Again.
Title: Dependence of Skin Permeability on Contact Area.
Author(s): Karande, Pankaj
Mitragotri, Samir
Source: Pharmaceutical Research; Feb2003, Vol. 20 Issue 2, p257,
7p, 1 chart, 2 diagrams, 5 graphs
Document Type: Article
Subject(s): SKIN -- Permeability
HYDRATION
DRUG delivery systems
Abstract: Purpose. We report that experimentally measured skin
permeability to hydrophilic solutes increases with decreasing contact
area between the formulation and the skin. Our results suggest that an
array of smaller reservoirs should thus be more effective in increasing
transdermal drug delivery compared to a large single reservoir of the
same total area. Methods. Experimental assessment of the dependence of
skin permeability on reservoir size was performed using two model
systems, an array of liquid reservoirs with diameters in the range of 2
mm to 6 mm and an array of gel disk reservoirs with diameters in the
range of 3 mm to 16 mm. Full thickness pig skin was used as an
experimental model. Two molecules, sodium lauryl sulfate (SLS) and oleic
acid, were used as model penetration enhancers. Results. Mannitol
transport per unit area into and across the skin increased with a
decrease in the contact area between the skin and the formulation.
Mannitol permeability increased approximately 6-fold with a decrease in
the reservoir size from 16 mm to 3 mm in presence of 0.5% SLS in PBS
(phosphate buffered saline) as a permeability enhancer. Similar results
were obtained when oleic acid was used as an enhancer. Conclusions. To
explain the observed dependence of transdermal transport on contact area
a simple mathematical model based on skin geometry in the reservoir was
developed. The model predicts a lateral strain in the skin due to
preferential swelling of skin upon penetration of water. We propose that
this lateral strain is responsible for the increased skin permeability
at lower reservoir sizes. [ABSTRACT FROM AUTHOR]
ISSN: 07248741
Accession Number: 9719933
Database: Academic Search Premier
_____
Record: 2
Title: The 500 Dalton rule for the skin penetration of chemical
compounds and drugs.
Author(s): Bos, Jan D.
Meinardi, Marcus M. H. M.
Source: Experimental Dermatology; Jun2000, Vol. 9 Issue 3, p165,
5p
Document Type: Article
Subject(s): SKIN -- Diseases -- Treatment
DERMATOLOGIC agents
TRANSDERMAL medication
Abstract: Human skin has unique properties of which functioning as
a physicochemical barrier is one of the most apparent. The human
integument is able to resist the penetration of many molecules. However,
especially smaller molecules can surpass transcutaneously. They are able
to go by the corneal layer, which is thought to form the main deterrent.
We argue that the molecular weight (MW) of a compound must be under 500
Dalton to allow skin absorption. Larger molecules cannot pass the
corneal layer. Arguments for this "500 Dalton rule" are; 1) virtually
all common contact allergens are under 500 Dalton, larger molecules are
not known as contact sensitizers. They cannot penetrate and thus cannot
act as allergens in man; 2) the most commonly used pharmacological
agents applied in topical dermatotherapy are all under 500 Dalton; 3)
all known topical drugs used in transdermal drug-delivery systems are
under 500 Dalton. In addition, clinical experience with topical agents
such as cyclosporine, tacrolimus and ascomycins gives further arguments
for the reality of the 500 Dalton rule. For pharmaceutical development
purposes, it seems logical to restrict the development of new innovative
compounds to a MW of under 500 Dalton, when topical dermatological
therapy or percutaneous systemic therapy or vaccination is the
objective. [ABSTRACT FROM AUTHOR]
ISSN: 09066705
Accession Number: 5237096
Database: Academic Search Premier
_____
Record: 3
Title: Transdermal drug delivery: Vehicle design and formulation.
Author(s): Pefile, Sibongile
Smith, Eric W.
