Medicinal adhesive for percutaneous administration

Disclosed herein is a medicinal adhesive for percutaneous administration of a drug consisting of a support (backing layer), an adhesive layer comprising an oil-soluble drug, an adhesive resin, a penetration enhancer, a water-absorptive material and a lenitive agent, and a separate liner, charaterized in that the adhesive layer has a laminated structure having 2 to 5 layers and each layer has different water absorption capacities, and the drug is a oil-soluble, non-steroidal drug. For the adhesive of the present invention, the lowest layer which is to be contacted with the skin has the lowest water absorption capacity and the most upper layer in contact with the support has the highest water absorption capacity, or vice versa.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a medicinal patch which continuously 
delivers a certain amount of oil-soluble drugs through the skin or mucous 
membranes. More specifically, the present invention relates to a medicinal 
patch which dissolves the maximum level of drug in the adhesive layer 
contacting with the skin and delivers percutaneously the necessary amount 
of drug and enhances the percutaneous penetration of drug. 
2. Description of the Prior Art 
It has been widely used to deliver drugs (physiologically active agents) 
through the skin by employing a patch, a sort of percutaneous 
administrating preparations, for the purpose of the systemic or topical 
delivery of drugs. These methods of percutaneous administration offers 
many advantages over the traditional oral administration of drugs. For 
example, in the method of oral administration, a great level of drug is 
degraded by the metabolism in the liver prior to exhibiting its efficacy 
at the target site. However, in the method of percutaneous administration, 
the efficacy of absorbed drug is not seriously degraded by the metabolism 
in the liver because the absorbed drug does not pass through the liver 
before its circulation in the body. Particularly in the case of 
non-steroidal anti-inflammatory agents, their percutaneous administration 
gives an advantage of reducing the risk of damage to the gastrointestine 
which frequently occurs by the oral administration. 
Based on the above-mentioned advantages, recently, studies on the 
transdermal drug delivery system which overcomes the first-pass effect or 
gastrointestinal damage induced in the oral administration and enhances 
the effectiveness and safety of drugs have been widely proceeded and, as a 
result, dermal compositions containing nitroglycerin, scopolamine and the 
like had been on the market. 
In the meanwhile, many drawbacks of the above transdermal drug delivery 
system have also been indicated in connection with the difficulty in 
applying it to various drugs. Because the human skin serves as a barrier 
to the invasion of pathogens and toxic materials, it is highly 
impermeable. Accordingly, extensive attempts have been made for the 
purpose of enlarging the utility of transdermal delivery system and 
enhancing penetration through the skin. 
It is possible to reduce the side effects caused by an administration of 
large amount of drug in a short time by regulating the absorption of the 
drug. It is also possible to maintain a constant level of drug in blood 
over a prolonged period by decreasing the frequency of administration. 
However, a percutneous administration of drug frequently causes poor 
bioavailability due to the difficulty of penetration of the drug across 
the skin. To solve this problem, attempts to increase the absolute amount 
of drug in a patch to a level of ensuring the percutaneous absorption of 
necessary amounts have been made. For example, preparations for 
percutaneous admistration which comprise drug dissolved in bases for 
patch, ointment, cream and the like to a level exceeding the saturation 
concentration and dispersed in the form of recrystallized minute particles 
had been reported. If the patch of this type is applied on the skin 
surface, the drug dissolved in base is absorbed percutaneously and then, 
the drug existed in the form of minute particles is gradually dissolved 
and supplemented the absorbed drug. However, in practical, the drug 
existed in the form of minute particles is scarcely dissolved in the base 
and consequently the absorption rate of the drug across the skin is not 
relatively high. 
Alternative methods of enhancing the percutaneous absorption of drug by 
occlusion have been also attempted. For example, methods for enhancing the 
percutaneous absorption of active agents by selecting substantially 
water-impermeable film as a backing layer of patch had been reported. 
However, these methods also have disadvantages that the sweat may arise 
skin-irritation and the patch is readily peeled off from the skin by the 
sweat. In order to eliminate the above problems, a plaster employing 
highly water-permeable materials such as non-woven fabric or hygroscopic 
urethane was proposed. However, these plasters have also failed in 
delivering the required amount of drug across the skin. 
To reduce the skin-irritation and improve the feeling of adhesiveness, 
methods of employing water-soluble vehicle such as gelatin, 
polyvinylalcohol, dextrin, arabic gum, carboxymethyl cellulose, 
methylcellulose, hydroxy ethyl cellulose, polyvinylpyrrolidone, sodium 
alginate, sodium polyacrylate and the like have been also proposed. 
However, since the patches prepared by the above methods show poor 
skin-adhesiveness, they can not be applied alone on the skin and must be 
used together with a fabric applied adhesive and moreover, the efficacy of 
delivering drug across the skin is not sufficient. 
