JP6984871B2 - Rivastigmine transdermal patch - Google Patents

Description

The present invention relates to a rivastigmine transdermal patch formulation, and more particularly to a rivastigmine transdermal patch formulation capable of suppressing volatilization of an active ingredient and cold flow.

Rivastigmine is a reversible and potent acetylcholinesterase inhibitor, and is a drug having an excellent therapeutic effect (including suppression and alleviation of progression of symptoms) for Alzheimer-type dementia and the like. So far, formulations 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 formulations containing rivastigmine. "(Hereinafter, the original product) is manufactured and sold.

Since these original plasters have viscous properties, a phenomenon called cold flow has become a problem. When the cold-flowing formulation is applied to the skin, adhesive residue (dark ring) is likely to occur. Even in the original product, it is known that adhesive residue is formed at the time of peeling after application to the patient, and it is possible that more drugs than specified are administered, which causes unfavorable side effects, etc. May cause problems

On the other hand, since rivastigmine is a liquid at room temperature, rivastigmine may volatilize during production or storage. Assuming that rivastigmine volatilizes, the content of rivastigmine in the formulation is expected to decrease, and it may not be sufficiently effective for treatment. It will be necessary, the cost will inevitably increase, and in some cases, more than the prescribed amount of rivastigmine may be administered.

As described in Patent Document 1, the loss due to volatilization of rivastigmine in the above-mentioned manufacturing process can be suppressed by adding a volatilization inhibitor to the plaster layer of the patched formulation containing rivastigmine as an active ingredient. .. However, when a sufficient amount of volatile inhibitor capable of suppressing the volatilization of rivastigmine is blended, the adhesiveness sufficient for treatment is impaired from the plaster layer containing the rivastigmine, causing peeling and curling, and cold flow. Increased risk reduces patient satisfaction with treatment. From the above, there is a demand for a rivastigmine transdermal patch formulation that suppresses volatilization of rivastigmine and is also excellent in suppressing cold flow.

U.S. Patent Application Publication No. 2010/0877768A

Therefore, it is an object of the present invention to provide a transdermal patch formulation containing rivastigmine as an active ingredient, which suppresses volatilization of rivastigmine and suppresses cold flow. ..

The present inventors have been diligently researching the composition of a patch containing rivastigmine in order to solve the above-mentioned problems. By blending the aminoalkylmethacrylate copolymer E in a specific pressure-sensitive adhesive base, rivastigmine is volatilized. We have found that the cold flow of the adhesive layer can be suppressed as well as suppressed, and the present invention has been completed.

That is, the present invention is a percutaneous absorption type patch-containing preparation containing a support, an adhesive layer and a release liner, and the adhesive layer is a pressure-sensitive adhesive group substantially free of an acrylic polymer having a carboxyl group as a functional group. It is a rivastigmine-containing transdermal absorption type patch formulation characterized by blending rivastigmine and aminoalkylmethacrylate copolymer E in the agent.

The transdermal patch of the present invention can suppress the volatilization of rivastigmine and suppress the cold flow, and it is not necessary to reduce the adhesive residue or excessively mix the drug, so that the therapeutic effect is stable. Can be enhanced.

The rivastigmine-containing transdermal patch formulation of the present invention is a transdermal patch containing a support, a pressure-sensitive adhesive layer containing rivastigmine, and a release liner in this order, and the pressure-sensitive adhesive layer containing rivastigmine is a functional group. Rivastigmine and aminoalkylmethacrylate copolymer E are blended in a pressure-sensitive adhesive base that does not substantially contain an acrylic polymer having a carboxyl group. In the present invention, the transdermal patch is mainly used as a medical adhesive patch, and a therapeutically effective amount of rivastigmine, which is an active ingredient, is applied on the skin and flows through the skin. It means something to move into.

The generic name of rivastigmine, which is an active ingredient of the rivastigmine-containing transdermal patch formulation (hereinafter referred to as "the present invention patch"), is (3-[(1S) -1- (dimethylamino) ethyl]]. Phenyl N-ethyl-N-methylcarbamate). As described above, this is a potent acetylcholinesterase inhibitor and has an excellent therapeutic effect on Alzheimer-type dementia and the like, and the rivastigmine in the present invention is a free form (free base form) thereof. However, any pharmaceutically acceptable salt (acid-added salt form) can be used, and among them, a free form of rivastigmine is preferably used.

