Adhesive composition for medical use

The present invention is directed to a sticky composition for medical use comprising a tackifier resin and an oxyalkylene polymer having a silicon-containing group which can be crosslinked by forming a siloxane bond, wherein silicon atom thereof is bound with a hydroxyl group or hydrolytic group, and to a transdermal drug delivery preparation incorporating said sticky composition as a drug carrier. The sticky composition of the present invention possesses excellent adhesive properties, very low skin irritancy and good compatibility with the site of plastering and thus perform as a very safe and effective medical adhesive. The transdermal drug delivery preparation of the present invention offers excellent drug release from the sticky composition.

FIELD OF THE INVENTION 
The present invention relates to a sticky composition for medical use and a 
transdermal drug delivery preparation incorporating it, more specifically 
to a sticky composition for medical use which causes little skin 
irritation and is hence safe and which has excellent adhesive properties 
and a transdermal drug delivery preparation for treating a diseased part 
of body or for delivering a drug to the circulatory system. 
BACKGROUND OF THE INVENTION 
Traditionally, plasters applied to the body to treat skin lesions or to 
transdermally deliver drugs to internal lesions or the circulatory system 
and other organs and other medical adhesives used in medical devices are 
prepared from polyvinyl alkyl ethers, poly(metha)acrylates, 2-ethylhexyl 
acrylate-2-ethylhexyl methacrylate copolymers, 2-ethylhexyl 
acrylate-vinylpyrrolidone copolymers, polyurethane, 
styrene-isoprene-styrene block copolymers, polyisobutylene rubber, 
polyisoprene rubber, butyl rubber, natural rubber, silicone resin and 
other substances. To give a pressure-sensitive adhesion property to these 
copolymers, known tackifiers, softening agents, fillers, anti-aging agents 
and other additives are added. 
These sticky compositions are required to be safe with little skin 
irritation and to have well-balanced adhesive properties (tack, adhesion, 
cohesion). However, none of them meets all these requirements. For 
example, sticky compositions based on acrylic resin are known to have skin 
irritancy causing skin sweating, flare or edema. Sticky compositions based 
on silicone resin are faulty in that the plaster is liable to detaching 
due to sweating or the plaster becomes more likely to be detached when it 
is attached to the joint. 
In recent years, there have been remarkable progress based on the concept 
of drug delivery system in the development of transdermal drug delivery 
preparations aiming at systemic action as well as action on skin lesions. 
These preparations have been increasingly recognized to be useful as 
sustained-release preparations. This kind of conventional transdermal drug 
delivery preparations includes those using a medical adhesive as an 
adhesive base comprising an adhesive polymer layer as described above 
which contains a drug and a release aid which promotes the release of the 
drug on a drug-impermeable backing material. By plastering them on the 
body, drugs are delivered to diseased parts of the body or to the 
circulatory system. 
The adhesive base for the transdermal drug delivery preparation is required 
to have high safety and well-balanced adhesive properties and offer good 
drug release. Particularly in transdermal drug delivery preparations 
aiming at systemic action, drug release from drug carrier is known to be a 
key factor. Although the silicone elastomer described above is widely used 
as a base for implantation preparations and transdermal drug delivery 
devices and as a drug carrier for various other preparations because it is 
very safe, it is known to have a problem in drug release in addition to 
the above-mentioned problems such as the tendency for plaster to be 
detached due to sweating when it is used as an adhesive base for 
transdermal drug delivery preparations. In transdermal drug delivery 
preparations incorporating a silicone elastomer as an adhesive polymer 
layer, i.e., an adhesive base, the releasing property for the drug 
retained by the silicone elastomer, i.e., an active ingredient 
pharmaceutical compound, is very high, provided that the drug has an 
extremely high vapor pressure like nitroglycerin; and very useful products 
of devices have been developed. However, the drug releasing property of 
silicone elastomer is usually very low; therefore, development of devices 
incorporating the silicone elastomer described above is limited to drugs 
whose effective dose is low like scopolamine. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to provide a sticky composition 
for medical use which causes very little skin irritation and which has 
excellent adhesive properties and good compatibility with the site of 
plastering. 
