U.S. patent application number 12/460146 was filed with the patent office on 2009-11-05 for nonaqueous pressure-sensitive adhesive for medicinal tape preparation for percutaneous absorption, medicinal tape preparation for percutaneous absorption, and process for producing the same.
This patent application is currently assigned to NIPRO PATCH CO., LTD. Invention is credited to Naohisa Kawamura, Takayuki Kobayashi, Hidenori Sawada.
Application Number | 20090274748 12/460146 |
Document ID | / |
Family ID | 33535049 |
Filed Date | 2009-11-05 |
United States Patent
Application |
20090274748 |
Kind Code |
A1 |
Kawamura; Naohisa ; et
al. |
November 5, 2009 |
Nonaqueous pressure-sensitive adhesive for medicinal tape
preparation for percutaneous absorption, medicinal tape preparation
for percutaneous absorption, and process for producing the same
Abstract
A nonaqueous pressure-sensitive adhesive for a medicinal tape
preparation for percutaneous absorption comprising (a) a support,
(b) a pressure-sensitive adhesive layer containing a drug and a
nonaqueous pressure-sensitive adhesive and (c) a release film
laminated in that order, and a medicinal tape preparation for
percutaneous absorption comprising the adhesive. The nonaqueous
pressure-sensitive adhesive may comprise a copolymer obtained by
copolymerization of a (meth)acrylic monomer having an acetoacetyl
group in the molecule and one or more monomers from among other
(meth)acrylic monomers without acetoacetyl groups and
copolymerizable vinyl monomers, in a nonaqueous solvent. Suitable
(meth)acrylic monomers having an acetoacetyl group in the molecule
are acetoacetoxyalkyl methacrylates, and especially
2-acetoacetoxyethyl methacrylate. The copolymer nonaqueous
pressure-sensitive adhesive of the invention, comprising a
(meth)acrylic monomer having an acetoacetyl group as a constituent
monomer, is capable of containing large amounts of lipophilic oily
substances in the pressure-sensitive adhesive layer, and during
heat drying, the acetoacetyl groups undergo self-crosslinking to
form a network structure as the solvent evaporates off, so that
large amounts of oily substances such as the plasticizer can be
included in the network structure. The pressure-sensitive adhesive
of the invention uses no polyamine derivatives, isocyanate
compounds, polyvalent metal chelate compounds, etc., as
crosslinking agents, and therefore toxicity is not a concern and
skin is not irritated. A medicinal tape preparation for
percutaneous absorption of the invention has superior adhesive
strength and cohesive strength, and is highly safe with low skin
irritation. It also has excellent drug release and percutaneous
absorption properties.
Inventors: |
Kawamura; Naohisa;
(Kasukabe-shi, JP) ; Sawada; Hidenori;
(Kasukabe-shi, JP) ; Kobayashi; Takayuki;
(Kasukabe-shi, JP) |
Correspondence
Address: |
OHLANDT, GREELEY, RUGGIERO & PERLE, LLP
ONE LANDMARK SQUARE, 10TH FLOOR
STAMFORD
CT
06901
US
|
Assignee: |
NIPRO PATCH CO., LTD
|
Family ID: |
33535049 |
Appl. No.: |
12/460146 |
Filed: |
July 14, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10561751 |
Dec 21, 2005 |
|
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|
PCT/JP04/08544 |
Jun 17, 2004 |
|
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12460146 |
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Current U.S.
Class: |
424/448 ;
523/111 |
Current CPC
Class: |
A61K 9/7061 20130101;
A61L 24/046 20130101; A61K 47/32 20130101; A61P 9/12 20180101; A61P
37/08 20180101; A61P 19/00 20180101; Y10T 156/1052 20150115; A61F
2013/00663 20130101 |
Class at
Publication: |
424/448 ;
523/111 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 47/32 20060101 A61K047/32 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 24, 2003 |
JP |
2003-179162 |
Claims
1. A nonaqueous pressure-sensitive adhesive for a medicinal tape
preparation for percutaneous absorption, characterized by
comprising a copolymer obtained by copolymerization of (i)
2-acetoacetoxyethyl acrylate or 2-acetoacetoxyethyl methacrylate,
(ii) one or more (meth)acrylic monomers selected from the group
consisting of 2-ethylhexyl acrylate, methyl methacrylate and butyl
acrylate, and (iii) one or more (meth)acrylic monomers selected
from the group consisting of diacetoneacrylamide, diethyleneglycol
dimethacrylate and tetraethyleneglycol dimethacrylate, in a
nonaqueous solvent.
2. A nonaqueous pressure-sensitive adhesive for a medicinal tape
preparation for percutaneous absorption according to claim 1,
characterized in that the copolymer is a copolymer obtained by
copolymerization of (i) 2-acetoacetoxyethyl methacrylate, (ii)
2-ethylhexyl acrylate and/or methyl methacrylate, and (iii) one or
more (meth)acrylic monomers selected from the group consisting of
diacetoneacrylamide, diethyleneglycol dimethacrylate and
tetraethyleneglycol dim ethacrylate.
3. A nonaqueous pressure-sensitive adhesive for a medicinal tape
preparation for percutaneous absorption according to claim 1,
characterized in that the copolymer is a copolymer obtained by
copolymerization of (i) 2-acetoacetoxyethyl methacrylate, (ii)
2-ethylhexyl acrylate and methyl methacrylate, and (iii)
diacetoneacrylamide and tetraethyleneglycol dimethacrylate.
4. A nonaqueous pressure-sensitive adhesive for a medicinal tape
preparation for percutaneous absorption according to claim 1,
characterized in that the copolymer has a calculated glass
transition temperature (Tg) of between -60.degree. C. and
-5.degree. C.
5. A medicinal tape preparation for percutaneous absorption
comprising (a) a support, (b) a pressure-sensitive adhesive layer
containing a drug and a nonaqueous pressure-sensitive adhesive and
(c) a release film laminated in that order, the medicinal tape
preparation for percutaneous absorption being characterized in that
said pressure-sensitive adhesive layer is formed by coating a
support or release film with a nonaqueous pressure-sensitive
adhesive comprising a copolymer obtained by copolymerization of (i)
2-acetoacetoxyethyl acrylate or 2-acetoacetoxyethyl methacrylate,
(ii) one or more (meth)acrylic monomers selected from the group
consisting of 2-ethylhexyl acrylate, methyl methacrylate and butyl
acrylate, and (iii) one or more (meth)acrylic monomers selected
from the group consisting of diacetoneacrylamide, diethyleneglycol
dimethacrylate and tetraethyleneglycol dimethacrylate, in a
nonaqueous solvent, together with a drug, and heating to
dryness.
6. A medicinal tape preparation for percutaneous absorption
according to claim 5, characterized in that the copolymer is a
copolymer obtained by copolymerization of (i) 2-acetoacetoxyethyl
methacrylate, (ii) 2-ethylhexyl acrylate and/or methyl
methacrylate, and (iii) one or more (meth)acrylic monomers selected
from the group consisting of diacetoneacrylamide, diethyleneglycol
dimethacrylate and tetraethyleneglycol dimethacrylate.
7. A medicinal tape preparation for percutaneous absorption
according to claim 5, characterized in that the copolymer has a
calculated glass transition temperature (Tg) of between -60.degree.
C. and -5.degree. C.
8. A medicinal tape preparation for percutaneous absorption
according to claim 5, characterized in that the pressure-sensitive
adhesive layer further comprises a plasticizer.
9. A medicinal tape preparation for percutaneous absorption
according to claim 8, characterized in that the plasticizer is one
or more oils selected from the group consisting of fatty acid
esters, higher alcohols and castor oil.
