Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents

A method of transdermally or transmucosally delivering a hydrophilic salt form of a drug with a water-based pressure sensitive hydrophobic adhesive matrix patch optionally containing a permeation enhancer is disclosed. A matrix patch comprising a water-based pressure sensitive hydrophobic adhesive, a hydrophilic salt form of a drug, and optionally a permeation enhancer for transdermal or transmucosal delivery of the hydrophilic salt form of the drug is also disclosed.

BACKGROUND OF THE INVENTION 
This invention relates to compositions and methods for delivery of drugs. 
More particularly, the invention relates to pressure sensitive adhesive 
matrix patches and methods of use thereof for transdermal delivery of 
hydrophilic salts of pharmaceutical agents. 
Transdermal delivery of various drugs is well known in the art of drug 
delivery. Pressure sensitive adhesive matrix patches for transdermal 
delivery of drugs are also known in the art. These matrix patches 
typically include an inert, impervious backing layer, a pressure sensitive 
adhesive layer containing the drug and optional selected excipients, and a 
release liner that is peeled off and discarded before applying the patch 
to the skin. Suitable pressure sensitive adhesives include polysiloxanes, 
polyacrylates, polyisobutylene, and the like. These pressure sensitive 
adhesive polymers are very hydrophobic and are typically purchased as 
solutions of polymer dissolved in organic solvents. The drug and selected 
excipients, if any, are directly incorporated into the 
organic-solvent-based pressure sensitive adhesive solution, mixed, cast as 
a thin film, and dried to evaporate the solvents, leaving a dried adhesive 
matrix film containing the drug and excipients. It is well known in the 
art that the drug has to be hydrophobic to be incorporated into the 
organic-solvent-based, hydrophobic adhesive. Hydrophilic salt forms of a 
drug are generally not compatible with such organic-solvent-based pressure 
sensitive adhesives and have to be converted to the more hydrophobic free 
acid or free base form for incorporation into the organic-solvent-based, 
hydrophobic adhesive. 
Keshary et al., U.S. Pat. No. 5,002,773, describe transdermal delivery of a 
calcium antagonist compound, "TA-3090," to patients in need of a calcium 
channel blocking effect. Keshary et al. state that the free base form of 
TA-3090 can generally be incorporated in polymeric matrix materials in a 
higher percent by weight than the maleate salt form of TA-3090 and that 
the free base form is preferred for transdermal delivery. Chandrasekaran 
et al., U.S. Pat. No. 4,201,211, disclose a gelled mineral 
oil-polyisobutylene-clonidine free base skin patch for antihypertensive 
effect, whereas the hydrochloride salt is used in the manufacture of oral 
clonidine tablets. Urquhart et al., U.S. Pat. No. 4,262,003, describe a 
gelled mineral oil-polyisobutylene-scopolamine free base transdermal patch 
for the administration of scopolamine base to inhibit nausea and emesis. 
These examples illustrate the conversion of a hydrophilic salt form of a 
drug into the more hydrophobic free base form to render it more compatible 
for incorporation into a hydrophobic pressure sensitive adhesive matrix 
patch. 
Water-based pressure sensitive adhesives are also commercially available. 
These water-based adhesives are formulated as emulsions wherein the 
hydrophobic pressure sensitive adhesive polymer is dispersed in water with 
the help of surfactants. Such water-based adhesives provide inherent 
advantages of safety and reduced environmental problems over solvent-based 
pressure sensitive adhesives, because the carrier is water and not an 
organic solvent. These water-based adhesives are widely used in the 
manufacture of medical tapes and bandages, and provide excellent skin 
adhesion. 
Coughlan et al., U.S. Pat. No. 4,564,010, disclose a pressure sensitive 
adhesive film for medical use comprising a base layer laminated to a 
water-based pressure sensitive adhesive coating formed of a mixture of a 
polyacrylic latex, an ester resin, and a thickening agent. Coughlan et al. 
teach that such films can be used in transdermal delivery systems, 
however, they fail to describe the types of drugs that may be suitable for 
transdermal delivery with such a system. Yeh et al., U.S. Pat. No. 
5,230,896, describe a transdermal delivery system for administration of 
nicotine comprising nicotine base, an acrylic polymer adhesive, a 
stabilizer, and a polyester film backing. It is stated that a nicotine 
salt is also contemplated in the practice of the invention. Such a 
nicotine salt is used to reduce volatility of the drug and is formed in 
situ by addition of acid. When an acid is used to produce the nicotine 
salt, an emulsion thickener is also required to increase the viscosity of 
the formulation. Nicotine is a unique compound in that both the free base 
and its salt forms are very water soluble. Sablotsky et al., U.S. Pat. No. 
5,186,938, describe the use of a water-based emulsion adhesive patch for 
the transdermal administration of nitroglycerin. 
Hydrophilic salt forms of hydrophobic drugs are generally readily soluble 
in water-based pressure sensitive adhesives because the solvent is water, 
not an organic solvent. What has hitherto gone unrecognized, and is the 
subject matter of the present invention, is that the hydrophilic salt form 
of a hydrophobic drug can not only be readily incorporated into the 
water-based hydrophobic pressure sensitive adhesive, but that the drug is 
then readily permeable across skin from the dried adhesive film. In fact, 
the skin flux of the hydrophilic salt form of a drug from a water-based 
pressure sensitive adhesive matrix is comparable to that of the 
hydrophobic free base or free acid form from an organic solvent-based 
pressure sensitive adhesive matrix patch. This finding is novel and 
contrary to conventional wisdom, which holds that hydrophilic compounds 
are much less permeable across skin than more hydrophobic substances. R. 
