NZ628326B2 - Transdermal Patch - Google Patents
Transdermal Patch Download PDFInfo
- Publication number
- NZ628326B2 NZ628326B2 NZ628326A NZ62832612A NZ628326B2 NZ 628326 B2 NZ628326 B2 NZ 628326B2 NZ 628326 A NZ628326 A NZ 628326A NZ 62832612 A NZ62832612 A NZ 62832612A NZ 628326 B2 NZ628326 B2 NZ 628326B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- rivastigmine
- sensitive adhesive
- pressure
- layer
- transdermal patch
- Prior art date
Links
- XSVMFMHYUFZWBK-NSHDSACASA-N EXELON Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims abstract description 184
- 229960004136 rivastigmine Drugs 0.000 claims abstract description 184
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 44
- 239000000853 adhesive Substances 0.000 claims abstract description 38
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- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 89
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- 238000004945 emulsification Methods 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 235000010350 erythorbic acid Nutrition 0.000 description 1
- 239000004318 erythorbic acid Substances 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000011086 glassine Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052809 inorganic oxide Inorganic materials 0.000 description 1
- 229920000554 ionomer Polymers 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 229910000460 iron oxide Inorganic materials 0.000 description 1
- KSOKAHYVTMZFBJ-UHFFFAOYSA-N iron;methane Chemical compound C.[Fe].[Fe].[Fe] KSOKAHYVTMZFBJ-UHFFFAOYSA-N 0.000 description 1
- 229940026239 isoascorbic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- NZIDBRBFGPQCRY-UHFFFAOYSA-N octyl 2-methylprop-2-enoate Chemical compound CCCCCCCCOC(=O)C(C)=C NZIDBRBFGPQCRY-UHFFFAOYSA-N 0.000 description 1
- ANISOHQJBAQUQP-UHFFFAOYSA-N octyl prop-2-enoate Chemical compound CCCCCCCCOC(=O)C=C ANISOHQJBAQUQP-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
- 229920005668 polycarbonate resin Polymers 0.000 description 1
- 239000004431 polycarbonate resin Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 239000011112 polyethylene naphthalate Substances 0.000 description 1
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- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- LYBIZMNPXTXVMV-UHFFFAOYSA-N propan-2-yl prop-2-enoate Chemical compound CC(C)OC(=O)C=C LYBIZMNPXTXVMV-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 229960001755 resorcinol Drugs 0.000 description 1
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- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
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- SJMYWORNLPSJQO-UHFFFAOYSA-N tert-butyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC(C)(C)C SJMYWORNLPSJQO-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
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Abstract
Provided is an adhesive skin patch containing rivastigmine, in which desired adhesion performance can be achieved satisfactorily and rivastigmine can exist highly stably for a long period without using any antioxidative agent, and which can be produced easily at reduced cost. Disclosed is an adhesive skin patch for use in the treatment of Alzheimer's disease, which comprises a support, a rivastigmine-containing layer, an adhesive agent layer and a release liner, wherein the rivastigmine-containing layer comprises rivastigmine and a (meth)acrylic acid alkyl ester resin, the adhesive agent layer comprises an acrylic adhesive agent comprising a (meth)acrylic acid ester having a hydroxy group, and each of the rivastigmine-containing layer and the adhesive agent layer does not contain any antioxidative agent. sive skin patch for use in the treatment of Alzheimer's disease, which comprises a support, a rivastigmine-containing layer, an adhesive agent layer and a release liner, wherein the rivastigmine-containing layer comprises rivastigmine and a (meth)acrylic acid alkyl ester resin, the adhesive agent layer comprises an acrylic adhesive agent comprising a (meth)acrylic acid ester having a hydroxy group, and each of the rivastigmine-containing layer and the adhesive agent layer does not contain any antioxidative agent.
Description
DESCRIPTION
TITLE OF THE INVENTION: TRANSDERMAL PATCH
TECHNICAL FIELD
The present invention relates to a transdermal patch containing
rivastigmine, and specifically relates to a transdermal patch for the treatment of
Alzheimer's disease ing two layers composed of a igmine~containing layer
and an acrylic pressure-sensitive adhesive layer.
BACKGROUND ART
Rivastigmine is one of the acetylcholine esterase inhibitors and is used as
a eutic agent for Alzheimer's dementia dementia drug).
For such an anti—dementia drug, oral administration such as a tablet, a e, syrup,
and granules, and administration by injection or through the rectum have been studied
depending on a medicinal agent or a e condition. In recent years, transdermal
administration, that is, administration using a transdermal patch has also been developed
for such an anti-dementia drug.
It is considered that the rivastigmine is relatively easily oxidized, and it is
indicated that decomposition products of the rivastigmine may increase with time. To
address this, a technique of adding an anti-oxidizing agent into a transdermal patch
containing the rivastigmine has been developed (for example, Patent Document 1 and
Patent nt 2). Patent Document 2 discloses a preparation in which a storage
layer containing the rivastigmine is laminated to a silicone pressure-sensitive adhesive.
However, the silicone pressure-sensitive ve itself is expensive and a e liner
for such a silicone pressure—sensitive adhesive needs special treatment. Hence, the
preparation has a problem of high cost.
Each transdermal patch disclosed in Patent Document 1 and Patent Document 2 uses
an acrylic pressure-sensitive adhesive containing a carboxy group. However, the use of
such an acrylic pressure-sensitive adhesive is considered to affect the oxidation of
rivastigmine to not a little . To address this, there is a report that the use of a
pressure-sensitive adhesive having no carboxy group and no hydroxy group as the acrylic
re-sensitive adhesive enables the formation of a transdermal patch excellent in
temporal stability of the rivastigmine (Patent nt 3).
In order to improve skin bility of the rivastigmine or to reduce skin
irritation caused by a pressure—sensitive adhesive layer, a transdermal patch using a
hydroxy group-containing acrylate-rubber hybrid pressure-sensitive ve (Patent
adhesive
Document 4) and a transdermal patch ing an acrylic re-sensitive
such as
layer that has a hydroxy group, etc. and that contains a nonvolatile substance
citric acid in order to reduce the loss of an active substance (medicinal agent) due to
vaporization in the production process (Patent Document 5) have been developed.
documents.
However, there is no discussion on the stability of the rivastigmine in these
Related Art Documents
Patent Documents
Patent Document 1: Japanese Translation of PCT International Application
Publication No. JP—T—2002-5001 78
Patent Document 2: Japanese Translation of PCT International Application
Publication No. JP-T—2009—5 17468
Patent Document 3: International ation pamphlet
Patent Document 4: US. Patent Application Publication No. 2011/0066120
specification
Patent Document 5 : European Patent No. 2172194 specification
Patent Document 6: Japanese Translation of PCT International Application
ation No. JP-T—9-503756
Non-Patent Document
Non-Patent Document 1: JYTTE ROED-PERERSEN et al.: Contact dermatitis from
idants HIDDEN SENSITIZERS IN TOPICAL MEDICATIONS AND FOODS,
British Journal of Dermatology (1976) 94, 233.
SUMMARY OF THE INVENTION
Problem to be Solved by the ion
As described above, in order to solve the temporal instability of the
rivastigmine due to oxidation, the addition of an anti-oxidizing agent and the use of a
pressure-sensitive adhesive having no carboxy group and no hydroxy group have been
developed. Thus, in a transdermal patch using an acrylic pressure—sensitive adhesive
containing a hydroxy group, the skin bility of the rivastigmine must be improved.
Also, the stability of the rivastigmine must be improved in another manner because the
pressure-sensitive adhesive layer used is considered to be unfavorable from the viewpoint
of oxidation stability. There is another demand for a transdermal patch containing no
anti-oxidizing agent, because adding an anti-oxidizing agent may cause skin tion
(Non-Patent Document 1).
In the tion of a conventional transdermal patch containing the
rivastigmine, a layer containing the medicinal agent and a pressure-sensitive adhesive is
typically formed by a spread coating method (a production method including forming a
layer containing a medicinal agent and a pressure-sensitive adhesive by coating followed
by a heating and drying process). However, in the spread g , an ve
for inhibiting the vaporization of a medicinal agent is added as described in Patent
Document 5, a coating is dried at a drying temperature of 60°C or higher (for example,
Patent Document 4 and Patent Document 5), or a medicinal agent is added to a
pressure-sensitive adhesive layer in an amount that is a certain amount more than
the assumption that the
ary in advance, that is, s addition" is performed, on
medicinal agent is volatilized during production. Such a method doest not consider the
effect of the "heating" (oxidation, etc.) during the tion process of a transdermal
patch. Therefore, there is a room for improvement in the production method of the
ermal patch for improving the temporal ity of the rivastigmine.
The present inventors provide a transdermal patch containing the
rivastigmine, which allows desired adhesive properties to be thoroughly obtained as well
an xidizing agent.
as has good temporal stability of the rivastigmine without using
In addition, the transdermal patch can be produced easily and with reduced cost.
Means for Solving the Problem
[0009] The present inventors have carried out intensive studies in order to solve the
problems described above and have studied the structure of a transdermal patch having
excellent al stability of the rivastigmine without using an anti-oxidizing agent.
