JP6841417B2 - Transdermal patch formulation that suppresses photodegradation of rivastigmine - Google Patents

Description

The present invention relates to a transdermal patch formulation comprising a support, a rivastigmine-containing adhesive layer and a release liner, and more particularly to a transdermal patch formulation that suppresses photodecomposition of rivastigmine.

Rivastigmine is a reversible and potent acetylcholinesterase inhibitor, and is a drug having an excellent therapeutic effect (including suppression and alleviation of symptom progression) for Alzheimer-type dementia and the like. So far, preparations containing rivastigmine as an active ingredient have been developed. For example, in Japan, "Ixeron (registered trademark) patch" and "Rivastouch (registered trademark) patch" are transdermal patch preparations containing rivastigmine. , Etc. are manufactured and sold.

It has been confirmed that rivastigmine is decomposed by exposure to light, and the decomposition of rivastigmine reduces the content in the base, so that the original medicinal effect is not exhibited, and the photodegraded product causes allergies. There is a possibility that problems such as causing undesired side effects may occur.

Patent Document 1 discloses a patch preparation in which photodecomposition of a drug is suppressed by blending an ultraviolet absorber in the base.

As described in Patent Document 1, as a means for maintaining the photostability of a drug in a patch formulation, it is widely known to add an ultraviolet absorber in the base thereof. In addition, the present inventors have confirmed that the decomposition of rivastigmine when exposed to light can be suppressed by adding an antioxidant to a transdermal patch preparation containing rivastigmine as an active ingredient. However, when an ultraviolet absorber or an antioxidant is blended in the base, skin irritation or the like occurs, and such a patch preparation may reduce the patient's satisfaction with treatment. Therefore, there has been a demand for a rivastigmine transdermal patch preparation that reduces skin irritation and has excellent photostability by adding an antioxidant or the like to the base.

Further, as described in Patent Document 2, it has been reported that the support is subjected to an ultraviolet shielding process as a means for maintaining the photostability of the drug in the patch formulation. However, it was confirmed that when the support was used in a transdermal patch preparation containing rivastigmine as an active ingredient, photostability could not be maintained and the decomposition of rivastigmine could not be suppressed by the above means alone.

Special Fair No. 5-8169 Japanese Patent No. 5044078

Therefore, the present invention is a transdermal patch preparation containing rivastigmine as an active ingredient, and suppresses the decomposition of rivastigmine due to light exposure without adding an antioxidant, and improves the stability of rivastigmine. An object of the present invention is to provide a transdermal patch preparation.

As a result of diligent research to solve the above problems, the present inventors have found that the decomposition of rivastigmine by light can be suppressed by blocking light in a specific wavelength range, and this finding is utilized. Then, it was found that a transdermal patch preparation capable of suppressing the decomposition of rivastigmine by light exposure can be obtained. In particular, by using a light shielding treatment support having a light transmittance of 0.2% or less at both wavelengths of 340 to 380 nm and 440 to 520 nm as a support for a transdermal patch preparation, it is remarkably made. The present invention was completed by finding that the photodegradation of rivastigmine is suppressed.

That is, the present invention is a transdermal patch preparation comprising a support, a rivastigmine-containing adhesive layer and a release liner, in which the support has a light transmittance of 0.2% or less at wavelengths of 340 to 380 nm and 440 to 520 nm. It is a transdermal patch preparation characterized by being a light-shielding treatment support.

The transdermal patch formulation of the present invention is excellent in photostability because it can suppress the decomposition of rivastigmine by light without using an antioxidant.

The transdermal patch formulation of the present invention is composed of a support, a rivastigmine-containing adhesive layer and a release liner, a rivastigmine-containing adhesive layer is provided on the support, and a release liner is further provided on the rivastigmine-containing adhesive layer. Is. Further, as the support of the transdermal patch preparation of the present invention, a light shielding treatment support having a light transmittance of 0.2% or less at any wavelength in the wavelength range of 340 to 380 nm and 440 to 520 nm is used. It is to be used. In the present invention, the transdermal patch preparation is a medical adhesive patch preparation, which means that a therapeutically effective amount of rivastigmine, which is an active ingredient, is applied on the skin and reaches the bloodstream through the skin. ..