J. Scheuplein et al., Permeability of the Skin, 51 Physiological Reviews 
702-47 (1972); G. L. Flynn, Mechanisms of Percutaneous Absorption from 
Physicochemical Evidence, in Percutaneous Absorption 27-51 (R. L. Bronaugh 
& H. I. Maibach eds., Marcel Decker, Inc. 1989). Gale et al., U.S. Pat. 
Nos. 4,645,502 and 4,904,475, disclose a reservoir patch device for 
transdermal delivery of highly ionized, fat-insoluble drugs. This 
invention is premised on the observation that unionized forms of most 
drugs are more permeable through skin than their ionized forms, i.e. the 
salt of a particular drug generally cannot be delivered through skin 
without significant permeation enhancement. For example, Keshary et al., 
U.S. Pat. No. 5,002,773, show that the free base form of TA-3090 is 7-10 
fold more permeable than the maleate salt of TA-3090 from organic solvent 
based pressure sensitive adhesive matrix systems. In view of the 
foregoing, it will be appreciated that compositions and methods for 
efficient transdermal delivery of hydrophilic salt forms of drugs with 
hydrophobic pressure sensitive matrix patches would be a significant 
advancement in the art. 
BRIEF SUMMARY OF THE INVENTION 
It is an object of the present invention to provide pressure sensitive 
adhesive matrix patches and methods of use thereof for transdermal and/or 
transmucosal delivery of hydrophilic salts of pharmaceutical agents. 
It is also an object of the invention to provide adhesive matrix patches 
and methods of use thereof that are compatible with hydrophilic salt forms 
of pharmaceutical agents for transdermal and/or transmucosal delivery 
thereof. 
It is another object of the invention to provide permeation enhanced 
transdermal and/or transmucosal delivery of hydrophilic salts of 
pharmaceutical agents with water-based pressure sensitive adhesive matrix 
patches. 
These and other objects can be achieved by providing a method of 
transdermally delivering a hydrophilic salt form of a drug comprising the 
steps of: 
(a) providing a pressure sensitive adhesive matrix patch device comprising 
a drug-containing adhesive matrix layer comprising a water-based polymeric 
adhesive having dissolved therein an effective amount of the hydrophilic 
salt form of the drug, and optionally an effective amount of a permeation 
enhancer, a proximal surface of the layer adapted to adhere to the skin 
and a distal surface of the layer adapted to adhere to a backing layer, 
and 
a backing layer that is substantially impermeable to the drug laminated to 
the distal surface; and 
(b) contacting a selected area of the skin with the matrix patch device 
such that the proximal surface of the drug-containing adhesive matrix 
layer adheres to and is in drug transfer relationship with the selected 
area of the skin. 
Preferred water-based adhesives include acrylic and polyisobutylene 
adhesives, and preferred drugs include ketorolac tromethamine, diclofenac 
sodium, buspirone HCl, lidocaine HCl, and clonidine HCl. Preferred 
permeation enhancers include cell envelope disordering compounds, 
solvents, and mixtures thereof. 
A pressure sensitive adhesive matrix patch device for transdermally 
delivering a hydrophilic salt form of a drug comprises 
a drug-containing adhesive matrix layer comprising a water-based adhesive 
having dissolved therein an effective amount of the hydrophilic salt form 
of the drug, and optionally an effective amount of a permeation enhancer, 
a proximal surface of the layer adapted to adhere to the skin and a distal 
surface of the layer adapted to adhere to a backing layer, and 
a backing layer that is substantially impermeable to the drug laminated to 
the distal surface.

DETAILED DESCRIPTION 
Before the present composition and method of use thereof for transdermal 
delivery of hydrophilic salts of pharmaceutical agents are disclosed and 
described, it is to be understood that this invention is not limited to 
the particular configurations, process steps, and materials disclosed 
herein as such configurations, process steps, and materials may vary 
somewhat. It is also to be understood that the terminology employed herein 
is used for the purpose of describing particular embodiments only and is 
not intended to be limiting since the scope of the present invention will 
be limited only by the appended claims and equivalents thereof. 
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 context clearly dictates otherwise. Thus, for example, 
reference to a composition for delivering "a drug" includes reference to 
two or more of such drugs, reference to "an adhesive" includes reference 
to one or more of such adhesives, and reference to "a permeation enhancer" 
includes reference to two or more of such permeation enhancers. 
In describing and claiming the present invention, the following terminology 
will be used in accordance with the definitions set out below. 