It is another object of the invention to provide a transdermal drug 
delivery preparation which is very safe and which offers good drug 
release. 
To solve the problems described above, the present inventor made 
investigations. As a result, the inventor found that a sticky composition 
comprising a tackifier and an oxyalkylene polymer having a 
silicon-containing group which can be crosslinked by forming a siloxane 
bond, wherein silicon atom thereof is bound with a hydroxyl group or 
hydrolytic group, can serve as a medical adhesive having excellent safety 
and adhesive properties, and developed the invention. Accordingly, the 
present invention is based on the finding that the sticky composition for 
medical use of the present invention causes very little skin irritation 
and has excellent adhesive properties. 
The inventor made further investigations to overcome the drawbacks of 
conventional transdermal drug delivery preparations and developed the 
transdermal drug delivery preparation of the present invention, which 
comprises a mixture of a transdermally absorbable pharmaceutical compound 
as an active ingredient and an auxiliary agent in an elastomer of the 
sticky composition described above as a base which offers good release of 
the active ingredient drug. 
Accordingly, the present invention comprises the following: 
(1) A sticky composition for medical use comprising a tackifier resin and 
an oxyalkylene polymer having a silicon-containing group which can be 
crosslinked by forming a siloxane bond, wherein silicon atom thereof is 
bound with a hydroxyl group or hydrolytic group. 
Examples of the silicon-containing group include those represented by the 
formula II: 
##STR1## 
wherein X represents an hydroxyl group or hydrolytic group; when there are 
two or more X groups, they may be identical or not; R.sup.2 represents a 
monovalent hydrocarbon group having 1 to 20 carbon atoms or a 
triorganosiloxy group represented by (R').sub.3 SiO-- (R' represents a 
monovalent hydrocarbon group having 1 to 20 carbon atoms; the three R' 
groups may be identical or not; when there are two or more R.sup.2 groups, 
they may be identical or not,; a represents 0, 1, 2 or 3; b represents 0, 
1 or 2; 1.ltoreq.a+mb, wherein m represents 0 or an integer of 1 to 19, 
and when m is 2 or more, the b numbers may not be identical. 
(2) A transdermal drug delivery preparation incorporating as a drug carrier 
a sticky composition comprising a tackifier resin and an oxyalkylene 
polymer having a silicon-containing group which can be crosslinked by 
forming a siloxane bond, wherein silicon atom thereof is bound with a 
hydroxyl group or hydrolytic group. 
Examples of the silicon-containing group used here include those 
represented by Formula II as in (1) above.

DETAILED DESCRIPTION OF THE INVENTION 
As an oxyalkylene polymer having a silicon-containing group in the 
molecular structure for the present invention, known polymers disclosed in 
Japanese Patent Examined Publication Nos. 36319/1970, 12154/1971 and 
32673/1974, Japanese Patent Laid-Open Nos. 156599/1975, 73561/1976, 
6096/1979, 82123/1980, 123620/1980, 125121/1980, 131022/1980, 135135/1980 
and 137129/1980 and other publications can be used with no limitation. 
The molecular chain of the oxyalkylene polymer preferably has a repeat unit 
essentially represented by the formula I: 
EQU --R.sup.1 --O-- (I) 
wherein R.sup.1 represents a divalent organic group, with most preference 
given to the case where the majority of R.sup.1 is a hydrocarbon group 
having 3 or 4 carbon atoms. Examples of R.sup.1 include the following: 
##STR2## 
The following compound is most preferable from the viewpoint of adhesive 
properties. 
##STR3## 
The molecular chain of oxyalkylene polymer described above may comprise 
only one kind of repeat unit or two or more kinds of repeat unit. 
The repeat unit represented by the formula --R.sup.1 --O-- is contained in 
the polymer at normally over 50% (% by weight, the same applies below), 
preferably over 70%, and still more preferably over 80%. 