The rivastigmine-containing adhesive layer in the transdermal patch formulation of the present invention contains rivastigmine (3-[(1S) -1- (dimethylamino) ethyl] phenyl N-ethyl-N-methylcarbamate) as an active ingredient. As the rivastigmine in the present invention, one or more selected from rivastigmine and its pharmaceutically acceptable salt (acid-added salt form) can be used, and among them, a free form of rivastigmine (free base form) can be used. Is preferably used.

The transdermal patch formulation of the present invention contains a therapeutically effective amount of rivastigmine. Since an effective amount of rivastigmine for the treatment of Alzheimer's disease is continuously transdermally administered to a patient for a long period of time, it is preferable to contain a certain amount of rivastigmine. The content of rivastigmine is preferably 1 to 50% by mass, more preferably 5 to 30% by mass, and further preferably 12 to 30% by mass with respect to the rivastigmine-containing adhesive layer. If the content of rivastigmine is less than 1% by mass, the therapeutic effect may not be sufficiently exhibited, and if it is more than 50% by mass, the content of the pressure-sensitive adhesive constituting the drug-containing layer is relatively small, which is sufficient. It may not be sticky to the skin and may be economically disadvantageous.

The transdermal patch formulation of the present invention contains an adhesive component in the rivastigmine-containing adhesive layer. Examples of the adhesive component include acrylic adhesives, rubber adhesives, silicone adhesives, and the like, and among these, acrylic adhesives are preferable. Here, the acrylic pressure-sensitive adhesive is a polymer or copolymer containing at least one (meth) acrylic acid ester, which does not have a functional group in the side chain in the monomer constituent unit or has a functional group. Also includes those that have. Examples of the acrylic pressure-sensitive adhesive having no functional group include 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate copolymer, methyl methacrylate, butyl methacrylate, and dimethylamino methacrylate. Examples thereof include an ethyl copolymer. Specific examples include commercially available DURO-TAK (registered trademark) acrylic adhesive series (manufactured by Henkel Japan), GELVA (registered trademark) acrylic adhesive series (manufactured by Monsanto), SK Dyne Matriderm (manufactured by Soken Kagaku Co., Ltd.), Eudragit (registered trademark) series (Higuchi Shokai), MAS series (manufactured by Cosmed Pharmaceutical Co., Ltd.), etc., among which Eudragit (registered trademark) EPO and DURO-TAK (registered trademark) 87-9301 (acrylic acid copolymer) ), 87-608A, 87-4098 (acrylic acid / vinyl acetate mixture), MAS683 and MAS811 are preferably used.

Examples of the acrylic pressure-sensitive adhesive having the above-mentioned functional group include acrylic pressure-sensitive adhesives having a hydroxyl group, a carboxyl group and the like as the functional group. Among them, the heat stability and the absorption of ribastigmine into the skin are considered. An acrylic pressure-sensitive adhesive having a hydroxyl group in terms of points is preferable. The acrylic pressure-sensitive adhesive having a hydroxyl group is a polymer or copolymer having at least one (meth) acrylic acid ester containing a free hydroxyl group in the side chain in the monomer constituent unit as a constituent monomer, and is, for example, ( Meta) Copolymers containing an acrylic acid hydroxyalkyl ester and the like are exemplified. Examples of the (meth) acrylic acid hydroxyalkyl ester include 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate and methacrylic acid. Examples thereof include 2-hydroxypropyl, 3-hydroxypropyl methacrylate and 4-hydroxybutyl methacrylate. Specifically, 2-ethylhexyl acrylate, hydroxylethyl acrylate, vinyl acetate copolymer, 2-ethylhexyl acrylate, vinylpyrrolidone, hydroxylethyl acrylate, vinyl acetate copolymer, 2-ethylhexyl acrylate, hydroxyl acrylate. Ethyl / glycidyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinyl acetate / 2-hydroxyethyl acrylate copolymer, 2-ethylhexyl acrylate / vinyl acetate / 2-hydroxyethyl acrylate / glycidyl methacrylate An example is a copolymer or the like. Examples of these commercially available products include hydroxyl group-containing types (DURO-TAK (registered trademark) 87-2516, 87-2525, 87-2979, 87) of the DURO-TAK (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel Japan Ltd.). -8287, 87-2510, 87-202A, 87-502A, 87-503A and the like can be mentioned.