10. A medicinal tape preparation for percutaneous absorption
according to claim 8, characterized in that the plasticizer content
is no greater than 50 wt % of the total weight of said
pressure-sensitive adhesive layer.
11. A medicinal tape preparation for percutaneous absorption
according to claim 9, characterized in that the plasticizer is one
or more fatty acid esters selected from the group consisting of
isopropyl myristate, isopropyl palmitate, medium-chain fatty acid
triglycerides, diethyl sebacate and diisopropyl adipate.
12. A medicinal tape preparation for percutaneous absorption
according to claim 11, characterized in that the plasticizer is
isopropyl myristate.
13. A medicinal tape preparation for percutaneous absorption
according to claim 8, characterized in that the nonaqueous
pressure-sensitive adhesive comprises a copolymer obtained by
copolymerization of (i) 2-acetoacetoxyethyl methacrylate, (ii)
2-ethylhexyl acrylate and methyl methacrylate, and (iii)
diacetoneacrylamide and tetraethyleneglycol dimethacrylate, in a
nonaqueous solvent and, the plasticizer is isopropyl myristate.
14. A medicinal tape preparation for percutaneous absorption
according to claim 5, characterized in that the drug is a
percutaneously absorbing drug selected from the group consisting of
steroid hormones, non-steroidal anti-inflammatory drugs,
tranquilizers, anti-hypertensive agents, ischemic heart disease
drugs, anti-histamines, antiasthmatic drugs, anti-Parkinson drugs,
cerebral circulation improvers, antiemetics, anti-depressants,
anti-dementia drugs, Sjogren's syndrome treatments, anti-arrhythmia
drugs, anticoagulants, gout suppressants, antifungal agents,
narcotic analgesics, beta blockers, .beta.1 agonists, .beta.2
agonists, antitumor agents, diuretics, antithrombotic agents,
histamine H1 receptor antagonists, histamine H2 receptor
antagonists, anti-allergic agents, serotonin receptor antagonists,
anti-hypercholesteremic agents and smoking cessation aids.
15. A process for production of a medicinal tape preparation for
percutaneous absorption comprising (a) a support, (b) a
pressure-sensitive adhesive layer containing a drug and a
nonaqueous pressure-sensitive adhesive and (c) a release film
laminated in that order, the process being characterized by coating
the surface of a release film or support with a nonaqueous
pressure-sensitive adhesive comprising a copolymer obtained by
copolymerization of (i) 2-acetoacetoxyethyl acrylate or
2-acetoacetoxyethyl methacrylate, (ii) one or more (meth)acrylic
monomers selected from the group consisting of 2-ethylhexyl
acrylate, methyl methacrylate and butyl acrylate, and (iii) one or
more (meth)acrylic monomers selected from the group consisting of
diacetoneacrylamide, diethyleneglycol dimethacrylate and
tetraethyleneglycol dimethacrylate, in a nonaqueous solvent, with a
drug and if necessary with a plasticizer, heating to dryness to
form a pressure-sensitive adhesive layer, and then laminating a
release film or support thereon and cutting it to a desired
size.
16. A process for production of a medicinal tape preparation for
percutaneous absorption according to claim 15, characterized in
that the pressure-sensitive adhesive layer is formed by heat drying
at 40-150.degree. C.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Continuation application of,
and claims benefit of, U.S. patent application Ser. No. 10/561,751,
filed on Dec. 21, 2005, which was the National Stage of, and claims
benefit of, International Application PCT/JP2004/008544, filed on
Jun. 17, 2004, which claims benefit of, and priority to, Japanese
Patent Application No. 2003-179162, filed on Jun. 24, 2003, all of
which are herein incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to a nonaqueous
pressure-sensitive adhesive for a medicinal tape preparation for
percutaneous absorption, comprising a copolymer obtained by
copolymerization of a (meth)acrylic monomer having an acetoacetyl
group in the molecule and one or more monomers selected from among
other (meth)acrylic monomers with no acetoacetyl group and
copolymerizable vinyl monomers, in a nonaqueous solvent, as well as
to a medicinal tape preparation for percutaneous absorption
produced by coating a nonaqueous pressure-sensitive adhesive onto
the top side of a support or release film, together with a drug and
plasticizer, and heating to dryness to form a pressure-sensitive
adhesive layer, and then further laminating a release film or
support over the pressure-sensitive adhesive layer, and to a
process for producing the same. The medicinal tape preparation for
percutaneous absorption according to the invention is a highly
stable tape preparation for percutaneous absorption which exhibits
excellent drug release from the preparation and excellent drug skin
permeability, with low skin irritation.
BACKGROUND ART
[0003] Paints, coatings and pressure-sensitive adhesives are known
wherein copolymers obtained by copolymerization of
acetoacetoxyalkyl methacrylates and other monomers are crosslinked
with crosslinking agents such as polyamine compounds or isocyanate
compounds. (See, for example, Patent document 1 and Patent document
2). However, no patent document or non-patent document can be found
which describes the use of a nonaqueous pressure-sensitive adhesive
comprising a copolymer obtained by copolymerization of a
(meth)acrylic monomer having an acetoacetyl group, and one or more
monomers selected from among other (meth)acrylic monomers and
copolymerizable vinyl monomers, as the pressure-sensitive adhesive
used in a medicinal tape preparation for percutaneous
absorption.
[0004] Tape preparations for percutaneous absorption have been
known which comprise a drug and plasticizer in a pressure-sensitive
adhesive layer, wherein a ketone group-containing
pressure-sensitive adhesive is substantially crosslinked with a
polyamine crosslinking agent. (See, for example, Patent document
3). However, no description is found of a tape preparation for
percutaneous absorption having a pressure-sensitive adhesive
comprising a copolymer with an acetoacetyl group.
[0005] There have also been known preparations for percutaneous
absorption which contain an isosorbide dinitrate coronary
vasodilator and a fatty acid ester in a crosslinked
pressure-sensitive adhesive comprising an acrylic copolymer
composed of an acrylic acid alkyl ester and a functional monomer as
essential components. (See, for example, Patent document 4).
However, this preparation for percutaneous absorption employs a
crosslinking agent, and it is stated that without a crosslinking
agent the pressure-sensitive adhesive layer lacks cohesive strength
and cannot be used in a preparation for percutaneous absorption. In
addition, Patent documents 3 and 4 do not provide examples of tape
preparations for percutaneous absorption with pressure-sensitive
adhesives comprising copolymers with acetoacetyl groups.
[0006] Patent document 1: Japanese Unexamined Patent Publication
HEI No. 6-108033
[0007] Patent document 2: Japanese Unexamined Patent Publication
HEI No. 7-238203
[0008] Patent document 3: Japanese Unexamined Patent Publication
No. 2002-535475
[0009] Patent document 4: Japanese Unexamined Patent Publication
HEI No. 8-81369
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0010] It is an object of the present invention to provide a
medicinal tape preparation for percutaneous absorption having a
drug-containing pressure-sensitive adhesive layer formed on a
support and a release liner laminated thereover, wherein a large
amount of a lipophilic oily substance can be included in the
pressure-sensitive adhesive layer and the preparation has excellent
adhesion, cohesive strength and stability, as well as a nonaqueous
pressure-sensitive adhesive for the preparation.
[0011] The pressure-sensitive adhesive layer of the medicinal tape
preparation for percutaneous absorption may also contain, in
addition to a drug, also a solvent for dissolution of the drug, a
percutaneous absorption accelerator to accelerate the percutaneous
absorption rate of the drug, a plasticizer for improved plasticity
of the pressure-sensitive adhesive or a tackifier for improved
adhesive strength, and in some cases it may be necessary to include
such components in significant amounts. The drug-dissolving
solvent, percutaneous absorption accelerator, plasticizer and
tackifier included with the drug in the pressure-sensitive adhesive
layer will usually be lipophilic oily substances.
