Vegetable oil-based skin permeation enhancer compositions, and associated methods and systems

Methods and compositions are provided which increase the permeability of skin to transdermally administered pharmacologically active agents. The compositions are formulated with one or more vegetable oils as skin permeation enhancers; a preferred composition contains both coconut oil and soybean oil. Drug delivery systems for administering drugs transdermally in combination with the vegetable oil-based enhancer compositions are provided as well.

TECHNICAL FIELD 
This invention relates generally to methods and compositions for enhancing 
the permeability of the skin to pharmacologically active agents, and more 
particularly to novel skin permeation enhancer compositions containing 
vegetable oil mixtures. 
BACKGROUND 
The delivery of drugs through the skin provides many advantages; primarily, 
such a means of delivery is a comfortable, convenient and noninvasive way 
of administering drugs. The variable rates of absorption and metabolism 
encountered in oral treatment are avoided, and other inherent 
inconveniences--e.g., gastrointestinal irritation and the like--are 
eliminated as well. Transdermal drug delivery also makes possible a high 
degree of control over blood concentrations of any particular drug. 
Skin is a structurally complex, relatively thick membrane. Molecules moving 
from the environment into and through intact skin must first penetrate the 
stratum corneum and any material on its surface. They must then penetrate 
the viable epidermis, the papillary dermis, and the capillary walls into 
the blood stream or lymph channels. To be so absorbed, molecules must 
overcome a different resistance to penetration in each type of tissue. 
Transport across the skin membrane is thus a complex phenomenon. However, 
it is the cells of the stratum corneum which present the primary barrier 
to absorption of topical compositions or transdermally administered drugs. 
The stratum corneum is a thin layer of dense, highly keratinized cells 
approximately 10-15 microns thick over most of the body. It is believed to 
be the high degree of keratinization within these cells as well as their 
dense packing which creates in most cases a substantially impermeable 
barrier to drug penetration. 
In order to increase skin permeability, and in particular to increase the 
permeability of the stratum corneum (i.e., so as to achieve enhanced 
penetration, through the skin, of the drug to be administered 
transdermally), the skin may be pretreated with a penetration enhancing 
agent (or "permeation enhancer", as sometimes referred to herein) prior to 
application of a drug. Alternatively, and preferably, a drug and a 
permeation enhancer are concurrently delivered. 
The present invention is directed to a novel method and composition for 
enhancing the penetration of a drug through skin. The invention is 
premised on the discovery that certain vegetable oils used individually or 
in combination are effective in enhancing the penetration of 
pharmacologically active agents through the skin. 
While there are a number of patents and publications which relate to the 
use of a variety of different skin permeation enhancers, applicants are 
unaware of any art which relates to the use of vegetable oils as disclosed 
herein as skin permeation enhancers. 
The following references relate generally to the use of permeation 
enhancers in transdermal formulations. U.S. Pat. Nos. 4,006,218, 3,551,554 
and 3,472,931, for example, respectively describe the use of 
dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and 
N,N-dimethylacetamide (DMA) to enhance the absorption of pharmacologically 
active agents through the stratum corneum. Other compounds which have been 
used to enhance skin permeability include: decylmethylsulfoxide (C.sub.10 
MSO); Transcutol, cited in the preceding section; polyethylene glycol 
monolaurate (PEGML); (see, e.g., U.S. Pat. No. 4,568,343); glycerol 
monolaurate (U.S. Pat. No. 4,746,515); propylene glycol monolaurate (see 
European Patent Application No. 87402945.7, Published as EP Publication 
No. 272 987, which derives from U.S. patent application Ser. No. 945,356, 
filed 22 Dec. 1986, of common assignment herewith); ethanol (e.g., as in 
U.S. Pat. No. 4,379,454); eucalyptol (U.S. Pat. No. 4,440,777); lecithin 
(U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, 
particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the 
trademark Azone.RTM. from Nelson Research & Development Co., Irvine, 
Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); 
propylene glycol in combination with a fatty acid such as linoleic acid 
(European Patent Publication No. 261429); "cell envelope disordering 
compounds" such as methyl laurate or oleic acid in combination with 
N-(hydroxyethyl) pyrrolidone (U.S. Pat. No. 4,537,776) or C.sub.3 -C.sub.4 
diols (U.S. Pat. No. 4,552,872, European Patent Application Publication 
No. 043738). U.S. Pat. No. 4,764,379 discloses a binary enhancer 
composition of ethanol and glycerol monolaurate. 
DISCLOSURE OF THE INVENTION 
Accordingly, it is an object of the present invention to provide a method 
for enhancing the flux of the drug through the skin comprising 
transdermally administering the drug in combination with a 
permeation-enhancing amount of a vegetable oil as will be described 
herein. 