The content of the acrylic pressure-sensitive adhesive in the transdermal patch formulation of the present invention is preferably 40 to 99% by mass, preferably 60 to 95% by mass, based on the rivastigmine-containing pressure-sensitive adhesive layer from the viewpoint of adhesive physical characteristics. Is more preferable.

The rivastigmine-containing adhesive layer of the percutaneous absorption type patch formulation of the present invention contains additional components such as a plasticizer, a cross-linking agent, and a transdermal absorption accelerator, if necessary, as long as the effects of the present invention are not impaired. You may. Further, if necessary, in order to control the transdermal absorption of rivastigmine, a release control film or the like can be added to the skin-attached side of the rivastigmine-containing adhesive layer.

Examples of the plasticizer include petroleum oils such as paraffin-based process oils, naphthen-based process oils, and aromatic process oils, and liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, and isopropyl linoleate. Kind, olive oil, camellia oil, castor oil, tall oil, vegetable oil such as lacquer oil, liquid rubber such as liquid polyisobutylene, liquid polybutene, liquid polyisoprene, glycerin, chlorobutanol, vinyl acetate resin, dimethylpolysiloxane / silicon dioxide Examples thereof include a mixture, D-sorbitol, medium chain fatty acid triglyceride, triacetin, pyrrolidones, phytosterol, propylene glycol, polyethylene glycol, polysorbate 80 (registered trademark), glycerin monostearate and the like.

Examples of the cross-linking agent include thermosetting resins such as amino resin, phenol resin, epoxy resin, alkyd resin and unsaturated polyester, isocyanate compounds, organic cross-linking agents, and inorganic cross-linking agents such as metals or metal compounds. Be done.

Further, the transdermal absorption promoter may be any compound that has been conventionally recognized to have an absorption promoting effect by transdermal administration, and for example, ancanolamine such as diisopropanolamine and triisopropanolamine, lauric acid, and olein. Fatty acids such as acids, isostearic acid, isopropyl myristate, octyldodecyl myristate, glycerin oleate monoester, hexyl decyl isostearate and their esters, alcohols such as oleyl alcohol, propylene glycol and polyethylene glycol monooleate and their esters. Alternatively, sorbitan esters such as ethers, sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate or ethers, phenols such as polyoxyethylene nonylphenyl ether and polyoxyethylene octylphenyl ether. Non-ionic surfactants such as ethers, castor oil or hardened castor oil, oleoyl sarcosine, betaine laurin dimethylaminoacetate, sodium lauryl sulfate, polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, dimethyl lauryl amine oxide, etc. Ionic surfactants, alkylmethyl sulfoxides such as dimethyl sulfoxide and decyl methyl sulfoxide, pyrrolidones such as 2-pyrrolidone and 1-methyl-2-pyrrolidone, 1-dodecyl azacycloheptane-2-one , 1-geranyl azacycloheptane-2-one and other azacycloalkanes, menthol, camphor, limonene and other terpenes, crotamitone and the like.

