Note: Descriptions are shown in the official language in which they were submitted.
CA 02282583 1999-08-17
DESCRIPTION
PLASTICIZER AND PATCH CONTAINING THE SAME
Technical Field
This invention relates to a plasticizer and a
patch containing the plasticizer.
In particular, this invention relates to such
a plasticizer that is excellent in plasticizing effect
on a base for a patch, high in safety, stability and
compatibility with the base, odorless and exhibits a
refreshing effect, and also relates to a cataplasm
(poultice) and a tape-aid (plaster) each containing
the plasticizer.
Background Art
Antiphlogistic and analgesic patches are
generally used for lumbago, sprain, muscular pain,
stiff shoulders, etc. from old times. However, those
conventional patches still leave room for improvement
in their overall feelings at the time of use, which
include adhesion, stickiness and fitness (fit feeling)
to the skin, pain caused on peeling, and odor.
Further, in the case of a so-called systemic
transdermal preparation which has often been used
recently and make a medicine therein percutaneously
absorbed to produce an intended therapeutic effect, it
is indispensable to keep the preparation in contact
with the skin for a long time. «'hen a patch
CA 02282583 1999-08-17
preparation is used for this purpose, the adhesion
thereof to the skin is necessitated much more than
usual because the therapeutic effect is greatly
influenced by the area of the patched skin.
The feelings realized by the application of a
patch to the skin, such as adhesion or fitness to the
skin and pain caused by peeling off the patch, depend
on the properties of the base of the patch.
Generally, as the base becomes softer, it is improved
in the adhesion and fitness and causes less pain upon
peeling. Therefore, incorporating into a base an
additive which plasticizes and softens the base is
supposedly the simplest and surest method in order to
easily improve the properties of the base without
significantly changing the formulation to obtain the
intended pharmaceutical characteristics.
However, at present, there is absolutely no
such excellent plasticizer as to exhibit high
compatibility with the base of the patch, plasticizing
effect, high safety and excellent feelings of use such
as smell.
Plasticizers now used for medicines include
glycols such as propylene glycol and polyethylene
glycol, some surfactants, fatty oils such as castor
oil, and fatty acid esters typified by isopropyl
myristate.
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However, when these plasticizers are used for
patches, fully satisfactory results cannot always be
obtained for the following reasons: their plasticizing
effects are insufficient for obtaining the intended
pharmaceutical characteristics; these plasticizers
have only low compatibility with the base to cause
bleeding with time; the use thereof is limited because
of their odor; decomposition or coloring is caused
with time because of instability of the plasticizers;
and unfavorable side effects are caused because the
plasticizers irritate the skin.
An object of the present invention is to
solve the above-described problems by providing a
plasticizes capable of showing an excellent effect of
plasticizing a base for a patch, and having high
safety, stability and compatibility with the base.
Another object of the present invention is to provide
a patch, particularly, a cataplasm and a tape-aid,
containing the plasticizes and having excellent
overall feelings when in use such as adhesion and
fitness to the skin and pain caused by peeling off the
patch.
Disclosure of the Invention
The above objects of this invention can be
attained by using 3-L-menthoxypropane-1,2-diol as a
plasticizes for the base of a patch.
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The crux of this invention resides in a
plasticizes composed of 3-L-menthoxypropane-1,2-diol,
and in a patch, particularly a cataplasm and a tape-
aid, containing the plasticizes in its base.
3-L-menthoxypropane-1,2-diol (which is also
called 3-{(1R, 2S, 5R)-[5-methyl-2-(1-methylethyl)
cyclohexyl]oxy}-1,2-propanediol) which is the
plasticizes of this invention, is a known substance
described in, e.g., .Japanese Pat. Appln. Laid-Open
Gazette No. Sho 58-88334 (88334/83) as a substance
having a cooling or refreshing activity. Further,
.Japanese Pat. Appln. Laid-Open Gazette No. Sho 60-
25908 (25908/85) discloses that this compound is
useful as a cosmetic material, has an excellent
cooling effect and is extremely safe for the skin.
However, there has not been found any example of using
said known substance as a plasticizes, to say nothing
of an attempt to plasticize or soften the base for a
patch by the use of this substance to obtain the
desired pharmaceutical characteristics. Such an
attempt has been made for the first time by the
inventors of the present invention and the invention
is based on this entirely new finding.
3-L-~lenthoxypropane-1,2-diol is present in
the forms of R- and S-optical isomers becwuse it has
an asymmetric carbon atom at the 2-position to which a
hydroxyl group is attached. In the present invention,
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this compound may be used as a plasticizer in the form
of racemic modification or singly in the R- or S-form
obtained by resolution.
The base for the patch of this invention
contains 3-L-menthoxypropane-1,2-diol in an amount of
preferably 0.1 to 20% by weight, more preferably 0.5
to 10% by weight, of the total amount of the base.
