Skin permeation enhancer compositions using glycerol monolaurate

A method for enhancing the transdermal flux of a transdermally deliverable drug through intact skin is described in which the drug is delivered simultaneously with glycerol monolaurate. Preferred embodiments of therapeutic systems for delivering drug and glycerol monolaurate employ matrix containing drug at a concentration above saturation.

FIELD OF THE INVENTION 
This invention relates to the transdermal delivery of drugs or other 
biologically active agents and more particularly to novel methods and 
compositions for enhancing the permeability of skin or other body surfaces 
to biologically active agents. 
RELATED PATENT APPLICATIONS 
This invention is related to the inventions disclosed in the copending, 
coassigned patent applications of Gale, et al for Transdermal 
Administration of Progesterone, Estradiol Esters and Mixtures Thereof, of 
Cheng, et al for Skin Permeation Enhancer Compositions using Sucrose 
Esters, and of Nedberge, et al for Transdermal Contraceptive Formulations, 
all of like date herewith. 
BACKGROUND OF THE INVENTION 
The transdermal route of parental delivery of drugs provides many 
advantages and transdermal systems for delivering a wide variety of drugs 
or other beneficial agents are described in U.S. Pat. Nos. 3,598,122, 
3,598,123, 4,379,454, 4,286,592, 4,314,557 and 4,568,343, for example, all 
of which are incorporated herein by reference. In many cases, drugs which 
would appear to be ideal candidates for transdermal delivery are found to 
have such low permeability through intact skin that they cannot be 
delivered at therapeutically effective rates from reasonably sized 
systems. In an effort to increase skin permeability it has been proposed 
to concurrently deliver the drug in the presence of a permeation enhancer. 
Various materials have been suggested for this purpose as described in 
U.S. Pat. Nos. 4,299,826, 4,343,798, 4,046,886, 4,130,643, 4,405,616, 
4,335,115, 4,130,667, 3,903,256, 4,379,454, 3,527,864, 3,952,099, 
3,896,238, 3,472,931 all of which are incorporated herein by reference, 
British Pat. No. 1,001,949 and Idson, Percutaneous Absorption, J. Phar. 
Sci., Vol. 64, No. b6, June 1975, pp. 901-924 (particularly 919-921). To 
be considered useful a permeation enhancer should possess certain 
characteristics in addition to its ability to enhance the permeability of 
at least one and preferably a large number of drugs. These characteristics 
include being non-toxic, non-irritating on prolonged exposure and under 
occlusion, and non-sensitizing on repeated exposure. Preferaly it should 
also be odorless and capable of delivering drugs without producing burning 
or tingling sensations. 
According to our invention, we have discovered that surfactants and in 
particular glycerol monolaurate (GML), are effective in enhancing the 
permeation of a large number of drugs and other therapeutic or beneficial 
agents through body surfaces and membranes, generally, and skin, 
particularly, and when formulated in pharmaceutical compositions with 
other materials appears to satisfy the criteria noted above. 
It is accordingly an object of our invention to increase the skin 
permeability of humans to the transport of drugs and other beneficial 
agents by the concurrent applications of the drug or beneficial agent and 
GML to the body surface. 
It is another object of our invention to provide compositions of matter for 
application to the skin which comprise GML and a transdermally deliverable 
drug or beneficial agent. 
It is another object of our invention to provide transdermal therapeutic 
systems for the concurrent delivery of GML and a drug or beneficial agent.

DESCRIPTION OF THE INVENTION 
According to our invention we have discovered that GML can be used to 
enhance the permeability to drugs and other beneficial agents of skin 
generally and, more particularly, to enhance the transdermal permeability 
of a multiplicity of drugs useful in the treatment of a wide variety of 
conditions and indications. As used herein the term "drug" relates to a 
biologically active agent, compound or composition of matter which is 
administered for the purpose of providing some beneficial or therapeutic 
effect. As used herein the term "transdermal" delivery relates to the 
delivery of a drug by passage through intact skin into the vascularized 
layers below the stratum corneum for absorption by the blood stream. Thus 
transdermal delivery is distinguished from topical application to the 
surface of intact skin for topical treatment or to application to open 
wounds or to skin lacking the stratum corneum such as burned or abraded 
skin. 
According to our invention GML and the biologically active agent (drug) to 
be delivered are placed in drug and GML transmitting relationship to the 
skin, preferably in a carrier therefor, and maintained in place for the 
desired period of time. The drug and GML are typically dispersed within a 
physiologically compatible matrix or carrier as more fully described below 
which may be applied directly to the body as an ointment, gel, cream, 
suppository or sublingual or buccal tablet for example but are more 
preferably administered from a transdermal therapeutic system as more 
fully described below. 
We have also found that GML, in addition to its known low toxicity and 
colorless and odorless nature, does not sensitize skin on repeated 
exposure. Further, it can be applied to the skin in compositions that do 
not produce irritation even on occulsion and repeated application to the 
same site and is capable of enhancing drug flux without producing 
objectionable skin sensations. 