U.S. Pat. No. 4,814,168 disclose a dermal composition suitable for use in 
the transdermal delivery of drugs, which composition permits a high 
loading of medicament into the formulation while maintaining acceptable 
shear, tack and peel as adhesive properties. The composition of the patent 
comprises a drug, a multi-polymer comprising vinyl acetate and ethylene 
monomers; a rubber and a tackifying agent. 
U.S. Pat. No. 5,176,916 discloses an adhesive comprising a base mainly 
composed of a hydrophobic polymer in which a medicinal ingredient which is 
difficult to absorb percutaneously; for example a medicinal ingredient 
having relatively high hydrophilicity, is incorporated and water as a 
solubilizer is further contained. According to the patent, water is 
incorporated as a solubilizer in an amount necessary for making the 
plaster layer a W/O type. 
However, the adhesive of U.S. Pat. No. 5,176,916 fits for relatively highly 
hydrophilic drugs and is not suitable for oil-soluble drugs, for example 
non-steroidal anti-inflammatory drugs since it contains water. 
In these circumstances, the present inventors have made extensive studies 
for the purpose of providing a adhesive suitable for oil-soluble drugs 
which makes it possible to stably release the drug and sustain the 
pharmacological effects over a long period and as a result thereof found 
that the above purpose can be accomplished by a adhesive containing 
multilayered adhesive layer of which each layer has different water 
absorption capacity. 
SUMMARY OF THE INVENTION 
Thus, an object of the present invention is to provide a medicinal adhesive 
for percutaneous administrating oil-soluble, non-steroidal drug consisting 
of a water-impermeable backing layer, an adhesive layer comprising an 
oil-soluble drug, an adhesive resin, a penetration enhancer, a 
water-absorptive material and a lenitive agent, and a separate liner, 
charaterized in that the adhesive layer has a laminated structure having 2 
to 5 layers and each layer has different water absorption capacity, and 
the lowest layer which is to be contacted with the skin has the lowest 
water absorption capacity and the most upper layer in contact with the 
backing layer has the highest water absorption capacity. 
Another object of the present invention is to provide a medicinal patch for 
percutaneous administration consisting of a water-permeable backing layer, 
an adhesive layer comprising an oil-soluble drug, an adhesive resin, a 
penetration enhancer, a water-absorptive material and a lenitive agent, 
and a separate liner, charaterized in that the adhesive layer has a 
laminated structure having 2 to 5 layers and each layer has different 
water absorption capacity, and the lowest layer which is to be contacted 
with the skin has the highest water absorption capacity and the most upper 
layer in contact with the backing layer has the lowest water absorption 
capacity.

DETAILED EXPLANATION OF THE INVENTION 
The drug in the plaster is transdermally absorbed into the skin based on 
the difference of the drug concentrations between in the plaster and in 
the skin. In practice, the drug is absorbed through the stratum corneum by 
way of the following steps: 
(1) Diffusion in a plaster; 
(2) Partition from the vehicle to the surface of stratum corneum; 
(3) Diffusion in the stratum corneum; 
(4) Partition from the stratum corneum to the lower epidermal tissue; 
(5) Diffusion in the epidermic and dermic layers; and 
(6) Transfer from the dermis to the blood vessel. 
It is generally considered that the process of the transdermal absorption 
of drug is divided into the diffusion process and the partition process. 
The diffusion can be described and calculated by Fick's the first law 
which shows the relationship between the concentration gradient and the 
penetration flux of drug and Fick's the second law which shows the change 
of drug concentration at a certain locus as a function of time. 
EQU J/A=-D C/x Fick's the first 
law 
EQU C/t=D.sup.2 C/x.sup.2 Fick's the 
second law 
wherein 
A=drug-diffused area 
C=drug concentration 
D=diffusion coefficient 
J=speed of penetration 
t=time 
x=location 
The transdermal penetration effect of a drug is determined, in many cases, 
by the penetration flux at the steady-state and the penetration flux at 
the steady-state(J) can be described by: 
EQU J=ACvKD/L 
wherein 
Cv=drug concentration in the vehicle, 
K=partition coefficient of the drug between the skin and the vehicle, 
L=effective skin thickness 
A & D=the same as defined above 
In addition, the penetration coefficient(Kp) can be described by: 
EQU Kp=KD/L 
wherein K, D and L represent the same as defined above. 
As can be seen in the above, it is advantageous to increase the drug 
concentration in the adhesive in order to deliver large amounts of the 
drug through the skin. However, the amount of drug which can be loaded in 
the adhesive is limited. 