When the amount is less than 0.1% by weight, no
sufficient effects as the plasticizer will be
exhibited, while when it exceeds 20% by weight, no
stable preparation will be prepared.
The drug to be used in the patch of this
invention is not particularly limited but may be
arbitrarily selected from among known conventional
drugs. Such drugs include steroidal anti-inflammatory
agents such as prednisolone, dexamethasone,
hydrocortisone, fluocinolone ac:etonide, betamethasone
valerate, betamethasone dipropionate, clobetasone
butyrate and prednisolone succinate; nonsteroidal
anti-inflammatory agents such as methyl salicylate,
glycol salicylate, indomethacin, diclofenac,
ibuprofen, ketoprofen, flufenamic acid, ketorolac,
flurbiprofen, felbinac, suprofen, pranoprofen,
tiaprofen, loxoprofen, tenidap, aspirin, ac:tarit,
mizoribine, oxaprozin, auranofin, indomethaoin
farnesyl, oxaprozin, mofezolac and etodolac:, and their
ester derivatives; antiallergic rig~ents such as
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tranilast, azelastine, ketotifen, ibudilast,
oxatomide, emedastine and epinastine; antihistamic
agents such as diphenhydramine, chlorphen~iramine,
promethazine and tripelennamine; central nervous
system stimulants such as chlorpromazine, nitrazepam,
diazepam, Phenobarbital and reserpine; hormones such
as insulin, testosterone, norethisterone,
methyltestosterone, progesterone and estradiol;
antihypertensive agents such as clonidine, reserpine,
guanethidine sulfate and efonidipine; c:ardiotonics
such as digitoxin and digoxin; antiarrhythmic agents
such as propranolol hydrochloride, procainamide
hydrochloride, ajimalin, pindolol and tulobuterol
hydrochloride; coronary vasodilators such as
nitroglycerin, isosorbide dinitrate, papaverine
hydrochloride and nifedipine; local anesthetics such
as lidocaine, benzocaine, procaine hydrochloride and
tetrac:aine; analgetic agents such as morphine,
aspirin, c:odeine, acetanilide and aminopyrine;
skeletal muscle relaxants such as eperisone,
tizanidine, tolperisone and inaperisone; antifungal
agents such as acetophenylamine, nitrofurazone,
pentamycin, naphthiomate, miconazole, omoconazole,
clotrimazole and butenafine hydrochloride;
antineoplastic agents such as 5-fluorourac:il,
busulfan, actinomycin, bleomycin and rnitomycin;
investigational agents for urinary incontinent:e such
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as terodiline hydrochloride and oxybutynin
hydrochloride; antiepileptics such as nitrazepam and
meprobamate; antiparkinson agents such as
chlorzoxazone and levodopa; assistants to the
prohibition of smoking such as nicotine; vitamins and
prostaglandins, though the drug usable in the patch is
of course not limited to them. Further, those drugs
may be used in the form of organic salt or inorganic
salt.
The content of the drug is preferably 0.1 to
20% by weight, more preferably 0.5 to 10% by weight,
of the total amount of the base for the patch, though
i.t is not particularly limited.
The patch according to this invention may
further contain various pharmacologically acceptable
additives, so far as the object of the invention is
not marred. Such additives include a stabilizer, an
antioxidant, a perfume, a filler, an ultraviolet
absorber, an antiseptic, an antimicrobial agent and a
percutaneous absorbefacient.
Then, detailed description will be made of
t:he cataplasm which is one of the pate:hes according to
t=his invention.
The c:ataplasm of this invention comprises in
its base a plasticizer consisting of 3-L-menthoxy-
propane-1,2-diol, a drug, a water-soluble polymer, a
polyhydric: alcohol and water.
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_ g _
As the base for the cataplasm of this
invention, a hydrophilic base c:omprising a water-
soluble polymer, a polyhydric alcohol and water is
preferable in consideration of long-term stability,
releasability and pert:utaneous absorbability of drug,
and safety for the skin.
The water-soluble polymer to be used in the
hydrophilic base may be one or more members suitably
selected from the group consisting of gelatin, casein,
pullulan, dextran, sodium alginate, soluble starch,
c:arboxystarch, dextrin, carboxymethylcellulose, sodium
c:arboxymethylcellulose, methylcellulose, ethylcellu-
lose, hydroxyethylcellulose, polyvinyl alcohol,
polyethylene oxide, polyacrylic acid, partially
neutralized polyacrylic acid, polyacrylamide,
polysodium acrylate, polyvinylpyrrolidone, carboxy
vinyl polymer, polyvinyl ether, methoxyethylene-malefic
anhydride copolymer, isobutylene-malefic anhydride
copolymer, N-vinylacetamide, copolymer comprising V-
vinylacetamide and acrylic acid and/or acrylate salt
and so forth. The content of the water-soluble
polymer is preferably 1 to 30% by weight, more
preferably 1 to 20% by weight, still more preferably 1
to 15% by weight, based on the total amount of the
hydrophilic; base. VYhen the content i.s less than 1°% by
weight, the resulting base will have too low a
viscosity to retain its shape, while when i.t= excveeds
_- _r____.