As used herein, "hydrophilic salt form" and similar terms mean an ionic 
form of a drug or pharmaceutical agent, such as sodium, potassium, 
ammonium, tromethamine, or other cation salts thereof, sulfate or other 
anion salts thereof, acid addition salts of basic drugs, and base addition 
salts of acidic drugs. Illustrative examples of such salts include sodium 
diclofenac, sodium cromolyn, sodium acyclovir, sodium ampicillin, 
ketorolac tromethamine, amiloride HCl, ephedrine HCl, loxapine HCl, 
thiothixene HCl, trifluoperizine HCl, naltrexone HCl, naloxone HCl, 
nalbuphine HCl, buspirone HCl, bupriprion HCl, phenylephrine HCl, 
tolazoline HCl, chlorpheniramine maleate, phenylpropanolamine HCl, 
clonidine HCl, dextromethorphan HBr, metoprolol succinate, metoprolol 
tartrate, epinephrine bitartrate, ketotofin fumarate, atropine sulfate, 
fentanyl citrate, apomorphine sulfate, propranolol HCl, pindolol HCl, 
lidocaine HCl, tetracycline HCl, oxytetracycline HCl, tetracaine HCl, 
dibucaine HCl, terbutaline sulfate, scopolamine HBr, and brompheniramine 
maleate. 
As used herein, "effective amount" means an amount of a drug or 
pharmacologically active agent that is nontoxic but sufficient to provide 
the desired local or systemic effect and performance at a reasonable 
benefit/risk ratio attending any medical treatment. An effective amount of 
a permeation enhancer as used herein means an amount selected so as to 
provide the selected increase in skin permeability and, correspondingly, 
the desired depth of penetration, rate of administration, and amount of 
drug delivered. 
As used herein, "transdermal" refers to delivery of a drug through the skin 
or mucosa and thus includes transmucosal. Similarly, "skin" is meant to 
include mucosa. Such mucosa include, without limitation, the buccal, 
nasal, rectal, and vaginal mucosa. 
As used herein, "drug," "pharmaceutical agent," "pharmacologically active 
agent," or any other similar term means any chemical or biological 
material or compound suitable for transdermal administration by the 
methods previously known in the art and/or by the methods taught in the 
present invention that induces a desired biological or pharmacological 
effect, which can include but is not limited to (1) having a prophylactic 
effect on the organism and preventing an undesired biological effect such 
as preventing an infection, (2) alleviating a condition caused by a 
disease, for example, alleviating pain or inflammation caused as a result 
of disease, and/or (3) either alleviating, reducing, or completely 
eliminating the disease from the organism. The effect can be local, such 
as providing for a local anaesthetic effect, or it can be systemic. This 
invention is not drawn to novel drugs or new classes of active agents. 
Rather it is limited to the mode of delivery of agents or drugs that exist 
in the state of the art or that may later be established as active agents 
and that are suitable for delivery by the present invention. Such 
substances include broad classes of compounds normally delivered into the 
body, including through body surfaces and membranes, including skin. In 
general, this includes but is not limited to: 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 potassium and calcium channel blockers, beta-blockers, 
alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and 
antidiuretics; vasodilators including general coronary, peripheral, and 
cerebral; central nervous system stimulants; vasoconstrictors; cough and 
cold preparations, including decongestants; hormones such as estradiol and 
other steroids, including corticosteroids; hypnotics; immunosuppressives; 
muscle relaxants; parasympatholytics; psychostimulants; sedatives; and 
tranquilizers. By the method of the present invention, ionized drugs can 
be delivered, as can drugs of either high or low molecular weight. 
As used herein, "permeation enhancer," "penetration enhancer," "chemical 
enhancer," or similar terms refer to compounds and mixtures of compounds 
that enhance the flux of a drug across the skin. Flux can be increased by 
changing either the resistance (the diffusion coefficient) or the driving 
force (the gradient for diffusion). 
Chemical enhancers are comprised of two primary categories of components, 
i.e., cell-envelope disordering compounds and solvents or binary systems 
containing both cell-envelope disordering compounds and solvents. The 
latter are well known in the art, e.g. U.S. Pat. Nos. 4,863,970 and 
4,537,776, incorporated herein by reference. 
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 comprehensive list of these compounds is 
described in European Patent Application 43,738, published Jun. 13, 1982, 
which is incorporated herein by reference. Examples of cell envelope 
disordering compounds that can be used as enhancers, without limitation, 
include saturated and unsaturated fatty acids and their esters, alcohols, 
monoglycerides, acetates, diethanolamides, and N,N-dimethylamides, such as 
oleic acid, propyl oleate, isopropyl myristate, glycerol monooleate, 
glycerol monolaurate, methyl laurate, lauryl alcohol, lauramide 
diethanolamide, and mixtures thereof. Saturated and unsaturated sorbitan 
esters, such as sorbitan monooleate and sorbitan monolaurate, can also be 
used. It is believed that any cell envelope disordering compound is useful 
for purposes of this invention. 
Suitable solvents include water; diols, such as propylene glycol and 
glycerol; mono-alcohols, such as ethanol, propanol, and higher alcohols; 
DMSO; dimethylformamide; N,N-dimethylacetamide; 2-pyrrolidone; 
N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 
1-dodecylazacycloheptan-2-one and other 
n-substituted-alkyl-azacycloalkyl-2-ones (azones) and the like. 
The present invention is based on the discovery that pressure sensitive 
adhesive matrix patches can be formulated for transdermal delivery of the 
hydrophilic salt form of a drug, wherein equivalent skin flux is obtained 
as compared to patches formulated with the free acid or free base form of 
the drug in an organic solvent-based pressure sensitive adhesive. 