According to the present invention, as one of the means to increase the 
drug solubility in the adhesive layer and reduce skin irritation, the drug 
concentration in the adhesive layer is adjusted to a level of the maximum 
value by selecting the adhesive resin having similar solubility parameter 
with the drug. As the most suitable adhesive for the abovementioned 
purpose, acrylic adhesives are included. The acrylic adhesives are 
advantageous in controlling the water content and the drug solubility in 
the adhesive layer since they are easy to regulate the incorporation ratio 
of the monomers to be polymerized. However, when a plaster comprising the 
above adhesive resins is applied on the skin, the solubility of drug in 
the adhesive layer is changed as the water content in the adhesive layer 
is increased due to the water transpired from the skin as compared with 
that of immediately after the patch was prepared, and the saturation 
solubility of the drug is also changed. Consequently, the solubility of 
the drug shows significant difference with the practical view and at the 
same time, the amount of the drug delivered through the skin and the 
adhesive property of the adhesive are seriously decreased. 
To overcome the above-mentioned problems, the present invention employs an 
adhesive comprising laminated adhesive layers, each having different water 
absorption capacity and containing no water. 2 to 5 adhesive layers may be 
laminated to form a adhesive multi-layer in which the lowest layer which 
is to be contacted with the skin has the lowest water absorption capacity 
and the most upper layer in contact with the backing layer has the highest 
water absorption capacity. Or, 2 to 5 adhesive layers may be laminated to 
form a adhesive multi-layer in which the lowest layer which is to be 
contacted with the skin has the highest water absorption capacity and the 
most upper layer in contact with the backing layer has the lowest water 
absorption capacity. 
With regard to FIG. 1, the adhesive consists of a support(1), a higher 
adhesive layer(2), a lower adhesive layer(3) and a separate liner(4). 
As the backing layer(1) of the adhesive, any supporting materials which are 
typically used in the art may be employed. Examples of such backing 
materials include cellulose acetate, ethyl cellulose, polyethylene 
terephthalate, plasticized vinyl acetate-vinylchloride copolymer, nylon, 
ethylene-vinyl acetate copolymer, plasticized polyvinylchloride, 
polyurethane, polyethylene, polyvinylidene chloride, aluminum and the 
like. These materials may be used, for example, in the form of a 
mono-layered sheet(film) or a two or more layered laminate. In addition to 
aluminum, cotton fabric or non-woven fabric may be also used as the 
backing layer. 
When the backing layer(1) is made from a water-impermeable materials and 
controlled release of drug is desired, the lower adhesive layer(3) has a 
lower water absorption capacity than that of the higher adhesive layer(2). 
In this case, the water transpired from the skin after the adhesive is 
applied on the skin moves to the lower adhesive layer(3) which contains 
water absorptive materials and the water in the layer(3) gradually moves 
into the higher adhesive layer(2) which has a higher water absorption 
capacity than that of the lower adhesive layer(3). At an equilibrium 
state, the higher adhesive layer(2) retains more water than the lower 
adhesive layer(3). At the same time, the drug in the lower adhesive 
layer(3) absorbed into the skin, and the more water migrates to the 
lower(3) and then higher(2) layers the faster the drug absorbed into the 
skin. Accordingly, since the water and other water-soluble excretions from 
the skin migrate into upper layers, the lowest layer which is in 
contacting with the skin always retains constant amount of drug and 
moisture, thereby reducing the skin irritation due to sweat or other 
excretions. 
Alternatively, when the backing layer(1) is made from the semipermeable 
orpermeable materials such as non-woven fabric, cotton fabric or any other 
air-permeable plastic film, the upper layer(2) has a considerably lower 
water absorption capacity than that of the lower layer(3) to prevent the 
migration of water evaporated from the skin to the upper layer(2) on order 
to attain a burst transdermal absorption of drug. For this purpose, the 
upper layer(2) may be made from a rubber resin and the lower layer(3) may 
be made from a acrylic resin and has water absorption capacity of about 1 
to 5%. 
The multi-layer adhesive according to the invention, of which water 
retention in each layer may be controlled its water retention, may be 
applied to control the release rate of the drug. 
The adhesive of the invention have a laminated adhesive layer having 2 to 5 
layers. The thickness of each layer is typically 2 to 150 .mu.m, 
preferably 10 to 100 .mu.m. And the overall thickness of the laminated 
adhesive layer is typically 30 to 500 .mu.m, preferably 30 to 200 .mu.m. 
The backing layer of the adhesive may be made from a mono- or multi-layered 
polyethylene, polypropylene, polyethyleneterephtalate, or non-woven 
fabric, cotton fabric or plastic films. 
The separate liner of the adhesive of the invention may be any one of those 
employed for the percutaneous preparations and is, for example, a film 
incorporated with silicone- or fluoro-type releasing agent. 
The laminated adhesive layer of the adhesive of the invention may comprise 
a drug, an adhesive resin, a penetration enhancer, a water absorptive 
material, a lenitive and a tackfying agent. 
As an adhesive resin, there may be included, but not intended to be limited 
thereto, silicone polymers, natural or synthetic rubbers, acrylic 
polymers. 