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;:30o by weight, the resulting mixture of the
constituents will have a high viscosity to lower the
workability in preparing a homogeneous paste of the
constituents or in applying the paste on a backing or
the like .
The polyhydric alcohol is one or more members
suitably selected from the group consisting of
polyethylene glycol, propylene glycol, dipropylene
glycol, polypropylene glycol, 1,3-butylene glycol,
1,4-butylene glycol, isobutylene glycol, glycerol,
diglycerol, sorbitol and so forth. The content of the
polyhydric alcohol is preferably 10 to 90~ by weight,
more preferably 10 to 70% by weight, still more
preferably 20 to 60% by weight, based on the total
amount of the hydrophilic base. When the content is
7_ess than 10% by weight, the resulting base will
exhibit poor humectant effect, while when it exceeds
90~ by weight, the solubility of the water-soluble
polymer will be adversely affected.
The content of water is preferably 10 to 90';,
by weight, more preferably 20 to 80 o by weight, based
on the total amount of the hydrophilic base. The
water is necessary in order to solubilize the water-
soluble polymer to thereby make the resulting base
develop its thickening, cohesive and shape-retaining
properties.
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If necessary, the hydrophilic base of the
cataplasm may further contain one or more c:rosslinking
agents in addition to the above essential components.
The c:rossliking agents include polyvalent metal
compounds such as aluminum hydroxide, aluminum
chloride, calcium hydroxide, calcium chloride,
a.Luminum sulfate, aluminum ammonium sulfate, aluminum
potassium sulfate, magnesium aluminometasilicate and
dihydroxyaluminum aminoac:etate; and compounds each
having at least tvo epoxy groups such as ethylene
glyc:ol diglyeidyl ether, polyethylene glycol
diglycidyl ether, propylene glycol diglycidyl ether,
polypropylene glycol diglycidyl ether, polytetramethy-
lene glycol diglycidyl ether, glycerol polyglycidyl
ether, polyglycerol polyglycidyl ether, sorbitol
polyglycidyl ether, sorbitan polyglycidyl ether,
trimethylolpropane polyglycidyl ether, pentaerythritol
polyglycidyl ether, resorcinol diglycidyl ether,
neopentyl glycol diglycidyl ether and 1,6-hexanediol
diglycidyl ether.
Further, the hydrophilic base of the
crltaplasm rnay contain one or more additives suitably
selected from among fillers such as kaolin, zinc
oxide, titanium dioxide, talc, bentonite and synthetic
a.Luminum silicate; antiseptics such as thymol, methyl
puraben, ethyl paraben and propyl paraben;
ani=ioxidant:s such as as<:orbic: aci.ct, stearic: esters,
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dibutylhydroxytoluene, butylhydroxyanisole, gallic
esters, vitamin E, vitamin E acetate and disodium
edetate; ultraviolet absorbers such as 2-hydroxy-4-
methoxybenzophenone, ethyl p-aminobenzoate, ~-(2-
hydroxy-5-methylphenyl)benzotriazole, glycol
salicylate, methyl salicylate and phenyl salicylate;
and emulsifying agents such as fatty acid esters of
sorbitan, fatty acid esters of glycerol, fatty acid
esters of decaglycerol, fatty acid esters of
polyoxyethylene sorbitan, fatty acid esters of
polyethylene glycol and polyoxyethylene alkyl ethers.
It is essential that the support of the
cataplasm of this invention be made of a material
which has no influence on the release of a drug, i.e.,
that the support neither interact with nor adsorb a
drug. The support is selected from the group
consisting of films and sheets of polyethylene,
polypropylene, polyvinyl chloride, polyester, nylon
and polyurethane; porous materials, expanded materials
and woven and nonwoven fabrics of these polymers;
laminates each comprising one or more members selected
from the group consisting of these films and sheets
and one or more members selected from the group
consisting of these materials and fabrics and so
forth. The release sheet of the c:ataplasrn according
to this invention may be selected from the group
c:onsisting~ of films of polyethylene, t»lyprc>pylene arid
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polyester; products of release treatment of these
films with silicone compounds; release paper and so
forth.
The preparation of the c:ataplasm of this
invention will now be described, though the c:ataplasrn
can be easily prepared by known processes.