The salt form of the drug is usually hydrophilic and insoluble in 
organic-solvent-based adhesives and cannot be incorporated into such 
organic-solvent-based adhesive patches to provide clinically meaningful 
skin flux. Such salt forms of drugs have previously had to be converted to 
the more hydrophobic free acid or free base form to be soluble and/or 
compatible in the organic-solvent-based adhesive to obtain clinically 
meaningful skin flux. This prior art procedure requires additional process 
steps, wherein the drug is converted from the FDA approved salt form to an 
unapproved free acid or free base form, thus introducing additional 
regulatory and/or toxicological hurdles to developing a matrix patch. 
These problems can be avoided by formulating the salt form of the drug in 
a water-based pressure sensitive adhesive such that skin flux equivalent 
to that of patches formulated with the free acid or free base form of the 
drug in an organic-solvent-based pressure sensitive adhesive is obtained. 
FIG. 1 shows an exemplary matrix patch 10 that is compatible with the 
present invention. The patch 10 is a laminated composite in which the 
backing layer 12 forms the top surface of the composite. The 
drug-containing adhesive matrix layer 14 is immediately below and adjacent 
to the backing layer. Prior to use, the laminate also includes a 
strippable protective release liner. The release liner can be in the form 
of two sheets, 16a and 16b, the first sheet 16a partially overlapping the 
second sheet 16b. Additional structural layers can also be present. 
The backing layer, which adheres to the drug-containing adhesive layer 
serves as the upper layer of the device during use and functions as the 
primary structural element of the device. The backing layer is made of a 
sheet or film of a preferably flexible elastomeric material that is 
substantially impermeable to the drug and any enhancer that may be 
present. This backing layer is typically about 0.001-0.004 inch in 
thickness and is preferably of a material that permits the device to 
follow the contours of the skin such that it can be worn comfortably on 
any skin area including joints or other areas of flexure. In this way, in 
response to normal mechanical strain, there is little or no likelihood of 
the device disengaging from the skin due to differences in the flexibility 
or resiliency of the skin and the device. Examples of polymers useful for 
the backing layer are polyethylene, polypropylene, polyesters, 
polyurethanes, polyethylene vinyl acetate, polyvinylidene chloride, block 
copolymers such as PEBAX, and the like. The backing layer can also 
comprise laminates of one or more of the foregoing polymers. 
The release liner is a disposable element that serves only to protect the 
device prior to application to the skin. Typically, the release liner is 
formed from a material impermeable to the drug, enhancer, and other 
components of the device, and is easily strippable from the pressure 
sensitive adhesive. Release liners can generally be made of the same 
materials as the backing layer. 
The drug-containing adhesive matrix layer can, in addition to the 
water-based or water-borne adhesive, drug, and optional permeation 
enhancer, also contain other optional ingredients, such as carriers, 
vehicles, excipients, diluents, and the like, which are materials without 
pharmacological activity that are suitable for administration in 
conjunction with the presently disclosed and claimed compositions. Such 
materials are pharmaceutically acceptable in that they are nontoxic, do 
not interfere with drug delivery, and are not for any other reasons 
biologically or otherwise undesirable. The pressure sensitive adhesives 
used in accordance with the present invention must also be 
pharmaceutically acceptable. Examples of illustrative materials include 
water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid 
sugars, waxes, petroleum jelly, and a variety of other oils and polymeric 
materials. 
Adhesive Matrix Preparation 
Pressure sensitive adhesive matrix systems were prepared as follows. First, 
the solids content of a selected water-based or solvent-based adhesive 
solution 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 content of solid adhesive in the solution was 
calculated by dividing the adhesive solid weight after drying by the 
initial total solution weight. For the preparation of polyisobutylene 
(PIB) adhesives in an organic solvent, solid PIB was first dissolved in 
heptane to achieve a final solid content of about 30% by weight, and then 
the exact solid content was determined as described above. Next, a weighed 
quantity of adhesive solution was added to a glass bottle, and the solid 
adhesive weight was calculated from the known solid fraction of the given 
adhesive solution. The drug substance (hydrophilic salt or free acid or 
free base) was weighed and added to the adhesive solution in a quantity 
necessary to achieve a selected dry matrix film composition. The solution 
containing the adhesive polymer drug substance was then mixed overnight. 
In some cases, the drug substance dissolved completely in the adhesive 
solution. In other cases, the drug did not completely dissolve, resulting 
in a liquid containing some drug crystals dispersed in the solution. 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 
0.05-0.1 mm. The cast was dried in a 70.degree. C. convection oven for 
15-30 minutes to yield a dried matrix onto which an 0.08 mm thick 
polyethylene backing film was laminated. These matrix systems were then 
used to conduct in vitro skin flux experiments as described below. 