It is another object of the present invention to provide such a method in 
which the vegetable oil composition is a mixture of vegetable oils. 
It is still another object of the invention to provide a composition of 
matter for delivering a drug through the skin which comprises: (a) a 
therapeutically effective amount of at least one drug; and (b) a 
permeation-enhancing amount of a vegetable oil composition as will be 
described in detail herein. 
It is a further object of the invention to provide transdermal delivery 
systems for using the aforementioned compositions and carrying out the 
administration method. 
Additional objects, advantages and novel features of the invention will be 
set forth in part in the description which follows, and in part will 
become apparent to those skilled in the art upon examination of the 
following, or may be learned by practice of the invention. 
In one aspect of the invention, a method is provided for enhancing the flux 
of the drug through the skin, comprising transdermally administering the 
drug in combination with a permeation-enhancing amount of a vegetable oil 
composition containing at least one vegetable oil selected from the group 
consisting of almond oil, babassu oil, castor oil, Clark A oil, coconut 
oil, corn oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, 
olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, 
sunflower-seed oil and wheat germ oil. Preferred vegetable oils are those 
which do not contain large amounts of saturated fatty acids or large 
amounts of fatty acids containing less than about eight or more than about 
fourteen carbon atoms. Accordingly, preferred vegetable oils within the 
aforementioned group include coconut oil, corn oil, cotton seed oil, 
linseed oil, mustard oil, olive oil, palm oil, peanut oil, safflower oil 
and soybean oil. With most drugs, mixtures of vegetable oils appear to be 
preferred rather than individual vegetable oils, and a particularly 
preferred vegetable oil composition for use herein is a mixture of coconut 
oil and soybean oil. 
In another aspect of the invention, a composition of matter is provided 
that is useful for the delivery of a drug through the skin, which 
comprises a therapeutically effective amount of the drug to be 
administered and a permeation-enhancing amount of a vegetable oil 
composition which contains at least one vegetable oil selected from the 
aforementioned group. 
In still another aspect of the invention, a transdermal system is provided 
which is useful for the administration of a drug through the skin, wherein 
the system includes a source of the drug to be administered, a source of a 
permeation enhancer composition effective to increase the flux of the drug 
through the skin, wherein the permeation enhancer composition contains at 
least one vegetable oil, and wherein the system further includes a means 
for maintaining the system in drug and enhancer composition transmitting 
relationship to the skin, e.g., a contact adhesive layer which serves as 
the basal surface of the system and adheres to the skin during use. 
MODES FOR CARRYING OUT THE INVENTION 
Before describing the present invention in detail, it is to be understood 
that this invention is not limited to particular drugs or transdermal 
systems described herein as such may, of course, vary. It is also to be 
understood that the terminology used herein is for the purpose of 
describing particular embodiments only, and is not intended to be 
limiting. 
It must be noted that, as used in this specification and the appended 
claims, the singular forms "a", "an" and "the" include plural referents 
unless the content clearly dictates otherwise. Thus, for example, 
reference to "a vegetable oil" includes a mixture of two or more vegetable 
oils, reference to "a drug" includes reference to one or more drugs, and 
the like. 
In describing and claiming the present invention, the following terminology 
will be used in accordance with the definitions set out below 
"Penetration enhancement" or "permeation enhancement" as used herein 
relates to an increase in the permeability of skin to a pharmacologically 
active agent, i.e., so as to increase the rate at which the drug permeates 
through the skin and enters the bloodstream. The enhanced permeation 
effected through the use of such enhancers, and, in particular, through 
the use of the enhancer composition of the present invention, can be 
observed by measuring the rate of diffusion of drug through animal or 
human skin using a diffusion cell apparatus as described in the Examples 
herein 
By "transdermal" delivery, applicants intend to include both transdermal 
(or "percutaneous") and transmucosal administration, i.e., delivery by 
passage of a drug through the skin or mucosal tissue and into the 
bloodstream. 
"Carriers" or "vehicles" as used herein refer to carrier materials suitable 
for transdermal drug administration, and include any such materials known 
in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, 
or the like, which is nontoxic and which does not interact with other 
components of the composition in a deleterious manner. Examples of 
suitable carriers for use herein include water, silicone, liquid sugars, 
waxes, petroleum jelly, and a variety of other materials. 