The content of rivastigmine in the adhesive layer in the patch formulation of the present invention may be a therapeutically effective amount, but when used for the treatment of Alzheimer-type dementia, for example, an effective amount of rivastigmine is continuously applied to the patient for a long period of time. For skin administration, it is preferable to contain a predetermined amount of rivastigmine in the adhesive layer.

The content of this rivastigmine is preferably 1 to 50% by mass, more preferably 5 to 30% by mass, and further preferably 12 to 30% by mass in the adhesive layer constituents. 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 adhesive component in the adhesive layer constituent component is relatively small, which is sufficient. It may not be possible to obtain a good skin adhesiveness, and it may be economically disadvantageous.

The aminoalkylmethacrylate copolymer E blended in the adhesive layer is a copolymer of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate, which is commercially available as Eudragit EPO, Eudragit E100, etc., and has a protective coating, masking, etc. It is used for purposes such as moisture proofing.

The content of the aminoalkyl methacrylate copolymer E in the adhesive layer of the patch of the present invention is preferably 1 to 40% by mass, preferably 5 to 30% by mass, in the adhesive layer constituents from the viewpoint of adhesive physical properties and prevention of volatilization of ribastigmine. More preferably, it is by mass.

On the other hand, the pressure-sensitive adhesive base used in the present invention does not substantially contain an acrylic polymer having a carboxyl group as a functional group.

Examples of such a pressure-sensitive adhesive base include those containing an acrylic pressure-sensitive adhesive component (excluding an acrylic polymer having a carboxyl group as a functional group), a rubber-based pressure-sensitive adhesive component, a silicone-based pressure-sensitive adhesive component, and the like. Among these, those containing an acrylic adhesive component are preferable. Here, the acrylic adhesive component 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 a functional group. Includes what you have.

Among these, acrylic adhesive components having no functional group include, for example, (meth) acrylic acid alkyl ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylic acid / dodecyl methacrylate copolymer. , Methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate copolymer and the like.

Commercially available DURO-TAK (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel Japan), GELVA (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Monsanto), and SK Dyne are commercially available products containing these. Matrixerm (manufactured by Soken Kagaku Co., Ltd.), MAS series (manufactured by Cosmed Pharmaceutical Co., Ltd.), etc. are mentioned, and among them, DURO-TAK (registered trademark) 87-9301, 87-608A, 87-4098, MAS683 and MAS811 are preferable. used.

In addition to the acrylic polymer having a carboxyl group, the acrylic polymer having a functional group (hereinafter, may be referred to as “carboxy-free acrylic polymer”) includes a hydroxyl group, an amino group, an amide group, and an epoxy as functional groups. Examples thereof include acrylic polymers having a group, and among these, an acrylic pressure-sensitive adhesive mainly containing an acrylic polymer having a hydroxyl group is preferable in terms of thermal stability and absorption of ribastigmin into the skin.

The acrylic polymer having a hydroxyl group is a polymer or a copolymer having at least one of (meth) acrylic acid esters containing a free hydroxyl group in the side chain in the monomer constituent unit as a constituent monomer, and is, for example, (meth). ) A polymer containing an acrylic acid hydroxyalkyl ester, a copolymer thereof, and the like are exemplified.

Examples of the (meth) acrylic acid hydroxyalkyl ester include acrylic acid 2-hydroxyethyl, acrylic acid 2-hydroxypropyl, acrylic acid 3-hydroxypropyl, acrylic acid 4-hydroxybutyl, methacrylic acid 2-hydroxyethyl, and methacrylic acid. Examples thereof include 2-hydroxypropyl acid, 3-hydroxypropyl methacrylate and 4-hydroxybutyl methacrylate. Specific examples of the copolymer containing the (meth) acrylate hydroxyalkyl ester include -2-ethylhexyl acrylate, hydroxylethyl acrylate, and vinyl acetate copolymer, and -2-ethylhexyl acrylate and vinylpyrrolidone. -Hydrethyl acrylate-vinyl acetate copolymer, -2-ethylhexyl acrylate-hydroxyl ethyl acrylate-vinyl acetate copolymer, -2-ethylhexyl acrylate-hydroxyl ethyl acrylate-glycidyl acrylate-vinyl acetate common weight Examples thereof include -2-ethylhexyl acrylate, vinyl acetate, -2-hydroxyethyl acrylate copolymer, -2-ethylhexyl acrylate, vinyl acetate, -2-hydroxyethyl acrylate, and glycidyl methacrylate copolymer. Will be done.

