Fatty acid esters of glycolic acid and its salts

A transdermal drug delivery system which enhances the delivery of the drug comprises a composition containing, as an enhancer, one or more C.sub.6 to C.sub.22 fatty acid esters of glycolic acid and its salts. These compositions are made up of a safe and effective amount of an active pharmaceutical permeant contained in a penetration-enhancing vehicle comprising, 0.25 to 50% w. of the fatty acid glycolic acid ester enhancer in a suitable carrier vehicle. These fatty acid glycolic acid ester enhancers may be used in various carrier vehicles to enhance the transdermal delivery of active permeants in either free form or used in an occlusive device, particularly in a transdermal patch in matrix or reservoir form. When used in matrix patch form, the fatty acid glycolic acid ester enhancers and permeants are incorporated into a biocompatible adhesive. When used in a reservoir type patch, the permeant and fatty acid glycolic acid ester enhancers are incorporated into a carrier fluid of controlled viscosity such as a gel or ointment preferably containing a lower alkanol and water. In free form, the enhancer and permeant may be incorporated into an ointment, lotion, cream, or similar formulation.

FIELD OF THE INVENTION 
The present invention relates to the use of fatty acid esters of glycolic 
acid and its salts as permeation enhancers. More particularly, this 
invention relates to the use of esters of one or more fatty acids and 
glycolic acid and salts thereof as permeation enhancers for the 
transdermal delivery of a wide range of active permeants. 
BACKGROUND OF THE INVENTION AND DESCRIPTION OF PRIOR ART 
The transdermal administration of drugs is becoming increasingly accepted 
as a preferred mode of delivery. 
Transdermal delivery of drugs provides many advantages over conventional 
oral administration. Advantages of transdermal systems include 
convenience, noninterrupted therapy, improved patient compliance, 
reversibility of treatment (by removal of the system from the skin), 
elimination of "hepatic first pass" effect, the high degree of control 
over blood concentration of any particular drug and consequent reduction 
of side effects. 
Although transdermal systems have many advantages, most drugs are not 
amenable to this mode of administration due to the well known barrier 
properties of the skin. Molecules moving from the environment into and 
through intact skin must first penetrate the stratum corneum and any 
material on its surface. The molecule must then penetrate the viable 
epidermis, the papillary dermis, and then the capillary walls and into 
systemic circulation. Along the way, each of the above mentioned tissues 
will exhibit a different resistance to penetration by the same molecule. 
However, it is the stratum corneum that presents the greatest barrier to 
absorption of topical compositions or transdermally administered drugs. 
The stratum corneum, the outer horny layer of the skin, is a complex 
structure of compact keratinized cell remnants separated by lipid domains. 
Compared to the oral or gastric mucosa, the stratum corneum is much less 
permeable to outside molecules. 
The flux of a drug across the skin can be increased by changing either a) 
the resistance (the diffusion coefficient), or b) the driving force (the 
solubility of the drug in the stratum corneum and consequently the 
gradient for diffusion). Many enhancer compositions have been developed to 
change one or more of these factors, and are known in the art. U.S. Pat. 
Nos. 4,006,218, 3,551,154 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 topically applied 
drugs through the stratum corneum. Combinations of enhancers consisting of 
diethylene glycol monoethyl or monomethyl ether with propylene glycol 
monolaurate and methyl laurate are disclosed in U.S. Pat. No. 4,973,468 as 
enhancing the transdermal delivery of steroids such as progestogens and 
estrogens. A dual enhancer consisting of glycerol monolaurate and ethanol 
for the transdermal delivery of drugs is shown in U.S. Pat. No. 4,820,720. 
U.S. Pat. No. 5,006,342 lists numerous enhancers for transdermal drug 
administration consisting of fatty acid esters or fatty alcohol ethers of 
C.sub.2 to C.sub.4 alkanediols, where each fatty acid/alcohol portion of 
the ester/ether is of about 8 to 22 carbon atoms. U.S. Pat. No. 4,863,970 
shows penetration-enhancing compositions for topical application 
comprising an active permeant contained in a penetration-enhancing vehicle 
containing specified amounts of one or more cell-envelope disordering 
compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic 
acid; a C.sub.2 or C.sub.3 alkanol and an inert diluent such as water. 
