JP7585656B2 - Patches - Google Patents

Description

The present invention relates to a patch for transdermal administration of the drug blonanserin.

Blonanserin (2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine) is known as a treatment for schizophrenia.

Blonanserin is sold as an oral agent (manufactured by Sumitomo Dainippon Pharma Co., Ltd. under the trade names "Lonasen Tablets" and "Lonasen Powder"). However, oral agents can cause problems such as degradation due to the first-pass effect in the liver, gastrointestinal disorders, and side effects due to rapid fluctuations in blood concentration.

Therefore, a method has been proposed for transdermally administering blonanserin by applying a patch containing blonanserin to the skin (for example, Patent Document 1).

JP 2006-505489 A

However, conventional patches have a problem of low percutaneous absorption of blonanserin. Therefore, in order to maintain a blood concentration of blonanserin that is effective for treatment, it is necessary to increase the content of blonanserin in the patch and to increase the application area of the patch. If the application area is large, the patient may feel uncomfortable while applying the patch, or the patch may be repeatedly applied to the same area when replacing the patch, causing skin irritation. Furthermore, even if a high content of blonanserin is contained in the patch, usually only about 5% by mass of blonanserin in the patch is absorbed by human skin, and the remaining 95% by mass remains in the patch. When the patch is applied to a skin part with damaged keratin, even blonanserin that was supposed to remain in the patch is absorbed by human skin, and the blood concentration of blonanserin becomes too high, which may cause unexpected side effects. In order to solve these problems, it is necessary to improve the percutaneous absorption of blonanserin in the patch.

Therefore, the present invention provides a patch with excellent transdermal absorption of blonanserin.

The patch of the present invention is characterized in that it comprises a support and an adhesive layer laminated and integrated on one side of the support, and the adhesive layer contains blonanserin, an organic acid, and an acrylic adhesive containing an acrylic polymer (A) that contains 5% by mass or more of an N-vinyl-2-pyrrolidone component and does not contain a functional group having affinity for the blonanserin, or, if it contains a functional group having affinity for the blonanserin, the content of a monomer component containing a functional group having affinity for the blonanserin is less than 1% by mass.

[Adhesive layer]
The patch includes an adhesive layer laminated and integrated on one surface of a backing, the adhesive layer containing blonanserin, an organic acid, and an acrylic adhesive.

(Blonanserin)
The adhesive layer contains the drug blonanserin, which (2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine) has a strong blocking effect on dopamine D2 receptors and serotonin 2 (5-HT2A) receptors, and is used as a treatment for schizophrenia, among other things.

Blonanserin includes free base and acid addition salt forms. The adhesive layer may contain at least one of free base and acid addition salt forms of Blonanserin. Of these, free base (free form) Blonanserin is preferred. Free base Blonanserin can provide a patch with superior transdermal absorbability of Blonanserin.

Blonanserin in the acid addition salt form is a physiologically acceptable acid addition salt of blonanserin in the free base form. Physiologically acceptable acid addition salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; and organic acid salts such as formate, acetate, trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipate, sorbate, lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, isostearate, succinate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), and benzenesulfonate (besylate). Blonanserin in the form of an acid addition salt may be used alone or in combination of two or more types.

The content ratio of blonanserin in the adhesive layer is preferably 0.1 parts by mass or more, more preferably 0.5 parts by mass or more, more preferably 1 part by mass or more, and particularly preferably 5 parts by mass or more, relative to 100 parts by mass of the total amount of blonanserin, organic acid, and acrylic adhesive. The content ratio of blonanserin in the adhesive layer is preferably 50 parts by mass or less, more preferably 30 parts by mass or less, relative to 100 parts by mass of the total amount of blonanserin, organic acid, and acrylic adhesive. When the content ratio of blonanserin is 0.1 parts by mass or more, the blood concentration of blonanserin can be increased to a desired range. When the content ratio of blonanserin is 50 parts by mass or less, excessive precipitation of an excess amount of blonanserin as crystals in the adhesive layer can be reduced, and the transdermal absorbability of the drug and the adhesiveness of the adhesive layer can be improved.

In particular, since the patch of the present invention has excellent transdermal absorption of blonanserin, a therapeutically effective blood concentration of blonanserin can be achieved even if the content of blonanserin in the adhesive layer is low. From this perspective, the content ratio of blonanserin in the adhesive layer is more preferably 10 parts by mass or less, and particularly preferably 8 parts by mass or less, per 100 parts by mass of the total amount of blonanserin, organic acid, and acrylic adhesive.