Source: South African Journal of Science; Apr97, Vol. 93 Issue
4, p147, 4p, 2 charts, 2 diagrams
Document Type: Article
Subject(s): TRANSDERMAL medication
Abstract: Describes the properties of the delivery system most
desirable for the formulation of transdermal drug delivery preparations.
Rate of diffusion; Bioavailability of the drug under different
physiological conditions; Factors to be taken into account for the
formulation of semi-solids.
Full Text Word Count: 4109
ISSN: 00382353
Accession Number: 9710054042
Database: Academic Search Premier
TRANSDERMAL DRUG DELIVERY: VEHICLE DESIGN AND FORMULATION
Until recently, administration methods for the transportation of drugs
across the skin have remained virtually unchanged. The ability to
produce the desired pharmacological response, however, has rarely
achieved satisfactory results when conventional topical drug delivery
formulations have been used to convey the desired amount of drug to a
specific site. As a result, many investigators are currently engaged in
the research, development and optimization of topical drug delivery
systems. The ability to deliver an efficacious quantity of a medicament
transdermally and the advantages of this form of application have made
it possible to minimize side-effects, enhance the accuracy of delivers'
and regulate the rate of drug release. From the patient's viewpoint,
topical drug delivery is a popular method of dosing as it is a
noninvasive and painless way of administering active drugs.[ 1] The main
problem facing the pharmaceutical formulator is devising a delivers'
system that will satisfy the need for optimal drug delivery, negligible
toxicity, drug and excipient stability and aesthetic acceptability. The
main purpose of this article is to describe those properties of the
deliver, system most desirable for the formulation of transdermal drug
delivery preparations.
The skin
The skin is one of the most readily accessible organs of the human body.
It is composed of three main layers: the epidermis, the dermis, and the
hypodermis or subcutaneous fat.[ 2] The outermost layer of the epidermis
consists of two principal layers: the stratum corneum and the viable
epidermis.[ 1] The stratum corneum is made up of flattened keratinized
cells which form the principal barrier to the ingress of exogenous
substances. The stratum corneum functions as a protective physical and
chemical barrier and is only slightly permeable to water. Below the
epidermis lies the dermis, a region highly perfused by blood and lymph
vessels. This microcirculatory network provides an efficient means of
drug removal into the systemic pool.[ 3] The deepest layer, the
hypodermis, contains adipose ceils which serve principally as an energy
source. Additionally, the tissue cushions the outer skin layers from
impact and its insulating properties contribute to the temperature
regulation of the skin.[ 4]
For many decades, the skin has been used as the site for the
administration of dermatological drugs, either to achieve a localized
pharmacological action in the skin tissues or a systemic effect in the
body. In the former case, the drug molecule diffuses to a target tissue
in the proximity of drug application to produce its therapeutic effect,
before it is distributed to the systemic circulation for elimination. A
few examples of localized drug application include the use of
hydrocortisone for dermatitis, benzoyl peroxide against ache and
neomycin for superficial use. When the skin serves as the portal of
administration for systemically active drugs, the drug applied topically
is distributed in the blood, following absorption, to achieve
therapeutic action. Substances that pass through the stratum corneum
move freely through the lower epidermal strata and into the dermis. From
here the compound reaches the systemic circulation by diffusion through
the walls of blood vessels or lymphatic vessels. This fairly new
application is exemplified by the transdermal controlled delivery of
nitroglycerin to the myocardium for the treatment of angina pectoris,[
3] of scopolamine to the central emetic centre for the prevention of
motion-induced sickness, and of oestradiol to the various
steroid-receptor sites for the relief of postmenopausal syndromes.