The use of sorbitan esters of long chain aliphatic acids as skin permeation 
enhancers is disclosed in U.S. Pat. Nos. 5,122,383; 5,212,199 and 
5,227,169. Skin permeation enhancement using aliphatic alcohol esters of 
lactic acid is disclosed in U.S. Pat. No. 5,154,122, World Patent 95/09006 
and in Dohi et al., Enhancing Effects of Myristyl Lactate and Lauryl 
Lactate on Percutaneous Absorption of Indomethacin, Chem Pharm. Bull. 38 
(October 1990) 2877-2879. U.S. Pat. No. 5,314,694 also makes reference to 
the use of esters of fatty acid alcohols, i.e. lauryl alcohol and lactic 
acid as a permeation enhancer component. 
World Patent 96/37231 teaches the use of acyl lactylates as permeation 
enhancers for drug delivery purposes. This patent is specific to esters of 
fatty acids and lactic acid such as caproyl lactylic acid and lauroyl 
lactylic acid. It is stated that the salt form of acyl lactylates are not 
effective as permeation enhancers. 
Skin permeation enhancement due to fatty acid sucrose esters is disclosed 
in U.S. Pat. No. 4,940,586. Penetration enhancement resulting from 
combining free base and acid addition salt combinations of drugs is taught 
in U.S. Pat. No. 4,888,354. Enhancement of drugs by means of subsaturation 
in a carrier is disclosed in U.S. Pat. No. 5,164,190. 
Occlusive adhesive devices, i.e. patches, for transdermal delivery of drugs 
is taught in U.S. Pat. Nos. 4,849,224; 4,983,395; 5,152,997 and 5,302,395. 
These patches are in reservoir or matrix forms as will be more fully 
characterized in the detailed description below. 
Many of the enhancer systems possess negative side effects such as 
toxicity, skin irritation and incompatibility with the drugs or other 
ingredients making up the transdermal system. 
U.S. Pat. No. 4,855,294 discloses compositions for reducing skin irritation 
caused by drug/enhancer compositions having skin irritation properties 
comprising a percutaneously absorbable drug, a binary enhancer composition 
consisting of a solvent and a cell envelope disordering compound, combined 
with an amount of glycerin sufficient to provide an anti-irritating 
effect. 
It would be desirable to have an enhancer composition which not only 
enabled the passage of drug compositions across the skin barrier but which 
was also beneficial to the moisturization, stability and overall vitality 
of the epidermis. Skin having properly moisturized stratum corneum is 
smooth to the touch, flexible and elastic due to the presence of 
sufficient bound water. A 1% variation of water content may be enough to 
modify skin elasticity and permeability. Suitable skin hydration also 
promotes transdermal delivery of drugs through the stratum corneum. 
Fatty acid lactylates and glycolates are known to be used as hair 
conditioners as shown by U.S. Pat. No. 3,728,447. Further, fatty acid 
lactylates and their salts, prepared from C.sub.6 to C.sub.22 fatty acids, 
are known to be used in cosmetics and have the ability to complex with 
skin proteins. See Murphy, et al., Acyl Lactylates in Cosmetics, D&CI 
(May, 1978) 35 ff and Murphy, et al., Sorption of acyl lactylates by hair 
and skin as documented by radio tracer studies, Cosmetics & Toiletries, 94 
(March 1979) 43-49. Combinations of acyl lactylates or glycolates with 
soaps or synthetic detergents in skin conditioning toilet bars is the 
subject of U.S. Pat. No. 4,198,311. The use of a salt of a fatty acid 
ester of lactylic acid as one of many components in a shaving cream 
formulation is taught in U.S. Pat. No. 4,761,279. 
Lanolinyl lactylates, are shown in U.S. Pat. No. 4,422,952 to be used in 
water-in-oil emulsions as cosmetic supports or pharmaceutical excipients, 
e.g. to be used in ointments, balms, creams and the like. No physiological 
effect is attributed to these esters. 
U.S. Pat. No. 4,822,601 is drawn to cosmetic base compositions exhibiting 
therapeutic properties including sucrose fatty acid esters and fatty acid 
lactylates, with or without shea butter. Following application to the 
skin, a thickening of the epidermal layer was noted indicating a healthier 
and less dry skin. It was noted that topical application of such 
compositions also demonstrated enhanced wound healing properties and 
decreased sensitivity to UV light. 
Extensive summaries of the prior art for acyl lactylates and of the 
properties of such for cosmetic use are found in U.S. Pat. No. 5,427,772 
and World Patent 96/37231. 
In none of the above is the use of fatty acid esters of glycolic acid and 
its salts as permeation enhancers for active pharmaceutical agents taught, 
suggested or demonstrated. 
OBJECTS AND BRIEF SUMMARY OF THE INVENTION 
Accordingly, it is an object of the present invention to provide a 
composition for enhancing the transdermal delivery of drugs which has good 
skin tolerability and presents minimal risks of skin toxicity or 
irritation. 