[0012] Problems have been encountered with conventional medicinal
tape preparations for percutaneous absorption employing a
non-crosslinked pressure-sensitive adhesive, in that it has not
been possible to hold large amounts of oily substances, or when
large amounts of oily substances are contained it has not been
possible to form tape preparations and the oily substances have
separated from the pressure-sensitive adhesive layers after
formation of the preparations, and therefore the amounts of oily
substances in pressure-sensitive adhesive layers have been
limited.
[0013] In order to overcome these problems, there have also been
studied tape preparations wherein a pressure-sensitive adhesive
obtained by polymerizing a functional group-containing monomer is
crosslinked with a crosslinking agent such as a polyamine compound,
isocyanate compound or polyvalent metal chelate compound. However,
such crosslinking agents are often toxic compounds or they have
undesirable effects on certain drugs, while restrictions are
necessary on their use or the amounts of their use.
[0014] Self-crosslinking pressure-sensitive adhesives employing no
crosslinking agents are known, such as pressure-sensitive adhesives
comprising N-methylolacrylamide as a constituent monomer, but such
adhesives are not preferred for medicinal pressure-sensitive
adhesive tapes due to gradually release of the harmful substance
formaldehyde.
[0015] There are also known copolymers comprising acetoacetyl
group-containing monomers as constituent monomers, for use as
paints, coating agents and adhesives, but all such compounds are
crosslinked using crosslinking agents such as polyamine
derivatives, isocyanate compounds and polyvalent metal chelate
compounds, and their use in medicinal tape preparations for
percutaneous absorption is not known. In addition, these
crosslinking agents are associated with such problems as toxicity
and unsuitability for certain types of drugs.
Means for Solving the Problems
[0016] As a result of much research conducted with the aim of
solving the problems described above, the present inventors
discovered that it is possible to hold large amounts of oily
substances such as plasticizers by using a nonaqueous
pressure-sensitive adhesive comprising a copolymer obtained by
copolymerization of a (meth)acrylic monomer having an acetoacetyl
group in the molecule and one or more monomers selected from among
other (meth)acrylic monomers with no acetoacetyl group and
copolymerizable vinyl monomers, in a nonaqueous solvent.
[0017] The nonaqueous pressure-sensitive adhesive used in the
medicinal tape preparation for percutaneous absorption of the
invention, comprising a copolymer obtained by copolymerization of a
(meth)acrylic monomer having an acetoacetyl group and one or more
vinyl monomers selected from among other (meth)acrylic monomers
with no acetoacetyl group and copolymerizable vinyl monomers, in a
nonaqueous solvent, undergoes self-crosslinking of the acetoacetyl
groups as the solvent evaporates during the step of coating onto a
support or release film together with a drug and plasticizer
followed by heating to dryness, thereby forming a network structure
with the oily substances such as the plasticizer held in the
network structure.
[0018] By adjusting the amount of acetoacetyl group-containing
(meth)acrylic monomer in the starting material, it is possible to
alter the degree of self-crosslinking of the pressure-sensitive
adhesive. It was discovered that, as a result, it is possible to
adjust the content of lipophilic oily substances such as
plasticizers, percutaneous absorption accelerators, drug dissolving
agents and the like in the pressure-sensitive adhesive layer, and
that by modifying the content ratio of the pressure-sensitive
adhesive and the plasticizer or percutaneous absorption accelerator
it is possible to produce suitable adhesion and cohesive strength
and obtain a stable tape preparation for percutaneous absorption;
the present invention was completed on the basis of this
discovery.
EFFECT OF THE INVENTION
[0019] In the step of heat drying the nonaqueous pressure-sensitive
adhesive copolymer comprising a (meth)acrylic monomer having an
acetoacetyl group as a constituent monomer according to the
invention, a network structure is formed by self-crosslinking of
the acetoacetyl groups as the solvent evaporates, so that large
amounts of oily substances such as the plasticizer can be included
in the network structure. The pressure-sensitive adhesive of the
invention uses no polyamine derivatives, isocyanate compounds or
polyvalent metal chelate compounds as crosslinking agents, and
therefore since toxicity is not a concern and the skin is not
irritated, the adhesive is suitable for medical use. The medicinal
tape preparation for percutaneous absorption of the invention has
excellent adhesive and cohesive strength, and is highly safe with
low skin irritation. Its properties of drug release and
percutaneous absorption are also excellent.
BEST MODE FOR CARRYING OUT THE INVENTION
[0020] The nonaqueous pressure-sensitive adhesive for a medicinal
tape preparation for percutaneous absorption according to the
invention may be obtained by copolymerization of a (meth)acrylic
monomer having an acetoacetyl group in the same molecule and one or
more monomers selected from among (meth)acrylic monomers with no
acetoacetyl group and copolymerizable vinyl monomers, in a
nonaqueous solvent.
[0021] As (meth)acrylic monomers having an acetoacetyl group there
may be mentioned acetoacetoxyalkyl methacrylates or
acetoacetoxyalkyl acrylates such as 2-acetoacetoxyethyl
methacrylate, 2-acetoacetoxyethyl acrylate, 3-acetoacetoxypropyl
methacrylate, 3-acetoacetoxypropyl acrylate, 4-acetoacetoxybutyl
methacrylate and 4-acetoacetoxybutyl acrylate, among which any one
or more may be used, although 2-acetoacetoxyethyl methacrylate and
2-acetoacetoxyethyl acrylate are preferred.
[0022] As other (meth)acrylic monomers having no acetoacetyl group
there may be used any (meth)acrylic monomers having a
copolymerizable double bond in the molecule, and one or more such
(meth)acrylic monomers may be used. As specific examples there may
be mentioned one or more (meth)acrylic monomers selected from the
group consisting of 2-ethylhexyl acrylate, 2-ethylhexyl
methacrylate, diacetoneacrylamide, butyl acrylate, butyl
methacrylate, ethyleneglycol dimethacrylate, diethyleneglycol
dimethacrylate, triethyleneglycol methacrylate, tetraethyleneglycol
diacrylate, tetraethyleneglycol dimethacrylate, hexaethyleneglycol
dimethacrylate, hexaethyleneglycol diacrylate, methyl methacrylate,
acrylamide, methacrylamide, 2-hydroxyethyl acrylate and acrylic
acid, of which there are preferred one or more acrylic monomers
selected from the group consisting of 2-ethylhexyl acrylate,
diacetoneacrylamide, butyl acrylate, tetraethyleneglycol
diacrylate, tetraethyleneglycol dimethacrylate and methyl
methacrylate.
[0023] The other vinyl compound which is copolymerizable with the
monomer having an acetoacetyl group need only have a
copolymerizable vinyl group in the molecule, and as examples there
may be mentioned vinyl derivatives such as N-vinyl-2-pyrrolidone
and vinyl acetate.
[0024] The content of the acetoacetyl group-containing monomer in
the copolymer used in the nonaqueous pressure-sensitive adhesive of
the invention is preferably 1-40 wt % and more preferably 5-40 wt %
with respect to the total weight of the copolymer. The proportion
is preferably not smaller than 1 wt %, because the oily
substance-holding power and the cohesive strength will be reduced,
and it is preferably not greater than 40 wt % because the network
structure will become too dense, reducing the holding power for the
plasticizer and other components.
[0025] The solvent of the nonaqueous pressure-sensitive adhesive
for the medicinal tape preparation for percutaneous absorption
according to the invention may be any organic solvent which
volatilizes in the heat drying step during the production process
for the medicinal tape preparation for percutaneous absorption of
the invention. Such a solvent may be any of various organic
solvents including acetic acid esters such as methyl acetate, ethyl
acetate, propyl acetate and butyl acetate, aliphatic hydrocarbons
such as hexane, heptane, octane and cyclohexane, aromatic
hydrocarbons such as benzene, toluene and xylene, ketones such as
acetone and methyl ethyl ketone, and ethers such as isopropyl
ether, tetrahydrofuran and dioxane, among which any may be used
alone, or two or more may be used in combination.