In the patch of the present invention, when calculating the content ratio of each component contained in the adhesive layer and the mass ratio or molar ratio (e.g., molar ratio, etc.) of the components contained in the adhesive layer, the mass of Blonanserin obtained by converting the acid addition salt form of Blonanserin to the free base form is used as the mass of the acid addition salt form of Blonanserin. The mass of Blonanserin obtained by converting the acid addition salt form of Blonanserin to the free base form is the mass of Blonanserin in the free base form in an amount equivalent to that of the acid addition salt form of Blonanserin.

(Organic Acid)
The adhesive layer contains an organic acid. The organic acid can dissolve Blonanserin well. Therefore, by using an organic acid, Blonanserin can be contained in a dissolved state in the adhesive layer. Blonanserin dissolved by an organic acid can easily diffuse and transfer in the adhesive layer, and has excellent skin permeability. Therefore, by using an organic acid, it is possible to provide a patch having excellent transdermal absorption of Blonanserin.

In particular, since blonanserin is a basic drug due to the inclusion of a tertiary amine structure containing a nitrogen atom, it can accept a proton in the adhesive layer to become a cation. Meanwhile, the organic acid has a carboxy group, and the carboxy group of the organic acid in the adhesive layer is ionized to become an anion ( ^-COO- ). Blonanserin accepts a proton to become a cation, while the carboxy group of the organic acid is ionized to generate an anion, and the cation derived from blonanserin and the anion derived from the organic acid form an ionic bond, which further improves the lipid solubility of blonanserin, making it easier for blonanserin to permeate the skin, and further improving the transdermal absorbability of blonanserin.

According to the present invention, the transdermal absorbability of blonanserin can be improved, and therefore the content of blonanserin in the patch can be reduced. This reduces the occurrence of unexpected side effects caused by excessive amounts of blonanserin being absorbed into the body. Furthermore, the application area of the patch can be reduced, reducing the discomfort felt by the patient while the patch is applied, and reducing repeated application of the patch to the same area when replacing the patch.

Examples of organic acids include monocarboxylic acids such as lactic acid, propionic acid, capric acid, sorbic acid, salicylic acid, gallic acid, acetic acid, butyric acid, valeric acid, levulinic acid, capric acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; dicarboxylic acids such as adipic acid, maleic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, phthalic acid, isophthalic acid, terephthalic acid, malic acid, and sebacic acid; and tricarboxylic acids such as citric acid. Among these, monocarboxylic acids are preferred, and lactic acid and levulinic acid are more preferred. These organic acids have excellent solubility for blonanserin. The organic acids may be used alone or in combination of two or more.

The content ratio of the organic acid in the adhesive layer is preferably 1 part by mass or more, more preferably 2 parts by mass or more, and particularly preferably 3 parts by mass or more, relative to 100 parts by mass of the total amount of blonanserin, organic acid, and acrylic adhesive. The content ratio of the organic acid in the adhesive layer is preferably 20 parts by mass or less, more preferably 15 parts by mass or less, and particularly preferably 12 parts by mass or less, relative to 100 parts by mass of the total amount of blonanserin, organic acid, and acrylic adhesive. By setting the content ratio of the organic acid to 1 part by mass or more, a sufficient amount of blonanserin can be dissolved in the adhesive layer, thereby improving the transdermal absorbability of blonanserin. By setting the content ratio of the organic acid to 20 parts by mass or less, the seepage (bleeding) of an excess amount of organic acid onto the adhesive layer surface can be reduced, thereby maintaining the excellent adhesive strength of the patch.

The molar ratio of the organic acid to blonanserin in the adhesive layer [(moles of organic acid)/(moles of blonanserin)] is preferably 1 or more, more preferably 2 or more, and particularly preferably 3 or more. On the other hand, the molar ratio of the organic acid to blonanserin in the adhesive layer [(moles of organic acid)/(moles of blonanserin)] is preferably 15 or less, more preferably 12.5 or less, and particularly preferably 10 or less. By setting the molar ratio at 1 or more, a sufficient amount of blonanserin can be dissolved in the adhesive layer, improving the transdermal absorbability of blonanserin. By setting the molar ratio at 15 or less, the inhibition of the diffusion and transfer of blonanserin by an excess amount of organic acid in the adhesive layer is reduced, and blonanserin can be stably released from the patch.

(Acrylic adhesive)
The adhesive layer contains an acrylic adhesive. The acrylic adhesive contains an acrylic polymer (A) that contains 5% by mass or more of an N-vinyl-2-pyrrolidone component and does not contain a functional group having affinity for the above-mentioned blonanserin, or, if it contains a functional group having affinity for the above-mentioned blonanserin, the content of a monomer component containing the functional group having affinity for the above-mentioned blonanserin is less than 1% by mass.