GML has utility in connection with the delivery of drugs within the broad 
class normally delivered through 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, anthemidines, antiarthritics, 
antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic 
agents, antidiarrheals, antihistamines, anti-inflammatory agents, 
antimigraine preparations, antimotion sickness, antinauseants, 
antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, 
antipyretics, antispasmodics, including gastrointestinal and urinary; 
anticholinergics, sympathomimetics, xanthine derivatives, cardiovascular 
preparations including calcium channel blockers, betablockers, 
antiarrythmics, antihypertensives, diuretics, vasodilators including 
general, coronary, peripheral and cerebral, central nervous system 
stimulants, cough and cold preparations, decongestants, hormones, 
hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, 
parasympathomimetics, pyschostimulants, sedatives and tranquilizers. 
We have demonstrated the utility of GML as a permeation enhancer for a 
large number of dissimilar drugs within some of these classes and believes 
it to be applicable to an even larger number of such drugs including, by 
way of example and not for purposes of limitation: scopolamine, isosorbide 
dinitrate, nitroglycerin, estradiol, clonidine, cortisone, hydrocortisone, 
theophylline, phenylephrine, terbutaline, ephedrine, narcotine, quinidine, 
estradiol diacetate, progesterone, pilocarpine, furosemide, tetracycline, 
insulin, chlorpheniramine, sulfathiazides, propanolol, testosterone, 
norgestrel, lidocaine, morphinone, morphine, dihydrocodeine, 
dihydromorphine, oxycodone, hydrocodone, codeine, norcodeine, 
hydromorphine, normophine, norlevorphanol, dihydrothebaine, ouabain, 
bromocyrptine, haloperidol, guanabenz, salbutamol, oxprenolol, tetracaine, 
dibucaine, altenolol, pindolol, and timolol, for example as well as to 
other drugs not specifically noted herein. 
The effect of GML as a permeation enhancer for other drugs not specifically 
set forth herein, may be readily determined by a worker skilled in the art 
from in vitro permeation meaurements performed on cadaver skins or other 
membranes in conventional diffusion cell tests as well as by in vivo 
measurements of blood or urine levels for example. 
GML has a permeation enhancing effect on the transport of drugs through 
body surface tissues generally in addition to the skin. Nevertheless, 
because skin is one of the most effective of the body's barriers to 
permeation of foreign substances, the effect of GML on skin permeation 
makes it extremely useful in transdermal drug delivery. The following 
description of preferred embodiments of the invention is therefore 
directed primarily to improving transdermal delivery of drugs. 
Referring now to FIG. 1, a transdermal therapeutic system 1 according to 
this invention is shown which comprises a drug/permeation enhancer 
reservoir 2 in the form of a matrix containing the drug and GML. The 
reservoir 2 is covered by an impermeable backing 3 which is preferably 
sized slightly larger in circumference than reservoir 2. Means 4 for 
maintaining the syste on the skin may either be fabricated together with 
or provided separately from the remaining elements of the system which 
means in the embodiment of FIG. 1 takes the form of an adhesive overlay. 
An adhesive overlay is used with this invention because GML adversely 
affects the adhesive properties of most pharmaceutically acceptable 
contact adhesives. For this reason, impermeable backing layer 3 is 
preferably sized slightly larger than the reservoir 2 to provide a 
peripheral area around reservoir 2 free of GML to prevent adverse 
interaction between the adhesive in the overlay 4 and any of the GML which 
may seep from under the base of reservoir 2 in use. A strippable release 
liner 5, adapted to be removed prior to application would normally be 
included in the packaged product. Various materials suited for the 
fabrication of the various layers are disclosed in the aforementioned 
patents. The composition of the matrix may, depending on the drug to be 
delivered, be either aqueous based or anydrous and suitable matrices or 
carriers described in the above identified patents. Suitable matrix 
materials include, without limitation, natural and synthetic rubbers such 
as polbutylene, polyisobutylene, polybutadiene, polyethylene, 
styrenebutadine, copolymers, polyisoprene, polyurethane, 
ethylene/propylene copolymers, polyalkylacrylate polymers, copolyesters, 
ethylene/acrylic copolymers, silicones and butadiene/acrylonitrile 
copolymers for example and other polymers such as the ethylene 
vinylacetate (EVA) polymers described in U.S. Pat. No. 4,144,317 (which is 
incorporated herein by reference), for example, gelled or thickened 
mineral oil, petroleum jelly and various aqueous gels and hydrophilic 
polymers. Typically the drug is dispersed through the matrix or carrier at 
a concentration in excess of saturation, the amount of the excess being a 
function of the intended useful life of the system. The drug, however, may 
be present at initial levels below saturation without departing from this 
invention. The GML is preferably dispersed through the matrix at a 
concentration sufficient to provide permeation enhancing concentrations of 
GML in the reservoir throughout the anticipated administration time. 
In addition to the drug and GML, which are essential to the invention, the 
matrix may also contain other materials such as dyes, pigments, inert 
fillers or other permeation enhancers, excipients, and conventional 
components of pharmaceutical products or transdermal therapeutic systems 
as known to the art. 
