Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Mark Pellett
Wyeth Consumer Healthcare, Havant, England
S. Lakshmi Raghavan and Jonathan Hadgraft
NRI, University of Greenwich, Chatham, England
Adrian Davis
GlaxoSmithKline Consumer Healthcare, Weybridge, England
I. INTRODUCTION
As discussed in previous chapters, the stratum corneum forms the main barrier
to percutaneous absorption, and a number of methods are available to enhance
the diffusion of compounds into and across it. Many of these techniques, for
example iontophoresis or chemical penetration enhancers, can give rise to local
intolerance either directly or through increased local delivery of other vehicle
excipients. Supersaturation provides an alternative mechanism of penetration en-
hancement that is specific to the drug and without the need to perturb the skin
barrier.
DAK
J⫽ (C v ⫺ C r )
h
where J is the flux, A is the area of diffusion, K is the membrane–vehicle partition
coefficient, D is the diffusion coefficient, Cv is the drug concentration in the
vehicle, Cr is the concentration in the receptor phase, and h is the diffusional
pathlength. Cr is usually very small, and under sink conditions, (Cv ⫺ Cr) is
generally approximated to Cv .
The flux of any given compound across a membrane from a saturated solu-
tion, irrespective of its concentration, is constant, provided that there are no inter-
actions between the membrane and the components of the formulation. This was
demonstrated by Twist and Zatz (1986), who showed that the flux of methyl
paraben from saturated solutions of different solvents was constant. Therefore,
under normal circumstances, the flux of a drug is limited by its saturated solubil-
ity, which in turn can also limit its bioavailability. The preparation of stable
supersaturated systems not only circumvents some of the safety issues that are
associated with other mechanisms of enhancement but can also lead to increased
bioavailability.
A. Binary Mixtures
This technique has received a great deal of attention in the last decade and unlike
other techniques, it is easier to control the desired degree of saturation, and manu-
facturing and packaging issues are more easily resolved. This technique involves
constructing a curve for the saturated solubility of the drug in a binary cosolvent
system where the drug is more soluble in one of the solvents than the other (Fig.
3). By preparing a saturated solution of the drug in solvent B and diluting with
solvent A, a point, E, is obtained along the line CD. This is a supersaturated
solution, and its degree of saturation is calculated by dividing the amount of drug
in solution by its saturated solubility in the same cosolvent mixture. In this exam-
ple, the solution E has two degrees of saturation. The problem of crystallization
is usually overcome by adding an antinucleant polymer to solvent A so that crys-
tallization is either inhibited or retarded.
Davis and Hadgraft (1991a, 1991b) investigated the stability of eight-times
supersaturated solutions of hydrocortisone acetate and the flux from a range of
subsaturated, saturated, and supersaturated solutions across a silicone membrane
soaked in isopropyl myristate. Supersaturated solutions were prepared by the bi-
phasic mixing of water, a desolubilizer, to a solution of the drug in propylene
glycol, a solubilizer; the antinucleant polymers polyacrylate, PVP, and HPMC
were investigated for their ability to maintain eight-times supersaturated solutions
of the drug. HPMC was demonstrated to be the most effective antinucleant poly-
mer, as it inhibited crystal growth for a period of 1 month, whereas crystallization
started within the first few hours with the other two polymers. Furthermore, a
study performed on 16 volunteers showed that a 0.02% supersaturated gel of
B. Evaporation
An increase in thermodynamic activity can also be achieved by evaporation of
the volatile components of a formulation. For example, a compound may be pres-
ent in a formulation in a subsaturated state, but when it is applied to the skin
surface, the volatile components may evaporate, resulting in a decreased solubil-
ity in the residual components on the skin surface. It is then possible that the
solubility of the compound on the skin surface is reduced to the extent that a
supersaturated state exists. In fact, it is almost inevitable that the application of
some products on the market, particularly lotions, are susceptible to the formation
of supersaturated states and may infer penetration enhancement by this means.
A number of investigators have studied this effect.
In the first of a series of publications, the transdermal delivery of nifedipine
centered around the production of supersaturated solutions using volatile: nonvol-
atile vehicles with antinucleant polymers to stabilize the supersaturated solutions
(Kondo and Sugimoto, 1987). At first, the diffusion of nifedipine from a range of
combinations of IPM, PG, and acetone vehicles across an ethylene–vinyl acetate
copolymer membrane was monitored, and initial flux values were found to be
greater than the final steady-state fluxes. This was explained by the initial evapo-
ration of the volatile components of the vehicle, giving rise to a supersaturated
solution, after which the drug crystallized out of solution. The incorporation of
polymers into the IPM :PG:acetone vehicle gave rise to up to five-times enhance-
ment in flux.
In the second paper (Kondo et al., 1987a), the diffusion of nifedipine from
ethanol :diethyl sebacate vehicles was investigated in vitro across ethylene–vinyl
acetate copolymer membranes and excised male Wistar rat skin. In vivo studies
were also performed on male Wistar rats. With both in vitro and in vivo experi-
ments, greatest diffusion was seen from 75: 25 ethanol :diethyl sebacate combina-
tions, which possessed 1.75 degrees of saturation after complete evaporation of
the ethanol.