The transfer of a drug across the stratum corneum is by passive
diffusion and, because of barriers imposed by the skin, this process
occurs very slowly. The tissue consists of aggregates of closely packed
cells and contains both lipid and aqueous regions (see Fig. 1).[ 4]
Lipid-soluble substances readily pass through the intercellular lipid
bilayers of the cell membranes whereas water-soluble drugs are able to
pass through the skin because of hydrated intracellular proteins.[ 4-6]
Further drug diffusion through the skin can occur by means of the skin
appendages. In this case, the barrier afforded by the stratum corneum is
circumvented, thus resulting in rapid drug ingress via eccrine sweat
glands and hair follicles. There is some evidence that compounds with
both lipophilic and hydrophilic properties, that is, with an oil-water
partition coefficient close to unity, are best able to pass through the
stratum corneum. Water-soluble ions, unless very small, do not normally
pass through the surface skin layer unless iontophoresis is used.
Factors influencing the rate of diffusion
During the development of a drug formulation, it is important to
determine whether the active ingredient will react with the excipients
(vehicle) used in drug compounding or with the substances normally
present in the stratum corneum. Unexpected complexes which may be formed
within the formulation can exert an adverse effect on the absorption of
the drug through the skin. The physical and chemical characteristics of
each excipient with respect to the active ingredient, other components
in the formulation and the skin must be taken into account with respect
to transdermal drug delivery.
Diffusant solubility. The thermodynamic activity of a drug in a
particular vehicle indicates the potential of the active substance to
become available for therapeutic purposes. A saturated solution is,
therefore, preferable for a topical drug delivery system as it
represents maximum thermodynamic activity (leaving potential).[ 7] The
level of saturation is dependent on the solubility of the drug in the
delivery formulation.[ 1] Less drug is released from sub-saturated
solvents than from saturated ones.
The diffusant solubility of a drug can also be affected by the presence
of a cosolvent in the formulation. Co-solvents that increase the
solubility of the active drug can produce greater concentrations across
the vehicle-skin interface.[ 8] However, enhanced solubility of the drug
in the solvent may result in reduced partitioning of the drug between
the membrane and the vehicle.[ 1] As a result, there is a need to keep
the solubility of the drug in the vehicle as near to the saturation
point as possible. It is therefore undesirable to use a drug that is
highly soluble in the base as the release of the drag will be retarded.
Pre-formulation studies on the solubility of the drug in the solvents
used in the preparation are essential for ensuring optimal drug release
from the topical base. There are several semi-empirical methods for
estimating the diffusion coefficient in terms of solute and solvent
properties. In addition, diffusivity data for many sob vents have been
compiled. Such information can assist the formulator in determining the
conditions necessary for both optimum drug solubility as well as
achieving maximum drug absorption.
Partition coefficient. The greater the partition coefficient of the drug
for the membrane it is to diffuse through, the greater the concentration
of drug in the proximal lamina of the membrane.[ 1] The vehicle to
stratum corneum partitioning often contributes to the rate-limiting step
in transdermal drug delivery.[ 1, 5] Partitioning of the drug to the
stratum corneum is dependent upon the affinity of the drug for the base
formulation and the absorption of the drug through the skin.[9]
Determination of drug solubility in the solvent systems used in
formulations can help establish the extent of drug binding to the
vehicle,[ 6] and thereby avoid a situation where minimal drug diffusion
takes place due to low partitioning of the drug into the stratum
corneum. For example, the absorption of chloramphenicol may be inhibited
by the formation of molecular complexes with agents containing amide
groups present in the topical base.
Furthermore, the extent of interaction between drug and vehicle plays a
significant role in determining the partition coefficient of a drug. The
nature of the vehicle controls drug activity, the rate of diffusion in
the vehicle, and the partition coefficient between the vehicle and the
skin. A high affinity of the base for the drug is not desirable.[ 1]
Drugs that complex with or bind to components of the vehicle are
released into the skin relatively slowly.[10] Hence, the release of a
drug is favoured by using a vehicle with relatively low affinity for it.
pH variation. Unionized molecules pass more readily across lipid
membranes than ionized molecules.[ 1] This is because unionized drugs
are more soluble in lipids whereas their ionized forms are more soluble
in aqueous media. The ionization of a drug is dependent upon the pH of
the vehicle in which the drug has been formulated.[ 1] An understanding
of pH effects is important in that their influence on the degree of
ionization may result in changes on both the activity and release of a
drug from its delivery system. Most drugs are either weak acids or weak
bases whose solubility in a given vehicle is determined by the pH of the
medium. When changing the pH of a formulation, the stability of the drug
as well as the stability of the preparation must be considered. The
formulator needs to be aware that the pH of optimum solubility is not
always the pH of maximum stability of the compound and therefore a
balance must be struck between optimum solubility and maximum stability.