[0026] The nonaqueous pressure-sensitive adhesive of the invention
may be produced by a well-known method in the relevant technical
field. A specific preferred method is dissolution of each of the
monomers in an organic solvent and polymerization with a radical
initiator.
[0027] Alternatives include dissolution of all of the monomers in a
prescribed organic solvent beforehand, nitrogen substitution, and
then heating for polymerization, or successive loading of the
monomer in separate amounts into the solvent for polymerization.
The monomer concentration in the organic solvent is preferably
10-80 wt %. The concentration is preferably not less than 10 wt %
because it will be difficult to achieve a high polymerization
degree, while it is preferably not greater than 80 wt % because
control of the heat of polymerization during the reaction will
become difficult. The organic solvent used for the polymerization
may be any single solvent selected from the group consisting of
organic solvents mentioned above, or a combination of two or more
thereof. Also, the same type or different types of solvents may be
added successively during the polymerization.
[0028] The radical initiator used for the invention may be a
compound selected from among peroxides, azo initiators and the
like, or a mixture thereof, and it is used in an amount of
preferably 0.001-2.00 parts by weight and more preferably 0.005-0.1
part by weight to 100 parts by weight of the monomer.
[0029] As specific peroxides there may be mentioned benzoyl
peroxide, lauroyl peroxide, tert-butyl hydroperoxide,
di(2-ethylhexyl)peroxydicarbonate and
1,1'-di-tert-butyl-peroxy-2-methylcyclohexane. As specific azo
initiators there may be mentioned 2,2'-azobisisobutyronitrile,
4,4'-azobis-4-cyanovaleric acid and 2,2'-azobis(2-amidinopropane)
dihydrochloride.
[0030] The polymerization temperature may be a temperature at which
the radical initiator generates a suitable level of radicals, and
in most cases it is preferably 50-120.degree. C.
[0031] The amount of residual monomer of the nonaqueous
pressure-sensitive adhesive of the invention is preferably
minimized for reduced skin irritation and improved drug stability,
and preferably it is no greater than 20,000 ppm with respect to the
solid portion of the pressure-sensitive adhesive. In order to
reduce the residual monomer, for example, additional radical
initiator may be added after completion of the polymerization, or
high-<temperature treatment may be carried out under pressurized
conditions.
[0032] A greater molecular weight of the copolymer of the
pressure-sensitive adhesive of the invention will result in
inferior adhesion, while a smaller molecular weight will result in
inferior cohesive strength. The molecular weight of the copolymer
may be a weight-average molecular weight of between several tens of
thousands to several million.
[0033] The glass transition temperature (hereinafter also referred
to as "Tg") of the copolymer of the pressure-sensitive adhesive of
the invention also has a significant effect on the adhesive and
cohesive strength of the pressure-sensitive adhesive, with a high
Tg tending to result in a harder pressure-sensitive adhesive and a
low Tg tending to results in a softer one, and therefore the Tg of
the copolymer is preferably in the range of -60.degree. C. to
-5.degree. C. The range is more preferably between -50.degree. C.
and -10.degree. C. If it is below -60.degree. C., the cohesive
strength of the pressure-sensitive adhesive will tend to be too
weak when the plasticizer is added, while a Tg of higher than
-5.degree. C. will tend to result in poor adhesive strength even
with addition of a large amount of plasticizer.
[0034] The glass transition temperature can generally be determined
by measurement with a DSC apparatus or measurement of the
viscoelasticity. It can also be derived by calculation using the
following formula 1, as the glass transition temperature of the
homopolymer.
100 Tg = Wi Tgi ( 1 ) ##EQU00001##
(wherein Wi represents the weight fraction (%) of the monomer of
component {"i", and Tgi represents the glass transition temperature
(.degree.K) of the homopolymer of component "i".)
[0035] The plasticizer included in the pressure-sensitive adhesive
layer of the medicinal tape preparation for percutaneous absorption
of the invention may be an oily substance with a high boiling point
in most cases. For example, there may be used fatty acid ester
derivatives such as isopropyl myristate, diethyl sebacate,
diisopropyl adipate, ethyl oleate, isopropyl palmitate, ethyl
laurate, octyl palmitate, isotridecyl myristate and medium-chain
fatty acid triglycerides; higher alcohol derivatives such as
hexyldecanol and octyldodecanol; polyalkylene glycols such as
polyethylene glycol and polypropylene glycol; and fats and oils
such as olive oil, castor oil and the like. These may be used alone
or in mixtures of two or more, but isopropyl myristate and
isopropyl palmitate are most preferred because they function as
plasticizers for the pressure-sensitive while also accelerating
diffusion of the drug in the tape preparation and promoting skin
permeability of the drug. The plasticizer content is preferably no
greater than 50 wt % and more preferably 10-40 wt % with respect to
the total weight of the pressure-sensitive adhesive layer. The
plasticizer content is preferably not greater than 50 wt % because
such an amount cannot be held in the pressure-sensitive adhesive
layer, and the oily substances will tend to bleed from the
pressure-sensitive adhesive layer.
[0036] The pressure-sensitive adhesive in the pressure-sensitive
adhesive layer of the medicinal tape preparation for percutaneous
absorption of the invention exhibits suitable adhesive strength
even alone if it contains a percutaneous absorbing drug and a
plasticizer in addition to the nonaqueous pressure-sensitive
adhesive, but if even stronger adhesive strength is desired, a
tackifier may be included in the pressure-sensitive adhesive layer
to increase the adhesive strength, and examples of tackifiers that
are suitable for use include alicyclic saturated hydrocarbon resins
and rosin ester derivatives. Alicyclic saturated hydrocarbon resins
include ALCON P-100 (trade name of Arakawa Chemical Industries Co.,
Ltd.) while rosin ester derivatives include ESTERGUM H (trade name
of Arakawa Chemical Industries Co., Ltd.), and any one or mixtures
of two or more may be used.
[0037] There are no particular restrictions on drugs to be
formulated in the tape preparation for percutaneous absorption of
the invention, and they may be selected to conform to the purpose
of treatment; examples of suitable drugs include steroid hormones,
non-steroidal anti-inflammatory drugs, tranquilizers,
anti-hypertensive agents, ischemic heart disease drugs,
anti-histamines, antiasthmatic drugs, anti-Parkinson drugs,
cerebral circulation improvers, antiemetics, anti-depressants,
anti-dementia drugs, Sjogren's syndrome treatments, anti-arrhythmia
drugs, anticoagulants, gout suppressants, antifungal agents,
narcotic analgesics, beta blockers, .beta.1 agonists, .beta.2
agonists, antitumor agents, diuretics, antithrombotic agents,
histamine H1 receptor antagonists, histamine H2 receptor
antagonists, anti-allergic agents, serotonin receptor antagonists,
anti-hypercholesteremic agents and smoking cessation aids, and any
percutaneously absorbed drugs may be used which do not reside on
the skin surface but penetrate to the subcutaneous layer or into
the blood to exhibit a local or systemic effect. Two or more of
such drugs may also be used together if necessary. Also, the
contents of the drugs may be appropriately set depending on the
type of drug, its effect and the purpose of administration.
[0038] If necessary, the pressure-sensitive adhesive layer of the
tape preparation for percutaneous absorption of the invention may
also include, in addition to the aforementioned drug,
pressure-sensitive adhesive and plasticizer, also a drug
solubilizer, percutaneous absorption accelerator and other
excipients.