It is still another object of the invention to provide a composition for 
the transdermal administration of drugs containing, as an enhancer, one or 
more C.sup.6 to C.sup.22 fatty acid esters of glycolic acid and its salts. 
Another object of the invention is to provide a method of enhancing the 
transdermal delivery of a variety of drugs having either or both 
hydrophobic and hydrophilic characteristics using one or more C.sub.5 to 
C.sub.21 fatty acid esters of glycolic acid and its salts as an enhancer. 
These and other objects may be realized by means of a composition for 
transdermal delivery consisting of a broad category of 
pharmaceutically-active agents which are lipophilic or hydrophilic, 
including salts, and which produce minimal or no skin irritation to human 
or animal tissue systems. The invention provides penetrating transdermal 
compositions based on the use of a pharmaceutically-active agent dissolved 
in, or admixed with, a penetration-enhancing amount of one or more C.sub.6 
to C.sub.22 fatty acid esters of glycolic acid or its salts as more fully 
described below, in a suitable carrier vehicle such as a member selected 
from the group consisting of a biocompatible pressure sensitive adhesive 
and a fluid, e.g. a suspension, emulsion or solution, of controlled 
viscosity. Suitable pressure sensitive adhesives will be subsequently 
described. Fluids of controlled viscosity include water, optionally 
containing a lower alkanol. Also, other inert ingredients which are 
soluble within the enhancer composition may be utilized in the place of 
water in forming fluids of any desired viscosity. Such fluids may be 
single phase, e.g. solutions, or phase separated systems such as 
suspensions or emulsions. The continuous phase forming such liquids can 
vary from hydrophilic to hydrophobic depending upon the desired 
combination. 
The drug enhancer combination is preferably contained in a device, 
preferably an occlusive device, for purposes of holding the composition 
against the skin or mucosa surface for administration. Such devices are 
generally patches for adhesion to the skin surface and may be in either 
matrix or reservoir form. 
The invention is therefore not limited to any specific category or 
categories of permeants, but is inclusive of all therapeutically active 
compounds, and their uses to which they are responsive as more fully set 
forth herein. The invention is also inclusive of mixtures of permeants 
which may be administered simultaneously. 
Also, the invention is drawn to treatment methods by means of which an 
effective amount of a permeant, combined with the enhancer system, is 
applied to the skin of a human or animal subject. 
While the combination of permeant and fatty acid esters of glycolic acid 
and its salts in a delivery system is not limited to any particular format 
or composition, delivery patches in liquid reservoir or matrix forms are 
preferred. Such patches may or may not contain an occlusive backing. Also, 
the simple application of a drug enhancer combination applied to the skin 
in free form as a viscous fluid such as a cream, gel, or ointment are all 
within the scope of the invention. The only limitation is that the 
composition must be effective for its intended use. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The following definitions will be useful in describing the invention and 
will eliminate the need for repetitive explanations. 
When used in context, the terms "enhancement", "penetration enhancement" or 
"permeation enhancement" relates to an increase in the permeability of the 
skin to a drug, so as to increase the rate at which the drug permeates 
through the skin. The enhanced permeation effected through the use of such 
enhancers can be observed, for example, by measuring the rate of diffusion 
of the drug through animal or human skin using a diffusion cell apparatus. 
The diffusion cell is described by Merritt et al. Diffusion Apparatus for 
Skin Penetration, J. of Controlled Release, 1 (1984) pp. 161-162. 
By "transdermal" delivery, is meant transdermal or percutaneous 
administration, i.e., delivery by passage of drug through the skin. Hence 
the terms "skin", "derma", "epidermis", and the like shall also be used 
interchangeably unless specifically stated otherwise. 
By "afflicted situs" is meant a localized area of pathology, discomfort, 
infection, inflammation or lesion, and the immediately surrounding area. 
By "application situs" is meant a site suitable for topical application 
with or without the means of a mechanical sustained release device, patch 
or dressing, e.g., behind the ear, on the arm, back chest, stomach, leg, 
top of foot, etc. 
"Carriers" or "vehicles" as used herein refer to carrier materials suitable 
for transdermal drug administration, and include any such materials known 
in the art, i.e., any liquid gel, solvent, liquid diluent, adhesive, or 
the like, which is nontoxic and which does not interact with other 
components of the composition in a deleterious manner. Carriers, which 
also may function as solvents in some instances, are used to provide the 
compositions of the invention in their preferred form. Examples include, 
but not limited to, water, ethanol, propanol, isopropanol, mineral oil, 
silicone oil, polyethylene glycol, polypropylene glycol, liquid sugars, 
waxes, petroleum jelly and a variety of other oils and polymeric materials 
along with adhesive materials such as polyacrylate, silicone, natural and 
synthetic rubbers or other adhesives. 