As a commercially available product of the above-mentioned pressure-sensitive adhesive (hydroxyacrylic pressure-sensitive adhesive) containing an acrylic polymer having a hydroxyl group, for example, the hydroxyl group-containing adhesive of the DURO-TAK (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel Japan Ltd.) is contained. Types (DURO-TAK® 87-2516, 87-2525, 87-2979, 87-4287, 87-2510, 87-202A, 87-502A, 87-503A, etc.) are mentioned, and these are included in the present invention. Can be used.

The content of the acrylic polymer having a hydroxyl group in the rivastigmine-containing adhesive layer is preferably 25 to 99% by mass, more preferably 35 to 86% by mass in the components of the adhesive layer from the viewpoint of adhesive physical characteristics. preferable.

By the way, as an acrylic adhesive component, an acrylic polymer having a carboxyl group as a functional group is well known, but in the present invention, it is inappropriate to blend such a polymer in the adhesive layer constituent component. Even if it is blended, the amount is evaluated to be substantially non-blended, for example, it is necessary to be 1% by mass or less in the components of the pressure-sensitive adhesive layer. The reason for this is the problem of pharmaceutical stability and absorbability. That is, in the preparation using a polymer having a carboxyl group (for example, DURO-TAK (registered trademark) 87-2052 (acrylic acid / vinyl acetate copolymer), DURO-TAK (registered trademark) 87-235A (acrylic acid)). This is because the decomposition products increase and the absorption from the skin is poor.

In addition, what kind of functional group is present in the pressure-sensitive adhesive composition can be investigated by, for example, the following method. That is, the pressure-sensitive adhesive composition having a carboxyl group and a hydroxyl group as functional groups can be confirmed by measuring by the potentiometric titration method specified in JIS-K0070 (1992) (reference; Patent No. 5922818, etc.). ..

Further, if necessary, additional components such as a transdermal absorption promoter, a plasticizer, and a cross-linking agent can be added to the adhesive layer of the patched product of the present invention as long as the effects of the present invention are not impaired. Of these, as the transdermal absorption promoting agent, any compound that has been conventionally recognized to have an absorption promoting effect by transdermal administration can be used, and examples thereof include ancanol amines such as diisopropanolamine and triisopropanolamine. Fatty acids such as lauric acid, oleic acid, isostearic acid, isopropyl myristate, octyldodecyl myristate, monoester glycerin oleate, hexyldecyl isostearate and their esters, alcohols such as oleyl alcohol, propylene glycol and polyethylene glycol monooleate. And their esters or ethers, sorbitan esters or ethers such as sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate, polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl. Phenolic ethers such as ethers, castor oil or hardened castor oil, oleoyl sarcosine, betaine laurindimethylaminoacetate, ionic surfactants such as sodium lauryl sulfate, polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, dimethyl lauryl amine Nonionic surfactants such as oxides, alkylmethylsulfoxides such as dimethylsulfoxyside and decylmethylsulfoxide, pyrrolidones such as 2-pyrrolidone and 1-methyl-2-pyrrolidone, 1-dodecylazacycloheptane. Examples thereof include azacycloalkanes such as -2-one and 1-geranylazacycloheptane-2-one, terpenes such as menthol, camflu and limonene, and crotamitone.

When the transdermal absorption accelerator is blended in the pressure-sensitive adhesive layer, the blending amount is preferably 0.1 to 45% by mass, more preferably 0.1 to 20% by mass, and further preferably 1 to 1 in the pressure-sensitive adhesive layer constituents. It is in the range of 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.

Examples of the plasticizers that can be blended include paraffin-based process oils, naphthen-based process oils, petroleum-based oils such as aromatic process oils, isopropyl myristate, hexyl laurate, diethyl sevacinate, diisopropyl sevacinate, and isopropyl linoleate. Liquid fatty acid esters, 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 Examples thereof include silicon dioxide mixture, D-sorbitol, medium chain fatty acid triglyceride, triacetin, pyrrolidones, phytosterol, propylene glycol, polyethylene glycol, polysorbate 80 (registered trademark), glycerin monostearate and the like.

Further, 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.

The storage elastic modulus of the adhesive layer of the adhesive layer of the present invention obtained as described above is preferably 2700 Pa or more, more preferably 2700 to 1.0 × 10 ¹⁰ Pa. If it is less than 2500 Pa, the plaster is likely to be cold-flowed, and if it ^{exceeds 1.0 × 10 10} Pa, it is more likely that the skin will not get wet and the peeling and curling will increase.

As the support used in the patch formulation of the present invention and holding the pressure-sensitive adhesive layer, 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, woven fabrics, non-woven fabrics, and paper materials formed from plant fibers. The thickness of the support is preferably 12 to 60 μm, more preferably 12 to 40 μm.