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 heat-separation method of Kligman & 
Christopher, 88 Arch. Dermatol. 702 (1963). This method involves the 
exposure of the full-thickness skin to water at 60.degree. C. for 60 
seconds. After this period, the epidermal membrane was gently peeled from 
the dermis and stored in aluminum foil at -5.degree. C. Prior to skin 
permeation experiments, the silanized release liner was removed from the 
adhesive matrix system, and the adhesive was affixed to the stratum 
corneum side of the thawed epidermal membrane, which was then cut to an 
appropriate size and placed 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 buffer 
appropriate to maintain sink conditions for the drug. All receiver media 
included 0.02% (w/w) sodium azide 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. At predetermined sampling 
intervals, the entire contents of the receiver compartment were collected 
for drug quantitation, and the receiver compartment was filled with fresh 
receiver 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 according to the following 
equation: 
##EQU1## 
where C.sub.t (.mu.g/cm.sup.3) is the concentration of the receiver 
compartment at sample time t (hours), V is the volume of the receiver 
compartment of the diffusion cell (6.3 cm.sup.3), and A is the diffusional 
area of the cell (0.64 cm.sup.2) 
EXAMPLE 1 
Ketorolac is an acidic non-steroidal anti-inflammatory drug, and the 
FDA-approved form of ketorolac is the hydrophilic tromethamine salt 
(2-amino-2-hydroxymethyl-1,3-propanediol). Pressure sensitive matrix 
systems with ketorolac free acid and ketorolac tromethamine were prepared 
in an organic solvent-based acrylic pressure sensitive adhesive (TSR; 
Sekisui Chemical Co., Osaka, Japan) at concentrations equivalent to 1% 
(w/w) of the tromethamine salt. The tromethamine salt did not completely 
dissolve in the organic solvent system, and the final dried cast was a 
dispersion of crystallized drug in an acrylic adhesive matrix. Ketorolac 
free acid completely dissolved in the organic solvent system, and the 
final dried cast was visually free of any crystals. An adhesive matrix 
system with ketorolac tromethamine at 1% (w/w) was also prepared in a 
water-based acrylic adhesive (NACOR 72-9965; National Starch and Chemical 
Co., New Jersey). The tromethamine salt dissolved completely in the 
water/emulsion system, and the dried cast was free of any drug crystals. 
The results of in vitro skin flux experiments using these matrix systems 
are summarized in Table 1. 
TABLE 1 
______________________________________ 
In vitro Permeation of Ketorolac.sup.a 
Skin TSR/salt.sup.b 
TSR/acid.sup.c 
NACOR/salt.sup.d 
______________________________________ 
1 2.78 .+-. 1.78 
2.18 .+-. 0.85 
7.34 .+-. 3.75 
(n = 5 cells) (n = 4 cells) 
(n = 5 cells) 
2 0.52 .+-. 0.23 
1.04 .+-. 0.28 
2.29 .+-. 0.46 
(n = 5) (n = 5) (n = 5) 
3 0.72 .+-. 0.29 
1.72 .+-. 0.72 
8.13 .+-. 1.74 
(n = 5) (n = 5) (n = 5) 
4 0.59 .+-. 0.37 
1.56 .+-. 0.41 
2.63 .+-. 0.87 
(n = 5) (n = 5) (n = 5) 
Total 1.15 .+-. 1.29 
1.59 .+-. 0.67 
5.10 .+-. 3.35 
(n = 20) (n = 19) (n = 20) 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b TSR/ketorolac tromethamine = 99%/1% (w/w) 
.sup.c TSR/ketorolac free acid = 99%/0.7% (w/w) 
.sup.d NACCR 729965/ketorolac tromethamine = 99%/1% (w/w) 
Unexpectedly, the in vitro permeation from a matrix system prepared with 
the tromethamine salt of ketorolac in a water-based acrylic adhesive was 
twice that of a matrix system prepared with an equal concentration of the 
free acid in an organic solvent-based acrylic adhesive. In addition, 
permeation from a matrix prepared with the salt form dispersed in an 
organic solvent-borne acrylic adhesive was lower than permeation from the 
other two systems wherein the drug was dissolved rather than dispersed in 
the adhesive. This example demonstrates that the hydrophilic salt form of 
the drug in a water-based hydrophobic adhesive matrix yields a skin flux 
comparable to or greater than that obtained with the more hydrophobic, 
free acid form of the drug in an organic solvent-based adhesive matrix. 
EXAMPLE 2 
Diclofenac is an acidic non-steroidal anti-inflammatory drug. The 
FDA-approved form of diclofenac is the sodium salt. Diclofenac is 
considerably more hydrophobic than ketorolac (Example 1); water solubility 
of diclofenac free acid is &lt;1 mg/ml. C. M. Adeyeye & L. Pui-Dai, 
Diclofenac Sodium, in 19 Analytical Profiles of Drug Substances (1990). 
Pressure sensitive matrix systems with diclofenac free acid and diclofenac 
sodium were prepared in the organic solvent-based acrylic adhesive, TSR, 
at molar concentrations equivalent to 1% or 2% (w/w) of diclofenac sodium. 
The sodium salt was not sufficiently soluble in the organic solvent system 
to dissolve completely, and the final dried cast was a dispersion of 
crystallized drug in an acrylic adhesive matrix. The free acid of 
diclofenac completely dissolved in the organic solvent system, and the 
final dried cast was visually free of drug crystals. Pressure sensitive 
adhesive matrix systems containing 1% or 2% (w/w) diclofenac sodium also 
were prepared in the water-borne acrylic adhesives NACOR 72-9965 and 
ROBOND PS20 (Rohm & Haas, Philadelphia, Pa.). The diclofenac sodium salt 
completely dissolved in these water-emulsion systems, and the dried cast 
was visually free of drug crystals. For the ROBOND PS20 adhesive it was 
necessary to add a thickening agent (2% KOLLIDON 90; BASF, Parsippany, 
N.J.) to achieve a viscosity adequate for wet film casting of the matrix. 