For example, a drug is solubilized in 3-L-
menthoxypropane-1,2-diol to form a solution (A) which
may, if necessary, be incorporated with one or more
additives selected from the group consisting of a
stabilizer, an antioxidant, an ultraviolet absorber,
an emulsifying agent, an antiseptic, an antimic:robial
and so forth. Separately, a water-soluble polymer is
mixed into, dispersed and solubilized in a polyhydric
alcohol and water to form a homogeneous paste (B).
The solution (A) is added to the paste (B) to form a
homogeneous dispersion. This dispersion is spread
directly on a support, or alternatively it is one:e
spread on a paper or film treated with a releasing
agent and thereafter transferred to a support by
pressing. Thus, a c:ataplasm according to this
invention is prepared. The above-mentioned mixing
order of base materials, a drug' and other components
is ,just one example, not limiting the mi.xing~ order for
preparing the cataplasm according to this invention.
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Next, detailed description will be made of
the tape-aid which is one of the patches of t=his
invention.
The tape-aid of this invention comprises in
its base a plastic:izer consisting of 3-L-ment=hoxy-
propane-1,2-diol, a drug, a rosin ester derivative,
either a styrene-isoprene-styrene block copolymer or
an acrylic adhesive, and a softener.
Preferable proportions of these components
are as follows: drug in an amount of 0.5 to 10% by
weight, rosin ester derivative in 5 to 70% by weight,
3-L-menthoxypropane-1,2-diol in 0.5 to 10% by weight,
styrene-isoprene-styrene block copolymer in ~ to 40%
by weight and softening agent in 10 to 75% by weight,
er.-zc:h percentage being based on the total amount of the
base.
The tape-aid according to this invention
comprises in its base, for example, (a) a nonsteroidal
anti-inflammatory agent as the drug selected from the
group consisting of diclofenac, ketoprofen, flurbipro-
fen, loxoprofen, ketorolac, felbinac, suprofen and
ester derivatives and salts of these drugs, (b) a
p.Lasticizer comprising 3-L-menthoxypropane-l.~-diol,
(c) a rosin ester derivative, (d) a styrene-isoprene-
styrene block copolymer or an acrylic adric~sive as the
base polymer and (a) a softening agent, and zz known
base material for tape-aid if necessary.
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The support for the tape-aid is selected from
among polypropyene fabrics and polyester fabrics which
have no influence on the release of a nonste.roidal
anti-inflammatory agent. The polyester fabric is
preferably one made of polyethylene terephthalate
(PET) or polybutylene terephthalate (PBT). In order
to attain excellent release of a nonsteroidal anti-
inflammatory agent, it is essential that the support
not interact with a nonsteroidal anti-inflammatory
agent, i.e., not adsorb it. From this standpoint, the
optimum polymer constituting the support is polypropy-
lene, PET or PBT. The use of a support made of
polypropylene, PET or PBT prevents the adsorption of a
drug to the support to enable excellent release of the
drug.
The tape-aid according to this invention is
desirably provided with such stretc:hability that the
average stresses at 50~ elongation in lengthwise and
widthwise directions are each 0.3 kg/c:m or below, so
that it can be applied also to a bend of human body.
By virtue of this stretchability, the tape-uid
according to this invention is capable not only of
being used expediently but also of following the move
of the skin so that the friction and pressure during
the use of the tape-aid on the skin are decrezzsed,
thus causing little side effects such as cont=ac:t
dermatitis.
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The rosin ester derivative is a resin which
is used for the purpose of providing the resulting
tape-aid with adhesion. The derivative is t:he product
prepared by esterifying various rosins and subjecting
the obtained esters to hydrogenation or purification.
The esters include methyl ester, glycerol ester and
pentaerythritol ester. The rosin ester derivatives
include Ester Gum A, AA-G, H and HP (trade names,
products of Arakawa Chemical Industry Co, L1'D. ) ,
H<3riester-L, S and P (trade names, products of Harima
Chemicals, Inc.), Super Ester A-75 (trade name, a
product of Arakawa Chemical Industry Co., Ltd.), KE-
3=L1 (trade name, a product of Arakawa Chemical
Industry Co., Ltd.), Hercolyn D (trade name, a product
of Hercules Inc:.) and Foral 85 and 10:p (trade names,
products of Hercules Inc.).
The base polymer of the tape-aid may be
suitably selected from conventional ones in
consideration of safety for the skin, releasability of
a drug and adhesion to the skin: for example, from the
standpoint of the release characteristics of a
nonsteroidal anti-inflammatory agent, it is preferable
Lhai: the base polymer be a styrene-isoprene-styrene
block copolymer having n particularly low polarity.
Such block copolymers include (:ariflex TR-17_07, TR-
7_111 , 'rR-111 and 'rR-1117 ( trade names , products of
Shel I_ (:her«ical ) and Solprene 4~H ( t:rmde rmmc~ . at
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product of Phillips Petroleum). These styrene-
isoprene-styrene block copolymers may be each used
together with other polymer such as polyisobutylene.