The silicon-containing group for the present invention is a well known 
functional group. Typical examples thereof include the group represented 
by the formula II: 
##STR4## 
wherein X represents an hydroxyl group or hydrolytic group; when there are 
two or more X groups, they may be identical or not; R.sup.2 represents a 
monovalent hydrocarbon group having 1 to 20 carbon atoms or a 
triorganosiloxy group represented by (R').sub.3 SiO-- (R' represents a 
monovalent hydrocarbon group having 1 to 20 carbon atoms; the three R' 
groups may be identical or not); when there are two or more R.sup.2 
groups, they may be identical or not; a represents 0, 1, 2 or 3; b 
represents 0, 1 or 2; 1.ltoreq.a+mb, wherein m represents 0 or an integer 
of 1 to 19, and when m is 2 or more, the b numbers may not be identical. 
From the economic and other viewpoints, the silicon-containing group 
described above is preferably a group wherein m is 0 and which is 
represented by the formula III: 
##STR5## 
wherein R.sup.2 has the same definition as above; n represents 1, 2 or 3. 
Examples of the hydrolytic group in Formula II include a halogen atom, 
hydrogen atom, alkoxy group, acyloxy group, ketoximate group, amino group, 
amide group, aminooxy group, mercapto group and alkenyloxy group, with 
preference given to an alkoxy group such as a methoxy group or ethoxy 
group, since they are mildly hydrolytic. 
Examples of the hydrocarbon group having 1 to 20 carbon atoms for R.sup.2 
in Formula II and of the monovalent hydrocarbon group having 1 to 20 
carbon atoms for R' in (R').sub.3 SiO-- include alkyl groups such as 
methyl group and ethyl group, cycloalkyl groups such as cyclohexyl group, 
aryl groups such as phenyl group and aralkyl groups such as benzyl group, 
with preference given to methyl group from the viewpoint of reactivity. 
For sufficient hardening set, the number of silicon-containing groups in 
the oxyalkylene polymer is normally not less than 1, preferably not less 
than 1.1, and still more preferably not less than 1.5 on average. 
Although the silicon-containing group may be located on a side chain of the 
molecular chain of the oxyalkylene polymer, it is preferably present in a 
terminal. The number-average molecular weight of the oxyalkylene polymer 
is normally 500 to 30000, preferably 3000 to 15000, and still more 
preferably 5000 to 10000. 
The oxyalkylene polymer may be used singly or in combination of two or more 
kinds. 
The oxyalkylene polymer for the present invention may be one of the known 
ones proposed in various publications as stated above. Therefore, these 
oxyalkylene polymers can easily be prepared by known methods disclosed in 
these known publications. Examples thereof include MS Polymer 20A 
(functional group: --SiCH.sub.3 (OCH.sub.3).sub.2, number-average 
molecular weight: 7500), MS Polymer #300 (functional group: --SiCH.sub.3 
(OCH.sub.3).sub.2, number-average molecular weight: 8500), SILYL 5A01 
(functional group: --SiCH.sub.3 (OCH.sub.3).sub.2, number-average 
molecular weight: 8500), SILYL 5B25 (functional group: --SiCH.sub.3 
(OCH.sub.3).sub.2, --NH.sub.2, number-average molecular weight: 8000), 
BILYL 5B30 (functional group: --SiCH.sub.3 (OCH.sub.3).sub.2, --NH.sub.2, 
number-average molecular weight: 5000), produced by Kanegafuchi Chemical 
Industry Co., Ltd.. 
The sticky composition of the present invention contains normally 10 to 140 
parts by weight of a compatible tackifier resin and 1 to 30 parts by 
weight of a setting catalyst, relative to 100 parts by weight of the 
oxyalkylene polymer. The amounts of tackifier resin below 10 parts by 
weight or above 140 parts by weight are undesirable because the adhesion 
is insufficient in the former case and no desired effect is obtained in 
proportion to the amount added and paste retention can occur on the 
subject of plastering in the latter case. 
The tackifier resin is not subject to limitation, as long as it is 
compatible with the oxyalkylene polymer for the present invention. Known 
tackifier resins can be used, such as rosin resins (rosin, rosin ester, 
hydrogenated rosin), phenol resins, terpene phenol resins, xylene resins, 
aliphatic petroleum resins, aromatic petroleum resins, terpene resins and 
cumarone resins, with preference given to rosin ester resins and terpene 
phenol resins. 