The results of in vitro skin flux experiments using these systems are 
summarized in Tables 2 and 3. 
TABLE 2 
______________________________________ 
No. In vitro Permeation of Diclofenac.sup.a 
Skin Cells TSR/saltb.sup. 
TSR/acid.sup.c 
NACOR/salt.sup.d 
______________________________________ 
1 5 0.87 .+-. 0.29 
1.18 .+-. 0.13 
4.40 .+-. 0.69 
2 5 0.93 .+-. 0.45 
0.97 .+-. 0.26 
9.47 .+-. 2.92 
3 5 0.60 .+-. 0.12 
0.59 .+-. 0.14 
7.38 .+-. 1.31 
4 5 2.52 .+-. 1.07 
1.47 .+-. 1.14 
10.90 .+-. 6.18 
Total 20 1.23 .+-. 0.95 
1.05 .+-. 0.64 
8.04 .+-. 4.07 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b TSR/diclofenac sodium = 99%/1% (w/w) 
.sup.c TSR/diclofenac free acid = 99.1%/0.9% (w/w) 
.sup.d NACOR 729965/diclofenac sodium 99%/1% (w/w) 
TABLE 3 
______________________________________ 
No. In vitro Permeation of Diclofenac.sup.a 
Skin Cells TSR/salt.sup.b 
TSR/acid.sup.c 
ROBOND/salt.sup.d 
______________________________________ 
1 5 1.1 .+-. 0.2 
2.5 .+-. 0.3 
28.1 .+-. 5.4 
2 5 0.5 .+-. 0.2 
1.0 .+-. 0.2 
14.3 .+-. 6.4 
3 5 1.4 .+-. 1.4 
3.4 .+-. 1.5 
22.2 .+-. 3.8 
Total 15 1.0 .+-. 0.9 
2.3 .+-. 1.3 
21.5 .+-. 7.6 
______________________________________ 
.sup.a Mean .+-. , .mu.g/(cm.sup.2 *24 h) 
.sup.b TSR/diclofenac sodium = 98%/2% (w/w) 
.sup.c TSR/diclofenac = 98.2%/1.8% (w/w) 
.sup.d ROBOND PS20/KOLLIDON 90/diclofenac sodium = 96%/2%/2% (w/w) 
In vitro permeation from the matrix prepared with the sodium salt of 
diclofenac in the water-borne adhesives was significantly greater than 
that from the systems prepared with the organic solvent-based acrylic 
adhesive. These results demonstrate that the hydrophilic salt form of the 
drug in a water-based pressure sensitive adhesive matrix exhibits a skin 
flux comparable to or greater than that obtained with the more hydrophobic 
free acid form of the drug in an organic solvent-based adhesive matrix. 
EXAMPLE 3 
Buspirone is an anxiolytic drug, and the FDA-approved form of the drug is 
the hydrochloride (HCl) salt. Pressure sensitive matrix systems with 
buspirone free base were prepared in two organic solvent-based acrylic 
adhesives, TSR and DURO-TAK 2516 (National Starch and Chemical Co.), at 
concentrations equivalent to 1% or 2% (w/w) of the HCl salt. The HCl salt 
did not dissolve completely in these organic solvent-based adhesives, and 
the final dried casts were dispersions with visible solid drug crystals in 
the adhesive matrix. A matrix system with Buspirone HCl at 1% or 2% (w/w) 
was prepared in a water-based acrylic adhesive, NACOR 72-9965. The HCl 
salt dissolved completely in this adhesive solution, and the matrix was 
visibly free of drug crystals. The results of in vitro skin flux 
experiments using these systems are summarized in Tables 4-6. 