V:istanex (trade name, a product of Exxon Kagaku) is
preferably used as the polyisobutylene.
The acrylic: adhesive includes as a preferable
example a polymer based on an alkyl (meth)ac:rylate.
The polymer may be a copolymer of an alkyl (meth)
ac:rylate and a compound polymerizable with the
(rneth)ac:rylate, such as a functional monomer,
multifunctional monomer or vinyl compound. Preferable
acrylic adhesive includes NISSETSU PE-300 (tradename,
mfd. by Nippon Carbide Industries Co., Ltd.).
The softening agent serves to plasticize or
soften the styrene-isoprene-styrene block copolymer
used as the base polymer to keep the adhesion of the
resulting tape-aid to the skin at a proper level. The
softening agent may be selected from the group
consisting of almond oil, olive oil, camellia oil,
pc~rsic oil, peanut oil, liquid paraffin and so forth.
The content of the softening agent is preferably 1~0
to 350 parts by weight per 100 part by weight of the
si=yrene-isoprene-styrene block copolymer.
The c:c>ntent o-f' a drug is preferazbly 70 to
1'>00 ug-/cm~ of the base from the stanclpoi.nts of
tfnerapc~utic:ally effective amount of a drug' to be
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released and availability thereof, though it is not
particularly limited.
The tape-aid according to this invention can
be easily prepared by known processes. For example,
it c:an be prepared by mixing a styrene-isoprene-
styrene block copolymer with a softening agent and a
rosin ester derivative under heating at 120 to 160°C
by the use of a mixing machine such as kneader or
mixer, adding a drug and 3-L-menthoxypropane-1,2-diol
to the obtained mixture, and applying the resulting
mixture to a support either by spreading the mixture
directly on a woven- or nomvoven-fabric: support of
polypropylene or polyester or by once spreading the
mixture on a paper or film treated with a releasing
agent and thereafter covering the spread mixture with
a desired support and then transferring the mixture to
the support by pressing.
Best ~~lode for Carrying Out the Invention
This invention will be illustrated in greater
detail with the following Examples etc. wherein svt.
is based on the total amount of the base. The
Examples though should not be construed as limiting'
the invention.
Example 1 <:ataplastn
(A) 3-L-menthoxypropane-1 , 2-dial 1 . 0'k, by we=fight=
dic:lofenac 0.:>'% by weight:
(B) purified water 48.5';, by weight:
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gelatin H.0'% by weight
kaolin 1.0% by weight
glycerol 35.0 % by weight
polysodium acrylate 2.0% by weight
polyvinyl alcohol 3.0% by weight:
aluminum hydroxide 1.0% by weight
The above ingredients wer e solubilize d
together and agitated to obtain a homogeneous paste.
The paste was applied on a polypro pylene wo ven
non
fabric with a spreader to obtain preparation layer
a
having a thickness of 1 mm. Then, the prepara tion
1<iyer was covered with a polypropy lene filmand
c:ut
into pieces each having a predeter mined to
size obtain
intended c:ataplasms.
Example 2 cataplasm
(A) 3-L-menthoxypropane-1,2-diol ~.0% by weight
loxoprofen 1.0% by weight
thymol 0.1% by weight
(B) purified water 6z.4'% by weight
gelatin
3. 0 % by weight
titanium oxide 1.0 % by weight
glycerol Z~ . 0% by weighs;
polysodium ac:ry:late 3.0';, by weight
carboxymethyl_ cellulose 1.0'k, by weight
ethylene glycol diglyc;idyl c: th e r 1 ty weighs:
. 0'..
sorbitan fatty acrid ester 0.:~':, by weighs:
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The above ingredients were solubilized
together and agitated to obtain a homogeneous paste.
The paste was applied on a polyester nonwo ven fabric:
with a spreader to obtain a preparation layer with a
thickness of 0.5 mm. Then, the preparation layer was
covered with a polyethylene film and cut into pieces
of a predetermined size to obtain intended cataplasms.
example 3 cataplasm
(A) (2S)-3-L-menthoxypropane-1,2-dial 3.0% by weight
c:lobetasone butyrate 0.5% by weight
ethyl paraben 0. 2 % by weight
(B) purified water 42.3% by weight
methoxyethylene-anhydrous
malefic acid copolymer 5.0% by weight
synthetic aluminium silicate 3.0% by weight
glycerol 40.0% by weight
polyac:rylic acid 2.0';. by weight
polyvinyl alcohol 2.:>'% by weight
calcium hydroxide 1 . ~ % by weight
The above ingredients were solubilized
together and agitated to obtain a homogeneous paste.