[0039] A drug solubilizer is a drug-dissolving solvent, and any
solvent which is not skin-irritating may be used. Specifically,
there may be used lower alcohols such as ethanol, propanol and
isopropanol, medium alcohols such as hexanol and octanol,
polyhydric alcohols such as glycerin, ethylene glycol and
diethyleneglycol, fatty acid esters, polyvinyl alcohols,
N-methylpyrrolidone, crotamiton and the like, any of which may be
used alone or in combinations of two or more as drug-dissolving
agents, although there is no limitation to these.
[0040] As drug percutaneous absorption accelerators there may be
used any which are commonly utilized in tape preparations for
percutaneous absorption, including fatty acid esters such as
isopropyl myristate, isopropyl palmitate and diisopropyl adipate,
fatty acid polyhydric alcohol esters such as caprylic
monoglyceride, caprylic triglyceride and sorbitan fatty acid
esters, and terpenes such as 1-menthol, peppermint oil and
limonene.
[0041] Examples of excipients include silicon compounds such as
silicic anhydride and light silicic anhydride, cellulose
derivatives such as ethyl cellulose, methyl cellulose,
carboxymethylcellulose sodium, hydroxypropyl cellulose and
hydroxypropylmethyl cellulose, water-soluble polymers such as
polyvinyl alcohol, antioxidants such as dibutylhydroxytoluene and
powders such as kaolin and titanium oxide, as well as aromatics and
coloring agents, and these may be added in medically acceptable
ranges.
[0042] There are no particular restrictions on the support for the
tape preparation for percutaneous absorption of the invention, and
there may be used stretchable or non-stretchable woven or nonwoven
fabric or knit textiles made of polyethylene, polypropylene,
polyester or the like, plastic films made of polyethylene,
polypropylene, polyester, ethylene-vinyl acetate copolymer, vinyl
chloride or the like, or foam films made of polyurethane or the
like, either alone or in laminated combinations, depending on the
purpose of use.
[0043] The release liner on the tape preparation for percutaneous
absorption of the invention serves to protect the
pressure-sensitive adhesive layer during storage, and there may be
used polyester, polyethylene, polypropylene, ethylene-vinyl acetate
copolymer resin, polyurethane, a metal foil thin-film, a film
having a laminated structure comprising a combination of such
materials, a film which has been silicon-treated on the surface to
be attached to the pressure-sensitive adhesive layer, or a film
having a metal such as aluminum vapor-deposited on the surface. In
addition, the release liner may be provided with a continuous or
non-continuous straight or curved notch for easier release.
[0044] The tape preparation for percutaneous absorption of the
invention may be produced by coating the surface of the release
liner with a solution containing the drug, plasticizer and if
necessary a drug-dissolving agent or percutaneous absorption
accelerator, with the pressure-sensitive adhesive, and then heating
to dryness at a temperature of 40-150.degree. C. to form a
pressure-sensitive adhesive layer, subsequently laminating a
support on the surface of the pressure-sensitive adhesive layer
opposite the side on which the release liner is attached, and
cutting it to an appropriate size. When a non-water-permeable
support is used as the support, a pressure-sensitive adhesive
solution containing the drug, plasticizer, etc. may be applied onto
the support and heated to dryness, and then the release liner
laminated thereon. The temperature for heating to dryness may be a
temperature above the volatilization temperature of the solvent.
The temperature is preferably not too low because the solvent will
not completely volatilize, and it is preferably not above
150.degree. C. because an adverse effect may be produced on the
drug, plasticizer and percutaneous absorption accelerator.
EXAMPLES
[0045] The nonaqueous pressure-sensitive adhesive for the medicinal
tape preparation for percutaneous absorption of the invention and
the medicinal tape preparation for percutaneous absorption will now
be further explained through the following examples, with the
understanding that the invention is in no way limited to these
examples.
Example 1
Production of Nonaqueous Pressure-Sensitive Adhesive 1
[0046] After charging 157.5 g of 2-ethylhexyl acrylate (hereinafter
abbreviated as 2EHA), 35 g of 2-acetoacetoxyethyl methacrylate
(hereinafter abbreviated as AAEM), 80.5 g of diacetoneacrylamide
(hereinafter abbreviated as DAAM) and 76 g of methyl methacrylate
(hereinafter abbreviated as MMA) in a 2-liter four-necked flask
equipped with a Dimroth condenser, thermometer, nitrogen gas
blow-in tube and stirrer, 525 g of ethyl acetate was added as a
solvent and the mixture was dissolved to uniformity. The
temperature was raised to 75.degree. C. while blowing in nitrogen
gas at flow rate of 100 ml/min. After holding at 75.degree. C. for
30 minutes, a solution of 0.21 g of benzoyl peroxide as an
initiator in 5 g of ethyl acetate was added, and the external
temperature was set to 85.degree. C. Subsequently, 300 g of toluene
was loaded in portions of 100 g at a time at 3, 5 and 7 hours after
adding the initiator. During the polymerization, nitrogen gas was
continuously blown in at a flow rate of 100 ml/min.
[0047] At 12 hours after the final toluene loading, 0.35 g of
benzoyl peroxide was loaded as an additional catalyst, and then
heat treatment for 12 hours at an external temperature of
95.degree. C. was followed by cooling to obtain nonaqueous
pressure-sensitive 1.
[0048] (Physical properties of solution of nonaqueous
pressure-sensitive adhesive 1)
Solution viscosity (measured with Brookfield viscometer): 30,000
mPas Solid portion (150.degree. C..times.1 hour treatment): 28.5%
Residual monomers: 300 ppm 2EHA, 20 ppm AAEM, 1000 ppm DAAM, 150
ppm MMA (measured by HPLC).
Example 2
Production of Nonaqueous Pressure-Sensitive Adhesive 2
[0049] A monomer solution was prepared by uniformly pre-dissolving
78.8 g of 2EHA, 78.8 g of n-butyl acrylate (hereinafter abbreviated
as BA), 105 g of AAEM, 87.5 g of MMA and 1.05 g of diethyleneglycol
dimethacrylate (hereinafter abbreviated as DEGMA). After adding 100
g of the monomer solution in a 2-liter four-necked flask equipped
with a Dimroth condenser, thermometer, nitrogen gas blow-in tube
and stirrer, 350 g of ethyl acetate was added as a solvent. The
temperature was raised to 75.degree. C. while blowing in nitrogen
gas at flow rate of 100 ml/min, and after holding at 75.degree. C.
for 30 minutes, a solution of 0.35 g of benzoyl peroxide as an
initiator in 5 g of ethyl acetate was added, and the external
temperature was set to 85.degree. C. Upon confirming reflux of the
solvent, the remaining monomer solution was loaded continuously for
3 hours. Next, one hour after the initial continuous loading of the
monomer solution, 500 g of ethyl acetate was continuously loaded
for 3 hours. After continuing to stir for 12 hours after loading
the ethyl acetate, 0.5 g of benzoyl peroxide was loaded as
additional catalyst and then heat treatment for 12 hours was
followed by cooling to obtain nonaqueous pressure-sensitive 2.
During the polymerization, nitrogen gas was continuously blown in
at a flow rate of 100 ml/min.
[0050] (Physical Properties of Solution of Nonaqueous
Pressure-Sensitive Adhesive 2)
Solution viscosity (measured with Brookfield viscometer): 25,000
mPas Solid portion (150.degree. C..times.1 hour treatment): 27.5%
Residual monomers: 1000 ppm 2EHA, 200 ppm BA, 100 ppm AAEM, 250 ppm
MMA, DEGMA below detection limit (measured by HPLC).
[0051] Nonaqueous pressure-sensitive adhesives 3-10 for Examples
3-10 shown in Table 1 were produced by the method described in
Example 2.