The present inventors have searched the structure of a ermal patch that can be
produced by a so-called "ointment coating method" while avoiding a heating process that
much as possible. As a result, the
may impair the stability of the rivastigmine, as
present inventors have developed a structure in which a medicinal agent—containing layer
and a pressure—sensitive adhesive-containing layer are separated, that is, a yer
adhesive
structure composed of a rivastigmine~containing layer and a pressure-sensitive
layer including a ular acrylic pressure—sensitive adhesive on a backing, and have
found that the structure can solve the problems, and the present invention has been
accomplished.
That is, the present invention relates to a transdermal patch for the treatment
ofAlzheimer's e. The transdermal patch includes a backing, a
rivastigmine-containing layer provided on the backing, a pressure-sensitive adhesive
layer provided on the rivastigmine-containing layer, and a release liner; or includes a
backing, a pressure-sensitive adhesive layer ed on the backing, a
rivastigmine-containing layer provided on the pressure-sensitive ve layer, and a
release liner. In the transdermal patch, the igmine-containing layer contains
igmine and an alkyl (meth)acrylate resin, the pressure-sensitive adhesive layer is
composed of an acrylic pressure—sensitive adhesive containing a (meth)acrylic acid ester
having a hydroxy group, and neither the rivastigmine-containing layer nor the
pressure-sensitive adhesive layer contains an anti-oxidizing agent.
The present invention further provides ments below.
1. In the transdermal patch for the ent ofAlzheimer's disease, the
rivastigmine-containing layer is a layer formed by using a solution containing the
rivastigmine under a condition at 1°C or higher and lower than 60°C.
2. In the transdermal patch for the treatment ofAlzheimer’s disease, the
rivastigmine—containing layer contains the rivastigmine in an amount of 20% to 95% by
mass based on a total mass of the layer.
3. In the ermal patch for the ent ofAlzheimer's disease, the
rivastigmine-containing layer is a layer having a thickness of 10 um to 80 um and the
pressure-sensitive adhesive layer is a layer having a thickness of 10 pm to 100 um.
The present invention also relates to a method for producing a transdermal
patch for the ent of mer’s e. The method includes i) a rivastigmine
layer formation step of applying a solution containing rivastigmine onto a backing to
form a rivastigmine—containing layer, a pressure-sensitive adhesive layer formation step
of applying a solution containing an acrylic pressure-sensitive adhesive onto a release
liner to form a pressure-sensitive adhesive layer, and a transdermal patch formation step
of bonding the rivastigmine~containing layer formed on the backing to the
pressure-sensitive ve layer formed on the release liner, includes ii) a
pressure-sensitive adhesive layer formation step of applying a solution ning an
acrylic pressure-sensitive adhesive onto a backing to form a pressure—sensitive adhesive
layer, a rivastigmine layer formation step of applying a solution containing rivastigmine
onto a release liner to form a rivastigmine-containing layer, and a transdermal patch
formation step of laminating the re-sensitive adhesive layer formed on the backing
to the rivastigmine-containing layer formed on the release liner, or includes iii) a
pressure-sensitive adhesive layer formation step of applying a solution containing an
c pressure-sensitive adhesive onto a g to form a pressure—sensitive adhesive
layer, a rivastigmine layer formation step of applying a solution containing rivastigmine
onto the pressure-sensitive ve layer to form a igmine-containing layer, and a
transdermal patch formation step of ting the rivastigmine-containing layer formed
on the pressure-sensitive adhesive layer on the backing to a release liner. In the method,
the solution containing rivastigmine contains the igmine and an alkyl (meth)acrylate
resin, the on containing an acrylic re-sensitive adhesive contains an acrylic
pressure-sensitive adhesive containing a (meth)acry1ic acid ester having a hydroxy group,
and neither the solution containing rivastigmine nor the solution containing an acrylic
pressure-sensitive adhesive contains an anti-oxidizing agent.
IO [0013] The present invention further provides embodiments below.
4. In the method, the igmine~containing layer ion step includes applying the
solution containing igmine onto the backing under a temperature condition of 1°C
or higher and lower than 60°C.
. The method further includes a cooling step of allowing the pressure-sensitive adhesive
layer to cool or forced-cooling the pressure—sensitive adhesive layer, after the
pressure-sensitive adhesive layer ion step and before the transdermal patch
formation step.
6. The method further includes an aging step before and after the cooling step.
The present invention further relates to a product of a transdermal patch for
the treatment ofAlzheimer's disease produced by sealing the transdermal patch for the
treatment ofAlzheimer's disease or a transdermal patch for the treatment of Alzheimer's
disease produced by the method in a package composed of a laminate of multi~layered
films or multi-layered sheets. The transdermal patch product has aspects below.
6. In the ermal patch product, an innermost layer of the e is a layer
containing polyacrylonitrile as a main component.
7. In the transdermal patch t, the package includes a film or a sheet having a layer
containing an oxygen absorber or an oxygen absorber is separately enclosed in the
package.
8. In the transdermal patch product, an atmosphere in the package is substituted and filled
with nitrogen.
The present invention also relates to a transdermal patch for the treatment of
Alzheimer's disease that includes a ter film backing, a rivastigmine-containing
layer provided on the backing, a pressure-sensitive adhesive layer provided on the
rivastigmine-containing layer, and a release liner. In the transdermal patch, the
rivastigmine-containing layer contains rivastigmine and an alkyl (meth)acrylate resin, the
pressure-sensitive adhesive layer includes an acrylic pressure-sensitive adhesive
containing a (meth)acrylic acid ester having a hydroxy group, neither the
rivastigmine-containing layer nor the pressure-sensitive adhesive layer contains an
anti-oxidizing agent or an acrylic pressure-sensitive adhesive containing a(meth)acry1ic
acid ester having a carboxy group, and the transdermal patch includes a degradation
product of the rivastigmine in a total amount of less than 0.50% by mass based on an
amount of the rivastigmine after storage under a severe condition (60°C) for two weeks
from a production date of the transdermal patch.
Effect of the Invention
The present invention can e a transdermal patch that has excellent
practical performance. The ermal patch is configured by providing two , i.e.,
an acrylic
a igmine-containing layer and a pressure—sensitive adhesive layer having
pressure-sensitive adhesive, on a backing. Thus, even without using an anti-oxidizing
agent and even when an acrylic re-sensitive ve containing a hydroxy group
that may affect the oxidation of the rivastigmine is used as the pressure—sensitive adhesive,
the transdermal patch can ss the formation of degradation ts of the
rivastigmine after the production of the transdermal patch, has excellent temporal
stability of the rivastigmine, and has adhesive properties required for a transdermal patch.
The on of the alkyl (meth)acrylate resin into the rivastigmine-containing layer
enables the ion of a rivastigmine-containing layer having excellent adhesive
properties to the backing and excellent attaching ties to a skin. The use of the
acrylic pressure—sensitive adhesive containing a (meth)acrylic acid ester having a hydroxy
group as the pressure-sensitive adhesive enables the formation of a pressure-sensitive
adhesive layer having ent attaching properties to a skin and excellent adhesive
properties to the backing.
The use of the rivastigmine-containing layer formed at a certain temperature or
lower can e a transdermal patch eliminating the oxidation effect on the
rivastigmine due to temperature.
The production method of the present invention does not require a heating
and stirring process or a heating and drying s, or the like for the formation of the
rivastigmine—containing layer. With this method, it is possible to produce a transdermal
patch While ating high temperature g processes that can affect the oxidation
of the rivastigmine as many as possible during the production of the transdermal patch.
Therefore, in the obtained transdermal patch, the formation of rivastigmine
degradation products due to heat is suppressed during the production of the transdermal
patch, and the method enables the formation of a ermal patch having excellent
stability of the rivastigmine.
In on, the transdermal patch of the present invention does not need "excess
addition", that is, adding a medicinal agent in an amount that is a certain amount more
than necessary in advance, and does not include an anti-oxidizing agent, which enables
cost reduction.
MODES FOR CARRYING OUT THE ION
The transdermal patch for the ent ofAlzheimer's disease of the
present invention is composed of a backing, a rivastigmine-containing layer, a
pressure-sensitive adhesive layer, and a release liner, and is characterized in that neither
the rivastigmine-containing layer nor the pressure-sensitive adhesive layer contains any
anti-oxidizing agent.
The transdermal patch of the present invention has a specific structure composed of
the rivastigmine-containing layer provided on the backing, the pressure-sensitive
adhesive layer provided on the rivastigmine-containing layer, and the release liner or a
specific structure composed of the backing, the pressure-sensitive adhesive layer
provided on the backing, the igmine-containing layer provided on the
pressure-sensitive adhesive layer, and the release liner.
[Rivastigmine-Containing Layer]
In the transdermal patch of the present invention, the igmine-containing layer
contains rivastigmine and an alkyl (meth)acrylate resin.
The rivastigmine
((S)-N-ethy1[l-(dimethylamino)ethyl]-N-methyl-phenyl~carbamate) used in the
present invention may be either in a free base form or in an acid addition salt form.