By the term "pharmacologically active agent" or "drug" as used herein is 
meant any chemical material or compound suitable for transdermal or trans 
mucosal administration which induces a desired systemic effect. Such 
substances include the broad classes of compounds normally delivered 
through body surfaces and membranes, including skin. In general, this 
includes: antiinfectives such as antibiotics and antiviral agents; 
analgesics and analgesic combinations; anorexics; antihelminthics; 
antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; 
antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory 
agents; antimigraine preparations; antinauseants; antineoplastics; 
antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; 
antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; 
cardiovascular preparations including calcium channel blockers and 
beta-blockers such as pindolol and antiarrhythmic; antihypertensives; 
diuretics; vasodilators including general coronary, peripheral and 
cerebral; central nervous system stimulants; cough and cold preparations, 
including decongestants; hormones such as estradiol and other steroids, 
including corticosteroids; hypnotics; immunosuppressives; muscle 
relaxants; parasympatholytics; psychostimulants; sedatives; and 
tranquilizers. 
Preferred drugs for use in conjunction with the enhancer composition of the 
present invention include narcotic analgesics such as buprenorphine or 
salts thereof (e.g., buprenorphine hydrochloride), antianxiety drugs such 
as alprazolam, hyponetic/sedative drugs such as triazolam, calcium channel 
blockers or anti-anginal drugs such as nifedipine, and antineoplastics 
such as tamoxifen. 
By "therapeutically effective" amount of a pharmacologically active agent 
is meant a nontoxic but sufficient amount of a compound to provide the 
desired therapeutic effect. An "effective" amount of a permeation enhancer 
as used herein means an amount that will provide the desired increase in 
skin permeability and, correspondingly, the desired depth of penetration, 
rate of administration, and amount of drug delivered. 
In a preferred embodiment, as noted above, the enhancer composition of the 
invention is a vegetable oil composition which contains at least one 
vegetable oil as described above. In a particularly preferred embodiment, 
the vegetable oil composition is a mixture of coconut oil and soybean oil; 
such compositions will include on the order of 10 wt. % percent to 90 wt. 
% coconut oil, and, correspondingly, 90 wt. % to 10 wt. % soybean oil. An 
exemplary coconut oil/soybean oil mixture is that manufactured and sold 
under the trademark Drewmulse.RTM. D-4661, available from Stepan, 
Marywood, N.J. The combination of coconut and soybean oil has been found 
by the inventors herein to be far superior to most other permeation 
enhancers which are currently commercially available and is, furthermore, 
superior to the use of particular vegetable oils used individually, at 
least with some drugs. 
The composition may in addition include one or more selected carriers or 
excipients, and various agents and ingredients commonly employed in 
dermatological ointments and lotions. For examples, fragrances, 
opacifiers, preservatives, anti-oxidants, gelling agents, perfumes, 
thickening agents, stabilizers, surfactants, emollients, coloring agents, 
and the like may be present. The composition may also include additional 
permeation enhancers, e.g., dimethylsulfoxide (DMSO), dimethyl formamide 
(DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C.sub.10 MSO), 
polyethylene glycol monolaurate (PEGML), glycerol monolaurate, lecithin, 
the 1-substituted azacycloheptan-2-ones, particularly 
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark 
Azone.RTM. from Nelson Research & Development Co., Irvine, Calif.), 
alcohols, and the like. Particularly preferred additional enhancers for 
use in conjunction with the present invention are those described in 
commonly assigned U.S. Pat. No. 5,059,426 to Chiang et al., i.e., 
containing an ether component selected from the group consisting of 
diethylene glycol monoethylether, diethylene glycol monomethylether, and 
mixtures thereof, and an ester component given by the formula [CH.sub.3 
(CH.sub.2).sub.m COO].sub.n R in which m is an integer in the range of 8 
to 16, n is 1 or 2, and R is a lower alkyl (C.sub.1 -C.sub.3) residue 
that is either unsubstituted or substituted with one or two hydroxyl 
groups. The disclosure of the aforementioned patent is hereby incorporated 
by reference in its entirety. 
The relative amounts of the components in these compositions can vary a 
great deal. For example, the amount of drug or drugs present in the 
composition will depend on a variety of factors, including the disease to 
be treated, the nature and activity of the drug, the desired effect, 
possible adverse reactions, the ability and speed of the drug to reach its 
intended target, and other factors within the particular knowledge of the 
patient and physician. The amount of enhancer present in the composition 
will similarly depend on a number of factors, e.g., on the depth of 
cutaneous penetration desired, the strength of the particular enhancer, 
the specific drug or drugs selected, and the like. Preferred compositions 
will typically contain on the order of about 1 wt. % to 10 wt. % drug, and 
about 5 wt. % to 25 wt. % enhancer, with the remainder of the composition 
being either a liquid or polymeric carrier (including optional additives 
as outlined above). The enhancer portion of the composition may contain 
only vegetable oil or it may contain vegetable oil in combination with 
additional skin permeation enhancers as described above. It is preferred, 
however, that the compositions of the present invention contain on the 
order of from about 5 wt. % to 10 wt. % vegetable oil. 