The paste was applied on a polyurethane film with a
spreader to obtain a preparation layer with a
thickness of 1 mm. Then, the preparation layer was
covered with a polyester film and c:ut into pieces of a
predetermined size to obtain i.ntendecl c:at=aplasms.
Exarnp le 4 c:ataplasm
(A) 3-L-menthoxypropane-1.3-dial. :>.0'bw weight:
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ketoprofen 0.5% by weight
(13) purified water 36.0 % by weight
N-vinylac:etarnide 5.0 % by weight
glycerol 47.0% by weight
polyacrylic acid 3.0% by weight
c:arboxymethyl cellulose 1.0% by weight
magnesium metasilicate alminate 1.5% by weight
glycerol fatty acid ester 1.0% by weight
The above ingredients were solubilized
together and agitated to obtain a homogeneous paste.
The paste was applied on a polyester nonwoven fabric
with a spreader to obtain a preparation layer having a
thickness of 1 mm. Then, the preparation layer was
covered with a polyester film and c:ut into pieces of a
predetermined size to obtain intended c:ataplasms.
Example 5 cataplasm
The procedure of Example 2 was followed
except that the content of 3-L-menthoxypropane-l,Z-
diol was reduced to 0.05 wt.% and the balance was made
up with purified water, thereby preparing cataplasms.
Example 6 cataplasm
The procedure of Example L was E'ollowed
except that 1=he content of 3-L-rnent=hoxypropane-1 , 2-
di.ol was increased to ~~ wt.'s and t=he purified water
was reduced by the amount oI' t:he diol increased.
thereby preparing c:a taplasms.
Example 7 tape-uid
styrene-isoprene-styrene
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bloc:k copolymer 2~.5',~ by weight
polyisobutylene 5.0'" by weight
tac:kifier (rosin ester) 7_5.0'.. by weight
liquid paraffin :W.O';, by weight
3-L-menthoxypropane-1 , 2-dial > . 0',~ by weight
ketotifen 0.5',. by weight
The above components were agitated under
heating, thereby obtaining a paste. The pas te was
spread on a support to obtain a des ired tape-aid
c:ontaining ketotifen.
Example 8 tape-aid
styrene-isoprene-styrene
block copolymer 20.0' by weight
(trade name: Cariflex TR-1107)
liquid paraffin 43.5a by weight
polyisobutylene 10.0~ by weight
(trade name: Vistanex)
rosin ester derivative 21.5x, by weight
(trade name: KE-311)
3-L-menthoxypropane-1,2-diol 4.0% by weight
diclofenac 1.0% by weight
The above components were mixed a ixer
by m to
obtain a paste. The paste was appl ied on plastic
a
I'ilrn previously endowed wit=h releasab.ilit=y,andthen
covered with a P13T nonwoven fabric:and pressure-
c:c>ni;rtet: transferred to obt=ain ired gape-aid.
a des
I?xmnple 9 trope-aid
at=yrene-isoprene-styrene
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block copolymer 16.0'a by weigh i=
(trade name: Cariflex TR-1111)
liquid paraffin 23.0' by weight
polyisobutylene 8.0~ by weight
(trade name: Vistanex)
rosin ester derivative 40.0% by weight
( trade name : Ester (~um H )
(2S)-3-L-menthoxypropane-1,2-dial 10.00 by weight
ketoprofen 3.0% by weight
The above components were mixed together by a
kneader to obtain a paste. The paste was applied on a
plastic: film previously endowed with releasability,
thereon covered with a polypropylene nonwoven fabric:
and pressure-c:ontac:t transferred to obtain a desired
tape-aid.
Example 10 tape-aid
The procedure of Example 8 was followed
except that the content of 3-L-rnenthoxypropane-1,Z-
dial was reduced to 0.0~ wt.% and the balance was made
up with liquid paraffin, thereby producing a tape-aid.
Example 11 tape-aid
The procedure of Example 8 was followed
except that the content of ,3-L-rnenthoxypropane-1,'_>>-
dial was increased to zl wt.°~ and the liquid paraffin
~5 was reduced by the amount of the diol_ increased,
thereby producing a tape-aid.
(;ornprirativc~ Example 1 c:ataplasrn
_ _ _.._ ....__~_-_______._.- -__T_. .___._ _____.._
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The procedure of Example 4 ryas L'ollowed
except that the 3-L-rnenthoxypropane-1 , 2-dial was
replaced with purified water, t=hereby producing
cataplasms.
Comparative Example 2 c:ataplasm
The procedure of Example 4 was followed
except that the 3-L-menthoxypropane-1,2-diol was
replaced with isopropyl myristai=e, thereby producing
cataplasms.