The amount of the igmine contained is not particularly d, but is, for
example, 20% to 95% by mass, ably 30% to 90% by mass, and more preferably
% to 90% by mass, based on the total mass of the igmine-containing layer.
The amount of the rivastigmine ned is, for example, 10% to 40% by mass,
preferably 10% to 35% by mass, and more preferably 10% to 25% by mass, based on the
total mass of the rivastigmine-containing layer and the pressure-sensitive adhesive layer
described later.
The alkyl (meth)acrylate resin contained in the rivastigmine-containing
layer works as a thickener and includes alkyl (meth)acrylate copolymers and c
pressure-sensitive adhesives containing a (meth)acrylic acid ester.
Specific examples of the alkyl (meth)acrylate mer include a
methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, a
methacrylic acid-methyl methacrylate copolymer, a methacrylic acid-ethyl acrylate
copolymer, an ethyl acrylate-methyl methacrylate copolymer, and a butyl
methacrylate—methyl methacrylate copolymer. The weight average molecular weight of
the alkyl acrylate copolymer is not particularly limited, but is 10,000 to 300,000
and preferably 100,000 to 200,000.
For such a copolymer, a commercial product may be appropriately used, and for
example, Eudragit (registered trademark, manufactured by Evonik Rohm GmbH)
products can be ly used. Specific examples of the commercial product include
Eudragit E100, Eudragit EPO, it L100, Eudragit L100-55, Eudragit 8100,
Eudragit RLlOO, Eudragit RLPO, Eudragit R8100, Eudragit RSPO, and Plastoid B.
Among these Eudragit products, Eudragit EPO is especially preferred from the
viewpoints of miscibility with the rivastigmine and adhesive properties to a backing.
Specifically, the acrylic pressure-sensitive adhesive containing a
(meth)acrylic acid ester is preferably a polymer obtained by copolymerization of one or
or more
more alkyl esters of (meth)acrylic acid as main monomer components with one
optional copolymerizable monomers (for example, 2-ethy1hexy1 acrylate,
yrrolidone, vinyl acetate, methoxyethyl te, yethyl acrylate, and acrylic
acid). Here, examples of the alkyl (meth)acrylate include alkyl acrylates such as methyl
acrylate, ethyl acrylate, isopropyl acrylate, n-butyl acrylate, t-butyl acrylate, isoamyl
acrylate, 2-ethylhexyl acrylate, n-octyl acrylate, isooctyl acrylate, isononyl acrylate, decyl
acrylate, and dodecyl acrylate; and alkyl methacrylates such as methyl methacrylate,
ethyl methacrylate, n-butyl rylate, isobutyl rylate, t-butyl methacrylate,
isoamyl methacrylate, lhexy1 methacrylate, n—octyl methacrylate, isooctyl
methacrylate, isononyl methacrylate, decyl rylate, and dodecyl methacrylate.
These alkyl (meth)acrylates may be used singly or in combination oftwo or more of them.
For example, n—butyl acrylate may be used in combination with methyl methacrylate.
The weight average molecular weight of the acrylic acid ester used for the acrylic
pressure-sensitive adhesive containing a (meth)acrylic acid ester is not particularly
limited, but is 0 to 1,000,000.
It is preferable that the acrylic pressure-sensitive adhesive containing a
(meth)acrylic acid ester do not substantially include a component containing both a
hydroxy group and a carboxy group. , Even when the acrylic pressure-sensitive adhesive
includes the component ning both a hydroxy group and a carboxy group, the
the total
ent is preferably included in an amount of 5% by mass or less based on
mass of the acrylic re-sensitive adhesive.
The amount of the alkyl (meth)acrylate resin included is not particularly
limited. In the case of the alkyl (meth)acrylate mer, the amount is, for e,
% to 25% by mass, preferably 5% to 20% by mass, and more preferably 5% to 15% by
mass, based on the total mass of the rivastigmine-containing layer. In the case of the
acrylic pressure-sensitive ve containing a (meth)acrylic acid ester, the amount is,
for e, 20% to 90% by mass, preferably 30% to 85% by mass, and more preferably
40% to 80% by mass, based on the total mass of the rivastigmine-containing layer.
Based on the total mass of the rivastigmine-containing layer and the
pressure-sensitive adhesive layer described later, in the case of the alkyl (meth)acrylate
copolymer, the amount of the alkyl (meth)acrylate resin included is, for example, 0.5% to
5.0% by mass, preferably 1.0% to 4.0% by mass, and more preferably 1.0% to 3.0% by
mass. In the case of the acrylic re-sensitive adhesive containing the (meth)acrylic
acid ester, the amount is, for example, 40% to 90% by mass, preferably 50% to 90% by
mass, and more preferably 60% to 90% by mass.
In the present invention, the rivastigmine-containing layer may r
include an additional additive such as a softener (plasticizer) and an inorganic filler, if
desired.
When the additional additive is included, the amount thereof is, for example, 0% to
% by mass and preferably 0% to 20% by mass based on the total mass of the
rivastigmine—containing layer. The amount of the additional additive included is, for
example 0% to 20% by mass and preferably 0% to 10% by mass based on the total mass
of the rivastigmine—containing layer and the pressure—sensitive adhesive layer described
later.
[Pressure—Sensitive Adhesive Layer]
The pressure-sensitive adhesive layer used in the transdermal patch of the present
invention is composed of an acrylic pressure-sensitive adhesive containing a
(meth)acrylic acid ester having a hydroxy group.
Specifically, the acrylic pressure—sensitive adhesive is preferably a
r obtained by copolymerization of one or more hydroxyalkyl esters of
acrylic acid with one or more optional copolymerizable monomers (for example,
2-ethylhexyl acrylate, vinylpyrrolidone, vinyl acetate, methoxyethyl acrylate,
yethyl acrylate, and acrylic acid).
Here, es of the hydroxyalkyl (meth)acrylate include an ester obtained from a
hydroxy group-containing primary to tertiary alcohol having a €2-18 alkyl group and
acrylic acid or methacrylic acid. Specific examples of the hydroxyalkyl (meth)acrylate
include 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate,
4-hydroxybutyl acrylate, 2—hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate,
3-hydroxypropyl methacrylate, and 4~hydroxybutyl methacrylate.
As the acrylic pressure—sensitive adhesive containing the acrylic acid ester having a
hydroxy group, a commercial product such as AK (registered trademark)
87—202A, DURO-TAK 87—208A, DURO—TAK 87—2510, DURO-TAK 87—208A,
DURO-TAK 87-2287, DURO—TAK 87-4287, DURO—TAK 87—2516, and AK
87-2525 (Henkel) may be suitably used.
It is preferable that the pressure—sensitive adhesive layer do not substantially include
an acrylic pressure-sensitive adhesive containing a carboxy group as the acrylic
pressure-sensitive adhesive. Even when the layer includes the'acrylic pressure—sensitive
adhesive containing a carboxy group, the c re-sensitive adhesive containing a
carboxy group is preferably ed in an amount of 5% by mass or less based on the
total mass of the pressure—sensitive adhesive layer.
In the present invention, the mass ratio of the pressure-sensitive ve layer is,
for example, 40% to 95% by mass, ably 50% to 90% by mass, and more preferably
60% to 90% by mass, in the total mass of the igmine—containing layer above and the
pressure—sensitive adhesive layer.
In the present invention, the pressure-sensitive adhesive layer may
further include an additional additive such as an additional medicinal agent, a tackifier, a
cross-linking agent, a softener (plasticizer), an absorption enhancer, polyhydric alcohols,
ne oils, an inorganic filler, and an ultraviolet absorber.
es of the tackifier include terpene tackifiers, terpene phenol tackifiers,
coumarone indene ers, styrene tackifiers, rosin tackifiers, xylene tackifiers, phenol
tackifiers, and petroleum tackifiers.
Various cross-linking agents may be further added into the pressure-sensitive
adhesive layer in order to increase a cohesive power of the acrylic pressure-sensitive
adhesive. Examples of the cross-linking agent include multifunctional isocyanate
compounds, multifunctional epoxy compounds, and polyvalent metal salts.
Polyisocyanates [for example, CORONATE (registered trademark) HL (hexamethylene
diisocyanate HDI—TMP adduct, manufactured by Nippon Polyurethane Industry Co.,
Ltd.)] is specifically preferred. Usable examples of the filler include calcium ate,
magnesium ate, silicates, zinc oxide, titanium oxide, magnesium e, and
calcium e.
Examples of the absorption enhancer include terpene oils such as d—limonene; fatty
acid esters such as glycerin monolaurate, glycerin monooleate, and diethyl sebacate; and
fatty acids such as Azone, Pirotiodecane, oleic acid, lauric acid, and myristic acid and
derivatives of them.
These additives are optionally added. The amount of the additional additive is, for
example 0% to 40% by mass and preferably 0% to 30% mass based on the total mass of
the pressure-sensitive adhesive layer and the rivastigmine-containing layer above.