Particularly, for the present invention, the acrylic polymers such as 
co(polymer) of C.sub.4 -C.sub.18 aliphatic alcohol with (meth)acrylic 
alkyl ester or the copolymer of (meth)acrylic alkyl ester having C.sub.4 
-C.sub.18 alkyl, (meth)acrylic acid and/or other functional monomers are 
preferably employed as the adhesive. 
Examples of the (meth)acrylic alkyl ester may include butyl acrylate, 
isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, 
iso-octyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, 
stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl 
methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, iso-octyl 
methacrylate, decyl methacrylate, etc. 
Examples of the functional monomers may include a monomer containing 
hydroxyl group, a monomer containing carboxyl group, a monomer containing 
amide group, a monomer containing amino group. Examples of the monomer 
containing hydroxyl group may include hydroxy alkyl (meth) acrylate such 
as 2-hydroxyethyl (meth)acrylate, hydroxypropyl (meth) acrylate and the 
like. Examples of the monomer containing carboxyl group may include 
.alpha.-.beta. unsaturated carboxylic acid such as acrylic acid, 
methacrylic acid and the like; maleic mono alkyl ester such as butyl 
malate and the like; maleic acid; fumaric acid; crotonic acid and the 
like; and anhydrous maleic acid. Examples of the monomer containing amide 
group may include alkyl (meth)acrylamide such as acrylamide, dimethyl 
acrylamide, diethyl acrylamide and the like; alkylethylmethylol (meth) 
acrylamide such as butoxymethyl acrylamide, ethoxymethyl acrylamide and 
the like; diacetone acrylamide; vinyl pyrrolidone; dimethyl aminoacrylate. 
In addition to the above exemplified monomers for copolymerization, vinyl 
acetate, styrene, .alpha.-methylstyrene, vinyl chloride, acrylonitrile, 
ethylene, propylene, butadiene and the like may be employed. 
Examples of the rubber which may be used as an adhesive resin incorporated 
into the adhesive layer in accordance with the present invention may 
include natural gum, polyisoprene, polyisobutylene, 
styrene-butadiene-styrene copolymer, styrene-isoprene-styrene copolymer, 
styrene-ethylene/propylene-styrene copolymer, 
styrene-ethylene/butylene-styrene copolymer, polyvinyl ether, 
polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene 
copolymer, styrene-isoprene-butylene block copolymer and the like. 
As the silicone resins, there may be included silicone gum such as 
polyorgano siloxane. 
When an acrylic polymer is employed as the adhesive resin for the adhesive 
layer, the adhesive layer may contain (meth)acrylic alkyl ester 
incorporated in an amount of 50% by weight or above. 
Further, for the purpose of increasing or decreasing the water absorption 
capacity of the adhesive layers, the acrylic polymer may be copolymerized 
with a hydrophilic monomer, a monomer containing carboxyl group, a monomer 
containing amide group, a monomer containing amino group and the like. 
Further, the rubbery or silicone resins are employed as the adhesive 
resin, there may be incorporated into the adhesive layer with a tackifying 
agent or other additives. 
Alternatively, the water absorption capacity of the adhesive layer can be 
also regulated by incorporating therein highly water-absorptive polymers, 
polyols and water-absorptive inorganic materials. Examples of the highly 
water-absorptive resins may include mucopolysaccharides such as hyaluronic 
acid, chondroitin sulfate, dermatan sulfate and the like; polymers having 
a large number of hydrophilic groups in the molecule such as chitin, 
chitin derivatives, starch and carboxy-methylcellulose; and semi-synthetic 
and synthetic highly water-absorptive polymers such as polyacrylic, 
polyoxyethylene, polyvinyl alcohol and polyacrylonitrile. Examples of the 
water-absorptive inorganic materials, which may incorporated into the 
adhesive layer to regulate its water absorptive capacity, may include 
powdered silica, zeolite, powdered ceramics and the like. 
Examples of the polyols may include propylene glycol, glycerin, sorbitol 
and the like. 
These substances for regulating the water-absorption capacity of the 
adhesive layer may be employed in an amount of 0.1-40% by weight, 
preferably 1-20% by weight. 
The adhesive layers may contain a tackfying agent and as a tackfying agent, 
there may be included, but not intended to be limited thereto, rosin 
esters, polyterpene resin, petroleum resin, terpene phenol resin. 