Further, in the patch formulation of the present invention, it is preferable to provide a release liner on the adhesive layer for the purpose of protecting the 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.

Next, the production of the patched product of the present invention is not particularly limited and can be carried out according to a known method. Preferred production methods include, for example, a pressure-sensitive adhesive base substantially free of ribastigmine, an aminoalkylmethacrylate copolymer E and an acrylic polymer having a carboxyl group as a functional group, and, if necessary, a pressure-sensitive adhesive such as a transdermal absorption promoter. The agent layer-forming component is dissolved in an organic solvent of toluene, methanol, hexane, ethyl acetate or a mixed solvent thereof, the solution is spread on a release liner or a support, and the solvent in the solution is evaporated to form an adhesive layer. A method of obtaining a patch by laminating a support or a release liner after forming the above-mentioned adhesive layer, or heating and dissolving the pressure-sensitive adhesive layer-forming component, spreading the melt on the release liner or the support, and containing a drug. Examples thereof include a method of obtaining a patched formulation by laminating a support or a release liner after forming a layer.

The patch pharmaceutical product of the present invention is a matrix-type patch pharmaceutical product comprising a support, an adhesive layer containing rivastigmine, and a release liner. Such a matrix-type patch is easy to design and does not have a complicated structure like a reservoir-type patch having a pressure-sensitive adhesive layer other than the adhesive layer containing rivastigmine. It is possible to reduce the cost at the time of manufacturing the pharmaceutical product. If necessary, in order to control the transdermal absorption of the active ingredient rivastigmine, for example, ethylene-vinyl acetate copolymer, polypropylene, polyacrylonitrile, etc. are pressure-bonded to the skin-attached side of the drug-containing layer. Can also be added as a release control film or the like.

The patched product of the present invention thus obtained is preferably provided 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.

Further, when the patched product of the present invention is stored in the packaging material, it is preferably in a sealed state. This sealed state is preferably 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 a method for setting the hypoxic state, a method of enclosing a substance having an oxygen adsorbing ability with the patch 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. Or may be used in combination with the above method.

Examples of the above-mentioned substances having an oxygen adsorbing ability include inorganic oxygen scavengers mainly composed of iron powder, zinc powder, hydrosulfite and the like, and organic oxygen scavengers such as ascorbic acid, polyhydric alcohol and activated charcoal. 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 Taisei Co., Ltd.). Oxygen (manufactured by Ueno Pharmaceutical Co., Ltd.), Keybit (manufactured by Drency Co., Ltd.), Keplon (manufactured by Keplon Co., Ltd.), Sansokat (manufactured by Iris Fine Products Co., Ltd.), Sansoles (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 (manufactured by Nippon Kayaku Food Techno Co., Ltd.) ), Wonder Keep (manufactured by Powder Tech Co., Ltd.), Freshness Preserving Agent C (manufactured by Letterpress Printing Co., Ltd.) and the like 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.

Example 1
<Manufacturing of rivastigmine transdermal patch preparation-1>
(1) Formulations 1, 3, 5, 7 of the present invention, comparative preparations 1, 3,:
According to the composition of Table 1, rivastigmine, an acrylic pressure-sensitive adhesive, a volatilization inhibitor, a transdermal absorption promoter, and a plasticizer were added to ethyl acetate and mixed by stirring to obtain a uniform lysate. The amount of ethyl acetate used was 1.5 times the total amount of rivastigmine and the acrylic pressure-sensitive adhesive. Next, this solution was spread on a release film (a PET film treated with silicone) using a doctor knife coating machine, dried with warm air in an environment of 25 ° C. for 40 minutes, and the solvent was distilled off. Then, a rivastigmine-containing adhesive layer having a thickness of 100 μm was formed. A support was attached to this rivastigmine-containing adhesive layer and ^{cut into 5 cm 2} to produce a transdermal patch of the present invention formulations 1, 3, 5, 7 and comparative formulations 1, 3.

(2) The product 2, 4, 6, 8 of the present invention, the comparative product 2, 4,:
The pharmaceutical products 2, 4, 6 and 8 of the present invention and the comparative pharmaceutical products 2 and 4 were produced in the same manner except that the temperature of the warm air drying of Example 1 (1) was changed to 60 ° C.