[Backing]
es of the backing used in the transdermal patch of the present invention
include flexible gs such as films, nonwoven fabrics, Japanese papers, cotton
fabrics, knitted fabrics, woven fabrics, and ted ite bodies of a nonwoven
fabric and a film. Such a backing is preferably composed of a soft material that can be
in close contact with a skin and can follow skin movement and of a material that can
the transdermal patch is attached for a long time.
suppress skin rash and other trouble after
Examples of the backing material include a material containing, as an ial
component, polyethylene, polypropylene, polyethylene terephthalate, polybutylene
terephthalate, polyethylene naphthalate, polystyrene, nylon, cotton, acetate rayon, rayon,
a rayon/polyethylene terephthalate composite body, polyacrylonitrile, polyvinyl alcohol,
acrylic polyurethane, ester ethane, ether ethane, a styrene-isoprene-styrene
copolymer, a styrene-butadiene-styrene copolymer, a styrene-ethylene-propylene-styrene
mer, styrene-butadiene rubber, an ethylene-vinyl acetate copolymer, or cellophane,
for example.
A preferred backing does not adsorb a medicinal agent and does not release a
medicinal agent tigmine). In order to suppress the adsorption and release of the
medicinal agent, to improve ermal absorbability of the medicinal agent, and to
includes one or more layers
suppress skin rash and other trouble, the backing preferably
composed of the material above and has a water vapor permeability in a certain range.
Specifically, the backing preferably has a water vapor bility (measured at 40°C
and 90% RH in accordance with .118 20208) of 300 g/m2 ° 24 hr or less and particularly 50
g/m2 ° 24 hr or less. The use of a backing having a water vapor permeability within the
and can ensure a suitable water
range can increase skin permeability of the rivastigmine
rash and other trouble.
vapor permeability for ssing skin
In order to make the transdermal patch inconspicuous when it is attached, that is, in
order to make it easy to show the skin color beneath the patch through it, a plastic film
having excellent transparency is preferably employed. A g such as fabrics can
obtain color that is a little ent from skin color by coloring the backing with a
ng agent into a color tone such as a flesh color.
The backing typically has a thickness of about 5 um to 1 mm. A fabric backing
preferably has a thickness of 50 pm to 1 mm, more preferably 100 um to 800 um, and
even more preferably 200 um to 700 pm. A plastic film backing preferably has a
thickness of 10 um to 300 pm, more preferably 12 pm to 200 um, and even more
preferably 15 pm to 150 um. A backing having a very small thickness of about 5 um to
um is preferably provided with a releasable carrier film layer on a face te to
re-sensitive adhesive layer or to the rivastigmine—containing layer that is formed on
the backing because handling properties as the ermal patch is improved. A
backing having a thickness of less than 5 mm reduces the strength and the handling
properties of the transdermal patch, makes attachment to a skin difficult, and may be torn
within
due to the contact with another member, for example, or be peeled off from a skin
a short period due to the contact with water in a bath, for example. A transdermal patch
ing a backing having an excessively large thickness (more than 1 mm) does not
easily follow skin movement and readily form a trigger for peeling-off at the periphery of
the transdermal patch. Hence, such a transdermal patch may be peeled off from a skin
within a short period or may increase uncomfortable feeling during attachment. In the
case of a film g, one side or both sides of the backing may be subjected to a
treatment such as a sandblast treatment and a corona treatment in order to improve
anchoring properties n the pressure—sensitive adhesive and the backing.
Furthermore, in order to readily take out the transdermal patch from a package, one side
other
or both sides of the backing may be provided with an uneven surface by a method
than the sandblast.
As a backing meeting the conditions such as the water vapor permeability, the
transparency, and the thickness, ter films are red and polyethylene
terephthalate films are especially preferred.
[0030] [Release Liner]
The release liner used in the transdermal patch of the t invention is preferably
composed of a material that is unlikely to absorb and adsorb a medicinal agent, for
example, in the pressure-sensitive adhesive. Examples of such a material include a
polyester film having one side or both sides treated with silicone, a polyethylene
laminated uality paper d with silicone, and a glassine paper treated with
silicone. The release liner may have an uneven surface in order to easily take out the
transdermal patch from a package. The release liner may have, for example, a
rectangular shape with rounded corners and a circular shape and has the same size as or a
size slightly larger than the size of the backing on which the rivastigmine-containing
layer and the pressure-sensitive adhesive layer are provided.
[Method for ing Transdermal Patch]
The transdermal patch for the treatment ofAlzheimer's disease of the present
ion can be produced h the steps described in i) or ii) below.
i) A rivastigmine layer formation step of applying a solution containing rivastigmine onto
a backing to form a igmine-containing layer, a pressure-sensitive adhesive layer
formation step of applying a solution containing an acrylic re-sensitive adhesive
onto a release liner to form a pressure-sensitive adhesive layer, and a transdermal patch
formation step of ting the igmine-containing layer formed on the backing to
the pressure-sensitive adhesive layer formed on the release liner.
ii) A pressure-sensitive adhesive layer formation step of applying a solution containing an
acrylic pressure-sensitive adhesive onto a backing to form a re—sensitive adhesive
layer, a rivastigmine layer formation step of applying a solution containing rivastigmine
onto a e liner to form a rivastigmine—containing layer, and a transdermal patch
formation step of laminating the re—sensitive adhesive layer formed on the backing
to the rivastigmine-containing layer formed on the release liner.
Alternatively, the transdermal patch of the present invention can also be ed,
for e, through the steps described in iii) below.
iii) A pressure-sensitive adhesive layer ion step of applying a solution containing
an acrylic pressure-sensitive adhesive onto a backing to form a pressure-sensitive
adhesive layer, a rivastigmine layer formation step of applying a solution containing
rivastigmine onto the pressure-sensitive adhesive layer to form a rivastigmine—containing
layer, and a transdermal patch formation step of laminating the igmine-containing
layer formed on the pressure-sensitive adhesive layer on the backing to a release liner.
[0032] The solution containing rivastigmine is a solution containing
rivastigmine and an alkyl (meth)acrylate resin. Examples of the alkyl (meth)acrylate
resin include the alkyl (meth)acrylate copolymers and the acrylic pressure-sensitive
adhesives containing a (meth)acrylic acid ester exemplified above. The solution may
further include an additional additive such as a er (plasticizer) and an inorganic
filler.
The solution containing an acrylic pressure—sensitive adhesive contains an acrylic
pressure—sensitive adhesive containing a (meth)acrylic acid ester having a hydroxy group.
es of the pressure-sensitive adhesive include the various pressure—sensitive
adhesives exemplified above. The solution may further include an additional additive
such as another medical agent, a tackifier, a cross—linking agent, a softener (plasticizer),
and an
an absorption enhancer, polyhydric alcohols, silicone oils, an inorganic filler,
ultraviolet absorber.
Each of the solution containing rivastigmine and the solution containing an acrylic
pressure-sensitive adhesive may appropriately include a solvent or the like, considering
the operability when such a solution is applied onto the backing, the e liner, and the
like. The solvent is not ularly d as long as the acrylic pressure-sensitive
ve containing a (meth)acrylic acid ester having a hydroxy group, the rivastigmine,
and the alkyl (meth)acrylate resin can be dissolved.
Each of the solution containing rivastigmine and the solution containing an acrylic
pressure-sensitive adhesive does not contain an anti-oxidizing agent.
The method for producing a transdermal patch of the present invention is
performed, for example, in the procedure below in the case of the s i).
The acrylic pressure—sensitive ve containing a (meth)acrylic acid ester having
a hydroxy group, and additional components except the medical agent and a solvent
(ethyl acetate, ethanol, and hexane, etc.) for dissolving the pressure-sensitive adhesive, if
desired, are stirred and mixed at a maximum temperature of room temperature to about
40°C so as to prepare a pressure~sensitive adhesive solution homogeneously containing
the components. The prepared solution is spread on a release liner or a backing with a
coater so as to give a thickness of 10 um to 100 um after drying the solvent, and then
dried at a temperature of 60°C to 120°C to form a pressure—sensitive adhesive layer.
Separately, the rivastigmine, the alkyl (meth)acrylate resin, and onal
components, if desired, are mixed at a maximum temperature of room ature or 1°C
or higher and lower than 60°C to e a rivastigmine~containing solution
neously containing the components. The prepared solution is spread on a
e liner or a backing with a coater so as to give a thickness of 10 pm to 80 um to
form a rivastigmine-containing layer. When an acrylic pressure-sensitive adhesive is
used as the alkyl (meth)acrylate resin, a solvent drying step may be included after the
spread on the release liner or the backing.
Finally, the pressure-sensitive adhesive layer formed on the release liner or the
backing and the rivastigmine-containing layer formed on the backing or the release liner
are opposed and laminated to each other, followed by cutting to produce a transdermal
patch having two layers composed of the pressure-sensitive adhesive layer containing the
acrylic pressure-sensitive ve and the rivastigmine—containing layer.
In the transdermal patch of the present invention, from the int of
the stability of the rivastigmine as the active component, it is preferred that the
rivastigmine layer formation step bed above is performed by a so-called "ointment
coating " in which a mixing step and a drying step are performed at a temperature
that is
as low as possible, rather than a calendering method or a hot melting method
employed for a common transdermal patch production and that includes a heating and
kneading (stirring) step or a spread g method that includes a g and drying
step after coating.