As setting catalysts, known tin or aluminum based catalysts, amines such as 
dibutylamine-2-ethylhexoate and other acidic or alkaline catalysts can be 
used, with preference given to aluminum based catalysts such as aluminum 
chelate and aluminum alcoholate. As anti-aging agents, known substances 
such as BHT (benzenehydroxytoluene) and vitamin E can be used. Also, these 
sticky compositions may be formulated with other known bases etc. for 
various purposes. 
The sticky composition for medical use of the present invention can be 
prepared by dissolving an oxyalkylene polymer, tackifier resin, setting 
catalyst, anti-aging agent and other additives as described above in a 
solvent such as isopropyl alcohol, ethanol, methanol, acetone, toluene or 
ethyl acetate. The preparation thus obtained can be used as a sticky 
composition after the process of coating, forming and setting, for 
instance. 
Although the solvent is not subject to limitation, it is preferable to use 
ethanol, isopropyl alcohol or the like from the viewpoint of safety. The 
sticky composition thus obtained can be used for medical use in plaster, 
adhesive sheet and other forms by conventional methods. Particularly, the 
sticky composition can be used as a drug carrier in the transdermal drug 
delivery preparation of the present invention. 
The skin irritancy of the sticky composition for medical use of the present 
invention is very low. To confirm this, the oxyalkylene polymer itself was 
tested for irritancy. It was found non-irritative, whose PCI (primary 
cutaneous irritation index) was 0 as determined by a primary skin 
irritation test in rabbits (Draize's method, 1959, FDA). Even when the 
tackifier resin, setting catalyst, anti-aging agent and other bases 
described above were added to the oxyalkylene polymer to yield a sticky 
composition, the PCI of the sticky composition was close to about 1. Since 
the PCI classification comprises three grades of "weak irritant" for 
scores 0 to 2, "moderate irritant" for 3 to 5 and "strong irritant" for 6 
to 8, the sticky composition for medical use of the present invention can 
be judged to have very low skin irritancy. 
With respect to properties other than the skin irritancy, sticky 
compositions for medical use are usually required to have sufficient vapor 
permeability and oxygen permeability, moderate flexibility, good stability 
to heat and light and well-balanced adhesive properties without involving 
deterioration of the sticky composition or adhesion failure between the 
sticky composition layer and the backing material. 
Since the sticky composition for medical use of the present invention meets 
all these requirements for properties and has sufficient vapor 
permeability, the plaster does not become detached from skin due to 
sweating. 
The transdermal drug delivery preparation of the present invention is 
characterized by the use of the sticky composition for medical use of the 
present invention described above as a drug carrier. The drug for the 
present invention, i.e., a pharmaceutical compound as an active 
ingredient, is not subject to limitation, as long as it is transdermally 
absorbable. Examples of such compounds include the following: 
a) Antibiotics such as penicillins, cephalosporins, erythromycins, 
tetracyclines, macrolides, aminoglycosides, fosfomycins and rifampicins. 
b) Antipyretics, analgesics and anti-inflammatory drugs such as mefenamic 
acid, flufenamic acid, indometacin, diclofenac, acetaminophen, alclofenac, 
oxyphenbutazone, phenylbutazone, ibuprofen, ketoprofen, salicylic acid, 
methyl salicylate, L-menthol, camphor, sulindac, naproxen, fenbufen, 
aspirin, sulpyrine, tiaramide hydrochloride and piroxicam. 
c) Antihistaminics such as .alpha.-chlorpheniramine maleate, 
diphenylpyraline, diphenhydramine, clemastine fumarate and promethazine 
hydrochloride. 
d) Psychotropic drugs for hypnosis, sedation and ataraxia such as diazepam, 
chlorpromazine hydrochloride, chlordiazepoxide, sulpiride, haloperidol, 
ethyl loflazepate, fluphenazine, thioridazine, fludiazepam, flunitrazepam, 
phenobarbital, amobarbital, cyclobarbital, triazolam and nitrazepam. 
e) Coronary vasodilators such as nitroglycerin, isosorbide dinitrate, 
nitroglycol, erythritol tetranitrate, pentaerythritol tetranitrate, 
verapamyl (hydrochloride), nifedipine, dipyridamole and diltiazem 
hydrochloride. 