By the term "permeant" or "drug" is meant any chemical material or compound 
suitable for transdermal administration which includes a desired 
biological or pharmacological effect by topical application to the 
"affliction situs" or by systemic delivery from the "application situs". 
Such substances include the broad classes of compounds normally delivered 
through body surfaces such as the skin. In general, this includes 
therapeutic agents in all of the major therapeutic areas including, but 
not limited to, anti-infectives such as antibiotics and antiviral agents, 
analgesics and analgesic combinations, anorexics, antidiarrheal, 
antihistamines, anti-inflammatory agents, antimigraine preparations, 
antimotion sickness agents, antinauseants, antineoplastic, 
antiparkinsonism drugs, antipruritic, antipsychotic, antipyretics, 
antispasmodics including gastrointestinal and urinary, anticholinergic, 
sympathomimetic, xanthine derivatives, cardiovascular preparations 
including calcium channel blockers, beta-blockers, antiarrythmics, 
antihypertensives, diuretics, vasodilator including general coronary, 
peripheral and cerebral, central nervous system stimulants including cough 
and cold preparations, decongestants, diagnostics, hormones, 
immunosupressives, muscle relaxants, parasympatholytic, 
parasympathomimetic, psychostimulants, sedatives and tranquilizers. The 
term "permeant" is also meant to include mixtures. By mixtures is meant 
combinations of permeants from different categories, mixtures of permeants 
from the same category and mixtures of free base and salt forms of the 
same or different permeants from the same or different categories. 
By "effective" amount of a drug or permeant is meant a nontoxic but 
sufficient amount of a compound to provide the desired local or systemic 
effect. An "effective" amount of permeation enhancer as used herein means 
an amount selected so as to provide the desired increase in transdermal 
permeability and, correspondingly, the desired depth of penetration, rate 
of administration and amount of drug. By "effective" amount of fatty acid 
ester of glycolic acid or its salts or any other enhancer or carrier 
component, e.g. lower alkanol or glycerin, is meant the amount found 
beneficial in a particular delivery system to achieve the desired delivery 
of the drug from the system. 
By "drug delivery system", "drug/enhancer composition" or any similar 
terminology is meant a formulated composition containing the drug to be 
transdermally delivered in combination with such "carriers" or "vehicles", 
penetration enhancers, excipients, or any other additives. 
By the term "matrix", "matrix patch" or "matrix system" is meant an active 
permeant homogeneously combined in a biocompatible pressure sensitive 
adhesive which may or may not also contain other ingredients or in which 
the enhancer is also homogeneously dissolved or suspended. A matrix system 
is usually an occlusive adhesive patch having an impermeable film backing 
and, before transdermal application, a release liner on the surface of the 
adhesive opposite the film backing. A matrix system therefore is a unit 
dosage form of a drug composition in an adhesive carrier, also containing 
the enhancer and other components which are formulated for maintaining the 
drug composition in the adhesive in a drug transferring relationship with 
the derma or skin. Adhesive patches having non-occlusive backings are also 
considered to be within the scope of this definition unless specifically 
excluded. 
By "fluid of controlled viscosity" is meant a vehicle or carrier in which 
the permeant, enhancer and solvent, along with any other additives, are 
contained in a single or phase separated fluid state. The fluid per se may 
serve as a solvent or a solvent or co-solvent may be added. Such fluids 
can be water or organic based and may contain a mixture of liquids or 
solvents appropriately gelled or thickened. In other words, such fluids 
may comprise, but are not limited to, solutions, suspensions, emulsions, 
gels, ointments, creams, pastes or any other similar state which permits 
the outward diffusion of the permeant and enhancer and, optionally, a 
solvent or other additives as desired. 
By the term "reservoir", "reservoir patch" or "reservoir system" is meant 
an active permeant combined in a fluid of controlled viscosity contained 
in an occlusive device having an impermeable back surface and an opposite 
surface configured appropriately with permeable membranes and adhesives 
for transdermal application. A reservoir system therefore is a unit dosage 
form of a drug composition in a fluid carrier of controlled viscosity, 
also containing the enhancer and other components which is formulated in 
an occlusive device for maintaining the drug composition in the carrier in 
a drug transferring relationship with the derma or skin. 
By "free form" is meant a gel, lotion, cream, paste, ointment and the like 
containing an active permeant combined in a fluid of controlled viscosity 
in which the enhancer is also dissolved or suspended and which may be 
applied directly to an afflicted situs. 