The adhesive layers may contain penetration enhancers, for example dodecyl 
sulfoxide mono- or dimethyl acetamide, N-hydroxy ethyl lactide, higher 
fatty acid ester, salicylic acid, sorbitol, urea, glycerin, squalene, 
squalane, acetylated lanolin, cetyl laurate, olive oil, castor oil, lauric 
acid, oleic acid, lauryl alcohol, oleyl alcohol, ethoxystearyl alcohol, 
liquid paraffin, vaseline, camphor, glycerin fatty acid ester, fatty acid 
mono- (or di-) ethanolamide, ethylene glycol mono ethyl ether, 
polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene 
alkyl ether, propylene glycol mono(di)alkyl ester, propylene glycol 
monolaurate, polyoxyethylene lauryl ether, pyrrolidone derivatives and the 
like. The amount of the penetration enhancer is 0.1 to 40% by weight, 
preferably 1 to 20% by weight. 
The present inventors had found that when the drug is of oil-soluble type, 
for example ketoprofen, a hydrophobic surfactant having a HLB value of 
less than 10, for example propylene glycol monolaurate or polyoxyethylene 
alkyl ether wherein the mole number of ethylene oxide is less than 7 is 
preferred as a penetration enhancer, since they help the migration of 
water transpired from the skin across the adhesive layers. 
The adhesive layer in accordance with the present invention also include a 
lenitive agent, for example alpha-bisabolol, camomile oil, allantoin and 
d-panthenol. The lenitive agents may be present in an amount of 0.01-10% 
by weight, preferably 0.1-5% by weight. 
The adhesive may further include a plasticizer, a filler, an antioxidant or 
a preservative, which may be commonly employed for the production of a 
medicinal plaster. As an antioxidant, tocopherol, tocopheryl acetate, BHA, 
BHT and the like are employed and the preservatives such as ethyl paraben, 
methyl paraben and butyl paraben may be employed. 
The drug which is incorporated into the adhesive layers is oil-soluble type 
and have the solubility that it requires 30 ml, preferably 100 ml, more 
preferably more than 1000 ml of water to dissolve 1 g or 1 ml of drug. In 
this regard, nonsteroidal anti-inflammatory drugs, specifically methyl 
salicylate, salicylic acid, ibuprofen, ketoprofen, flurbiprofen, 
indomethacin, diclofenac, flufenamic acid, naproxen, mefenamic acid, 
fenoprofen, fenclofenax, piroxicam and the precursors thereof can be used. 
The drug may be incorporated in an amount of 0.1-40% by weight. 
Examples of the water-absorptive materials which may be employed to improve 
the absorptive capacity of the adhesive layer may include polyvinyl 
alcohol, polyvinyl pyrrolidone, alginic acid, hyaluronc acid, cellulose, 
chitin and their derivatives, zinc oxide, calcium oxide, silica, kaolin, 
talc or titanium oxide. The materials may be present in an amount of 
0.1-30% by weight, preferably 0-10% by weight. 
PREFERRED EMBODIMENT OF THE INVENTION 
The present invention will be embodied by way of the following examples. 
However, these examples are provided for the illustration purpose only and 
should not be construed as limiting the scope of the invention, which is 
properly delineated in the accompanying claims. 
EXAMPLE 1 
(A) Preparation of adhesive resin(1) 
To a reaction vessel equipped with a reflux condenser and a stirrer, 97.4 
parts of 2-ethylhexyl acrylate, 2.5 parts of methacrylic acid, 0.1 parts 
of polyethylene glycol diacrylate, 1.0 parts of benzoyl peroxide and 100 
parts of ethyl acetate were added and, under nitrogen atmosphere, the 
polymerization reaction was carried out under stirring. 
In order to regulate the polymerization degree, 100 parts of ethyl acetate 
was added to the reaction mixture gradually during the polymerization 
reaction, and the reaction was conducted for 9 hours. The polymerization 
degree was 99.9%. 
To the resulting polymer solution, ethyl acetate was added to adjust the 
solid content to about 40% by weight. Finally, there was obtained a 
copolymer of ehtylhexylacrylate, methacrylic acid and polyethyleneglycol 
dimethacrylate, which is employed as an adhesive resin. 
(B) Preparation of adhesive resin(2) 
Under the same conditions as described above, the copolymerization reaction 
was carried out by employing 70 parts of 2-ethylhexylacrylate, 10 parts of 
acrylic acid, 1.0 parts of benzoyl peroxide (BPO) and 20 parts of vinyl 
acetate. 
The polymerization degree was more than 99.9%. Aluminum acetate was added 
to the polymerization product under stirring(200 rpm) to obtain a 
self-curable product. To the resulting polymer solution, ethyl acetate was 
added to adjust the solid content to about 40% by weight. 
Finally, there was obtained a copolymer of ehtylhexylacrylate, methacrylic 
acid and polyethyleneglycol dimethacrylate, which is employed as an 
adhesive resin. (C) Preparation of the adhesive lower layer(3) in FIG. 1. 
To the adhesive resin(1) obtained in the above, ketoprofen was added in an 
amount of 20% by weight based on the solid content and dissolved therein 
to a concentration exceeding the saturation solubility. 