Comparative Example 1
Production of Comparison Pressure-Sensitive Adhesive 1
[0052] Polymerization and synthesis were conducted by the same
method as for pressure-sensitive adhesive 1 of Example 1 using a
monomer composition of 90 g 2EHA, 90 g BA, 80.5 g DAAM, 87.5 g MMA
and 1.0 g DEGMA, to produce comparison pressure-sensitive adhesive
1.
[0053] (Physical Properties of Solution of Comparison
Pressure-Sensitive Adhesive 1)
Solution viscosity (measured with Brookfield viscometer): 38,000
mPas Solid portion (150.degree. C..times.1 hour treatment): 28.5%
Residual monomers: 300 ppm 2EHA, 200 ppm BA, 1500 ppm DAAM, 100 ppm
MMA, DEGMA below detection limit (measured by HPLC).
Comparative Example 2
Preparation of Comparison Pressure-Sensitive Adhesive 2
[0054] Polymerization and synthesis were conducted by the same
method as in Example 2 using a monomer composition of 130 g 2EHA,
130 g BA and 90 g MMA, to produce comparison pressure-sensitive
adhesive 2.
[0055] (Physical Properties of Solution of Comparison
Pressure-Sensitive Adhesive 2)
Solution viscosity (measured with Brookfield viscometer): 28,000
mPas Solid portion (150.degree. C..times.1 hour treatment): 27.5%
Residual monomers: 500 ppm 2EHA, 300 ppm BA, 150 ppm MMA (measured
by HPLC).
[0056] The monomer compositions, solvents and calculated Tg values
for the nonaqueous pressure-sensitive adhesives of Examples 1-10
and Comparative Examples 1 and 2 are shown in Table 1.
TABLE-US-00001 TABLE 1 Nonaqueous pressure-sensitive adhesives
Monomer Calculated Example AAEM DAAM MMA 2EHA BA DEGMA TEGMA
Solvent Tg value 1 10.0 23.1 21.8 45.1 EtOAc, -12.3 toluene 2 29.9
24.9 22.5 22.5 0.2 EtOAc, -15.0 toluene 3 0.1 28.9 35.4 35.4 0.2
EtOAc, -32.2 toluene 4 1.0 29.0 34.8 35.0 0.2 EtOAc, -31.6 toluene
5 5.0 25.0 34.8 35.0 0.2 EtOAc, -33.7 toluene 6 10.0 10.0 40.0 39.8
0.2 EtOAc, -47.6 toluene 7 10.0 22.9 21.8 45.0 0.3 EtOAc, -12.0
toluene 8 20.0 20.0 29.8 30.0 0.2 EtOAc, -29.3 toluene 9 30.0 25.0
22.4 22.4 0.2 EtOAc, -15.0 toluene 10 40.0 19.9 20.0 19.9 0.2
EtOAc, -27.5 toluene Comp. 0 23.1 25.1 25.8 25.8 0.2 EtOAc, -9.2
Ex. 1 toluene Comp. 0 25.8 37.1 37.1 EtOAc, -36 Ex. 2 toluene AAEM:
2-acetoacetoxyethyl methacrylate; DAAM: diacetoneacrylamide; MMA:
methyl methacrylate; 2EHA: 2-ethylhexyl acrylate; BA: n-butyl
acrylate; DEGMA: diethyleneglycol dimethacrylate; TEGMA:
tetraethyleneglycol dimethacrylate; EtOAc: ethyl acetate The values
in the monomer columns are the weight percentages of each monomer
with respect to 100 as the total dry copolymer weight.
Test Example 1
[0057] The nonaqueous pressure-sensitive adhesives 1-10 of the
invention and the comparison pressure-sensitive adhesives 1 and 2
shown in Table 1, and the commercially available acrylic
solvent-type (nonaqueous) pressure-sensitive adhesive S-3403
(ARONTACK S-3403, trade name of To a Gosei Co., Ltd.) were used for
coating and drying onto a support to produce tapes 2-1 to 2-21 and
comparison tapes 3-5, and the compatibility of the
pressure-sensitive adhesives and oily substances, the adhesive and
cohesive strengths of the pressure-sensitive adhesives were
evaluated.
[0058] 1) Tape Production Methods
[0059] Production of Tape 2-1
[0060] A 38.69 g portion of pressure-sensitive adhesive 1 was
placed in a screw-cap bottle and stirred for more than an hour in
the bottle. A coating tester (LTE-S, Wener Mathis AG) was used for
coating and drying of the solution onto a support (polyester film)
to a dried coating weight of 70 mg/10 cm.sup.2, and then a liner
(silicon-treated polyester film) was used to cover it with the
silicon side contacting the pressure-sensitive to obtain tape
2-1.
[0061] Production of Tape 2-2
[0062] A 38.69 g portion of pressure-sensitive adhesive 1, and then
1.2 g of isopropyl myristate (IPM), were placed in a screw-cap
bottle and stirred for more than an hour in the bottle. A coating
tester (LTE-S, Wener Mathis AG) was used for coating and drying of
the solution onto a support (polyester film) to a dried coating
weight of 70 mg/10 cm.sup.2, and then a liner (silicon-treated
polyester film) was used to cover it with the silicon side
contacting the pressure-sensitive to obtain tape 2-2.
[0063] Pressure-sensitive adhesives and corresponding plasticizers
were used in the same method as the production method of tape 2-2
to produce tapes 2-3 to 2-21 and comparison tape 3-5.
[0064] 2) Evaluation of Compatibility Between Pressure-Sensitive
Adhesives and Oily Substances
[0065] The preparation liners were released and an optical
microscope was used to observe the condition of liquid substance
adhering to the liner surface.
[0066] Evaluation:
[0067] .smallcircle.: No liquid substance on the liner surface
[0068] x: Liquid substance on the liner surface
[0069] 3) Evaluation of Tape Adhesive Strength
[0070] After releasing the liner of the preparation, the
pressure-sensitive adhesive side was touched with a finger and
evaluated based on the following evaluation scale.
[0071] .smallcircle.: (excellent) Adhesive strength comparable to
MOHRUS TAPE (trade name of Hisamitsu Pharmaceutical) and YAKUBAN
(trade name of Mikasa Seiyaku) which employ
styrene-isoprene-styrene copolymer.
[0072] .DELTA.: (good) Adhesive strength comparable to SERASTAR
(trade name of Yamanouchi Pharmaceutical) and FALZY (trade name of
Sawai Pharmaceutical) which employ natural rubber latex.
[0073] x: (poor) Adhesive strength below that of commercial
products.
[0074] -: Evaluation impossible due to significantly low cohesive
strength (semi-solid state).
[0075] 4) Evaluation of Tape Cohesive Strength (Hardness)
[0076] After releasing the liner of the tape, the
pressure-sensitive adhesive side was touched with a finger and
evaluated based on the following evaluation scale.
[0077] Evaluation:
[0078] .smallcircle.: (excellent) Cohesive strength comparable to
SERASTAR (trade name of Yamanouchi Pharmaceutical) and FALZY (trade
name of Sawai Pharmaceutical) which employ natural rubber
latex.
[0079] .DELTA.: (good) Cohesive strength comparable to MOHRUS TAPE
(trade name of Hisamitsu Pharmaceutical) and YAKUBAN (trade name of
Mikasa Seiyaku) which employ styrene-isoprene-styrene
copolymer.
[0080] x: (poor) Cohesive strength below that of commercial
products.
[0081] Tapes 2-1 to 2-21 and comparison tape 3-5 were used for
evaluation of the compatibility of the pressure-sensitive adhesives
and oily substances, the adhesive and cohesive strengths, giving
the results shown in Table 2. The comparison tapes 3 and 4, and
comparison tape 5 which employed a commercially available acrylic
pressure-sensitive adhesive, all exhibited inadequate adhesive and
cohesive strength, while tapes 2-1 to 2-21 which were prepared
using nonaqueous pressure-sensitive adhesives of the invention
exhibited adequate adhesive and cohesive strength.