In the present specification, the ”ointment coating method" is a method of forming a
layer at a low temperature, for example, at a temperature of 1°C or higher and lower than
60°C, preferably under a temperature condition of 20°C to 34°C, and more preferably
26°C to 34°C. In other words, in the present invention, the ”ointment g method'l
means a method of forming the rivastigmine—containing layer under the temperature
condition mentioned above by coating or tion. The alkyl (meth)acrylate resin in
the rivastigmine-containing layer is preferably an alkyl (meth)acrylate mer having
can be
a weight average molecular weight of 300,000 or less because the coating
performed at a lower temperature.
[003 5] In the transdermal patch of the present invention, the pressure-sensitive
adhesive layer formation step can be performed by any conventional methods for forming
emulsion method,
a pressure-sensitive adhesive layer such as a spread g method, an
a hot melting method, and an electron beam curing method. That is, in the present
invention, the pressure-sensitive adhesive layer formation step means a step of kneading,
ng, curing, and drying a pressure—sensitive adhesive and the like at a high
temperature (for example 60°C to 180°C) to form a pressure~sensitive adhesive layer on a
backing or a release liner.
Preferably, the method for producing a transdermal patch of the present
invention further includes a cooling step of allowing the pressure-sensitive adhesive layer
to cool or forced-cooling the pressure-sensitive adhesive layer, after the
pressure-sensitive ve layer ion step and before the transdermal patch
formation step. In other words, it is preferable that a transdermal patch formation step
in which the re-sensitive adhesive layer is directly brought into contact with the
igmine layer be not performed immediately after the formation of the
pressure-sensitive adhesive layer but the transdermal patch formation step be med
after cooling the pressure—sensitive adhesive layer.
The reason for this is as follows. The pressure-sensitive adhesive layer formation
step is performed at a high temperature. ingly, the pressure-sensitive adhesive
layer has a very high temperature immediately after the formation of the
re-sensitive adhesive layer. When such a re—sensitive adhesive layer is
directly brought into contact with the rivastigmine-containing layer, the rivastigmine
layer is heated to so that the temperature of the layer increases, which may affect the
stability of the rivastigmine.
Therefore, in the present invention, it is preferable that the rivastigmine layer
formation step and the pressure-sensitive ve layer ion step be not performed
in an integrated system, that is, these steps do not proceed at the same time and are
separately performed (in a non—integrated system).
A specific example of the procedure for the non-integrated system will
be described below.
First, when the pressure-sensitive adhesive layer formation step is performed by, for
example, a spread coating , a pressure-sensitive adhesive is diluted with a solvent
such as toluene, hexane, ethyl acetate, and ethanol and is spread on a backing or a release
liner. The solvent is evaporated at a high temperature (for example 120°C), and a
pressure-sensitive adhesive layer is formed on the backing or the release liner. A
plurality of layers containing the pressure—sensitive adhesive layer and the backing or
containing the pressure-sensitive adhesive layer and the release liner obtained by the
formation step are defined as a bulk tape. In the bulk tape, on the assumption that it is
left standing for a predetermined period of time for the temperature decrease as described
later, a release sheet that is removed at the transdermal patch formation step may be
laminated on the pressure-sensitive adhesive layer provided on the backing or the release
liner, in order to suppress drying of the pressure-sensitive adhesive layer or to avoid
contamination. Examples of the material for the release sheet include those exemplified
for the release liner above.
After the preparation of the bulk tape, a cooling step of cooling the bulk tape to
reduce the temperature is provided after the pressure—sensitive adhesive layer ion
step and the temperature of the bulk tape is reduced to about room temperature.
Examples of the temperature control (cool) means used for the cooling step include a
method of bringing the bulk tape into contact with a water cooled roll at a low
and a
temperature, a method of applying an air flow at a low temperature to the bulk tape,
method of winding the bulk tape onto a roll and then leaving the bulk tape standing at
room temperature for a predetermined period of time for cooling (allowing the bulk tape
to cool). The production method may r include an aging step for an aging period
under a certain ion (40°C to 50°C, one day to two weeks) before and after the
cooling step. h the aging step, the bulk tape obtains increased cohesiveness to
achieve stable adhesive power.
Using the bulk tape that is allowed to cool to about room temperature and, if
possible, left at room temperature for several days as above, the rivastigmine layer
formation step and the transdermal patch ion step are performed in another
working environment equipped with an air ioning apparatus capable of setting the
environment at a low temperature (preferably 20°C to 34°C and more preferably 26°C to
34°C). In the transdermal patch formation step, the ature of the bulk tape may be
controlled at, for example, 10°C to 40°C, preferably 20°C to 34°C, and more preferably
26°C to 34°C, using the temperature control means. The temperature in each step can
be ascertained by means such as a contact thermometer, a non—contact room thermometer,
and an ed thermo sensor.
In this manner, by controlling the temperature of the bulk tape and each temperature
in the rivastigmine layer formation step and the transdermal patch formation step, the
lamination of the bulk tape and the rivastigmine layer is smoothly performed and the two
layers are readily ated. However, it should be noted that when the lamination is
performed at room temperature or below (less than 20°C), the produced transdermal
patch may be separated into two layers when such a transdermal patch is applied onto a
skin and the pressure—sensitive ve layer is likely to remain on a skin side.
In the production method, the pressure-sensitive adhesive layer formation step and
the rivastigmine layer formation step are not performed at the same time, and the
transdermal patch formation step is med a predetermined time after the
pressure—sensitive adhesive layer ion step. This tates the control of the
temperature in each working environment as well as can diversify or reduce the risk when
malfunction occurs in the steps.
[0038] By bringing the pressure-sensitive ve layer into contact with the
rivastigmine—containing layer, the rivastigmine serving as the active component is
permeated and diffused from the rivastigmine—containing layer into the pressure-sensitive
adhesive layer. Thus, a transdermal patch is obtained that includes two layers composed
of the rivastigmine layer and the pressure-sensitive adhesive layer in which the active
component is substantially equally contained. For example, with respect to a
pressure-sensitive adhesive layer having a thickness of 10 um to 100 pm, the
igmine-containing layer is brought into contact by coating or lamination to produce
a transdermal patch. Then, the transdermal patch is subjected to aging under a low
temperature condition (1°C or more and less than 50°C) for a day to about two weeks.
Thus, the transdermal patch having the pressure-sensitive ve layer in which the
rivastigmine is evenly diffused and permeated can be obtained.
It is preferred that the ermal patch of the present invention
produced as above is enclosed in a package prepared from a packing material having high
sealing performance and high light blocking performance and stored until immediately
before the use.
For the packing material having high g mance and high light blocking
performance used for the package, a material commonly used for the package of a
ermal patch can be used. Examples of the packing material having high sealing
performance include polyolefin resin films such as polyethylene films, opylene
films, and polymethylpentene films; vinyl resin films such as polyvinyl chloride films,
polyvinylidene chloride films, polyvinyl alcohol films, polystyrene films,
polyacrylonitrile films, and ionomer films; ter resin films such as polyethylene
terephthalate films; ide resin films such as nylon films; ose resin films such
films of them.
as cellophane; polycarbonate resin films; and lamination Examples of the
packing material having high light blocking performance in addition to the high sealing
performance include: lamination films of aluminum and the resin film above or a
lamination film of the resin films; and pigment—added resin films that is obtained by
adding a black pigment, for example, to the resin film above. These resin films,
lamination films, and the like may be used in various combinations as a laminate.
The transdermal patch is enclosed in the package prepared from the laminate, then
the package can be sealed for storage by a known method such as heat sealing.
In particular, the innermost layer of the package is preferably a layer
having no adsorptive property with respect to the rivastigmine. For e,
polyacrylonitrile is ably used as the innermost layer.
The package preferably has a film or a sheet that includes a layer ning an
of the stability of the rivastigmine. Examples of
oxygen adsorber from the viewpoint
such as
the oxygen absorber include, but are not necessarily limited to, inorganic oxides
of a
cesium oxide, zinc oxide, titanium dioxide, and iron oxide; es composed
metal
powder of iron such as iron and iron carbide and an electrolyte such as halogenated
salts; reducing inorganic salts such as sulfite salts, thiosulfate salts, and ferrous salts;
polyphenols such as hydroquinone, catechol, resorcin, and pyrogallol; reducing sugars
such as glucose; any composition containing a reducing agent including reducing higher
alcohols such as ascorbic acid and erythorbic acid as a main active component;
compositions containing an unsaturated organic compound such as unsaturated fatty acid
compounds and chain hydrocarbon polymers having an unsaturated group or a
thermoplastic polymer such as ides and polyolefins as a main component and
ning an oxygen absorption promoting substance such as transition-metal salts; and
mixtures of them. Examples of the packing material containing an oxygen absorber
include Oxyguard (registered trademark) (manufactured by Toyo Seikan Kaisha, Ltd.)
and OxyCatch (registered trademark) actured by Kyodo Printing Co., Ltd). The
well as contained in the
oxygen absorber may be separately enclosed in a package as
package (in a packing material).