Referring now to FIG. 2 another embodiment of this invention is shown in 
place upon the skin 17 of a patient. In this embodiment the transdermal 
therapeutic system 10 comprises a multilaminate drug/enhancer reservoir 11 
having at least two zones 12 and 14. Zone 12 consists of a drug reservoir 
substantially as described with respect to FIG. 1. Zone 14 comprises a GML 
reservoir which is preferably made from, but not limited to, substantially 
the same matrix as used to form zone 12 and which is substantially free of 
any undissolved drug. A rate-controlling membrane 13 for controlling the 
release rate of GML from zone 12 to the skin may also be utilized between 
zones 12 and 14 if desired. Suitable rate-controlling membranes may be 
formed from polymers having a permeability to GML lower than that of zone 
12. Alternately, membrane 13 may control the release rate of both the 
permeation enhancer and the drug. In that case, zone 14 would contain both 
the drug and the permeation enhancer reserves. 
An advantage of the system described in FIG. 2 is that the drug loaded zone 
12 is concentrated at the skin surface rather than throughout the entire 
mass of the reservoir. This functions to reduce the amount of drug in the 
system while maintaining an adequate GML supply. 
Superimposed over the drug/enhancer reservoir 11 is an impermeable backing 
15 and adhesive overlay 16 as described above with respect to FIG. 1. In 
addition, a strippable release liner (not shown) would preferably be 
provided on the system prior to use as described with respect to FIG. 1 
and removed prior to application to the skin 17. 
With both FIGS. 1 and 2, the adhesive overlays can be eliminated if the 
skin contacting layer can be made adhesive. Use of such an in-line contact 
adhesive would mainly be limited by the compatability of the adhesive with 
the GML component of the drug delivery system. 
In the embodiments of FIGS. 1 and 2 the carrier or matrix material has 
sufficient viscosity to maintain its shape without oozing or flowing. If 
the matrix or carrier is a low viscosity flowable material, the 
composition can be fully enclosed in a pouch or pocket between the 
impermeable backing and a permeable or microporous skin contacting 
membrane as known to the art from U.S. Pat. No. 4,379,454, noted above, 
for example. Although the invention is most useful with drugs whose 
permeability is too low for therapeutic effects to be obtained in the 
absence of an enhancer; its use with systems employing drug rate 
controlling membranes such as disclosed in U.S. Pat. Nos. 3,598,122 and 
3,598,123 noted above is also contemplated. 
EXAMPLE I 
A transdermal therapeutic system as described with respect to FIG. 1 for 
administration of progesterone was formulated from progesterone (10%), 
GML, EVA 40 and Staybelite Ester #5 (Hercules, Inc.). This system was 
tested on a human subject by application of an 80 cm.sup.2 patch on the 
upper outer arm. A similar system for the administration of estradiol was 
formulated from estradiol valerate (10%), GML, EVA 40 and Staybelite Ester 
#5 and simultaneously tested by application of an 80 cm.sup.2 patch on the 
chest of the aforementioned human subject. 
Measurement of the plasma progesterone and estradiol levels after a 24 hour 
period indicated an increase in progesterone of 70 ng/dl and an increase 
in estradiol of 4.7 ng/dl. 
EXAMPLE II 
The following table provides in vitro progesterone skin flux data for 
various formulations. Comparisons are made with other permeation 
enhancers: glycerol monooleate (GMO) and sucrose monococoate (SMC) sucrose 
recinoleate (SR) and polyethylene glycol (PEG 40) with castor oil. 
TABLE I 
______________________________________ 
PROGESTERONE 
SKIN FLUX, 
FORMULATION, weight percent 
.mu.g/cm.sup.2 /hr 
______________________________________ 
24.2% GML, 5.8% Progesterone, 
2.26 
38.8% EVA 40, 31.2% Staybelite Ester #5 
25.2% GML, 10.0% Progesterone, 
3.19 
35.9% EVA 40, 28.9% Staybelite Ester #5 
2.5% Progesterone, 97.5% EVA 51 
0.14 
25.0 GMO, 10.0% Progesterone, 
2.38 
36.0% EVA 40, 29.0% Staybelite Ester #5 
25.5% SMC, 10.0% Progesterone, 
2.33 
35.8% EVA 40, 28.7% Staybelite Ester #5 
25.5% SR, 8% Progesterone, 
1.01 
39.1% EVA 40, 27.4% Staybelite Ester #5 
25.4% PEG 40 Castor Oil, 8% 
0.75 
Progesterone, 39.1% EVA 40, 27.5% 
Staybelite Ester #5 
25.0% GML, 10% Progesterone, 
3.08 
35.9% EVA 40, 28.9% Staybelite Ester #5 
______________________________________ 
Having thus generally described our invention and having provided specific 
embodiments thereof it will be readily apparent to workers skilled in the 
art that various modifications and substitutions can be made without 
departing from the scope of this invention which is limited only to the 
following claims.