(.'.omparative Example 3 c:ataplasrn
The procedure of Example 4 was followed
except that the 3-L-menthoxypropane-l,~-diol was
replaced with triac:etin, thereby producing c:ataplasms.
(.'.omparative Example 4 c:ataplasm
The procedure of Example 4 was followed
except that the 3-L-menthoxypropane-1,2-dial was
replay:ed with macrogol 400, thereby producing
cataplasms.
Comparative Example 5 cataplasrn
The procedure of Example 4 was followed
except that the 3-L-menthoxypropane-1,2-ct:iol was
replaced with propylene glycol, thereby producing
c:ataplasms .
(;omparrttive Cxample 6 c:atap I_msrn
The procedure of ExmapJc~, 4 wits ('ol.Lowed
except that t=ho 3-L-rnenthoxyproprme-1. , ~-dio I. wus
.__._..~_-._._ _- T___.
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replaced with c;astor oil, thereby produc:ing-
cataplasms.
(:omparative Example 7 <:ataplasm
The procedure of Example 4 was followed
exc:ept that the 3-L-menthoxypropane-1 , ~-dial was
replaced with glycerin monostearate, thereby producing
c:ataplasms .
Test Example 1
The cataplasms of Examples 2 , :p and 6 were
each measured with a viscotester for the viscosity of
their plaster (base) at the time of spreading the base
on their own support to evaluate the spreadability of
the plaster and further the adhesion, stic:l<iness and
stability with the lapse of time (exudation) of the
plaster after being cured and stabilized. 'fire result=s
are given in 'fable 1.
T a b 1 a 1
ViscositySpreadabilityAdhesionStickinessExudation
(poise)
Ex. 32, 000 O O O O
2
Ex. 45, 000 D X O O
5
Ex. 21.000 x p x x
6
O: flood D : a little no good x ; no good
It is apparent from the results given above
that the plaster (barse) coI' tare c:~zt:upLmsrn of Exarnplc-
which contained 3-L-rnenttoxyproparro-1 .'~-diol. in mr
optimum conc:entrat=ion ('~ . by we Lyfr t: ) . cWa i f~ i t-.c~d a
CA 02282583 1999-08-17
proper viscosity when being spread and also exhibited
good results in all of the other items. On the other
h.=md, in Cxamples :~ ~znd 6 wherein the <:oncent;r~zi:ion of
the dial was outside an optimum range of 0.1 to ~0
by weight, the obtained cut~zplasms were unsat=isfac:tory
as compared with that of IJxarnple 2. These results
prove that the optimum concentration of 3-L-
menthoxypropane-1 , 2-diol in a c:atapl~zsrn is 0 . 1 to 20 ';,
by weight based on the whole base.
Test hxample 2
The tape-aids of Cxamples 8, 10 and 11 were
eac:h measured with a viscotester for the viscosity of
their plaster (base) at the time of spreading the base
on their' own support in the same manner as that of
Test IJxample 1 to evaluate the spreadability of the
p7_aster and further the adhesion, stickiness and
stability with the lapse of time [tongwing out:
flowing out of part of the plaster (base) from between
the support and the base] of the plaster after being
ZO c:ured and stabilized. The results ~zre given in Table
T a b 1 a 2
ViscositySpreadabilityAdhesionStickinessTonguing
(poise)
hx. 29, 000 O O O O
8
Cx. 41, 000 D x O O
10
Iix. 19, 000 x O x x
11
O ; good D ; a little no good x ; no good
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It is apparent from the results given above
that the plaster (base) of the tape-aid of Example 8,
which contained 3-L-menthoxypropane-1 , z-dial in an
optimum c:oncentration ( 4 '~ by weight ) , exhibited a
proper vis<:osity when being spread and also exhibited
good results in all of the other items. On the other
hand, in Examples 10 and 11 wherein the concentration
of the diol was outside an optimum range of 0.1 to 20
% by weight, the obtained tape-aids were
unsatisfactory as compared with that of Example 8.
These results prove that the optimum concentration of
3-L-menthoxypropane-1,2-diol in a tape-aid is 0.1 to
% by weight based on the whole base.
Test Example 3 Determination of gel strength and
15 organoleptic: test:
Only the prepared plaster (base) of each of
the cataplasms of Example 4 and (;omparative Examples 1
to 7 was packed in a hermetically closed vessel, and
taken out after being cured and stabilized to
z0 determine the gel strength of the base with a
rheometer. At the same tune, each cataplasm was
evaluated for overall feeling realized by the use
thereof (which inc:hides adhesion, fitness and
sti.cki.ness to the skin, bleeding of i=he plastic:izer,
~5 smell, remains of the plaster, and pain caused on
p.°eling) by orgmnolepti.c tests. Each <:atapl_asrn was
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_ Z7 _
applied to the elbow for four hours. The results are
given in Table 3.