It is particularly preferable that an atmosphere in the package be substituted and
filled with nitrogen with a vacuum gas packaging machine or the like after the
transdermal patch is enclosed in the package, from the Viewpoint of the stability of the
rivastigmine.
The transdermal patch of the present invention obtained as above has an
advantage of ent temporal stability of the rivastigmine. For example, the
ermal patch of the present invention includes degradation products of the
rivastigmine in a total amount of less than 0.2% by mass immediately after the
production based on the amount of the rivastigmine, and includes the degradation
products in a total amount of less than 0.50% by mass and ably less than 0.35% by
the amount of
mass after storage under a severe condition (60°C) for two weeks based on
the rivastigmine.
Examples
after, the present invention will be bed in further detail with
reference to examples; however, the present invention is not limited to these examples.
<Production of Transdermal Patch (l)>
[Example 1: Production of Transdermal Patch by nt Coating Method (1)]
At room temperature, 40% by mass of DURO-TAK (registered trademark) 87-2516
(containing a hydroxy group, Henkel) as an acrylic pressure-sensitive adhesive and 60%
of ethyl acetate were mixed to prepare an acrylic pressure—sensitive adhesive solution (the
value (%) is based on the total mass of the pressure-sensitive adhesive solution). Next,
the solution was applied onto a silicone release-treated PET film (FILMBYNA
(registered trademark) 7513-0010 No. 23, manufactured by Fujimori Kogyo Co., Ltd.)
having a thickness of 75 um so as to give a thickness of 80 um after drying, and the
coated film was dried at 60°C to 100°C to form a pressure—sensitive adhesive layer.
Each of 90% by mass of rivastigmine and 10% by mass of Eudragit (registered
trademark) EPO (Evonik Degussa) was weighed, charged in a glass bottle, and dissolved
at room temperature so that a rivastigmine on (the value (%) is based on the total
mass of the rivastigmine solution) was obtained. The obtained igmine solution
was applied onto a PET film (LUMIRROR (registered trademark) S l 0, manufactured by
Toray Industries Inc.) having a thickness of 25 mm as a backing so as to give a thickness
of 20 um to form a rivastigmine-containing layer.
The pressure-sensitive adhesive layer formed on the silicone release-treated PET
film and the rivastigmine-containing layer formed on the PET film were d and
laminated to each other to produce a transdermal patch having two layers of the
pressure-sensitive ve layer containing the acrylic pressure—sensitive adhesive and
the rivastigmine-containing layer.
The produced preparation was sealed in an aluminum package having the innermost
layer mainly composed of polyacrylonitrile, and nitrogen substitution in the package was
carried out using a vacuum gas packaging machine.
[Comparative Example 1: Production of Transdermal Patch by Ointment
Coating Method (2)]
A ermal patch was produced in the same manner as in e 1 except that
AK (registered trademark) 87-2194 (containing a carboxy group, ) was
used as an c re-sensitive adhesive in place of DURO-TAK (registered
trademark) 87-2516 (Henkel) and the pressure-sensitive adhesive layer had a thickness of
60 um after .
[Comparative Example 2: Production of Transdermal Patch by Ointment
Coating Method (3)]
A transdermal patch was produced in the same manner as in Example 1 except that
AK (registered trademark) 87-2516 (containing a hydroxy group, ) and
DURO-TAK (registered trademark) 87-2194 (containing a carboxy group, Henkel) were
used in combination in equivalent amounts as acrylic pressure-sensitive adhesives in
place of DURO-TAK (registered trademark) 87-2516 (Henkel) alone and the
pressure—sensitive adhesive layer had a thickness of 60 um after drying.
rative e 3: Production of Transdermal Patch by Spread
Coating Method (1)]
In accordance with the formulation of 75.0% by mass of DURO-TAK tered
trademark) 87-2516 (containing a hydroxy group, Henkel) as an acrylic
pressure—sensitive adhesive, 2.5% by mass of Eudragit (registered trademark) EPO, and
22.5% by mass of igmine (the value (%) is based on the total mass of the
pressure-sensitive adhesive layer), the components were mixed, and diluted with ethyl
acetate so as to give a solid content of 35% to 40%, and the mixture was stirred at room
temperature (about 25°C) to prepare a homogeneous pressure—sensitive adhesive solution.
Next, the pressure-sensitive adhesive solution was spread on a silicone
release-treated PET film (FILMBYNA (registered trademark) 75E-0010 No. 23,
manufactured by Fujimori Kogyo Co., Ltd.) having a thickness of 75 um so as to give a
thickness of 80 um after , and the coated film was dried at 60°C to 100°C to form a
pressure-sensitive adhesive layer. Onto the pressure—sensitive ve layer, a PET
film (LUMIRROR (registered trademark) SlO, manufactured by Toray Industries Inc.)
having a thickness of 25 um was laminated as a backing to produce a transdermal patch.
The transdermal patch es one layer of the pressure-sensitive adhesive layer
containing the acrylic pressure-sensitive adhesive and the rivastigmine n the
backing and the release liner.
The produced preparation was sealed in an aluminum package having the innermost
layer mainly composed of polyacrylonitrile, and nitrogen tution in the package was
d out using a vacuum gas packaging machine.
[Comparative Example 4: Production of ermal Patch by Spread
g Method (2)]
A transderrnal patch was produced in the same manner as in Comparative e
3 except that DURO-TAK (registered trademark) 87-2194 (containing a carboxy group,
Henkel) was used as an acrylic pressure-sensitive adhesive in place of DURO-TAK
(registered trademark) 87-2516 (Henkel). The transdermal patch es one layer of
the pressure—sensitive adhesive layer containing the acrylic pressure-sensitive adhesive
and the rivastigmine between the backing and the release liner.
[Comparative Example 5: Production of Transdermal Patch by Spread
Coating Method (3)]
A transdermal patch was produced in the same manner as in Comparative Example
3 except that DURO-TAK (registered trademark) 87-2516 (containing a hydroxy group,
Henkel) and Durotak 87-2194 (containing a carboxy group, Henkel) were used in
ation in equivalent amounts as c pressure—sensitive adhesives in place of
DURO-TAK (registered trademark) 87-2516 (Henkel) alone. The transdermal patch
includes one layer of the pressure—sensitive adhesive layer containing the acrylic
pressure—sensitive adhesive and the rivastigmine between the backing and the release
liner.
<Stability Evaluation of Transdermal Patch (l)>
(1) Amount of Degradation Product ned Immediately After Production of
Transdermal Patch
The total amount (% by mass) of ation products contained was measured
immediately after the tion in accordance with the following procedure, in each
ermal patch produced in Example 1 and Comparative Example 1 to Comparative
Example 5.
The obtained results are shown in Table 1.
[Measurement Procedure for Amount of Degradation t ned]
The measurement method of the amount of degradation products contained was as
follows. That is, the release liner of the transdermal patch was removed; the
transdermal patch was immersed in a le glass container containing tetrahydrofuran
to dissolve the pressure-sensitive adhesive; then purified water was added to the solution;
and the diluted solution was analyzed by high performance liquid chromatography
(HPLC). The amount of degradation products contained was determined in accordance
with the formula below. The peak area of each degradation product was calculated with
respect to the peak area of the rivastigmine, and the total sum of the peak areas of
degradation products was calculated as the total amount (%) of the degradation products.
Amount of degradation products contained (%) = [peak area of degradation
products/peak area of rivastigmine] x 100
[0050] Table l
Pressure-sensitive ning OH group Containing COOH group Containing OH group/COOH
adhesive group
g method Ointment Spread Ointment. Spread Ointment Spread coating
coating coating coati_ng coating coating
ermal Example Comparative Comparative ative Comparative Comparative
atch No. 1 Example 3 Example l Example 4 Example 2 Example 5
Total amount of 0.783 0.126 0.310 0.439
ation
roducts *
* Each value represents an amount in terms of % by mass with respect to rivastigmine.
As shown in Table 1, in each transdermal patch using the acrylic
pressure-sensitive adhesive containing a hydroxy group, the acrylic re-sensitive
adhesive ning a carboxy group, or the acrylic pressure-sensitive adhesives
containing a hydroxy group and a y group, the obtained results revealed that each
transdermal patch (Example 1, ative Example 1, and Comparative Example 2)
produced by the ointment coating method contained the degradation products in a very
small amount, as compared with that of each transdermal patch (Comparative Example 3,
Comparative Example 4, and Comparative Example 5) produced by the spread coating
method.
(2) Change in Total Amount of Degradation Products after Storage of
Transdermal Patch under Severe Condition (1)
The total amount of degradation products was measured after the storage under a
severe condition (60°C) for a week and two weeks in ance with [Measurement
Procedure for Amount of Degradation Product Contained] above, in each transdermal
patch produced in Example 1, Comparative Example 1, Comparative Example 3, and
Comparative Example 4.
The obtained results are shown in Table 2 and Table 3.