TABLE-US-00002 TABLE 2 Compatibilities, adhesive strengths and
cohesive strengths of nonaqueous pressure-sensitive adhesive tapes
Tape Monomer Adhesive Cohesive No. AAEM DAAM MMA 2EHA BA DEGMA
TEGMA Solvent Plasticizer Compatibility strength strength 2-1 10.0
23.1 21.8 45.1 EtOAc, toluene -- .smallcircle. .smallcircle.
.smallcircle. 2-2 10.0 23.1 21.8 45.1 EtOAc, toluene IPM 10
.smallcircle. .smallcircle. .smallcircle. 2-3 10.0 23.1 21.8 45.1
EtOAc, toluene IPM 20 .smallcircle. .smallcircle. .smallcircle. 2-4
10.0 23.1 21.8 45.1 EtOAc, toluene IPM 30 .smallcircle.
.smallcircle. .smallcircle. 2-5 10.0 23.1 21.8 45.1 EtOAc, toluene
IPM 40 .smallcircle. .smallcircle. .smallcircle. 2-6 10.0 23.1 21.8
45.1 EtOAc, toluene IPP 20 .smallcircle. .smallcircle.
.smallcircle. 2-7 10.0 23.1 21.8 45.1 EtOAc, toluene HD 20
.smallcircle. .smallcircle. .smallcircle. 2-8 10.0 23.1 21.8 45.1
EtOAc, toluene DES 20 .smallcircle. .smallcircle. .smallcircle. 2-9
10.0 23.1 21.8 45.1 EtOAc, toluene DPA 20 .smallcircle.
.smallcircle. .smallcircle. 2-10 10.0 23.1 21.8 45.1 EtOAc, toluene
MFTG 20 .smallcircle. .smallcircle. .smallcircle. 2-11 10.0 23.1
21.8 45.1 EtOAc, toluene PETA 20 .smallcircle. .smallcircle.
.smallcircle. 2-12 10.0 23.1 21.8 45.1 EtOAc, toluene Castor oil 20
.smallcircle. .smallcircle. .smallcircle. 2-13 29.9 24.9 22.5 22.5
0.2 EtOAc, toluene IPM 20 .smallcircle. .smallcircle. .smallcircle.
2-14 0.1 28.9 35.4 35.4 0.2 EtOAc, toluene IPM 20 .smallcircle.
.smallcircle. .DELTA. 2-15 1.0 29.0 34.8 35.0 0.2 EtOAc, toluene
IPM 20 .smallcircle. .smallcircle. .smallcircle. 2-16 5.0 25.0 34.8
35.0 0.2 EtOAc, toluene IPM 20 .smallcircle. .smallcircle.
.smallcircle. 2-17 10.0 10.0 40.0 39.8 0.2 EtOAc, toluene IPM 20
.smallcircle. .smallcircle. .smallcircle. 2-18 10.0 22.9 21.8 45.0
0.3 EtOAc, toluene IPM 20 .smallcircle. .smallcircle. .smallcircle.
2-19 20.0 20.0 29.8 30.0 0.2 EtOAc, toluene IPM 20 .smallcircle.
.smallcircle. .smallcircle. 2-20 30.0 25.0 22.4 22.4 0.2 EtOAc,
toluene IPM 20 .smallcircle. .smallcircle. .smallcircle. 2-21 40.0
19.9 20.0 19.9 0.2 EtOAc, toluene IPM 20 .smallcircle.
.smallcircle. .smallcircle. Comp. 0 23.1 25.1 25.8 25.8 0.2 EtOAc,
toluene IPM 20 .smallcircle. -- x Ex. 3 Comp. 0 25.8 37.1 37.1
EtOAc, toluene IPM 20 .smallcircle. -- x Ex. 4 Comp. Acrylic
solvent-type pressure-sensitive adhesive: S-3403 IPM 20
.smallcircle. -- x Ex. 5 (ARONTACK S-3403 Toa Gosei Co., Ltd.)
AAEM: 2-acetoacetoxyethyl methacrylate; DAAM: diacetoneacrylamide;
MMA: methyl methacrylate; 2EHA: 2-ethylhexyl acrylate; BA: n-butyl
acrylate; DEGMA: diethyleneglycol dimethacrylate; TEGMA:
tetraethyleneglycol dimethacrylate; EtOAc: ethyl acetate; IPM:
isopropyl myristate; IPP: isopropyl palmitate; HD: hexyldecanol;
DES: diethyl sebacate; DPA: diisopropyl adipate; MFTG: medium chain
fatty acid triglyceride; PETA: polyester adipate. The values in the
monomer columns are the weight percentages of each monomer with
respect to 100 as the total dry copolymer weight. The values in the
plasticizer column are the weight percentages of each plasticizer
with respect to 100 as the total weight of the pressure-sensitive
adhesive layer.
Example 11
Production of Tape Preparation for Percutaneous Absorption 11
[0082] A 36.2 g portion of pressure-sensitive adhesive 7, and then
1.5 g of ketoprofen, were placed in a screw-cap bottle and stirred
for more than an hour in the bottle. A coating tester (LTE-S, Wener
Mathis AG) was used for coating and drying of the solution onto a
support (polyester film) to a dried coating weight of 140 mg/10
cm.sup.2, and then a liner (silicon-treated polyester film) was
used to cover it with the silicon side contacting the
pressure-sensitive to obtain tape preparation for percutaneous
absorption 11. The ketoprofen content of the obtained preparation
was 10 w/w %.
Example 12
Production of Tape Preparation for Percutaneous Absorption 12
[0083] A 35.69 g portion of pressure-sensitive adhesive 7, and then
3.0 g of IPM and 1.5 g of ketoprofen, were placed in a screw-cap
bottle and stirred for more than an hour in the bottle. A coating
tester (LTE-S, Wener Mathis AG) was used for coating and drying of
the solution onto a support (polyester film) to a dried coating
weight of 140 mg/10 cm.sup.2, and then a liner (silicon-treated
polyester film) was used to cover it with the silicon side
contacting the pressure-sensitive to obtain tape preparation for
percutaneous absorption 12. The ketoprofen content of the obtained
preparation was 10 w/w %.
Examples 13-16
Production of Tape Preparations for Percutaneous Absorption
13-16
[0084] Tape preparations for percutaneous absorption 13-16 were
each produced by the same method as Example 11 or Example 12, using
pressure-sensitive adhesive 7, a drug and if necessary IPM
plasticizer.
Comparative Examples 6-9
Production of Comparison Tape Preparations for Percutaneous
Absorption 6-9
[0085] Comparison tape preparations for percutaneous absorption 6-9
were produced by the same method as in Example 12, using a specific
drug and plasticizer, with a commercially available solvent-type
acrylic pressure-sensitive adhesive for Comparative Examples 8 and
9 and addition of an isocyanate crosslinking agent for Comparative
Examples 6 and 7.
[0086] The compatibility evaluation and tape adhesive and cohesive
strength evaluation described in Test Example 1 were conducted
using the tape preparations for percutaneous absorption 11-16
obtained in Examples 11-16, and the comparison tape preparations
for percutaneous absorption 6-9. The tape preparations for
percutaneous absorption according to the invention exhibited
satisfactory adhesive and cohesive strength, while the comparison
tape preparations for percutaneous absorption exhibited inferior
adhesive and cohesive strength. The results are shown in Table
3.
TABLE-US-00003 TABLE 3 Compatibilities, adhesive strengths and
cohesive strengths of medicinal tapes for percutaneous absorption
Pressure-sensitive Crosslinking Plasticizer Drug Adhesive Cohesive
Example adhesive agent (amount) (amount) (amount) Compatibility
strength strength 11 Adhesive 7 -- -- ketoprofen 10 .smallcircle.