When the percutaneous absorption accelerator is blended in the rivastigmine-containing adhesive layer of the transdermal patch preparation of the present invention, the blending amount is preferably 0.1 to 45% by mass, more preferably 0, based on the rivastigmine-containing adhesive layer. It is in the range of 1 to 20% by mass, more preferably 1 to 15% by mass. If the blending amount of the transdermal absorption promoter is less than 0.1% by mass, the skin permeation promoting effect may not be observed, and if it exceeds 45% by mass, skin irritation derived from the transdermal absorption promoter develops. At the same time, the physical properties of the preparation may deteriorate and a sticky feeling may occur.

The support in the percutaneous absorption type patch formulation of the present invention is a light shielding treatment support having a light transmittance of 0.2% or less at any wavelength in the wavelength range of 340 to 380 nm and 440 to 520 nm, preferably. A light shielding treatment support of 0.2% or less at any wavelength in the wavelength range of 310 to 550 nm, more preferably a light shielding processing support of 0.1% or less at any wavelength of the wavelength range of 310 to 550 nm. It is to be used. Such a light shielding treatment support can be obtained, for example, by subjecting a support used as a support for a general transdermal patch preparation to a light shielding process or the like. If the light transmittance exceeds 0.2% at any wavelength in the wavelength range of 340 to 380 nm and 440 to 520 nm, decomposition products increase and safety concerns arise. Further, even if a light shielding treatment support having a light transmittance of 0.2% or less is used only at wavelengths having a wavelength range of less than 310 nm or more than 550 nm, the effect of suppressing the decomposition of rivastigmine cannot be obtained.

Examples of the method for light-shielding the support include a method of applying a colorant to the support, a method of blending a colorant in the support, and the like, and in particular, the support is exposed to light. A method of applying a colorant to the side (non-rivastigmine-containing adhesive layer side) is preferable.

Examples of the method of applying the colorant to the support include printing, and the thickness of the printing layer is preferably 1 to 4.8 μm, more preferably 1.4 to 3.6 μm. By applying the colorant to the support in this way, the support is coated with the colorant. Further, as a method of blending the colorant in the support, for example, kneading and the like can be mentioned, and the colorant is contained in the support by these methods.

The colorant is not particularly limited, but is one or two selected from, for example, aluminum, silica, titanium oxide, carbon black, copper phthalocyanine blue, naphthol red, dimethylquinacridone, monoazo yellow, and copper phthalocyanine green. It is preferable to use the above.

Further, as the support in the transdermal patch preparation of the present invention, it is preferable to use a drug-impermeable, stretchable or non-stretchable support. Materials and forms constituting the support include films and sheets formed of synthetic resins such as polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), nylon, and polyurethane. Examples thereof include these laminates, porous bodies, foams, and paper materials formed from plant fibers. As the form of the support, it is preferable not to use a woven fabric or a non-woven fabric. The thickness of the support is preferably 12 to 60 μm, more preferably 12 to 40 μm.

Further, the light shielding treatment support in the transdermal patch formulation of the present invention is preferably one capable of blocking the invasion of water vapor, oxygen, etc. in consideration of suppressing the production of decomposition products derived from rivastigmine. Oxygen permeability of light shielding processing support is preferably not more than ^{80cc / m 2 · atm · day} , more preferably at most ^{40cc / m 2 · atm · day} .

In the transdermal patch formulation of the present invention, a release liner is provided on the rivastigmine-containing adhesive layer for the purpose of protecting the rivastigmine-containing adhesive layer until use. The release liner is not particularly limited as long as it is a drug-impermeable release liner, but for example, a film made of a polymer material such as polyethylene, polypropylene, or polyester, a film on which aluminum is vapor-deposited, or on paper. Examples include those coated with silicone oil or the like. Among them, a polyester film is preferable in terms of processability and low cost because it does not allow the active ingredient or oxygen to permeate, and a polyethylene terephthalate (PET) film is particularly preferable. Further, as the release liner, a laminated film or the like in which a plurality of materials are bonded may be used.