[0053] Table 2
Pressure-sensitive
adhesive 7 c pressure—sensitive adhesive containing OH group
Transdermal patch
ating method ' Example l/ointment coating TComparative Example 3fspread coating
Time course Immediately After a After ately After a Alter
after week two after week two
production weeks roduction weeks
i Total amount of 0.191 0.280 0.345 0.783 0.946 1.104
degradationmducts *
Change in amount 0.0772 0.1607
(slope) **
* Each value ents an amount in terms of % by mass with respect to igmine.
** The slope of an approximate line determined from plots of the total amount of
degradation products with respect to the time course
Table 3
Pressure-sensitive l Acrylic pressure-sensitive adhesive containing COOl-I group
adhesive
Transdermal patch Comparative Example l/ointment Comparative Example 4/spread coating
LNoJcoatirrgmethod coating
Time course Tmmediately After a After Immediately Afier
L after two after
reduction I‘week weeks roduction
Total amount of 0.126 0.454 0.682
de radation roducts *
Change in amount 0.2780
(slope) **
* Each value represents an amount in terms of% by mass with respect to igmine.
** The slope of an approximate line determined from plots of the total amount of
degradation products with respect to the time course
As shown in Table 2 and Table 3, in each transdermal patch using the
acrylic pressure-sensitive adhesive containing a hydroxy group or the acrylic
re-sensitive adhesive containing a carboxy group, the ed results ed that
each transdermal patch (Example 1 and Comparative Example 1) produced by the
ointment coating method contained the degradation products in a very small , as
compared with that of each transdermal patch (Comparative Example 3 and Comparative
Example 4) produced by the spread coating method after the storage for two weeks.
In the transdermal patches produced by the ointment coating method, the obtained
results revealed that the transdermal patch (Example 1) using the acrylic
pressure-sensitive ve containing a y group contained the degradation
products in an amount smaller than that of the transdermal patch rative Example
1) using the c pressure—sensitive adhesive containing a y group after the
storage for two weeks.
The s with time in the total amount of degradation products ned were
compared as the slope of an approximate line determined from plots of the total amount
of ation products with respect to the time course. The obtained results revealed
that the transdermal patch using the hydroxy—containing acrylic pressure-sensitive
adhesive and produced by the ointment coating method had the smallest slope, that is,
had the smallest change with time in the total amount of degradation products and had
high stability.
[0055] <Production of Transdermal Patch (2)>
[Example 2]
A ermal patch was produced in the same manner as in Example 1 except that
the pressure-sensitive adhesive layer had a thickness of 60 mm.
[Example 3]
A transdermal patch was produced in the same manner as in Example 1 except that
AK (registered trademark) 87-2287 (containing a hydroxy group, Henkel) was
used as an acrylic pressure-sensitive adhesive in place of DURO-TAK (registered
trademark) 87-2516 (Henkel) and the pressure—sensitive adhesive layer had a thickness of
60 mm.
[0057] [Comparative Example 6]
A transdermal patch was produced in the same manner as in Example 1 except that
MAS683 (acrylic pressure-sensitive adhesive containing a pyrrolidone ring, CosMED
Pharmaceutical Co. Ltd.) was used as an acrylic pressure-sensitive adhesive in place of
DURO-TAK (registered trademark) 87-2516 l) and the pressure-sensitive
adhesive layer had a thickness of 60 um.
[Comparative Example 7: Commercial Product]
In ative Example 7, RIVASTACH (registered trademark) Patch 18 mg
(manufactured by Ono Pharmaceutical Co., Ltd.) that is a commercially available
transdermal patch ning the rivastigmine was used.
<Stability Evaluation of Transdermal Patch (2)>
(3) Change in Total Amount of Degradation Products after Storage of Transdermal Patch
under Severe Condition (2)
The total amount of degradation products contained was measured immediately
after the production and after the storage under a severe condition (60°C) for a week and
two weeks in accordance with rement Procedure for Amount of Degradation
Product ned] above, in each transdermal patch produced in Example 2, e 3,
Comparative Example 6, and Comparative Example 7.
The obtained results are shown in Table 4 and Table 5.
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As shown in Table 4 and Table 5, the obtained results revealed that each
transdermal patch (Example 1 to Example 3) using the c pressure-sensitive adhesive
containing a hydroxy group contained the degradation products in an amount (total
amount) smaller than those of each ermal patch (Comparative Example 1 and
Comparative Example 6) using a pressure—sensitive adhesive other than the acrylic
pressure-sensitive adhesive ning a hydroxy group and of the commercially
available transdermal patch (Comparative Example 7) after the storage for two weeks.
Also in the change with time in the total amount of degradation products contained
that was ated as the slope of an approximate line determined from plots of the total
amount of degradation products with respect to the time course, the obtained results
revealed that each transdermal patch (Example 1 to Example 3) using the c
pressure-sensitive adhesive containing a hydroxy group had a slope smaller than those of
the other transdermal patches and had high stability.
<Performance Evaluation of Transderrnal Patch>
Using each transdermal patch of Example 1 and Comparative Example 3, the
holding force to a glass plate and the probe tack were measured in accordance with the
following procedures.
(1) g Power With Respect To Glass Plate
The measurement of holding power with t to a glass plate was carried out in
accordance with JIS 2—0237. A sample having a width of 12 mm was laminated to a
glass plate so as to give an area of 12 mm x 20 mm at a temperature of 23°C in an
atmosphere of 50% RH, and was pressed for laminating by one set of reciprocal
nt of a 2-kg rubber roller at a speed of 300 mm/min. After the sample was left
standing for 20 s, the pressure-sensitive adhesive sheet was vertically hung, then a
load of 100 g was applied to the sheet, and the displaced length was measured after 15
minutes and 30 minutes. The obtained results are shown in Table 6.
(2) Probe Tack
The measurement of probe tack was carried out in accordance with nce 5 in
JIS 2—0237 (1991). Using a probe tack tester from Nichiban, a smooth leading end face
of a metal cylindrical probe having a diameter of 5 mm was laminated to a e of a
pressure-sensitive adhesive at a temperature of 23°C in an here of 50% RH while
applying a load of 0.98 N/cm2 (100 i l gf/cmz) for 1.0 i 0.1 second, and the resistance
value was measured when the probe was peeled at 10 i 0.1 mm per second. The
obtained results are shown in Table 6.
Table 6
uresensitive adhesive _[_Acrylic pressure—sensitive adhesive containinLOH group
Coating method I Ointment coating Spread coating
1 Transderma_lp_atch No. I e 1 Compgative Example 3
Holding power with respect to After 15 0.9 2.]
glass plate (mm/12 x 20 mm, minutes ]
load 100 g) ‘ After 30 2.1 Fallen
minutes ‘
I Probe tack (N/5 mm (In) | 5.54 5.10 |
As shown in Table 6, the obtained results revealed that the ermal
patch of Example 1 produced by the ointment coating method had a holding power with
respect to a glass plate and a probe tack which are both better than those of the
transdermal patch of Comparative e 3 produced by the solvent coating method.
<Production of Transdermal Patch (3)>
[Example 4]
A transdermal patch was produced in the same manner as in Example 1 except that
DURO-TAK (registered trademark) 87—2287 (containing a hydroxy group, Henkel) was
used as an acrylic pressure—sensitive adhesive in place of DURO-TAK (registered
trademark) 87-2516 (Henkel), the pressure-sensitive adhesive layer had a thickness of 60
after the sealing of the produced
um, and the nitrogen substitution was not performed
ation in a package.
[Comparative Example 8]
A transdermal patch was produced in the same manner as in Example 1 except that
MAS683 (acrylic pressure-sensitive ve containing a idone ring, CosMED
Pharmaceutical Co. Ltd.)) was used as an acrylic pressure-sensitive ve in place of
DURO-TAK (registered trademark) 87-2516 l), the pressure-sensitive adhesive
layer had a thickness of 60 um, and the nitrogen substitution was not performed after the
sealing of the produced preparation in a package.
<Stability Evaluation of Transdermal Patch (3)>
(4) Change in Total Amount of Degradation Products after Storage of Transdermal Patch
under Severe Condition (3)
The total amount of degradation products was measured in accordance with
[Measurement Procedure for Amount of Degradation Product Contained] above
immediately after the tion and after the storage under a severe condition (60°C) for
two weeks, in each transdermal patch produced in e 4 and Comparative Example
The obtained results are shown in Table 7.
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As shown in Table 7, the obtained results revealed that by sealing the
produced preparation in the aluminum package having the innermost layer mainly
composed of polyacrylonitrile, and then performing the en substitution in the
e using a vacuum gas packaging machine, it is le to e a transdermal
patch having a smaller amount (total amount) of degradation products contained after the
storage for two weeks, having a r change with time in the total amount of
degradation products contained that is calculated as the slope of an approximate line
determined from plots of the total amount of degradation products with respect to the
time course, and having higher stability.