In the present invention, the use of an organic acid in the adhesive layer allows Blonanserin to exist in a dissolved state. However, since the organic acid has low affinity with the adhesive, it may bleed excessively onto the surface of the adhesive layer, reducing the adhesive strength of the adhesive layer. Therefore, in an adhesive layer using an organic acid, it may be difficult to achieve both the transdermal absorbability of Blonanserin and adhesive strength. However, the acrylic polymer (A) contains 5% by mass or more of an N-vinyl-2-pyrrolidone component, so that its affinity for the organic acid is appropriately improved. By using this acrylic polymer (A) as an acrylic adhesive, it is possible to appropriately retain the organic acid in the adhesive layer, reduce the excessive bleed of the organic acid onto the surface of the adhesive layer, and the adhesive layer can exhibit excellent adhesive strength. Therefore, according to the present invention, by using an organic acid in combination with the acrylic polymer (A), it is possible to provide a patch that achieves both the transdermal absorbability and adhesive strength of Blonanserin.

Blonanserin is present in a dissolved state in the adhesive layer, but some of the blonanserin may precipitate as crystals. The storage temperature of the patch may change during storage of the patch, but even if the storage temperature of the patch changes, it is preferable that the dissolved and precipitated states of blonanserin in the adhesive layer are maintained unchanged before and after storage. If the dissolved and precipitated states of blonanserin change, the transdermal absorbability of blonanserin may also change, and the expected medicinal effect may not be obtained, affecting treatment. In particular, if excessive crystals of blonanserin precipitate due to a change in the storage temperature of the patch, the transdermal absorbability of blonanserin may become uneven or decrease.

As described above, in the present invention, by using an acrylic polymer (A) containing 5% by mass or more of an N-vinyl-2-pyrrolidone component, an appropriate amount of organic acid can be retained in the adhesive layer. This allows the dissolved state of blonanserin to be stably maintained in the adhesive layer. Therefore, even if the storage temperature of the patch changes, changes in the dissolved and precipitated states of blonanserin in the adhesive layer can be reduced, and changes in the transdermal absorbability of blonanserin can also be reduced. In this way, according to the present invention, it is possible to provide a patch that also has excellent storage stability of blonanserin.

The content of the N-vinyl-2-pyrrolidone component in the acrylic polymer (A) is 5% by mass or more, preferably 7% by mass or more, and more preferably 9% by mass or more. The content of the N-vinyl-2-pyrrolidone component in the acrylic polymer (A) is preferably 40% by mass or less, more preferably 35% by mass or less, and particularly preferably 30% by mass or less. By making the content of the N-vinyl-2-pyrrolidone component 5% by mass or more, it is possible to improve the affinity of the acrylic polymer (A) for the organic acid, thereby allowing the organic acid to be appropriately retained in the adhesive layer and reducing excessive seepage of the organic acid onto the surface of the adhesive layer. On the other hand, by making the content of the N-vinyl-2-pyrrolidone component 40% by mass or less, it is possible to appropriately maintain the cohesive force of the adhesive layer and maintain excellent adhesive force of the adhesive layer.

Furthermore, the acrylic polymer (A) does not have a functional group having affinity for blonanserin, or, if the acrylic polymer (A) has a functional group having affinity for blonanserin, the content of the monomer component containing a functional group having affinity for blonanserin in the acrylic polymer (A) is less than 1 mass%.

A functional group having affinity for blonanserin is a functional group that can be ionized in the adhesive layer to become an anion and form an ionic bond with blonanserin. When the acrylic polymer (A) has a functional group having affinity for blonanserin, the affinity of this functional group makes it difficult for blonanserin to diffuse and transfer in the adhesive layer, and blonanserin may remain in the adhesive layer, thereby reducing the transdermal absorbability of blonanserin. Therefore, in the present invention, the acrylic polymer (A) does not have a functional group having affinity for blonanserin, or even if the acrylic polymer (A) has a functional group having affinity for blonanserin, the content of the monomer component containing a functional group having affinity for blonanserin is less than 1 mass%, and an acrylic polymer (A) having a small content of functional groups having affinity for blonanserin is used. By using such an acrylic polymer (A), the transdermal absorbability of blonanserin can be improved.

Specific examples of functional groups having affinity for blonanserin include anionic functional groups such as _a carboxy group (--COOH), a sulfonic acid group ( _--SO.sub.3H ), and a phosphate group ( _{H.sub.2PO.sub.4--} ) represented by the following chemical formula (1).