The compositions of this invention require, at a minimum, a permeant 
capable of producing systemic effects, or producing or possessing local 
activity, in a carrier vehicle containing, as an enhancer, a fatty acid 
ester of glycolic acid or a salt thereof. Such carrier vehicle may be a 
pressure sensitive adhesive or fluid of controlled viscosity. Such fluids 
may be water based and contain a C.sub.2 or C.sub.3 alcohol with or 
without other optional ingredients within suitable ranges. However, 
solvents or liquids other than water may also be used as a base fluid 
phase. In addition, the fatty acid esters of glycolic acid or a salt 
thereof may be combined with other enhancers, such as cell envelope 
disordering compounds and solvents other than water and C.sub.2 and 
C.sub.3 alcohols. 
Cell envelope disordering compounds are known in the art as being useful in 
topical pharmaceutical preparations. These compounds are thought to assist 
in skin penetration by disordering the lipid structure of the stratum 
corneum cell-envelopes. A representative listing of these compounds is 
described in the patents cited in the prior art section above which are 
incorporated herein by reference. 
For purposes of definition herein, cell-envelope disordering compounds and 
solvents other than water, ethanol, propanol and isopropanol shall be 
referred to as "secondary enhancers". This is an arbitrary definition for 
use in this disclosure as such "secondary enhancers" are known in the art 
to function as sole or primary enhancers. 
Glycolic acid and its salts that are useful the preparation of esters are 
those represented by the formula: 
EQU H--(--CH.sub.2 --CO).sub.a O!.sub.b M 
where a is an integer of 1 to 4, b is 1 or 2 and M is H or a 
pharmaceutically acceptable counterion having a valency of 1 or 2. When M 
is other than H, any pharmaceutically acceptable counterion having a 
valency of 1 or 2 may be utilized in salt formation. Alkali, alkaline 
earth, ammonium and amine salts are suitable counterions. Representative 
of these are alkali metal salts such as sodium and potassium; alkaline 
earth metal salts such as magnesium and calcium and ammonium and amine 
salts. The amines may be primary, secondary or tertiary and may be alkyl, 
aryl, alkaryl and aralkyl amines wherein the aliphatic terms are as those 
defined above. By alkyl and alkenyl is meant any straight or branched, 
saturated or unsaturated, chain having from 1 to 22 carbon atoms and by 
aryl is meant any carbocyclic or heterocyclic group having properties of 
aromaticity. 
Fatty acids used in the preparation of esters are those represented by the 
formula RCOOH, where R is a C.sub.5 to C.sub.21 alkyl or alkenyl chain 
which may be either straight or branched chained and which may contain 
hydroxy substituents. Straight C.sub.8 to C.sub.18 alkyl, alkenyl or 
hydroxy substituted alkyl or alkenyl chains are preferred. Representative 
of saturated acids, where R is alkyl, are caproic acid, caprylic acid, 
capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and 
the like. Representative of unsaturated acids, where R is alkenyl, are 
palmitoleic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic 
acid, arachidgnic acid and the like. Mixtures of acids, including mixtures 
of saturated and unsaturated acids may also be used. 
The fatty acid esters of glycolic acid and its salts may be represented by 
the formula: 
EQU RCO--(O--CH.sub.2 --CO).sub.a O!.sub.b M 
where R, M, a and b are as represented above. Preferably M is a member 
selected from the group consisting of H, Na, K, Ca, Mg and ammonium or 
amines salts. Since these fatty acid esters of glycolic acid and glycolic 
acid salts are described in the prior art, further definition is not 
necessary. These compounds, sometimes also described as acyl glycolates 
are available from R.I.T.A. Corporation (Woodstock, Ill.). 
Particularly preferred fatty acid esters of glycolic acid and its salts are 
members selected from the group consisting of lauroyl glycolate, caproyl 
glycolate, cocoyl glycolate, isostearoyl glycolate, sodium lauroyl 
glycolate, tromethamine lauroyl glycolate and the like. 
The fatty acid esters of .alpha.-hydroxy acid when used as enhancers, may 
be present in an enhancer/carrier system in amounts ranging from between 
about 0.25 to 50% w. The effective amount of enhancer may vary depending 
on whether the delivery composition is for use in a reservoir or free form 
composition or a matrix patch and may vary depending on any number of 
factors such as the hydrophilic/hydrophobic properties of the drug, drug 
concentration, whether the enhancer is used in free acid or salt form, the 
particular matrix or reservoir components, etc. In all systems ranges of 
between about 0.25 and 30% w are preferable. Most preferably the enhancer 
content will range between about 0.5 to 15% w regardless of the particular 
system. 