[0072] <Production of Transderrnal Patch (4)>
[Example 5]
A transdermal patch was produced in the same manner as in Example 1 except that
DURO-TAK (registered trademark) 87-2516 (containing a hydroxy group, ) and
DURO-TAK tered trademark) 87-2287 (containing a hydroxy group, Henkel) were
used in combination in equivalent amounts as acrylic pressure-sensitive adhesives in
place of DURO-TAK (registered trademark) 87-2516 (Henkel) alone and the produced
preparation was sealed in OxyCatch (registered trademark) actured by Kyodo
Printing Co., Ltd.) as a package containing an oxygen er in place of the aluminum
package having the innermost layer mainly ed of polyacrylonitrile.
[0074] <Stability Evaluation of Transdermal Patch (4)>
(5) Change in Total Amount of Degradation Products after Storage of Transdermal Patch
under Severe Condition (4)
The total amount of degradation products was measured in accordance with
[Measurement Procedure for Amount of Degradation Product Contained] above
immediately after the production and after the storage under a severe ion (60°C) for
a week, in the transdermal patch produced in Example 5.
The obtained results are shown in Table 8.
Table 8
Pressure-sensitive adhesive Acrylic pressure-sensitive (reference) RIVASTACH
adhesive containing OH group
Transdermal patch No. Example 5
(shown a_ain)
Time course Immediate 1 week Immediate 1 week
Lgoducts *Total amount of degradation 0.185 0.273 L0.169 0.322
Chflgg in amount (slolyiM 0.0880 0.1033
* Each value represents an amount in terms of % by mass with t to rivastigmine.
** The slope of an approximate line determined from plots of the total amount of
degradation products with respect to the time course
As shown in Table 8, the obtained results revealed that the sealing of the
produced preparation in the package containing the oxygen absorber in place of the
aluminum e having the ost layer mainly composed of polyacrylonitrile can
produce the ermal patch having further improved stability.
Claims (16)
1. A transdermal patch for ent ofAlzheimer's disease, comprising: a backing; a rivastigmine-containing layer provided on the backing; a pressure-sensitive adhesive layer ed on the rivastigmine-containing layer; a release liner, or sing: a backing; 10 a pressure-sensitive adhesive layer provided on the backing; a rivastigmine—containing layer provided on the pressure-sensitive adhesive layer; a release liner, wherein the rivastigmine-containing layer contains rivastigmine and an alkyl (meth)acry1ate 15 resin, the pressure-sensitive ve layer is composed of an acrylic pressure-sensitive adhesive containing a (meth)acrylic acid ester having a hydroxy group, and neither the igmine-containing layer nor the pressure-sensitive adhesive layer contains an anti-oxidizing agent.
2. The transdermal patch for treatment ofAlzheimer’s disease according to claim 1, wherein the rivastigmine-containing layer is a layer formed by using a solution containing the rivastigmine under a condition at 1°C or higher and lower than 60°C. 25
3. The ermal patch for treatment of Alzheimer's disease according to claim 1 in an amount of or 2, wherein the rivastigmine-containing layer ns the rivastigmine 20% to 95% by mass based on a total mass of the layer.
4. The transdermal patch for treatment ofAlzheimer's disease according to any one of claims 1 to 3, n the rivastigmine-containing layer is a layer having a thickness of 10 pm to 80 pm and the pressure-sensitive adhesive layer is a layer having a thickness of 10 pm to 100 pm.
5. A method for producing a transdermal patch for treatment ofAlzheimer's disease, the method comprising: a rivastigmine layer formation step of applying a solution containing rivastigmine onto a backing to form a rivastigmine-containing layer; a pressure—sensitive adhesive layer formation step of applying a solution containing 10 an c pressure-sensitive adhesive onto a release liner to form a pressure-sensitive adhesive layer; and a transdermal patch formation step of laminating the rivastigmine-containing layer formed on the backing to the re-sensitive adhesive layer formed on the release liner, wherein 15 the solution containing rivastigmine contains the igmine and an alkyl (meth)acrylate resin, the solution containing an acrylic pressure-sensitive adhesive contains an acrylic pressure-sensitive adhesive containing a (meth)acrylic acid ester having a hydroxy group, 20 r the on containing rivastigmine nor the solution containing an acrylic pressure-sensitive adhesive contains an anti-oxidizing agent.
6. A method for producing a transdermal patch for treatment ofAlzheimer's e, the method comprising: 25 a pressure-sensitive adhesive layer formation step of applying a solution containing an acrylic pressure—sensitive adhesive onto a backing to form a re-sensitive adhesive layer; a rivastigmine layer formation step of applying a solution containing rivastigmine onto a release liner to form a rivastigmine-containing layer: and a transdermal patch formation step of laminating the pressure-sensitive adhesive layer formed on the backing to the rivastigmine-containing layer formed on the release liner, n the solution containing igmine contains the rivastigmine and an alkyl (meth)acrylate resin, the solution containing an acrylic pressure—sensitive adhesive contains an acrylic pressure—sensitive adhesive containing a (meth)acrylic acid ester having a hydroxy group, neither the solution containing rivastigmine nor the solution containing an acrylic 10 pressure-sensitive adhesive contains an xidizing agent.
7. A method for ing a transdermal patch for treatment ofAlzheimer's disease, the method sing: a pressure-sensitive adhesive layer formation step of applying a solution containing 15 an acrylic re-sensitive adhesive onto a backing to form a pressure-sensitive adhesive layer; a igmine layer formation step of applying a solution containing rivastigmine onto the pressure-sensitive adhesive layer to form a rivastigmine-containing layer; and a ermal patch formation step of laminating the rivastigmine—containing layer 20 formed on the pressure—sensitive adhesive layer on the backing to a release liner, wherein the solution containing rivastigmine contains the rivastigmine and an alkyl (meth)acrylate resin, the solution containing an acrylic re-sensitive adhesive contains an c pressure-sensitive adhesive containing a (meth)acrylic acid ester having a hydroxy group, 25 and neither the solution containing rivastigmine nor the solution containing an acrylic pressure-sensitive adhesive contains an anti-oxidizing agent.
8. The method according to any one of claims 5 to 7, wherein the rivastigmine layer formation step comprises applying the solution containing rivastigmine under a temperature ion of 1°C or higher and lower than 60°C.
9. The method according to any one of claims 5 to 8, further comprising a g step of allowing the pressure-sensitive adhesive layer to cool or forced-cooling the pressure-sensitive adhesive layer, after the pressure-sensitive ve layer formation step and before the transdermal patch ion step.
10. The method according to claim 9, further comprising an aging step before and 10 after the cooling step.
11. A product of a transdermal patch for treatment ofAlzheimer's disease produced by sealing the transdermal patch for treatment ofAlzheimer's disease according to any one of claims 1 to 4 or a transdermal patch for treatment ofAlzheimer‘s disease produced 15 by the method ing to any one of claims 5 to 10 in a package composed of a te of multi-layered films or layered sheets, wherein an ost layer of the package is a layer containing polyacrylonitrile as a main component. 20
12. A product of a transdermal patch for treatment ofAlzheimer‘s disease produced by sealing the transdermal patch for treatment ofAlzheimer's disease according to any one of claims 1 to 4 or a transdermal patch for treatment ofAlzheimer's disease produced by the method according to any one of claims 5 to 10 in a package composed of a laminate of multi-layered films or multi—layered sheets, wherein 25 the package sing a film or a sheet including a layer containing an oxygen absorber or an oxygen absorber is tely enclosed in the package.
13. A product of a transdermal patch for treatment ofAlzheimer's disease produced by sealing the transdermal patch for treatment ofAlzheimer's disease according to any one of claims 1 to 4 or a transdermal patch for treatment of Alzheimer's disease ed by the method according to any one of claims 5 to 10 in a package composed of a laminate of multi-layered films or multi-layered sheets, wherein an atmosphere in the e is substituted and filled with nitrogen.
14. A transdermal patch for treatment of Alzheimer's disease comprising: a polyester film backing; a rivastigmine-containing layer ed on the backing; a re-sensitive adhesive layer provided on the rivastigmine-containing layer; 10 and a release liner, wherein the rivastigmine-containing layer contains rivastigmine and an alkyl (meth)acrylate resin, the pressure-sensitive adhesive layer includes an acrylic pressure-sensitive adhesive 15 containing a (meth)acrylic acid ester having a hydroxy group, each of the rivastigmine-containing layer and the pressure-sensitive adhesive layer does not contain an anti-oxidizing agent or an acrylic pressure-sensitive ve containing a (meth)acrylic acid ester having a carboxy group, and the transdermal patch includes a degradation product of the rivastigmine in a total 20 amount of less than 0.50% by mass based on an amount of the rivastigmine after storage under a severe ion (60°C) for two weeks from a production date of the ermal patch.
15. A transdermal patch according to claim 1 or claim 14, ntially as herein 25 described with reference to any one of the accompanying examples thereof.
16. A method according to any one of claims 5 to 7, substantially as herein described with reference to any one of the accompanying examples thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/JP2012/054907 WO2013128562A1 (en) | 2012-02-28 | 2012-02-28 | Adhesive skin patch |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ628326A NZ628326A (en) | 2015-08-28 |
| NZ628326B2 true NZ628326B2 (en) | 2015-12-01 |
Family
ID=
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