Example 2
<Quantification of rivastigmine content>
The transdermal patchable formulations 1 to 8 and the comparative formulations 1 to 4 of the present invention are peeled off from each one, and placed in a 50 mL centrifugal settling tube, to which 8 mL of tetrahydrofuran and 2 mL of the internal standard solution are added. , Shake 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. The operation of high performance liquid chromatography is that the column is Xbridge sheld 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 / phosphorus. Using acid (10000: 1, v / v) (mobile phase A) and acetonitrile for liquid chromatography (mobile phase B), the mobile phase is fed by mixing mobile phase A and mobile phase B under arbitrary conditions. The gradient was controlled.

In addition to measuring the content of rivastigmine in each transdermal patch, if the content is 5% lower than the theoretical content, there is a concern that the cost will increase due to increased preparation and that it will deviate from the standard due to long-term storage. A product having a decrease of less than 5% was evaluated as ◯, and a product having a decrease of 5% or more from the theoretical content was evaluated as x. The results are shown in Table 2.

Example 3
<Finger tack test>
The panelists evaluated the adhesiveness of the pressure-sensitive adhesive layer when the release liners of the pharmaceutical products 1, 3, 5, 7 and Comparative Formulation 1 of the present invention were peeled off and the pressure-sensitive adhesive layer was touched with a finger. The pharmaceutical product that adhered to the finger was marked with ◯, and the pharmaceutical product that did not adhere to the finger was marked with x. Table 3 shows the finger tack test results of each transdermal patch.

Example 4
<Manufacturing of rivastigmine transdermal patch formulation-2>
According to the composition of Table 4, the transdermal patchable formulations of the present invention formulations 9, 10, 11, 12 and the comparative formulations 5 and 6 were produced by the same method as the present invention formulation 1. In addition, in Table 4, the one shown in Table 1 is also reprinted.

Example 5
<Cold flow evaluation>
The formulations 1, 3, 5, 7, 9 to 12 of the present invention and the comparative formulations 1, 5 and 6 were punched out with a punch having a diameter of 13 mm, the release liner was peeled off, and then the mixture was attached to a slide glass. After imaging using a surface microscope, a liner, a slide glass, and a weight (1 kg) were placed on the test product, and then the mixture was allowed to stand for 5 hours.

After removing the weight, an image was taken using a surface microscope, the captured image was analyzed, the area of cold flow was calculated, and the cold flow rate of each transdermal patch was compared.

Those with the same or lower cold flow than the original product (Ixeron patch) were marked with ◯, and those with higher cold flow than the original product were marked with ×. Table 5 shows the cold flow evaluation results of each transdermal patch.

Example 6
<Viscoelasticity measurement>
Each test preparation was cut into a size of 8 cm × 4.5 cm to prepare a test sample. The liner on one side was peeled off from each of the two test samples, and the plaster surfaces were bonded to each other and pressure-bonded with a roller. This operation was repeated for each test sample to prepare a sample of 8 cm × 4.5 cm and a thickness of about 0.5 to 1 mm, respectively.

The sample was punched into a circle with a diameter of 25 mm with a leather punch, the liner on one side was peeled off, and the center of the jig disk and the center of the sample were carefully attached and fixed to a 25 mm size jig (parallel plate). The liner on the other side was peeled off from the fixed sample, and the measurement was performed under the following conditions. The results are shown in Table 6.

(Measurement condition)
Measurement mode: Frequency dependence measurement
Measurement frequency: 0.07 to 1.27Hz
Measurement temperature: 32 ° C

As is clear from the results in Table 6, the storage elastic modulus of the transdermal patch formulation of the present invention formulations 1, 3, 5, 7, 9 to 12 is the same as that of the transdermal patch formulation of Comparative Formulas 1, 5, and 6. Compared, it was a high price. From this result and the results in Table 5, it was clarified that the minimum value of the storage elastic modulus without cold flow was about 2700 Pa or more.

Since the transdermal patch formulation of the present invention can suppress cold flow while blending a volatilization inhibitor, it contributes to cost reduction and can reduce adhesive residue. Therefore, the transdermal patch of the present invention can effectively and sustainably utilize the pharmacological effect of rivastigmine, and is particularly useful for the treatment of Alzheimer's disease and the like.

Claims (1)

A transdermal patch containing a support, an adhesive layer and a release liner, wherein the adhesive layer contains rivastigmine and Eudragit® EPO in DURO-TAK® 87-2516. what der those, DURO-TAK content of (R) 87-2516 is 35-86 mass% in the adhesive layer, the content of rivastigmine 12 to 30 wt%, content of Eudragit (R) EPO the amount is 1 to 40% by mass Rukoto rivastigmine-containing transdermal characterized patch preparation (except those containing organic acid in the pressure-sensitive adhesive base).