f) Antiarrhythmics and antihypertensive drugs such as propranolol 
(hydrochloride), pindolol, clonidine (hydrochloride), bupranolol, 
indenolol, nilvadipine, nipradilol, bucumolol, hydrazinc hydrochloride and 
rescinnamine. 
g) Hypotensive diuretics such as hydrothiazide, benzylhydrochlorothiazide 
and cyclopenthiazide and diuretics such as furosemide, mefruside, 
trichlormethiazide and thiobromine. 
h) Chemotherapeutic drugs such as aciclovir, nalidixic acid and sulfa 
drugs. 
i) Anticancer agents such as 5-FU, vincristine, adriamycin, bleomycin, 
mitomycin, cisplatin and therarubicin. 
j) Antiemetics agents such as metoclopramide, clebopride, scopolamine 
(hydrobromide) and domperidone. 
k) Vitamins such as vitamin A, vitamin E, vitamin K, ergocalciferol, 
cholecalciferol, octotiamine and riboflavin tetrabutyrate. 
l) Antispasmodics such as nitrazepam, clonazepam, baclofen and meprobamate. 
m) Antitussives such as dextromethorphane, terbutaline (sulfate), ephedrine 
(hydrochloride), salbutamol (hemisulfate), isoproterenol and trimetoquinol 
hydrochloride. 
n) Cardiacs such as prenylamine lactate, digitoxin and digoxin. 
o) Anesthetics such as lidocaine, benzocaine and ethyl-p-aminobenzoate. 
p) Cerebrovascular improvers such as Hydergine, ergot alkaloid and 
ifenprodil. 
q) Antifungal drugs such as pentamycin, amphotericin B, pyrrolnitrin, 
clotrimazole, benzalkonium chloride, nitrofurazone, nystatin and 
acetosulfamine. 
r) Steroids such as hydrocortisone, prednisolone, paramethasone, 
beclomethasone dipropionate, flumethasone, betamethasone, betamethasone 
valerate, dexamethasone, triamcinolone, triamcinolone acetonide, 
fluocinolone, fluocinolone acetonide, clobetasol propionate, progesterone, 
testosterone and estradiol. 
s) Anti-parkinsonism drugs such as L-dopa, bromocriptine mesilate, 
trihexyphenidyl hydrochloride, mazaticol hydrochloride and biperiden 
hydrochloride. 
t) Biologics such as TRH, LHRH, TNF, lymphotoxin, interferon, urokinase, 
insulin, calcitonin, their derivative polypeptides and prostaglandins. 
u) Others such as tolbutamide and other antidiabetic drugs, colchicine and 
other anti-gout drugs and nicotine and other smoking suppressors. 
These drugs may be used in combination of two or more kinds as necessary. 
The transdermal drug delivery preparation of the present invention can be 
prepared as follows. A drug, i.e., a pharmaceutical compound as an active 
ingredient, is normally uniformly mixed in alcohol along with an auxiliary 
agent to yield a pasty or dissolved mixture. The auxiliary agent is used 
as necessary. Examples thereof include plasticizers such as liquid 
silicone, absorption promoters such as isopropyl myristate, azone, urea, 
glycerol, monoglyceride and diisopropyl adipate and fillers such as 
silica, potassium carbonate, kaolin and talc. 
Examples of alcohols which are normally used as solvents include isopropyl 
alcohol, methanol, ethanol and butanol, with preference given to isopropyl 
alcohol and ethanol from the viewpoint of safety. 
The resulting dissolved or pasty mixture is uniformly mixed in the sticky 
composition described above to dissolve or disperse as fine powder. When 
the sticky composition has been formulated with a setting catalyst, it is 
placed in an appropriate mold and set and formed at room temperature or 
increased temperature to yield the transdermal drug delivery preparation 
of the present invention. When the sticky composition has not been 
formulated with a setting catalyst, a setting catalyst is appropriately 
added to the mixture and thoroughly mixed quickly, after which the mixture 
is placed in an appropriate mold and set and formed at room temperature or 
increased temperature to yield the transdermal drug delivery preparation 
of the present invention. 