The bulk of the enhancer/carrier system is preferably an adhesive, in the 
case of a matrix device, or a mixture of lower alkanol, preferably ethanol 
or isopropanol, and inert carrier, preferably water, with or without a 
gelling agent, in the case of a reservoir or free form composition. 
In the reservoir or free form systems the enhancer will generally be 
present in the enhancer/carrier system in ranges of between about 0.25 and 
50% w with ranges of between about 0.25 and 30 being preferable and ranges 
of between about 0.5 to 15% w being most preferable. 
In such systems, the concentration of water may be present in amounts of 
between about 0 to 99% w. When water is present, the range may vary 
between about 1 and 99% w with ranges of between about 5 to 50 percent 
being preferred. The lower alcohol content may vary between about 0 and 
89% by weight of the enhancer/carrier system. When alcohols are present 
the range may vary between about 1 and 89% w with alcohol concentrations 
of between about 30 and 65% w. being most preferred. 
Gelling or thickening agents will also preferably be utilized in the 
reservoir or free form compositions. These may be present in amounts 
ranging from between about 0.5 to 20% by weight with ranges between about 
0.5 and 5% being preferred. 
Additionally, glycerin may be added as an anti-irritant or to modulate the 
delivery of the active permeant and may be present in amounts of from 0 to 
60% by weight. When used, glycerin is present in amounts of between about 
1 and 60% with amounts of 10 to 50% by weight being preferred. 
Free form compositions, for application directly to an afflicted situs as a 
gel or ointment, may be similar in content to the reservoir formulations 
for containment in an occlusive device. 
Suitable thickening agents include hydrophilic polymers such as 
hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy 
ethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran, 
gaur-gum, polyvinylpyrrolidone, pectins, starches, gelatin, casein, 
acrylic acid, acrylic acid esters, acrylic acid copolymers, vinyl 
polymers, vinyl copolymers, vinyl alcohols, alkoxy polymers, polyethylene 
oxide polymers, polyethers, and the like. 
In matrix systems the adhesive is present in amounts ranging from 50 to 
99.75% by weight and will preferably be present in amounts of between 
about 70 and 99.5% by weight. The enhancer is also homogeneously dissolved 
or suspended in the adhesive matrix and is present in amounts of between 
about 0.25 and 50% by weight with ranges of between about 0.5 to 30% w 
being preferred and 0.5 to 15% w being most preferred. 
In the matrix systems the carrier is primarily the pressure sensitive 
adhesive in which the enhancer and an effective amount of an active 
permeant or drug are homogeneously combined. 
Suitable pressure sensitive adhesives may include acrylic copolymer 
adhesives or "acrylic adhesive", (e.g. National Starch Durotak 80-1196, 
National Starch Nacor 72-9965 and Monsanto Gelva 737), rubber based 
adhesives or "rubber adhesive", such as polyisobutylene or "PIB adhesive", 
(e.g. Adhesive Research MA-24), ethylene-vinylacetate copolymer adhesives 
or "EVA adhesive" (e.g. National starch EVA-TACK 33-4060), styrene 
butadiene rubber adhesives or "SBR adhesives", (e.g. National Starch Nacor 
72-8725) and silicone based adhesives or "silicone adhesive", (e.g. Dow 
Bio-PSA). However, any other suitable pressure sensitive adhesives may 
also be used which are compatible with the active permeant and enhancer 
when utilized. 
The cell envelope disordering compounds as secondary enhancers may be 
present in the enhancer/carrier in amounts that do not add to the overall 
enhancer content as designated above. Rather, part of the fatty acid 
esters of glycolic acid or a salt thereof, or primary enhancer, is 
replaced by the secondary enhancer such that the weight ratio of primary 
enhancer to secondary enhancer is between about 5:1 to 1:3 with ratios of 
between about 2:1 to 1:2 being preferred and ratios of about 1:1 being 
most preferred. 
Preferred secondary enhancers or cell-envelope disordering compounds are 
members selected from the group consisting of methyl laurate, lauryl 
alcohol, glycerol monolaurate, oleic acid, oleyl alcohol, glycerol 
monooleate, glycerol dioleate and glycerol trioleate and mixtures thereof. 
Suitable solvents, other than or in addition to water, ethanol, propanol 
and isopropanol include diols, such as propylene glycol and glycerol; 
C.sub.4 -C.sub.10 mono-alcohols; DMSO, dimethylformamide; 2-pyrrolidone; 
N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 
1-dodecylazacycloheptan-2-one and other 
n-substituted-alkyl-azacycloalkyl-2-ones (azones) and the like. 