Diffusion coefficient. The diffusion coefficient of a drug, either in a
topical vehicle or in the skin, depends on the properties of the drug,
the diffusion medium and the interaction between the two.[11] Diffusion
decreases as the viscosity of the vehicle increases. Of concern to the
formulator of a topical drug delivery system are the physical
interactions which the active ingredient may undergo when in solution.
If such interactions between the drug and the solvent are high then the
diffusion coefficient will be low and, hence, the release of the active
substance to the stratum corneum will be decreased, and vice versa. In
order to obtain maximum bid availability from a topical formulation, it
is necessary to have the relevant information relating to the
transdermal kinetics of the drug concerned before it is formulated.
Biological factors influencing transdermal delivery
In order to provide optimum bioavailability of a topical drug one must
take into account that disease, the age of the skin and the site of drug
application usually violate the constraints of the simple diffusion
theory. Investigation of the physicochemical nature of the different
formulation bases and of those components in the topical product which
will influence the bidavailability of the drug under different
physiological conditions is essential for achieving suitable drug
design.
Skin age. The design of a topical drug delivery system must be adapted
to suit the physiological conditions under which it may be used. With
increasing age, the elasticity and hence the permeability of the skin
decreases.Care must, therefore, be exercised in administering topical
preparations to young children as their skins are more permeable and one
runs the risk of overdosing paediatric patients and underdosing
geriatric ones. This means that the concentration of the active
ingredient in a paediatric formulation may need to be less than that
used for an elderly patient.
Skin condition and sites. Intact skin presents a barrier to absorption
that can be reduced considerably when the skin is damaged or is in a
diseased state. Broken, damaged and inflamed skin has increased
permeability,[12] whilst calluses and corns, on the other hand, have
reduced permeability. Transdermal absorption is not only influenced by
the physical state of the skin but also by the area to which the
preparation is applied. The size of the ceils and bilayer lipid
composition in the stratum corneum will affect the extent of transdermal
drug delivery. In addition, the diffusion of a substance across the skin
is inversely proportional to the thickness of the stratum corneum. The
thinner the epidermal layer, as found on the abdomen, for example, the
greater the permeability of the drug through the skin's surface. To
produce an effective dermatological preparation the formulator must
consider how the site and condition of the skin will affect drug
absorption through the stratum corneum. An attempt can be made to assess
the effect of regional and physiological variations in permeability by
measuring a pharmacological response such as the erythema reaction
produced by vasodilators like histamine.
Skin metabolism and circulatory effects. The skin is a metabolically
active organ which has the ability to metabolise many drugs such as
steroids, and therefore reduces their therapeutic efficacy and
absorption. Below the stratum corneum lies the viable epidermis, the
most metabolically active layer in the skin. Percutaneous metabolism in
the viable epidermis (see Fig. 2) may reduce the pharmacological
potential of the active drug through cutaneous first-pass effects.[13]
It is essential to inquire into the extent of percutaneous absorption
which a topical drug undergoes as this will determine the deposition of
the substance in other parts of the skin and delivery to the capillaries
in the dermis.[l3]
Drug absorption from the dermis into the systentic circulation is
enhanced by good circulation in the dermis. This is because enhanced
blood flow at the absorption site increases the concentration gradient
to the dermis through constant removal of the drug from the site.
Certain drugs, such as topical steroids, have a vasoconstriction effect
on the skin. These agents will reduce their own clearance from the skin
due to decreased blood flow at the absorption site. Once again, the
formulator must bear in mind that the skin is a physiologically active
region which can influence the extent of drug delivery into the systemic
circulation.