The third and final paper in this series examined the in vivo penetration of
nifedipine from a range of combinations of propylene glycol, isopropyl myristate,
and acetone vehicles across male Wistar rat skin in vivo (Kondo et al., 1987b).
The initial plasma concentrations from the rats dosed with the binary cosolvent
vehicles of propylene glycol:acetone and isopropyl myristate :acetone were
D. Reactions
In some instances, it is possible to attain supersaturated states when two reactants
give rise to a product that has a lower solubility than the reactants in the reaction
media. No specific examples of this technique could be found for topical and
transdermal drug delivery.
Pellett et al. (1998) studied the synergistic effects on the enhancement of flurbi-
profen permeation across human skin using supersaturated solutions and oleic
acid (OA). Oleic acid is thought to exhibit an enhancing effect by increasing
the diffusivity of a drug in the stratum corneum (Mak et al., 1990), whereas
supersaturated systems increase the concentration in the vehicle. Therefore in-
creasing both these parameters would be expected to result in a multiplicative
effect on flux. Such a result would also imply independent mechanisms of action
for the two methods of enhancement. Multiplicative, synergistic enhancement of
flurbiprofen across human skin using these two types of penetration enhancement
(supersaturation and chemical enhancers) was investigated by pretreating stratum
corneum for 1 h with a 2.8% ethanolic solution of oleic acid and then applying
a supersaturated solution with 6 degrees of saturation. Flux values were deter-
mined using Fick’s first law, and enhancement ratios were calculated (Table 1).
The enhancement ratio for the 6-fold supersaturated solution after pretreat-
ment with ethanol was 4.5, and the enhancement ratio observed after pretreatment
with OA was 2.1. Therefore a multiplicative effect would be expected to result
in a 9.5-fold increase (4.5 ⫻ 2.1) in penetration. In fact, a 9.9-fold increase was
observed.
V. ANTINUCLEANT POLYMERS
The precise mechanism of nucleation and subsequent crystal growth is not fully
understood. Frank (1949) suggests that if a molecule diffuses to the flat surface
of a crystal it only has one binding surface, but if it arrives at a kink or step, it
has more than one binding surface with which to anchor itself to the crystal. With
screw dislocations, the crystal can continue to grow in a “spiral staircase” manner.
Four models predicting crystal growth of theophylline monohydrate were pre-
sented by Rodriguez-Hornedo and Hsui-Jean (1991):
1. Solute transport within the bulk solution to the crystal surface
2. Attachment of growth units to a surface that is “rough” on a molecular
scale
3. Nucleation of two-dimensional clusters to the surface, which expand
and merge to form new layers
4. Spreading of layers from a screw lattice dislocation, which acts as a
continuous source of steps
They showed that the crystals grew according to the screw dislocation theory.
In a similar manner, the mechanism of action of antinucleant polymers is also
the drug in the presence of a number of polymers. According to their model (Fig.
6), crystallization is inhibited by the association of the polymer onto the drug,
and crystal growth is inhibited by the adsorption of the polymer onto the growing
crystal surface through hydrogen bonding. Additionally, accumulation of the
polymer in the hydrodynamic layer surrounding the crystal increases the resis-
tance to diffusion to the crystal surface. In crystal growth, it is well known that
there is a stagnant boundary layer at the interface between the growing crystal
face and the bulk solution. In agitated systems, this layer is very thin or almost
nonexistent. In a stagnant solution, as in this method, this layer can be very thick,
especially in the presence of the polymer, and will provide a diffusional barrier
for the diffusion of the drug molecules.
The adsorption of the polymer onto the crystal surface, according to the
model, is due to hydrogen bonding between the drug and the polymer. The extent
to which adsorption occurs will depend on the nature and strength of hydrogen
bonding between the drug and the polymer. The presence of hydrogen bonding
was established from infrared spectroscopic studies on solid dispersions of hydro-
cortisone acetate and polyvinyl pyrrolidone. In this example, Raghavan et al.
(2001a) found a distinct development of the drug–polymer IR band, which re-
placed the two hydroxyl bands of hydrocortisone acetate. Such an existence of
hydrogen bonding was also observed between ibuprofen and hydroxypropyl
methylcellulose by Iervolino et al. (2001).
Both Raghavan et al. (2001b) and Iervolino et al. (2001) also found that
both a crystal’s size and its morphology were modified in the presence of poly-
mers. The particle sizes were found to be smaller when the polymer was present.
Moreover, the morphologies were different in the presence of different polymers,
indicating that the drug–polymer interactions are dependent on the nature of the
polymer. The formation of smaller and differently shaped crystals in the presence
VI. CONCLUSIONS
Supersaturation can be useful in dermal and transdermal drug delivery, but pro-
ducing stable supersaturated states is not easy. There is increased knowledge of
the mechanisms of supersaturation, but there is still much to be learned, particu-
REFERENCES