The method for producing the transdermal patch formulation of the present invention is not particularly limited, and can be produced according to a known method. As a preferable known production method, for example, rivastigmine and an adhesive component, and if necessary, a transdermal absorption accelerator and the like are dissolved in an organic solvent of toluene, methanol, hexane, ethyl acetate or a mixed solvent thereof, and this lysate is dissolved. A transdermal absorption type patch is prepared by spreading on a release liner or a light shielding support, evaporating the solvent in the solution to form a drug-containing layer, and then adhering the light shielding support or the release liner. The method for obtaining the substance, the active ingredient and the adhesive, and if necessary, a transdermal absorption accelerator and the like were melted by heating, and the melt was spread on a release liner or a light shielding support to form a drug-containing layer. After that, a method of obtaining a percutaneous absorption type patch by laminating a light shielding treatment support or a release liner can be mentioned.

The transdermal patch formulation of the present invention is a matrix-type patch comprising a support, a rivastigmine-containing adhesive layer, and a release liner. Since such a matrix-type patch formulation is easy to design and does not have a complicated structure like a reservoir-type patch formulation having a pressure-sensitive adhesive layer other than the rivastigmine-containing adhesive layer, the patch formulation is manufactured. The cost of time can be reduced. If necessary, a release control film or the like can be added to the skin-attached side of the rivastigmine-containing adhesive layer in order to control the percutaneous absorption of the active ingredient.

The transdermal patch preparation of the present invention thus obtained has suppressed photodegradation of rivastigmine. Therefore, the transdermal patch preparation of the present invention maintains the medicinal effect of rivastigmine and is excellent in safety. The transdermal patch preparation of the present invention preferably has a low peroxide value of the rivastigmine-containing adhesive layer in consideration of suppressing the formation of decomposition products derived from rivastigmine. As a specific value of the peroxide value, it is preferably 6 meq / kg or less, more preferably 3 meq / kg or less, and further preferably 1 meq / kg or less.

Further, the transdermal patch formulation of the present invention is preferably in the form of a package that is stored in the packaging material until it is used. The packaging material is preferably one that can block the intrusion of water vapor, oxygen, ultraviolet rays, etc. in consideration of suppressing the formation of decomposition products derived from rivastigmine. Examples of such materials include metal foils such as acrylonitrile methyl acrylate copolymers, polyolefins, cyclic polyolefins, ethylene-vinyl alcohol copolymers, heat-sealed PETs, and aluminum foils; ethylene vinyl alcohol copolymer films, metal (aluminum, etc.) laminates. Examples thereof include films having low oxygen permeability such as plastic films, metal-deposited plastic films, and ceramics (silicon oxide and the like) vapor-deposited plastic films; metals such as stainless steel; and glass. Among these, it is preferable to use a metal foil, a metal laminated plastic film, a metal-deposited plastic film, or the like in consideration of low permeability of oxygen or the like, manufacturing cost, and the like.

The transdermal patch formulation of the present invention is preferably stored in a packaging material in a sealed state. In the sealed state, it is preferable to set it in a hypoxic state in consideration of suppressing the formation of decomposition products derived from rivastigmine. Specifically, a method of removing air in the packaging material and sealing it (a state like a vacuum pack), a method of replacing the air in the packaging material with an inert gas such as nitrogen gas or argon gas and sealing it. Can be mentioned.