Physicochemical factors affecting transdermal drug delivery
Skin hydration and temperature. Compounds that hydrate the skin cause it
to swell and, therefore, increase its permeability; lipids in ointment
formulations and in water-in-oil emulsions, for example, prevent water
loss and therefore keep the skin hydrated. Many topical formulations
cause increased skin hydration by reducing evaporation with an occlusive
layer. Careful selection of the topical base can influence the degree of
skin hydration so as to obtain the desired conditions. For instance,
topical bases containing paraffin retard moisture loss from the skin
whilst those which contain propylene glycol are hygroscopic. That is,
they withdraw water from the skin especially when in high
concentrations.
The penetration rate of compounds through human skin can also be
accelerated by raising its surface temperature.[14] As the surface
temperature rises, the kinetic activity of the skin increases, thus
resulting in enhanced drug permeability across the stratum corneum. This
is because, with temperature rise, the lipid layer of the stratum
corneum becomes less viscous and thus the activation energy for
diffusion is decreased. Consequently, there is an increase in kinetic
energy leading to enhanced drug permeability. Clinically, skin
temperature increases under occlusive bases or in diseased states. Under
occlusion, sweat cannot evaporate nor can heat radiate as readily from
the skin surface and, therefore, skin temperature may rise by a few
degrees. The penetration rate of a material through the skin can be
altered by the type of topical base used (occlusive or nonocclusive) and
the physical state of the skin.
Drug-to-skin binding. Prolonged binding of the drug to the molecules in
the stratum corneum, such as when using sun screens and topical
corticosteroids, reduces the absorption of the drug into the viable
epidermis and dermis.[ 1] Recent studies have demonstrated that
drug-skin binding has given rise to the so-called reservoir effect in
which topically applied agents form a depot or reservoir in the stratum
corneum. The mechanism of reservoir formation most probably arises from
the physicochemical nature of drug solubility and diffusion within the
stratum corneum. The therapeutic potential of reservoirs is restricted
to highly potent compounds because of the relatively small amounts that
can be retained in the stratum corneum. It is necessary to note that
reservoir formation takes place on top of or in the upper layers of the
stratum corneum and loss of this depot effect can occur via evaporation,
chemical and mechanical removal.[15] Abrasion of the stratum corneum
leads to mechanical removal whilst solvation of the compound and
subsequent rinsing leads to chemical removal of the reservoir
effect.[15] The mechanism of the surface reservoir must be taken into
account to understand the processes of skin evaporation and topical
absorption of certain drugs.
Vehicle formulation. Factors such as drug stability, specific product
use, site of application and product type must be considered in the
formulation of a vehicle for topical drug application. These varying
properties must be combined in a dosage form which will readily release
the drug when placed in contact with the skin. Further, the release
characteristics of the vehicle are dependent on the physicochemical
properties of the specific drug to be delivered to the skin. The
formulator needs to develop a total composition in which the drug is
stable and safe and able to achieve optimum drug delivery.[10] Table 1
presents a list of the general factors which a manufacturer evaluates
for a new semi-solid (as these formulations are known), both during
developmental studies and as a function of storage time.
However well a topical vehicle may be designed to maximize drug
bioavailability, it is still important to ensure that the preparation is
aesthetically acceptable to the patient. A product that is unappealing
to the user for whatever reason may lead to noncompliance and thereby
put treatment at risk. Although a consumer may apply less stringent
acceptability criteria to a dermatological cream than to, say, a
cosmetic preparation, patients still generally prefer a product which is
easy to remove from the container and which spreads readily and smoothly
yet adheres to the treated area while being neither tacky nor difficult
to take off. Table 2 is a summary of some of the more important cosmetic
and usage criteria relevant to the formulation of a dermatological
product.
