (1.084nm).
Figure 6: Diffractograms of unloaded lipid matrix.
Again, in the presence of 0.3 % nicotine the
crystallinity has been greatly reduced, but returns at
the higher concentration of 3 & 5 % .
CONCLUSION
Nicotine is soluble in the SC lipid matrix up to
approx 3%. However, formation of the lamellar
matrix is disturbed at low nicotine concentrations
since no crystalline areas are visible (Figure 2).
Additionally the characteristic peak pattern is absent
in the diffractogram. At higher concentrations the
lamillarity returns (Figs 3 & 8), but the intensity is
lower than in the unloaded matrix. All matrices with
nicotine show a lower PTT than the unloaded
matrix. Liquid nicotine has therefore perturbs the
lamellar structure of the selected SS lipid matrix.
This must be considered when determining saturated
solubility of the drug in the lipid matrix.