Preferred solvents are members selected from the group consisting of a 
C.sub.3 or C.sub.4 diol, DMSO, DMF, DMA, 
1-n-dodecylcyclazacycloheptan-2-one. N-methyl-pyrrolidone and 
N-(2-hydroxyethyl)pyrrolidone and mixtures thereof. 
Provided there is no negative effect on the functionality of the 
formulation, the drug delivery composition may, in addition, include one 
or more carriers, vehicles, or excipients, and various agents and 
ingredients commonly employed in dermatological and cosmetic gels, creams 
and ointments or other preparations. Examples are, but not limited to, 
fragrances, pacifiers, preservatives, anti-oxidants, emollients, oils, 
stabilizers, coloring agents and the like. 
It will be appreciated by those skilled in the art that relative amounts of 
the other components in these compositions can vary greatly. For example, 
the amount of drug present in a given composition will depend upon a 
variety of factors, including but not limited to, the disease or condition 
to be treated, the nature of the drug, the activity of the drug, the 
desired effect, the situs of application, possible adverse reactions, the 
cost and availability of the drug, solubility of the drug, and other 
factors within the particular knowledge of the patient and physician. 
The method of application of the present invention may vary within limits, 
but necessarily involves applying the selected drug composition to the 
skin or other tissue where drug delivery is initiated and continues at a 
relatively sustained rate for a period of time sufficient to provide the 
desired pharmacological or biological response. When applied to an 
"afflicted situs" the method may involve a gel, lotion, cream, ointment, 
or the like. When applied to an "application situs" for systemic the 
method may involve the use of a drug delivery system device as taught, for 
example, in U.S. Pat. Nos. 3,742,951, 3,797,494, 4,568,343, 4,849,224 or 
4,983,395. Alternatively, in suitable situations, drug delivery system 
devices may also be applied to an "afflicted situs". 
In either event the reservoir or matrix device is brought in contact with 
the skin at the application situs and is held in place on the skin at the 
application situs by a suitable adhesive. In the reservoir device, the 
drug enhancer composition may be applied to the skin through a permeable 
membrane forming the reservoir floor which is in diffusional contact with 
the skin. 
It is to be understood that while the invention has been described in 
conjunction with the preferred specific embodiments thereof, that which 
follow are intended to illustrate and not limit the scope of the 
invention. Other aspects of the invention will be apparent to those 
skilled in the art to which the invention pertains. 
Experimental 
The following experiments relate to combinations of a pharmaceutically 
active substance and a fatty acid ester of either a glycolate in which the 
transdermal permeation of the active substance is shown to be 
substantially increased by the presence of glycolate fatty acid esters. 
The examples given below illustrate the transdermal permeation enhancing 
effect of these enhancers for acidic, basic, and non-ionic drugs, though 
it is understood that the invention will not be limited to the drug 
substances contained in these examples. 
Adhesive Matrix Preparation 
Pressure sensitive adhesive matrix systems were prepared according to the 
following steps. First, the solids content of the adhesive solution (water 
or organic solvent based) was determined by placing a known weight of 
solution in a weighed aluminum dish and evaporating the solvents overnight 
in a 70.degree. C. convection oven. The solid adhesive content of the 
solution was calculated by dividing the adhesive solid weight after drying 
by the initial total solution weight. Next, a weighed quantity of adhesive 
solution was added to a glass bottle and the drug substance, permeation 
enhancer, and other excipients were weighed and added to the adhesive 
solution in a quantity necessary to achieve the desired dry matrix film 
composition. The solution containing the adhesive polymer, drug substance, 
and other excipients as necessary was then mixed overnight. After mixing, 
approximately 8 ml of the solution was dispensed on a silanized polyester 
release liner and film cast using a casting knife with a gap size 
appropriate to achieve a final dried thickness of approximately 0.05 mm. 
The cast film was dried in a 70.degree. C. convection oven until all 
solvents had evaporated to yield a dried matrix (15 minutes for organic 
solvent based adhesives, 30 minutes for water emulsion based adhesives). 
Finally, an 0.08 mm thick occlusive polyethylene backing film was 
laminated onto the dried adhesive matrix, and these systems were then used 
to conduct in vitro skin flux experiments as described below. 
Reservoir or Free Form Hydroalcoholic Gel Preparation 
Hydroalcoholic gels were prepared on a 10 ml scale as follows. Ethyl 
alcohol (190 proof ethanol), water, glycerin, enhancer and drug were 
combined in the appropriate proportions and mixed for several hours. The 
gelling agent (e.g. carbomer) was added and the solution was mixed briefly 
at high shear, then mixed at low shear until a gel was formed. 