The resulting mixture was coated on to the siliconetreated PET separate 
liner. At this time, the amount of the mixture was adjusted in such a way 
that the coating thickness after drying become 50 .mu.m. The water 
absorption capacity of this adhesive layer was 1.9% in terms of water 
content. 
(D) Preparation of the adhesive upper layer(2) in FIG. 1. 
To the adhesive resin(2) obtained in the above, ketoprofen was added in an 
amount of 20% by weight and dissolved therein to a concentration exceeding 
the saturation solubility. The resulting mixture was coated on to the 
silicone treated releasing paper to a thickness of 30 .mu.m after drying. 
The water absorption capacity of this adhesive layer was 3.6% in terms of 
water content. 
(E) Fabricaton of adhesive 
The upper adhesive layer(2) was adhered by rolling onto a 
support(polyethylene film) and then, the lower adhesive layer(3) was 
laminated thereonto to produce a medicinal adhesive of the present 
invention depicted in FIG. 1. Thereafter, the adhesive was dried by 
allowing to stand at normal temperature for 15 minutes and then at 
90.degree. C. for 10 minutes. 
EXAMPLE 2 
(A) Preparation of the adhesive layers (2) and (3) 
To the adhesive resin(1) obtained in Example 1(A), ketoprofen was added in 
an amount of 25% by weight based on the solid content and dissolved 
therein to a concentration exceeding the saturation solubility. 
After hyaluronic acid powder of 5% by weight was added to the resulting 
mixture and dispersed uniformly therein to give an adhesive layer(3). The 
adhesive layer(3) has a water absorption capacity of 2.1% in terms of 
water content. 
(B) Fabricaton of adhesive 
The adhesive layer(3) was coated on to the silicone-treated releasing paper 
to a thickness of 40 .mu.m after drying. 
Besides, the adhesive layer(2) obtained in Example 1(D) was adhered by 
rolling onto a support(polyester film) and then, the above lower adhesive 
layer(3) was laminated thereonto to produce a medicinal adhesive of the 
present invention depicted in FIG. 1. Thereafter, the adhesive was dried 
by allowing to stand at normal temperature for 15 minutes and then at 
90.degree. C. for 10 minutes. 
EXAMPLE 3 
(A) Preparation of an adhesive layer(3) 
To the adhesive resin(1) obtained in Example 1(A), ketoprofen was added in 
an amount of 35% by weight based on the solid content and dissolved 
therein to a concentration exceeding saturation solubility. To the 
resulting mixture, polyoxyethylene(E.O.=3) lauryl ether of 10% by weight 
as a penetration enhancer and tocopherol acetate of 0.5% by weight as an 
antioxidant were added and dissolved. Then, colloidal silica of 3% by 
weight was incorporated as a tackifying agent to reduce the decrease in 
adhesiveness due to the addition of the penetration enhancer. 
The adhesive layer(3) obtained in the above, which has a water absorptive 
capacity of 2.0% in terms of water content, was coated on to a releasing 
paper to a thickness of 60 .mu.m after drying. 
(B) Preparation of an adhesive layer(2) 
To the adhesive resin(2) obtained in Example 1(B), ketoprofen was added in 
an amount of 23% by weight based on the solid content and dissolved to a 
concentration exceeding the saturation solubility. After 10% by weight of 
polyoxyethylene(E.O=3) lauryl ether was added to the mixture as a 
penetration enhancer, 0.5% by weight of tocopheryl acetate as an 
antioxidant was also added and dissolved. Thus obtained adhesive layer(2) 
has a water absorption capacity of 3.6% in terms of water content. 
(C) Fabrication of adhesive 
The adhesive layer(3) was adhered by rolling to a polyester film and the 
above adhesive layer(2) was laminated thereon to produce a medicinal 
adhesive of the present invention depicted in FIG. 1. Thereafter, the 
adhesive was dried by allowing to stand at normal temperature for 17 
minutes and then at 86.degree. C. for 10 minutes. 
EXAMPLE 4 
(A) Preparation of adhesive layer(3) 
To the adhesive resin(2) obtained in Example 1(B), ketoprofen was added in 
an amount of 28% by weight based on the solid content and dissolved 
therein to a concentration exceeding saturation solubility. 
After 10% by weight of propylene glycol monooleate as a penetration 
enhancer was added to the mixture, 0.5%by weight of tocopherol as an 
antioxidant and 2% by weight of bisabolol as a lenitive agent were added 
thereto. 
Thereafter, 3% by weight of zinc oxide powder(diameter of particles 5-15 
.mu.m) as a water content controlling agent was uniformly dispersed 
therein. Thus obtained adhesive layer(3) has a water absorptive capacity 
of 4.2% in terms of water content and was coated on to a releasing paper 
to a thickness of 70 .mu.m after drying. 