The transdermal drug delivery preparation of the present invention is 
preferably prepared to a composition of 0.05 to 40 parts by weight of 
pharmaceutical compound, 1 to 30 parts by weight of auxiliary agent and 30 
to 90 parts by weight of sticky composition, though the content of the 
pharmaceutical compound in the finished preparation varies depending on 
the kind of the drug used, i.e., the pharmaceutical compound as an active 
ingredient and the kind of target disease. 
The transdermal drug delivery preparation thus obtained comprises the 
sticky composition of the present invention described above as a drug 
carrier and offers excellent drug release. 
Various experimental models for drug release are known. For example, in 
drug release experiments using a diffusion cell, the transdermal drug 
delivery preparation of the present invention offers quicker and more 
release in comparison with conventional preparations incorporating a 
silicone elastomer. 
The transdermal drug delivery preparation of the present invention is used 
in accordance with ordinary methods, though dosage, administration 
frequency and other factors vary depending on the kind of the drug used, 
i.e., the pharmaceutical compound as an active ingredient and the kind of 
target disease. 
As stated above, the sticky composition for medical use of the present 
invention possesses excellent adhesive properties, very low skin irritancy 
and good compatibility with the site of plastering and thus perform as a 
very safe and effective medical adhesive. This sticky composition for 
medical use can be used for artificial anus, medical tapes, prevention of 
bedsores, attaching medical devices or their terminals to the human body 
and other purposes as well as for percutaneous and permucosal 
administration. 
Incorporating an oxyalkylene polymer, the transdermal drug delivery 
preparation of the present invention offers excellent drug release from 
the sticky composition of the invention, which is a drug carrier. 
Therefore, the transdermal drug delivery preparation of the present 
invention allows absorption of a sufficient amount of drug via skin, which 
is thus easy to apply and permits a high level of drug concentration in 
blood. 
EXAMPLES 
The present invention is hereinafter described in more detail by means of 
the following working examples and test examples, but the invention is not 
limited by these examples and affords various applications, as long as 
they are not deviated from the technical scope of the invention. 
Preparation of oxyalkylene polymer 
The oxyalkylene polymer for the present invention, having a 
silicon-containing group which can be crosslinked by forming a siloxane 
bond, wherein silicon atom thereof is bound with a hydroxyl group or 
hydrolytic group, can be prepared as follows. First, 320 g of a 
polyoxypropylene glycol having an average molecular weight of 3200 (of the 
total terminal group content, allyl ether groups account for 15%, propenyl 
ether groups account for 3% and hydroxyl groups account for 82%) was taken 
in a nitrogen-substituted 1-liter pressure-resistant reactor equipped with 
a stirring rod. Subsequently, 40.8 g of powdered caustic soda (purity 98%) 
was added, and the temperature was raised to 60 .degree. C. Then, 7.76 g 
of bromochloromethane was added, followed by 10 hours of reaction at 
60.degree. C. Subsequently, the temperature in the reaction part was 
reduced to 50 .degree. C., and 9.2 g of allyl chloride was added, followed 
by 10 hours of reaction at 50 .degree. C. After completion of the 
reaction, the reaction product was transferred to a beaker, diluted with 
1000 g of normal hexane and then treated with 50 g of aluminum silicate at 
normal temperature for 1 hour while stirring. After filtration, the 
resulting cake was washed with normal hexane several times. The volatile 
substances were evaporated off from the filtrate to yield 300 g of a 
propylene oxide polymer having an average molecular weight of 8000. The 
terminal groups of the polymer were 90% of allyl ether groups, 8% of 
propenyl ether groups and 2% of hydroxyl groups. 84 g of the polymer 
obtained on a 500-ml pressure-resistant reactor equipped with a stirring 
rod was taken. 0.05 ml of catalyst solution of chloroplatinic acid (2 g of 
H.sub.2 PtCl.sub.6.6H.sub.2 O was dissolved in 20 ml of isopropanol and 78 
ml of tetrahydrofuran) and 2.1 g of methyl dimethoxysilane were added, 
followed by 8 hours of reaction at 100.degree. C. Then, the volatile 
substances were evaporated off to yield an alkylene oxide polymer wherein 
the group represented by the following formula accounts for 82% of the 
terminal groups. 