TABLE 4 
______________________________________ 
No. In vitro Permeation of Buspirone.sup.a 
Skin Cells TSR/salt.sup.b 
TSR/base.sup.c 
NACOR/salt.sup.d 
______________________________________ 
1 5 1.53 .+-. 0.70 
15.54 .+-. 7.01 
3.18 .+-. 0.50 
2 5 4.46 .+-. 1.55 
21.22 .+-. 4.36 
9.16 .+-. 1.84 
3 5 9.17 .+-. 4.95 
27.40 .+-. 4.06 
12.26 .+-. 2.67 
4 5 4.02 .+-. 1.09 
17.96 .+-. 1.37 
9.54 .+-. 1.86 
Total 20 4.80 .+-. 3.75 
20.53 .+-. 6.25 
8.53 .+-. 3.82 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b TSR/buspirone HCl = 99%/1% (w/w) 
.sup.c TSR/buspirone free; base = 99.1%/0.9% (w/w) 
.sup.d NACOR 729965/buspirone HCl 99%/1% (w/w) 
TABLE 5 
______________________________________ 
No. In vitro Permeation of Buspirone.sup.a 
Skin Cells TSR/salt.sup.b 
TSR/base.sup.c 
NACOR/salt.sup.d 
______________________________________ 
1 5 15.11 .+-. 2.42 
71.48 .+-. 2.94 
56.13 .+-. 4.59 
2 5 6.57 .+-. 0.58 
43.76 .+-. 7.02 
34.08 .+-. 1.71 
3 5 9.38 .+-. 1.78 
63.17 .+-. 2.27 
32.30 .+-. 6.35 
4 5 13.49 .+-. 3.46 
67.81 .+-. 4.81 
48.82 .+-. 6.87 
Total 20 11.14 .+-. 4 05 
61.55 .+-. 11.77 
42.83 .+-. 11.35 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b TSR/buspirone HCl = 98%/2% (w/w) 
.sup.c TSR/buspirone free base = 98.2%/1.8% (w/w) 
.sup.d NACOR 729965/buspirone HCl 98%/2% (w/w) 
TABLE 6 
______________________________________ 
In vitro Permeation of Buspirone.sup.a 
No. DURO- DURO- 
Skin Cells TAK/salt.sup.b 
TAK/base.sup.c 
NACOR/salt.sup.d 
______________________________________ 
1 5 15.0 .+-. 1.3 
76.5 .+-. 5.3 
31.8 .+-. 8.8 
2 5 11.2 .+-. 2.2 
87.3 .+-. 13.5 
24.5 .+-. 7.2 
3 5 8.9 .+-. 2.0 
66.7 .+-. 7.1 
28.3 .+-. 3.8 
4 5 13.0 .+-. 1.2 
62.5 .+-. 30.3 
28.2 .+-. 6.0 
Total 20 12.3 .+-. 3.1 
73.2 .+-. 18.6 
28.2 .+-. 6.7 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b DUROTAK 2516/buspirone HCl = 98%/2% (w/w) 
.sup.c DUROTAK/buspirone free base = 98.2%/1.8% (w/w) 
.sup.d NACOR 729965/buspirone HCl 98%/2% (w/w) 
Permeation from the matrix prepared with the salt form of the drug in the 
water-based adhesive was two to four times that obtained from the matrix 
prepared with the salt form of the drug in the organic solvent-based 
adhesive. In addition, permeation from the matrix prepared with the salt 
form of the drug in the water-based adhesive was comparable to permeation 
from the matrix prepared with the free base in the organic solvent-based 
adhesives. The results of this example demonstrate delivery of a 
hydrophilic salt form of a basic drug with a water-based adhesive matrix. 
EXAMPLE 4 
Lidocaine is an analgesic drug that is pharmaceutically approved in both 
the hydrochloride salt and free base forms. Pressure sensitive matrix 
systems with lidocaine free base and lidocaine HCl were prepared in an 
organic solvent-based acrylic adhesive, DURO-TAK 2516, at concentrations 
equivalent to 1%(w/w) of the HCl salt. The HCl salt did not dissolve 
completely in the organic solvent-based adhesive, and the final dried cast 
was a dispersion with visible solid drug crystals in the adhesive matrix. 
A matrix system with lidocaine HCl at 1% (w/w) was prepared in a 
water-based acrylic adhesive, NACOR 72-9965. The HCl salt dissolved 
completely in this adhesive solution, and the matrix was visibly free of 
drug crystals. The results of in vitro skin flux experiments using these 
systems are summarized in Table 7. 
TABLE 7 
______________________________________ 
No In vitro Permeation of Lidocaine.sup.a 
Skin Cells TSR/salt.sup.b 
TSR/base.sup.c 
NACOR/salt.sup.d 
______________________________________ 
1 5 2.97 .+-. 0.35 
24.01 .+-. 2.53 
12.14 .+-. 1.87 
2 5 6.75 .+-. 2.24 
23.15 .+-. 2.76 
11.11 .+-. 2.16 
3 5 6.49 .+-. 1.77 
33.30 .+-. 2.10 
14.73 .+-. 3.31 
4 5 10.07 .+-. 2.99 
32.73 .+-. 2.32 
21.34 .+-. 2.32 
Total 20 6.57 .+-. 3.20 
28.30 .+-. 5.35 
14.83 .+-. 4.68 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b TSR/lidocaine HCl = 99%/1% (w/w) 
.sup.c TSR/lidocaine free base = 99.14%/0.86% (w/w) 
.sup.d NACOR 729965/lidocaine HCl 99%/1% (w/w) 
Permeation with the matrix prepared with the salt form of the drug in the 
water-based adhesive was greater than that obtained with the matrix 
prepared with the salt form of the drug in the organic solvent-based 
adhesive and was comparable to permeation with the free base form of the 
drug in the organic solvent-based adhesive. These results demonstrate 
delivery of the hydrophilic salt form of a basic drug with a water-borne 
pressure sensitive adhesive matrix. 
EXAMPLE 5 
Clonidine is an antihypertensive drug approved for oral administration as 
the hydrochloride salt and for transdermal delivery as the free base. 
Conversion to the free base form was required because the salt form was 
insoluble in the organic solvent-based polyisobutylene adhesive used in 
the transdermal patch. A pressure sensitive adhesive matrix system with 
clonidine free base was prepared in an organic solvent-based 
polyisobutylene adhesive, 33% VISTANEX MM L-100/66% VISTANEX LM-MH (Exxon, 
Houston, Tex.), at a concentration equivalent to 2% (w/w) of the HCl salt. 
Another matrix system with clonidine HCl at 2% (w/w) was prepared in a 
water-based polyisobutylene adhesive, 33% LORD PIB 500/66% LORD BUTYL 100 
(Lord Corporation, Pompano Beach, Fla.). The HCl salt dissolved completely 
in this water-based adhesive solution, and the matrix was visibly free of 
drug crystals. The results of in vitro skin flux experiments using these 
systems are summarized in Table 8. 