Further, as the method for setting the hypoxic state, a method of enclosing a substance having an oxygen adsorbing ability with the transdermal patch preparation of the present invention, a method of using a packaging material containing a substance having an oxygen adsorbing ability, and the like can be mentioned. , The method may be used alone or in combination with the above methods. Examples of the substance having such an oxygen adsorbing ability include inorganic oxygen scavengers mainly composed of iron powder, zinc powder, hydrosulfite and the like, and organic materials such as ascorbic acid type, polyhydric alcohol type and activated carbon type. Oxygen scavengers include, for example, Pharmakeep (manufactured by Mitsubishi Gas Chemical Co., Ltd.), Ageless (manufactured by Mitsubishi Gas Chemical Co., Ltd.), StabilOx (manufactured by Multisorb), Wellpack (manufactured by Taisei Co., Ltd.), Everfresh. (Manufactured by Tori Shigeru Sangyo Co., Ltd.), Oxyter (manufactured by Ueno Fine Chemicals Industry Co., Ltd.), Keybit (manufactured by Drainy Co., Ltd.), Keplon (manufactured by Keplon Co., Ltd.), Sansokat (manufactured by Iris Fine Products Co., Ltd.) , San Soles (manufactured by Hiroyo Co., Ltd.), Secure (manufactured by Nisso Resin Co., Ltd.), Tamotu (manufactured by Oe Chemical Industry Co., Ltd.), Vitalon (manufactured by Tokiwa Sangyo Co., Ltd.), Modulan (Nippon Kayaku Food Techno (Nippon Kayaku Food Techno) Commercially available products such as (manufactured by Co., Ltd.), Wonder Keep (manufactured by Powder Tech Co., Ltd.), and freshness preservative C (manufactured by Toppan Printing Co., Ltd.) may be used.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples, and various modifications can be made without departing from the technical idea of the present invention. Is.

<Manufacturing of light shielding support>
Light shielding support 1:
Colorants (carbon black, naphthol red, monoazo yellow, titanium oxide, silica) were dissolved in ethyl acetate and toluene and stirred uniformly to prepare a beige coloring solution. This coloring solution was applied to the non-plaster contact side of the PET film (about 25 μm) by printing and dried. The same printing as described above was repeated once more on the printed surface to obtain a light shielding processed support 1.

Light shielding support 2-4:
Light shielding treatment supports 2 to 4 were obtained by the same method as that of the light shielding treatment support 1 except that the color of the coloring solution of the light shielding treatment support 1 was changed. Titanium oxide and silica were used as the white coloring solution, and silica and monoazo yellow were used as the yellow coloring solution.

Comparative support 1:
A comparative support 1 was obtained by the same method as that of the light shielding treatment support 1 except that the coating treatment of the coloring solution of the light shielding treatment support 1 was changed to one time.

Comparative support 2:
Colorants (carbon black, naphthol red, monoazo yellow, titanium oxide, silica) were dissolved in ethyl acetate and toluene and stirred uniformly to prepare a beige coloring solution. This coloring solution was blended with polyester to produce a woven fabric, and a comparative support 2 (410 μm) was obtained.

Table 1 shows the light shielding treatment supports 1 to 4 and the comparative supports 1 to 2.

Test Example 1 (light transmission test)
Light transmission tests were performed on the light shielding treatment supports 1 to 4 and the comparative supports 1 to 2. Each light shielding treatment support cut into 2 cm × 2 cm was attached to the cell window of an ultraviolet-visible spectrophotometer (manufactured by JASCO Corporation), and the light transmittance (%) was measured. Table 2 shows the maximum value (%) of the light transmittance in the range of 340 to 380 nm and 440 to 520 nm and the maximum value (%) of the light transmittance in the range of 310 to 550 nm.

Rivastigmine transdermal patch formulation:
Example 1
According to the composition of the pressure-sensitive adhesive layer 1 in Table 3, rivastigmine, an acrylic pressure-sensitive adhesive, a transdermal absorption accelerator, and a plasticizer were added to ethyl acetate and mixed by stirring to obtain a uniform solution. The amount of ethyl acetate used was 1.5 times the total amount of rivastigmine and the acrylic pressure-sensitive adhesive. Next, this melt was spread on a release film (a PET film treated with silicone) using a doctor knife coating machine, and the solvent was distilled off to form a rivastigmine-containing adhesive layer having a thickness of 100 μm. did. The non-light-shielding treated side of the above-mentioned light-shielding treatment support 1 was bonded to the rivastigmine-containing adhesive layer and cut into a desired size to produce a transdermal patch preparation.