##STR6## 
Example 1 
To 100 parts by weight of an oxyalkylene polymer (SILYL 5A01, produced by 
Kanegafuchi Chemical Industry Co., Ltd.), which has a molecular weight of 
8500 and a terminal silicon-containing group represented by --SiCH.sub.3 
(OCH.sub.3).sub.2, 80 parts by weight of rosin ester (ester gum AAG, 
produced by Arakawa Kagaku) as a tackifier resin, 10 parts by weight of a 
setting catalyst (aluminum chelate ALCH, produced by Kawaken Fine 
Chemical) and 0.5 part by weight of an anti-aging agent BHT were added, 
and a sticky composition polymer was prepared using isopropyl alcohol. The 
sticky composition polymer was coated and dried on a polyethylene film of 
80 .mu.m in thickness subjected to corona discharge treatment on one face 
to a dry film thickness of 50 .mu.m to yield an adhesive plaster. 
Example 2 
To 100 parts by weight of an oxyalkylene polymer (SILYL 5A01, produced by 
Kanegafuchi Chemical Industry Co., Ltd.), which has a molecular weight of 
8500 and a terminal silicon-containing group represented by --SiCH.sub.3 
(OCH.sub.3).sub.2, 40 parts by weight of terpene phenol resin (YS Polyster 
S145, produced by Yasuhara Chemical) as a tackifier resin, 10 parts by 
weight of a setting catalyst (aluminum chelate ALCH, produced by Kawaken 
Fine Chemical) and 0.5 part by weight of an anti-aging agent BHT were 
added, and a sticky composition polymer was prepared using isopropyl 
alcohol. The sticky composition polymer was coated and dried on a 
polyethylene film of 80 .mu.m in thickness subjected to corona discharge 
treatment on one face to a dry film thickness of 50 .mu.m to yield an 
adhesive plaster. 
Example 3 
To 100 parts by weight of an oxyalkylene polymer (MS polymer 20A, produced 
by Kanegafuchi Chemical Industry Co., Ltd.), which has a molecular weight 
of 7500 and a terminal silicon-containing group represented by 
--SiCH.sub.3 (OCH.sub.3).sub.2, 80 parts by weight of rosin ester (ester 
gum AAG, produced by Arakawa Kagaku) as a tackifier resin, 10 parts by 
weight of a setting catalyst (aluminum chelate ALCH, produced by Kawaken 
Fine Chemical) and 0.5 part by weight of an anti-aging agent BHT were 
added, and a sticky composition polymer was prepared using isopropyl 
alcohol. The sticky composition polymer was coated and dried on a 
polyethylene film of 80.mu.m in thickness subjected to corona discharge 
treatment on one face to a dry film thickness of 50 .mu.m to yield an 
adhesive plaster. 
Example 4 
To the sticky composition polymer prepared in Example 1, testosterone as a 
drug was added to a concentration of 2.5 wt. %, followed by setting and 
forming to yield the transdermal drug delivery preparation of the present 
invention. 
Example 5 
To the sticky composition polymer prepared in Example 1, progesterone as a 
drug was added to a concentration of 2.5 wt. %, followed by setting and 
forming to yield the transdermal drug delivery preparation of the present 
invention. 
Example 6 
To the sticky composition polymer prepared in Example 1, estradiol as a 
drug was added to a concentration of 2.5 wt. %, followed by setting and 
forming to yield the transdermal drug delivery preparation of the present 
invention. 
Example 7 
To the sticky composition polymer prepared in Example 3, testosterone as a 
drug was added to a concentration of 2.5 wt. %, followed by setting and 
forming to yield the transdermal drug delivery preparation of the present 
invention. 
Example 8 
To the sticky composition polymer prepared in Example 3, progesterone as a 
drug was added to a concentration of 2.5 wt. %, followed by setting and 
forming to yield the transdermal drug delivery preparation of the present 
invention. 
Example 9 
To the sticky composition polymer prepared in Example 3, estradiol as a 
drug was added to a concentration of 2.5 wt. %, followed by setting and 
forming to yield the transdermal drug delivery preparation of the present 
invention. 