Skin Flux Studies 
In vitro skin flux studies were conducted using human cadaver epidermal 
membrane in modified Franz non-jacketed diffusion cells. The epidermal 
membrane (stratum corneum and epidermis) was separated from whole skin 
(epidermal membrane and dermis) by the method of Kligman and Christopher 
(Arch. Dermatol. 88:702 (1963)). This method involves the exposure of the 
full-thickness skin to water at 60.degree. C. for a time period of 60 
seconds. After this period, the epidermal membrane was gently peeled off 
the dermis and stored for later use in aluminum foil at -5.degree. C. 
Prior to each permeation experiment with a matrix system, the matrix system 
was cut into a circular sample of 0.7 cm.sup.2 area and the silanized 
release liner was removed. The adhesive was affixed to the stratum corneum 
side of the thawed epidermal membrane which was then cut to an appropriate 
size and clamped in place between the two halves of the diffusion cell 
with the stratum corneum facing the donor compartment. The receiver 
compartment was filled with water or an aqueous solution appropriate to 
maintain sink conditions for the drug. All receiver solutions included 
0.02% (w/w) sodium azide (NaN.sub.3) to inhibit bacterial growth. The 
diffusion cell was placed in a temperature controlled circulating water 
bath calibrated to maintain the surface temperature of the skin at 
32.degree. C. The receiver compartment was constantly stirred by a 
magnetic stir-bar in the receiver compartment agitated by a magnetic 
stirring module placed under the water bath. 
Permeation experiments with hydroalcoholic gels were performed using both 
finite occluded doses and thin unoccluded films. The occluded dose is an 
appropriate in vitro model for the application of a transdermal patch drug 
delivery system containing a liquid or gel reservoir, while the thin 
unoccluded film is an in vitro model for free form topical application. 
Occluded dosing experiments were set-up according to the following 
procedure. Prior to skin permeation experiments, the epidermal membrane 
was cut to an appropriate size and placed between the two halves of the 
diffusion cell with the epidermal side facing the receiver compartment. 
The receiver compartment was filled with an appropriate solution then the 
diffusion cell was placed in a circulating water bath calibrated to 
maintain the temperature of the skin surface at 32.degree. C. and allowed 
to hydrate overnight. After hydration, a sample of the gel (75 .mu.l) was 
pipetted into a cavity created by placing a polyethylene washer over the 
stratum corneum surface. This cavity was covered with an occlusive backing 
film which was clamped in place. 
Thin film unoccluded dosing experiments with hydroalcoholic gels were 
set-up using the following procedure adapted from Chiang et al. (Int J. 
Pharm. 49: 109-114 (1989)). The stratum corneum side of a piece of 
epidermal membrane was attached to one side of an adhesive-coated metal 
shim with a circular hole of 0.64 cm.sup.2 area cut in the center. The 
epidermal side of the membrane-metal shim assembly was kept overnight on 
Whatman filter paper saturated with an appropriate receiver solution in 
order to hydrate the membrane. 
After hydration the membrane-shim assembly was placed epidermal side down 
on a flat glass surface. A small sample of the formulation to be tested 
(about 20 .mu.l) was dispensed into the central cavity of the shim and a 
flat glass plate was used to spread the gel evenly in the annular space in 
the center of the shim and to remove the excess gel. The gel remaining on 
the skin after this procedure is completed forms a thin film with a total 
volume of 7 .mu.l over the 0.64 cm.sup.2 skin surface area (equivalent to 
a dose of 11 .mu.l/cm.sup.2 which is typical for free form topical 
applications). The membrane-shim assembly is then clamped in place on a 
temperature-controlled diffusion cell as described above with the 
epidermal side of the membrane facing the receiver compartment. 
The following sampling procedure was used for all dosage forms. At 
predetermined sampling time points, the entire contents of the receiver 
compartment were collected for drug quantitation and the receiver 
compartment was filled with fresh solution, taking care to eliminate any 
air bubbles at the skin/solution interface. The cumulative amount of drug 
permeated per unit area at any time t(Q.sub.t, .mu.g/cm.sup.2) was 
determined as follows: 
##EQU1## 
where C.sub.N is the concentration (.mu.g/ml) of the drug in the receiver 
sample for the corresponding sample time, V is the volume of fluid in the 
receiver chamber (.about.6.3 cm.sup.3), and A is the diffusional area of 
the cell (0.64 cm.sup.2).