Examples 2-8 and Comparative Examples 1-4
A transdermal patch preparation was produced by the same method as in Example 1. The supports and adhesive layers used are shown in Table 4.

Test Example 2 (optical stability test)
The transdermal patch preparations of Examples 1 to 8 and Comparative Examples 1 to 4 ^{were cut into 5 cm 2} pieces and allowed to stand in a photostability test device so as to be exposed to light from the support side. It was stored until the total illuminance reached 1.2 million Lx · h, and the amount of decomposition products produced before and after storage was measured. The release sheet of each transdermal patch was peeled off, placed in a 50 mL centrifuge tube, 10 mL of tetrahydrofuran was added, and the mixture was shaken for 20 minutes. 10 mL of water / methanol (2: 1, v / v) was added to this solution, and the mixture was shaken for 20 minutes. The supernatant was diluted with the mobile phase at an arbitrary ratio and quantified by high performance liquid chromatography. For the operation of high performance liquid chromatography, the column is Xbridge shiled C18 RP (3.5 μm, 3.0 mm × 10 cm; manufactured by Nippon Waters Co., Ltd.), the detection wavelength is 215 nm, and the mobile phase is water / phosphoric acid. (10000: 1, v / v) (mobile phase A) and acetonitrile for liquid chromatography (mobile phase B), the liquid transfer of the mobile phase is performed by mixing mobile phase A and mobile phase B under arbitrary conditions and controlling the concentration gradient. I went. Table 5 shows the amounts of rivastigmine degradation products in each transdermal patch formulation. The decomposition product of rivastigmine is a substance derived from rivastigmine (a substance that is not expressed in a preparation not containing rivastigmine), and the smaller the amount of this decomposition product, the more the decomposition of rivastigmine is suppressed. Is shown.

As is clear from the results in Table 5, the transdermal patch preparations of Examples 1 to 8 have a smaller amount of decomposition products than the transdermal patch preparations of Comparative Examples 1 to 4, and photodecomposition of rivastigmine. It was confirmed that it suppresses. Further, from the transdermal patch preparations of Examples 1 to 8, it was confirmed that the more the support having the lower light transmittance was used, the more the production of the rivastigmine decomposition product was suppressed. If the amount of rivastigmine decomposition product is 0.5% or more, there is a concern about safety. Therefore, the evaluation is evaluated as x, while the amount of rivastigmine decomposition product is less than 0.5%. It was marked as ○.

The transdermal patch formulation of the present invention is excellent in safety during use and stability of rivastigmine because it can suppress photodecomposition of rivastigmine without using additives such as antioxidants. is there. Therefore, since the transdermal patch preparation of the present invention can prevent deterioration of quality with time, it is possible to effectively and sustainably utilize the pharmacological effect of rivastigmine, and in particular, Alzheimer-type cognition. It is a useful preparation for the treatment of diseases.

Claims (5)

A transdermal patch consisting of a support, a rivastigmine-containing adhesive layer, and a release liner, wherein the support is a light-shielding treatment support having a light transmittance of 0.2% or less at wavelengths of 340 to 380 nm and 440 to 520 nm. A transdermal patch preparation characterized by being. The transdermal patch formulation according to claim 1, wherein the light shielding treatment support covers and / or contains a colorant. The transdermal color according to claim 1 or 2, wherein the colorant is one or more selected from aluminum, silica, titanium oxide, carbon black, copper phthalocyanine blue, naphthol red, dimethylquinacridone, monoazo yellow, and copper phthalocyanine green. Absorption-type patch formulation. The transdermal patch according to any one of claims 1 to 3, wherein the rivastigmine-containing adhesive layer contains an acrylic pressure-sensitive adhesive. The transdermal absorption type patch according to any one of claims 1 to 4, wherein the acrylic pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive having a hydroxyl group and / or an acrylic pressure-sensitive adhesive having no functional group.