Test Example 1 
Test for changes in appearance and adhesive properties 
With respect to the adhesive plasters prepared in Examples 1, 2 and 3, 
appearance, finger stickiness and tack value were examined immediately 
after preparation, after storage at room temperature for 60 days and after 
storage in aluminum foil package at 40.degree. C. for 60 days. 
For changes in appearance, the sample had a totally milky white, uniform 
adhesive layer immediately after preparation, which appearance remained 
unchanged even after 60 days of storage at room temperature and after 60 
days of storage in aluminum foil package at 40.degree. C. 
As for finger stickiness, good results were obtained immediately after 
preparation and after storage. 
Tack value (J. Dow's method, JIS Z 0237) was about 20 immediately after 
preparation, which remained unchanged even after storage. Good adhesive 
properties were noted. 
Test Example 2 
Practical application test for plastering to the human body 
With respect to the adhesive plasters prepared in Examples 1, 2 and 3, 1 
cm.times.1 cm test pieces cut from the adhesive plasters immediately after 
preparation and after 60 days of storage at room temperature, 
respectively, were simultaneously plastered to the upper arm in 10 
subjects, and changes in the adhesion condition was monitored for 24 
hours. 
Good results were obtained in all 10 subjects; none of the test pieces 
became detached after 24 hours. Skin compatibility during plastering was 
good. 
Test Example 3 
Primary skin irritation test 
With respect to the adhesive plasters prepared in Examples 1, 2 and 3, 2.5 
cm.times.2.5 cm test pieces cut from the adhesive plasters immediately 
after preparation and after 60 days of storage at room temperature, 
respectively, were simultaneously plastered to the upper arm in 10 
subjects, and the plasters were removed after 24 hours. Within 30 to 60 
minutes after removal, the plastering site was visually examined for the 
degree of erythema. Nothing more than very slight erythema was observed. 
Test Example 4 
Evaluation of drug release 
Drug release from each of the testosterone, progesterone and estradiol 
preparations obtained in Examples 4 through 9 was compared with drug 
release from each of testosterone, progesterone and estradiol preparations 
prepared using a silicone elastomer. 
The silicone elastomer used was a product of Dow Corning (Dow Corning.RTM. 
2920 Medical Adhesive), to which testosterone, progesterone or estradiol 
was added to reach a concentration of 2.5 wt. %, followed by setting and 
forming. For this test, each sample was made to have a film thickness of 
50 .mu.m. After loading on a vertical diffusion cell produced by 
Crown-Glas Company, each sample was tested for drug release in a saline 
containing 40% polyethylene glycol 400 as a elution solvent. 
Cumulative release of testosterone, progesterone or estradiol was 
determined by HPLC on a time basis. HPLC determinations were made using a 
Cosmosil 5 CN-R column (4.6 mm.times.150 mm) at a flow rate of 1.0 ml/min 
in a CH.sub.3 CH/H.sub.2 O (40/60) solvent system for testosterone, 
progesterone or estradiol. 
The results are shown in FIG. 1. From FIG. 1, it is evident that drug 
release from the preparations obtained in Examples 4 though 6 was better 
than that from the control preparation incorporating a silicone elastomer. 
The same tendency was noted in the preparations obtained in Examples 7 
through 9 (data is not given in FIG. 1). In the transdermal drug delivery 
preparation of the present invention, drug release from the sticky 
composition as a drug carrier is extremely higher than that obtained by 
using the control silicone elastomer. 
Test Example 5 
Determination of drug concentration in blood 
Male rats at 7 weeks of age with their hair clipped using electric clippers 
were subjected to plastering of the estradiol preparation of Example 6 or 
9 or a control estradiol preparation incorporating the same silicone 
elastomer as used in Test Example 4 in the form of a 5 cm.sup.2 piece 
(n=3). At 2, 8 and 24 hours following plastering, blood was collected and 
serum was separated. The serum samples thus obtained were subjected to 
radioimmunoassay to determine the estradiol concentration. 
The results are shown in FIG. 2. The estradiol preparations according to 
the present invention yielded good drug concentrations in blood and 
offered good sustained release. On the other hand, the rats to which the 
control estradiol preparation was plastered had very low drug 
concentrations in blood.