T a b 1 a 3
Gel AdhesionFit StickinessBleedingOdorPlasterPeeling
Strength Feeling QemainsPain
(g)
Ex. 173 ~ O O O O O
4
comp.225 O O O O O O O
Ex.
1
comp.169 O O D x O D O
Ex.
2
comp.188 O O D x O O O
Ex.
3
Comp.220 O D x O O O D
Ex.
4
Comp.170 O O x D O D D
Ex.
5
Comp.175 p O x x p p O
Ex.
6
Comp.208 O O D x O O O
Ex.
7
0: better than conventional ones O: as good as conventional ones
D: Worse than conventional ones x ; no good
ZO It is apparent from the results given above
that the plaster (base) of Example 4 containing 3-L-
menthoxypropane-1,2-diol was very lowered in gel
strength and was plasticized and softened as compared
with that of (;ornparative Example 1. containing no
~5 pl_astic::izer.
rI'he plasters ( brisc~s ) c>f' (;ornparat ive hxarnples
to 7 were also lowered in gel strengt;h, 1 wo~ver,
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scarcely improved in the adhesion and fitness to the
skin. Even Comparative Example 5 which was only
improved in adhesion vvas rather inferior t:o
conventional products in the overall feeling when in
use such as bleeding (c:ompatibility of the plastic:izer
with the base), stic:kiness, and remains of the
plaster.
On the other hand, the c:ataplasm of Example 4
c:ontaining 3-L-menthoxypropane-1,~-diol was superior
to the conventional products in adhesion and fitness
to the skin, and pain when peeling. Thus, the
cataplasrn of Example 4 had the intended
characteristics, which proves the utility of 3-L-
menthoxypropane-1,Z-dial as the plasticizer for the
base of a c:ataplasm.
Test Example 4 Test on safety for the skin
The cataplasms of Examples 1 to 4 and
Comparative Examples z to 3 were examined for safety
for the skin.
The safety of each cataplasm for the skin was
determined by 30 healthy male and fernrzle suhjec:ts
ar:c;ording~ to the 48-hour closed patch test. The
change in the s4<in of each subject was observed 1 and
~4 hours after the peel_:ing of the c;rit~rplusrn to
c~valurite t:he irrit:at:i.veness of the <:at:aplasrn to the
slci.n accc>rdi.ng i:o the following criteria. 'l'he result:s
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are given in 'fables 4 and 5. Sub,je<:ts scored ~ or
more (~, + or ++) were regarded us pos:it;ivc~.
no change in ttne sL<in
~: slight rubefaction
+: clear rubefac:tion
++: heavy contact dermatitis
T a b 1 a 4
Lapse of time after peeling off poultice: 1 hour
SamplesNu mber Subjects Percentage of
1 0 of
Positive Reaction
-f--1--f- - (%)
( or more)
Cx. 0 0 0 30 0.0
1
Cx. 0 0 1 29 3.3
2
Cx. 0 0 0 30 0.0
3
Gx. 0 0 1 29 3.3
~
Comp. 0 0 5 25 16.7
Cx.
2
Comp. 0 1 3 26 13.3
Cx.
3
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T a b 1 a 5
Lapse of time after peeling off poultice: 24 hours
SamplesNu mber Subjects Percentage of
of ti
(%)
P
iti
8
++ + - eac
on
os
ve
( or more)
Ex. 0 0 0 30 0.0
1
Ex. 0 0 0 30 0.0
2
Ex. 0 0 0 30 0.0
3
Ex. 0 0 0 30 0.0
4
Comp. 0 0 2 28 6.7
Ex.
2
Comp. 0 0 3 27 10.0
Ex.
3
fhe above results show l:hrzt; the catapl~zsms of
Cxamples 1 to 4 of this invention ure extremely high
in safety for the skin.
Industrial ApPlicabilit
According to the present invention. ,3-L-
z0 menthoxypropane-1 , 2-dial which hms been known ns a
refrigerant is c:ontuined ors n plant::i.cizer in t:ho husc~
of a patch. !-1s a result, the dial <~xhibits excellent:
pl_astic:izing effect on the pat<:h brio and i s fi.gh i.n
safety, stability and compatibility with the base.
Therefore, when.the patch containing t:he dial. i.s
mpplied t:o the skin, i:he patch exhibit:s unproved
overml.l_ fec~ ling~s such ors mllres ion rrnd (' it:ncss t:o give
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stein, and pain when peeling. Further, su<:h a pat:<:Ir
does not cause skin irritation such as contact
dermatitis even when applied and peeled repeatedly,
and is t=hus highly safe. Furthermore, the patch is
odorless and serves c:omfortable refreshing
refrigeration to the skin.
Therefore, the plastic:izer and patch of this
invention are suited for use in medical products, thus
having high industrial applicability.
15
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