The method of delivery of the present compositions may also vary, but 
necessarily involves application of the selected composition to a defined 
surface of the skin or other tissue for a period of time sufficient to 
provide the desired blood level of drug for the desired period of time. 
The method may involve direct application of the composition as an 
ointment, gel, cream, or the like, or may involve use of a drug delivery 
device as taught, for example, in U.S. Pat. Nos. 3,742,951, 3,797,494 and 
4,568,343. The method may also involve pre-treatment of the skin with a 
vegetable oil enhancer to increase the permeability of the skin to the 
applied drug. 
A transdermal delivery system can be constructed with the enhancer 
composition described hereinabove to deliver drugs for sustained drug 
delivery. The targeted skin flux for delivery of a particular drug can be 
achieved by adjusting vehicle composition and vehicle loading, as well as 
by adjusting the surface area through which the compositions are 
administered to skin. 
Preferred transdermal drug delivery systems for use herein contain one or 
more drug/permeation enhancer reservoirs, a backing layer, and optionally 
one or more additional layers as those skilled in the art of transdermal 
drug delivery will readily appreciate. 
The drug/permeation enhancer reservoir(s) will typically be in the form of 
a matrix comprising rubber or other polymeric material, e.g., natural and 
synthetic rubbers such as polybutylene, polyisobutylene, polybutadiene, 
polyethylene, styrene-butadiene copolymers, polyisoprene, polyurethane, 
copolyesters, ethylene/acrylic copolymers, polyether amides, silicones and 
their copolymers, and butadiene/acrylonitrile copolymers, ethylene vinyl 
acetate, gelled or thickened mineral oil, petroleum jelly and various 
aqueous gels and hydrophilic polymers that may serve as thickening agents. 
The matrix is applied to skin using a suitable adhesive as described, for 
example, in U.S. Pat. No. 4,568,343, supra. In some cases, the matrix may 
itself be comprised of an adhesive material. 
The drug reservoir layer is formulated so as to contain the selected 
pharmacologically active agent(s) as well as the above enhancer 
composition. In a preferred embodiment, the layer will contain about 1 wt. 
% to 10 wt. % drug, 5 wt. % to 25 wt. % total enhancer and 65 wt. % to 94 
wt. % polymeric adhesive and optionally tackifiers, surfactants or other 
additives. The pressure-sensitive adhesive which serves as the reservoir 
for this mixture is typically a polyisobutylene, silicone or acrylate 
adhesive. The layer may be formulated so that the selected drug is 
contained therein below saturation, at saturation, or in excess. 
The backing membrane, which may be either occlusive or nonocclusive, is 
preferably comprised of a flexible, stretchable, polymer film, e.g., of 
polyether urethane, polyester urethane, polyamide, or other related 
copolymers. The material and thickness selected for the backing membrane 
is preferably such that a transdermal system can be provided having good 
wearability for at least a seven-day application. 
The vegetable oil skin permeation enhancer compositions of the present 
invention give rise to a number of advantages which are unsuggested by the 
prior art of which applicants are aware. First, the particularly preferred 
mixture of soybean oil and coconut oil provides for a very high skin flux 
relative to other types of enhancers (as may be deduced in the examples 
below). In addition, it has been found that vegetable oils in general 
produce virtually no skin irritation or sensitization problems. Indeed, 
the inclusion of vegetable oils in transdermal formulations appears to 
reduce the skin irritation and sensitization which is problematic with 
some drugs. Finally, the vegetable oil compositions that are the focus of 
the present invention have been found to be completely compatible with a 
wide variety of drugs in transdermal formulations. 
It is to be understood that while the invention has been described in 
conjunction with the preferred specific embodiments thereof, that the 
foregoing description as well as the examples which follow are intended to 
illustrate and not limit the scope of the invention. Other aspects, 
advantages and modifications within the scope of the invention will be 
apparent to those skilled in the art to which the invention pertains 
EXPERIMENTAL 
In vitro Franz flow-through cells were used to compare the penetration of 
various drug-enhancer formulations through skin. A piece of human cadaver 
skin was mounted between the two half-cells and fastened with a clamp. 
Drug-enhancer solutions (prepared with different drugs and enhancers as 
will be described individually for each example herein) were applied to 
the donor compartment to start the experiment. The receiver compartment 
was filled with distilled, deionized water and the temperature was 
maintained at 32.degree. C. Samples were taken at preset time intervals 
and assayed by HPLC. The flux was calculated from the slope of the 
cumulative amounts of drug in the receiver compartment versus time.