.smallcircle. .smallcircle. 12 Adhesive 7 -- IPM 20 ketoprofen 10
.smallcircle. .smallcircle. .smallcircle. 13 Adhesive 7 -- --
indomethacin 10 .smallcircle. .smallcircle. .smallcircle. 14
Adhesive 7 -- IPM 20 indomethacin 10 .smallcircle. .smallcircle.
.smallcircle. 15 Adhesive 7 -- -- tulobuterol 10 .smallcircle.
.smallcircle. .smallcircle. 16 Adhesive 7 -- IPM 20 tulobuterol 10
.smallcircle. .smallcircle. .smallcircle. Comp. Ex. 6 Nissetsu
PE300 CK101 IPM 20 ketoprofen 10 .smallcircle. -- x 0.1 Comp. Ex. 7
Nissetsu PE300 CK101 IPM 20 indomethacin 10 .smallcircle. -- x 0.1
Comp. Ex. 8 Nissetsu PE300 tulobuterol 10 .smallcircle. -- x Comp.
Ex. 9 Nissetsu PE300 IPM 20 tulobuterol 10 .smallcircle. -- x
CK101: isocyanate crosslinking agent CK101 (Nippon Carbide
Industries Co., Ltd.); Nissetsu PE300: Solvent-type acrylic
pressure-sensitive adhesive, Nissetsu PE300 (Nippon Carbide
Industries Co., Ltd.); IPM: isopropyl myristate. The values for the
crosslinking agents, plasticizers and drugs are weight percentages
with respect to 100 as the total dry weight of the
pressure-sensitive adhesive layer.
Test Example 2
Drug Release Test
[0087] Each preparation was applied onto extracted skin of a
Yucatan micropig (YMP) and allowed to stand under conditions of
32.degree. C.-60% RH. After 24 hours, the preparation was peeled
off and the residual drug content of the preparation was measured
by HPLC. The residual drug content was used to calculate the drug
release rate (%) from the preparation.
(drug content before application-residual drug content)/drug
content before application.times.100=drug release rate (%).
Test Example 3
Hairless Mouse Extracted Skin Permeability Test
[0088] After placing 0.05 mol/L McIlvaine Buffer (pH 7.4) on the
cutis side (receiver side) of the extracted skin in a vertical
diffusion cell, the preparation was applied to the horny layer
side. The receiver solution was sampled at different time points,
and then an equivalent amount of 0.05 mol/L McIlvaine Buffer was
added. The drug concentration of the sampling solution was measured
by HPLC, and the flux, lag time and 24 hr cumulative permeation
were calculated.
TABLE-US-00004 TABLE 4 Drug release rates and skin permeabilities
of medicinal tapes for percutaneous absorption Cumulative
Pressure-sensitive Plasticizer Drug Release rate Lag Time FLUX
permeation adhesive (amount) (concentration) (%) (hr)
(.mu.g/cm.sup.2/hr) (.mu.g/cm.sup.2/24 hr) Example 15 Adhesive 7 --
tulobuterol 10 95.7 .+-. 0.8 2.31 .+-. 0.98 1.757 .+-. 0.398 17.71
.+-. 4.27 Example 16 Adhesive 7 IPM 20 tulobuterol 10 96.1 .+-. 0.3
0.17 .+-. 0.17 3.620 .+-. 0.057 29.40 .+-. 1.23 Comp. Ex. 8
Nissetsu PE-300 -- tulobuterol 10 88.9 .+-. 0.2 5.14 .+-. 1.93
0.335 .+-. 0.133 3.30 .+-. 1.12 Comp. Ex. 9 Nissetsu PE-300 IPM 20
tulobuterol 10 83.0 .+-. 0.4 1.10 .+-. 0.28 2.238 .+-. 0.008 20.98
.+-. 2.24 IPM: isopropyl myristate; Nissetsu PE300: Solvent-type
acrylic pressure-sensitive adhesive Nissetsu PE300 (Nippon Carbide
Industries Co., Ltd.). The values for the plasticizer and drug are
the weight percentages with respect to 100 as the total weight of
the pressure-sensitive adhesive layer.
[0089] A drug release test and skin permeability test were
conducted for Test Examples 2 and 3, using the tape preparations
for percutaneous absorption 15 and 16 of the examples and the tape
preparations for percutaneous absorption 8 and 9 of the comparative
examples. The results are shown in Table 4. The tape preparations
for percutaneous absorption of the examples according to the
invention had significantly superior drug release rates and skin
permeabilities compared to the tape preparations for percutaneous
absorption of the comparative examples.
Test Example 4
Cumulative Skin Irritation Test (Rabbit)
[0090] Rabbits used for the test were shaved on the back with an
electric razor up to the day prior to the test.
[0091] The preparation was applied onto the back of a rabbit or
guinea pig, impermeable oiled paper was laid thereover, a nonwoven
fabric pressure-sensitive adhesive bandage (MESHPORE, Nichiban) was
attached firmly over it, and the entire application site was
covered with gauze and then covered with a pressure-sensitive
adhesive elastic bandage (ELASTOPORE, Nichiban). After 6 hours, the
test preparation was removed and the site of application was
lightly scraped with absorbent cotton wetted with lukewarm water
and allowed to stand for 30 minutes, after which the site of
application was observed. After observation was complete, the test
preparation was applied at the same site and the same procedure was
repeated for 7 days. The application site was observed in the same
manner at 48 and 72 hours after final removal of the preparation,
and a rating was assigned based on the following evaluation scale
of Draize et al.
[0092] Evaluation scale of Draize et al.
[0093] A: Erythema and scab formation
[0094] No erythema: 0; Very mild erythema: 1; Apparent erythema: 2;
Medium to severe erythema: 3; Severe erythema to slight scab
formation: 4.
[0095] B: Edema formation
[0096] No edema: 0; Very mild edema: 1; Mild edema: 2; Moderate
edema (approximately 1 mM protrusions): 3; Severe edema: 4.
[0097] The 7-day cumulative skin irritation test described in Test
Example 4 was conducted using a Japanese Pharmacopeia bandage and
tapes 2-18 of the invention shown in Table 2, and the rabbit skin
cumulative skin irritation scores were determined. As a result, the
score for tapes 2-18 using pressure-sensitive adhesives of the
invention was 4.0 while the score for the Japanese Phanmacopeia
bandage was 14.6, thus indicating that the pressure-sensitive
adhesives of the invention are highly safe, with low irritation on
rabbit skin.
TABLE-US-00005 TABLE 5 Rabbit 7-day cumulative skin irritation test
Cumulative irritation (7 days) Japan Pharmacopeia bandage 14.6
Invention tapes 2-18 4.0
The average scores were calculated by the following formula. The
7-day cumulative irritation represents the cumulative total of the
average scores from day 1 to day 9.
Average score=[(total of erythema scores)+(total of edema
scores)]/5.
INDUSTRIAL APPLICABILITY
[0098] In the process of heat drying, the nonaqueous
pressure-sensitive adhesive of the invention forms a network
structure by self-crosslinking of the acetoacetyl groups, so that
large amounts of oily substances such as the plasticizer can be
included in the network structure. The pressure-sensitive adhesive
of the invention uses no polyamine derivatives, isocyanate
compounds, polyvalent metal chelate compounds or the like as
crosslinking agents, and therefore since toxicity is not a concern
and the skin is not irritated, the adhesive is suitable for medical
use. The medicinal tape preparation for percutaneous absorption of
the invention is superior from the standpoint of adhesive strength,
cohesive strength, safety, drug release property and percutaneous
absorption.
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