Classification of topical semi-solids
Creams. Creams are viscous semi-solids and are usually oil-in-water
emulsions (aqueous creams) or water-in-oil emulsions (oily creams). The
type of cream used depends on the solubility of the drug. Water-soluble
drugs are dispersed in oilin-water emulsions whereas lipid-soluble drugs
are incorporated in water-in-oil emulsions.[ 4] Creams are used to apply
solutions or dispersions of medicaments to the skin for therapeutic or
prophylactic purposes where a highly occlusive effect is not necessary.[
4] In common use are creams applied for their emollient, cooling or
moistening effects on the skin. They are frequently chosen for wet and
weepy skin conditions. They are more readily spread, are not
particularly greasy and rub into the skin leaving little or no trace.
Gels. Gels are transparent or translucent semi-solid or solid
preparations consisting of solutions or dispersions of one or more
active ingredients in hydrophilic or hydrophobic bases. As vehicles for
the presentation of water-soluble medicaments, gels are ideal because of
their high water content. Gel products tend to be smooth, elegant and
produce cooling effects because the associated water evaporates; they
may dry out to form films which adhere well to the skin and are usually
easily removed by washing. For the presentation of insoluble materials,
hydrophilic gels have the limitation that the resultant products may
lack clarity and smoothness. Owing to the nongreasy nature, transparent
appearance and easy removal of gels, they are ideal for use on hairy
parts of the body and the face.
Ointments. Ointments are semi-solid preparations intended to adhere to
the skin or certain mucous membranes; they are usually solutions or
dispersions of one or more medicaments in non-aqueous bases. Ointments
are used as vehicles for medicaments intended to produce a
pharmacological effect at or near the application site. There is a
greater emphasis on the emollient and protective functions of ointments
because of their highly occlusive nature. Ointments prevent water loss
from the surface of the stratum corneum, resulting in increased skin
hydration and therefore a marked increase in drug permeability. Due to
the presence of a continuous lipid phase, ointments are particularly
suitable for chronic dry skin lesions and disadvantageous in moist skin
conditions.
Pastes. Pastes are much stiffer than ointments and usually contain a
high proportion of finely ground insoluble powders dispersed in a fatty
or aqueous base. Because of their consistency, they are commonly used as
adsorbents, antiseptics, protectives or to smooth broken skin surfaces.
Pastes are, therefore, particularly useful for circumscribed lesions
such as those associated with psoriasis or chronic eczema as they adhere
well to the skin and for relatively long periods.
The objective when selecting a suitable base is to optimize drug
delivery through the skin. In reality, optimum delivery is rarely
achieved as one needs to consider the aesthetic appeal of the
formulation, its conditions of use and the convenience of application.
This will require that the formulator assess the physical and chemical
properties of each base. Ultimately, one would like to ensure that the
drug in the final preparation is stable, safe to administer and
efficacious.
Why transdermal delivery? Its benefits may be summarized as follows:[ 3,
5]
1. production of a sustained, constant and controlled level of drug
in the plasma or the subcutaneous site;
2. avoidance of the degradation of the active drug by the liver if
ingested by mouth;
3. patient compliance;
4. simple, rapid termination of drag therapy should undesirable
side-effects arise;
5. adjustment of dosage frequency and magnitude with corresponding
moderation of side-effects.
The principal problems with transdermal drug delivery stem from the fact
that:[ 1]
1. percutaneous absorption rates are variable and not always
predictable;
2. the stratum corneum is an extremely efficient barrier to most
compounds, therefore curbing the topical route of administration for
many drugs;
3. there may be activation of allergic responses.
In order to overcome these obstacles to optimal transdermal drug
delivery, scientists have developed techniques and delivery systems to
increase and control the rate of percutaneous absorption. These new
approaches, such as transdermal patches, absorption enhancers and
iontophoretic techniques, have paved the way for the administration of
many more compounds that were previously unable to be delivered via the
topical route. Such advances in technique increase the diversity and
utility of the skin as an effective drug delivery medium.
Table 1.