(B) Preparation of an adhesive layer(2) 
To the adhesive resin(1) obtained in Example 1(A), ketoprofen was added in 
an amount of 26% by weight based on the solid content and dissolved to a 
concentration exceeding the saturation solubility. After 10% by weight of 
polyoxyethylene(E.O=3) lauryl ether was added to the mixture as a 
penetration enhancer, 0.5% by weight of tocopheryl acetate as an 
antioxidant was also added and dissolved. Thus obtained adhesive layer(2) 
has a water absorption capacity of 1.4% in terms of water content. 
(C) Fabrication of adhesive 
The adhesive layer(2) was adhered by rolling to a nonwoven fabric and the 
above adhesive layer(3) was laminated thereon to produce a medicinal 
adhesive of the present invention depicted in FIG. 1. Thereafter, the 
adhesive was dried by allowing to stand at normal temperature for 17 
minutes and then at 86.degree. C. for 10 minutes. 
Quantitative determination of the water content 
Water was extracted from the pieces of the size of 5.times.5cm.sup.2 cut 
out from each adhesive layers which are coated into a polyester film to a 
thickness of 100 .mu.m after drying of Examples 1 to 4 with anhydrous 
methanol with sufficient care prohibiting entry of external moisture and 
subjected to chromatography to quantitatively determine the water content 
in the adhesive layers. Experimental Example 1 
Percutaneous penetration test 
Using a male guinea pig weighing about 350 g, the abdominal hair was 
removed using a hair clipper Then, a part of the abdominal skin was 
excised, stored in a refrigerator (below -20.degree. C.) and used after 
thawing at needs. 
The excised skin was placed in the middle of the Franz-type diffusion cell 
with its corneous side looking upward and the space below the cell was 
charged with 0.05M phosphate buffered saline(pH 7.4). The adhesives shown 
in Table 1 below were applied on the skin while the buffer 
solution(receiver solution) was stirred at a constant speed of 600 rpm. 
At varying intervals, a portion of the receiver solution was taken for the 
test and a fresh buffer solution was supplemented in the same amount as 
taken therefrom. From the test solution, the concentration of ketoprofen 
was determined by High Pressure Liquid Chromatography(HPLC). 
Analysis condition for HPLC 
Column: C.sub.18 .mu.Bondapak [Waters Chromatography, Inc., milton 
Massachusetts 01757 USA] 
Mobile phase: 55:45 V/V mixture of methanol: 0.02M phosphate buffered 
solution(pH 4.0) 
Flow rate: 1 ml/min. 
Detector: 254 nm wave length ultraviolet 
The results are shown in Table 2 below. 
TABLE 1 
__________________________________________________________________________ 
Adhesive formulations used for the percutaneous 
penetration test 
Propylene 
Polyoxyet- 
glycol hylene(3) 
Glycerol 
Adhesive 
Ketoprofen 
monolaurate 
lauryl 
monooleate 
Zinc oxide 
Tocopheryl 
No. Conc. (%) 
(%) ether (%) 
(%) (%) acetate (%) 
__________________________________________________________________________ 
1 10 5 1 
2 20 5 1 
3 25 5 1 
4 30 5 1 
5 40 5 1 
6 10 10 5 1 
7 10 20 5 1 
8 30 10 5 1 
9 10 10 5 1 
10 10 10 5 1 
11 20 5 5 1 
12 20 5 5 1 
13 10 10 2 
14 10 5 10 2 
15 15 5 10 2 
__________________________________________________________________________ 
TABLE 2 
______________________________________ 
Comparison of the penetration flux ratio 
of ketoprofen of the adhesives in Table 1 
Skin penetration 
Lag 
Adhesive 
Flux time Skin penetration 
No. (.mu.m/cm.sup.2 /hr) 
(hrs) flux ratio* 
______________________________________ 
1 15.5(2.62) 2.19(0.31) 
1.00 
2 20.7(3.01) 1.96(0.41) 
1.34 
3 24.5(2.87) 1.93(0.45) 
1.58 
4 31.7(1.71) 1.47(0.21) 
2.05 
5 34.6(2.30) 1.38(0.39) 
2.23 
6 26.8(3.68) 1.95(0.51) 
1.73 
7 35.7(2.96) 2.01(0.47) 
2.30 
8 45.3(4.17) 1.58(0.40) 
2.92 
9 34.2(3.91) 1.94(0.52) 
2.21 
10 36.2(4.25) 2.09(0.63) 
2.34 
11 33.2(3.75) 1.68(0.37) 
2.14 
12 35.2(3.75) 1.96(0.31) 
2.26 
13 20.5(2.15) 2.53(0.74) 
1.32 
14 34.4(1.78) 1.57(0.45) 
2.22 
15 35.1(2.35) 1.64(0.76) 
2.26 
______________________________________ 
Note: 
*Each value is an average of 4(four) repeats 
*The skinpenetration flux ratio was relatively calculated as taking 1.00 
when the content of ketoprofen was 10% and no penetration enhancer was 
employed. 