TABLE 8 
______________________________________ 
In vitro Permeation of 
No. Clinidine.sup.a 
Skin Cells VISTANEX/base 
LORD/salt.sup.c 
______________________________________ 
1 5 8.6 .+-. 5.7 
13.2 .+-. 6.1 
2 4 14.0 .+-. 4.0 
7.2 .+-. 0.9 
Total 9 11.0 .+-. 5.5 
10.5 .+-. 5.3 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b VISTANEX L100/LM-MH/clonidine = 33.1/65.2/1.7% (w/w) 
.sup.c LORD PIB500/BL-100/clonidine HCl = 33%/65%/2% (w/w) 
Permeation with the matrix prepared with the salt form of the drug in the 
water-based adhesive was comparable to that obtained with the matrix 
prepared with the free base form of the drug in the organic solvent-based 
adhesive. These results demonstrate delivery of a hydrophilic salt form of 
a basic drug with a water-based pressure sensitive adhesive matrix. 
EXAMPLE 6 
Permeation enhancers can optionally be incorporated into a water-based 
adhesive matrix system, as shown in this example for an acidic drug 
(diclofenac sodium) and two basic drugs (buspirone HCl and clonidine HCl). 
Pressure sensitive adhesive matrix systems were prepared with the salt 
forms of these drugs at a concentration of 2% (w/w) in a water-based 
acrylic adhesive, NACOR 72-9965. Additional systems were also prepared 
with 2.5% (w/w) of a non-ionic permeation enhancer, lauryl lactate 
(CERAPHYL 31; ISP, Van Dyk, N.J.). The results of in vitro skin flux 
experiments with these systems are shown in Tables 9-11. 
TABLE 9 
______________________________________ 
No. In vitro Permeation of Diclofenac.sup.a 
Skin Cells NACOR/salt.sup.b 
NACOR/salt/enhancer.sup.c 
______________________________________ 
1 5 20.73 .+-. 1.72 
30.47 .+-. 8.23 
2 5 2.13 .+-. 0.44 
3.40 .+-. 0.82 
Total 10 11.43 .+-. 9.87 
16.94 .+-. 15.29 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b NACOR 729965/diclofenac sodium = 98%/2% (w/w) 
.sup.c NACOR 729965/diciofenac sodium/lauryl lactate = 95.5%/2%/2.5% (w/w 
TABLE 10 
______________________________________ 
No In vitro Permeation of Buspirone.sup.a 
Skin Cells NACOR/salt.sup.b 
NACOR/salt/enhancer.sup.c 
______________________________________ 
1 5 2.60 .+-. 0.97 
4.20 .+-. 1.76 
2 5 37.91 .+-. 2.50 
48.28 .+-. 3.60 
Total 10 20.26 .+-. 18.70 
26.24 .+-. 23.38 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b NACOR 729965/buspirone HCl = 98%/2% (w/w) 
.sup.c NACOR 729965/buspirone HCl/lauryl lactate = 95.5%/2%/2.5% (w/w) 
TABLE 11 
______________________________________ 
No. In vitro Permeation of Clonidine.sup.a 
Skin Cells NACOR/salt.sup.b 
NACOR/salt/enhancer.sup.c 
______________________________________ 
1 5 3.0 .+-. 0.7 
3.7 .+-. 1.1 
2 5 12.8 .+-. 5.7 
15.4 .+-. 9.4 
Total 10 8.5 .+-. 6.6 
9.6 .+-. 8.8 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b NACOR 729965/clonidine HCl = 98%/2% (w/w) 
.sup.c NACOR 729965/clonidine HCl/lauryl lactate = 95.5%/2%%2.5% (w/w) 
The results of these experiments illustrate that effective amounts of 
permeation enhancers can be incorporated advantageously into water-based 
adhesive matrix systems. 
EXAMPLE 7 
An additional example of the incorporation of a permeation enhancer in a 
water-based adhesive was prepared using buspirone HCl as a model drug and 
sucrose laurate, a known permeation enhancer. Pressure sensitive adhesive 
matrix systems were prepared with buspirone HCl at a concentration of 2% 
(w/w) and sucrose laurate at 5% (w/w) (Ryoto LWA 1570; Mitubishi-Kagaku 
Foods Corporation, Tokyo, Japan) in a water-based acrylic adhesive, NACOR 
72-9965. The results of in vitro skin flux experiments with this system 
are shown in Table 12. 
TABLE 12 
______________________________________ 
No. In Vitro Permeation of Buspirone.sup.a 
Skin Cells NACOR/salt/enhancer.sup.b 
______________________________________ 
1 5 23.0 .+-. 3.5 
2 5 14.2 .+-. 1.0 
3 5 53.6 .+-. 8.9 
4 5 23.7 .+-. 6.6 
Total 20 28.6 .+-. 16.2 
______________________________________ 
.sup.a Mean .+-. SD, .mu.g/(cm.sup.2 *24 h) 
.sup.b NACOR 729965/buspirone HCl/Ryoto LWA 1570 = 93/2/5% 
These results further illustrate that permeation enhancers may be readily 
incorporated into a water-based adhesive matrix system.