1.Drug stability (chemical and physical)
2.Stability of the excipient (vehicle)
3.Rheological (frictional) properties of the preparation
4.pH effects
5.Effect of volatility and loss of water
6.Stability of the vehicle in terms of phase separation and homogeneity
7.Particle size and particle size distribution of the vehicle
8.Particulate and microbial contamination.
Table 2.
1. Visual appearance
2. Odour of the formulation
3. Sampling characteristics of product
4. Ease of application (e.g. spreadability, penetrability)
5. Residual impression after application (e.g. ease of application and
removal)
ILLUSTRATION: Fig 1. Routes of drug penetration through the skin
DIAGRAM: Fig. 2. Schematic diagram of the stages in percutaneous
absorption and the concentration gradient of the drug across the skin
layers.
1. Danewarts M.P. (1991). Percutaneous absorption and transdermal
patches. S. Afr. pharm. J. 58, 314-318.
2. Chien Y.W. (1987). Development of transdermal drug delivery
systems. Drug Dev. Ind. Pharm. 13, 589-651.
3. Guy R.H. and Hadgraft J. (1985). Transdermal drug delivery: the
ground rules are emerging. Pharm. Int. 6, 112- 116.
4. Topical semi-solids (1994). In The British Pharmaceutical Codex,
12th edn, ed. W. Lund, chap. 1, p. 134. The Pharmaceutical Press,
London.
5. Lee C.K., Uchida K., Kitagawa K., Yagi Kim N. and Goto S.
(1993). Skin permeability of various drugs with different lipophilicity.
J. pharm. Sci. 83( 4), 562-565.
6. Abraham M.H., Chadha H.S. and Mitchell R.C. (1995). The factors
that influence skin penetration of solutes. J. Pharm. Pharmacol. 47,
8-16.
7. Kemken J., Zilger A. and Muller B.W. (1992). Influence of
supersaturation on the pharmacodynamic effect of bupranolol after dermal
administration using microemulsions as vehicle. Pharm. Res. 9( 4),
554-558.
8. Pellet M.A., Davis A.E and Hadgraft J. (1994). Effect of
supersaturation on membrane transport: 2 Piroxicam. Int. J. Pharm. 111,
1-6.
9. Watkinson A.C., Joubin H., Green D.M., Brain K.R. and Hadgraft
J. (1995). The influence of vehicle on permeation from saturated
solutions. Int. J. Pharm. 121, 27-35.
10. Epidermal and Transdermal Drug Delivery, Remmington's
Pharmaceutical Sciences (1985), 17th edn., ed. A. Gennard, chap 88, p.
1567. Mack Publishing, Easton, Pennsylvania.
11. Barry B.W. (1983). In Dermatological Formulations, chap. 6, p.
330. Marcel Dekker, New York.
12. Bronaugh R.L. and Stewart R.F. (1985). Methods for percutaneous
absorption studies V: Permeation through damaged skin. J. pharm. Sci.
74(10), 1062-1066.
13. Martin R.J., Denyer S.P. and Hadgraft J. (1987). Skin metabolism
of topically applied compounds. Int. J. Pharm. 39, 23-32.
14. Ohara N., Takayama K. and Nagai T. (1995). Influence of
temperature on the percutaneous absorption for lipophilic and
hydrophilic drugs across the rat skin pretreated with oleic acid. Int.
J. Pharm. 123, 281-284.
15. Percutaneous Absorption -- Mechanisms -- Methodology -- Drug
Delivery (1989), eds R.L. Bronaugh and H.I. Maibach, chap. 19, p. 314.
Marcel Dekker, New York.
~~~~~~~~
By Sibongile Pefile and Eric W. Smith
The authors are in the School of Pharmaceutical Sciences, Rhodes
University, Grahamstown, 6140 South Africa (e-mail:
[email protected]).
_____
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Source: South African Journal of Science, Apr97, Vol. 93 Issue 4, p147,
4p
Item: 9710054042
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