[Results] 
The skin-penetration flux ratio of ketoprofen was increased when the 
content of ketoprofen in the adhesive layer was increased to a 
concentration exceeding the saturation solubility. 
Contrary to the general phenomenon that when the penetration enhancer is 
incorporated into the adhesive layer by conventional techniques, the 
penetration enhancement of drug is reduced due to a sharp decrease of the 
adhesiveness, the adhesive layer according to the present invention 
retained its good adhesiveness. 
Experimental Example 2 
Skin primary irritation test 
A adhesive prepared in the same manner as described in Example 1 was cut to 
the size of 2.5 cm.sup.2 and after the separate liner was removed 
therefrom, the adhesive was applied on the forearm of a healthy man for 24 
hours. 
24 hours later, the adhesive was removed and, after 30 minutes, the level 
of the skin primary irritation was observed and estimated according to the 
following standard. 
______________________________________ 
Score The level of irritation 
______________________________________ 
0 No irritation 
1 The minimum irritation 
2 A little irritation (erythema) 
3 Severe irritation (erythema, edema) 
4 Extremely severe irritation 
(erythema, edema) 
______________________________________ 
By using the score of irritation, the reactivity was calculated according 
to the following equation : 
##EQU1## 
The results are shown in Table 3. 
TABLE 3 
__________________________________________________________________________ 
Skin primary irritation test 
Propylene 
Polyoxyet- Frequency 
glycol hylene(3) 
Adhesive of skin 
Adhesive 
Ketoprofen 
monolaurate 
lauryl 
resin (1) 
bisabolol 
No. of irritation 
No. Conc.(%) 
(%) ether(%) 
(%) (%) subjects 
Reactivity 
occurance 
__________________________________________________________________________ 
1 10 10 90 17 2.9 2/17 
2 10 10 80 17 5.9 4/17 
3 10 10 80 15 6.7 4/15 
4 10 10 79.5 0.5 15 5.0 3/15 
5 10 10 79 1 15 0.0 0/15 
6 10 10 78 2 15 0.0 0/15 
7 10 20 75 5 15 5.0 3/15 
8 20 58 2 17 4.4 3/17 
9 10 10 78 2 15 1.7 1/15 
10 20 10 69 1 17 0.0 0/17 
__________________________________________________________________________ 
As can be seen from the above Table 3, the adhesives of the present 
invention arise no skin irritation. 
Comparative Example 1 
The adhesive layer(2) prepared in Example 1(D) was singly coated on a 
separate liner and then laminated onto a polyethylene film to produce a 
mono-layered adhesive. 
Comparative Example 2 
To the adhesive layer(1) prepared in Example 1(C), 5% by weight of 
tocopherol as an antioxidant, 10% by weight of propylene glycol monooleate 
as a penetration enhancer and 2% by weight of bisabolol as a lenitive 
agent were added and dissolved. The resulting mixture was coated on a 
releasing paper to a thickness of 70 .mu.m and dried. 
Experimental Example 3 
Penetration test 
By the same manner as described above in Experimetal Example 1, the 
adhesives of Examples 1-4 and Comparative examples 1-2 were tested and the 
results are shown in Table 4. 
TABLE 4 
______________________________________ 
Comparison of the skin 
penetration flux of ketoprofen 
Skin 
Adhesive Skin penetration 
Lag time penetration 
(Example No.) 
flux(.mu.g/cm.sup.2 /hr) 
(hr) flux ratio 
______________________________________ 
Ex. 1 17.7(3.79) 2.78 .+-. 0.74 
1.97 
Ex. 2 15.6 .+-. 2.28 
3.14 .+-. 1.45 
1.73 
Ex. 3 27.4 .+-. 2.11 
1.75 .+-. 1.23 
3.04 
Ex. 4 18.8 .+-. 3.18 
2.20 .+-. 0.79 
2.09 
Comp. 1 9.0 .+-. 3.45 
3.05 .+-. 1.05 
1.00 
Comp. 2 22.4 .+-. 2.79 
1.67 .+-. 0.68 
2.49 
______________________________________ 
Experimental Example 4 
Skin primary irritation test 
By the same manner as described above in Experimental Example 2, the 
adhesives prepared in Examples 1-4 and Comparative examples 1-2 were 
tested and the results are shown in Table 5. 
TABLE 5 
______________________________________ 
Adhesive No. of Frequency of skin- 
(Example No.) 
subjects Reactivity (%) 
irritation occurance 
______________________________________ 
Ex. 1 13 3.8 2/13 
Ex. 2 13 1.9 1/13 
Ex. 3 13 3.8 2/13 
Ex. 4 13 0.0 0/13 
Comp. 1 13 3.8 2/13 
Comp. 2 13 1.9 1/13 
______________________________________