Blonanserin is a basic drug due to the inclusion of a tertiary amine structure containing a nitrogen atom, and becomes a cation by accepting a proton (H ⁺ ) in the adhesive layer. When the acrylic polymer (A) has an anionic functional group such as a carboxyl group, a sulfonic acid group, or a phosphate group as a functional group having affinity for blonanserin, these anionic functional groups, after ionization, generate -COO ^- , -SO ₃ ^- , or a structure represented by the following chemical formula (2) (-OPO ₃ ^2- ) as a residue portion remaining bonded to the polymer chain of the acrylic polymer (A), and become anions. In this case, an ionic bond is generated between the portion of blonanserin that has become a cation and the anionic portion consisting of the residue portion of the anionic functional group remaining bonded to the polymer chain of the acrylic polymer (A), and blonanserin is captured by the acrylic polymer (A), making it difficult for blonanserin to diffuse and transfer in the adhesive layer.

Examples of monomers containing a functional group having affinity for blonanserin include vinyl monomers containing a functional group having affinity for blonanserin. Examples of vinyl monomers containing a functional group having affinity for blonanserin include, for example,
Carboxy group-containing vinyl monomers such as acrylic acid, methacrylic acid, itaconic acid, maleic acid, mesaconic acid, citraconic acid, glutaconic acid, and butyl maleic acid;
Sulfonic acid group-containing (meth)acrylates such as 3-sulfopropyl (meth)acrylate; and phosphoric acid group-containing (meth)acrylates such as 2-acryloyloxyethyl acid phosphate and 2-methacryloyloxyethyl acid phosphate;
The monomer containing a functional group having affinity for blonanserin may be used alone or in combination of two or more kinds.

When the acrylic polymer (A) has a functional group having affinity for blonanserin, the content of the monomer component containing a functional group having affinity for blonanserin in this acrylic polymer (A) is less than 1 mass%, preferably 0.9 mass% or less, more preferably 0.5 mass% or less, more preferably 0.1 mass% or less, and particularly preferably 0.05 mass% or less. When the acrylic polymer (A) has a functional group having affinity for blonanserin, the content of the monomer component containing a functional group having affinity for blonanserin in this acrylic polymer (A) exceeds 0 mass%. If the content of the monomer component containing a functional group having affinity for blonanserin is less than 1 mass%, even if the acrylic polymer (A) has a functional group having affinity for blonanserin, the inhibition of diffusion and migration of blonanserin in the adhesive layer due to the affinity of the functional group can be reduced, and the transdermal absorbability of blonanserin can be improved.

In the acrylic polymer (A), the content of the monomer component containing a functional group having affinity for blonanserin is less than 1 mass %, and the acrylic polymer (A) may have a low proportion of functional groups having affinity for blonanserin. However, in the present invention, it is particularly preferable that the acrylic polymer (A) does not contain a functional group having affinity for blonanserin. In other words, it is particularly preferable that the content of the monomer component containing a functional group having affinity for blonanserin in the acrylic polymer (A) is 0 mass %.

The acrylic polymer (A) preferably contains a vinyl monomer component that does not contain a functional group that has affinity for blonanserin. The acrylic polymer (A) is preferably a copolymer of N-vinyl-2-pyrrolidone and a vinyl monomer that does not contain a functional group that has affinity for blonanserin. By using a vinyl monomer component that does not contain a functional group that has affinity for blonanserin, it is possible to impart excellent adhesive strength to the adhesive layer while suppressing a decrease in the transdermal absorbability of blonanserin due to the functional group that has affinity for blonanserin.

The vinyl monomer refers to a monomer having an ethylenically unsaturated double bond. Note that N-vinyl-2-pyrrolidone is excluded from vinyl monomers that do not contain a functional group having affinity for blonanserin.

Examples of vinyl monomers that do not contain a functional group having affinity for blonanserin include alkyl (meth)acrylates, vinyl acetate, vinyl chloride, α-olefins, and styrene. Examples of α-olefins include ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 4-methyl-1-pentene, 1-octene, 1-nonene, 1-decene, 1-tetradecene, 1-hexadecene, 1-octadecene, and 1-eicosene. Among these, alkyl (meth)acrylates are preferred. The alkyl (meth)acrylate component can impart an appropriate cohesive force to the adhesive layer and improve the adhesive strength of the adhesive layer. The vinyl monomers that do not contain a functional group having affinity for blonanserin may be used alone or in combination of two or more. In addition, (meth)acrylate means acrylate or methacrylate.

The alkyl group of the alkyl (meth)acrylate is a group represented by -C _n H _2n+1 (wherein n is a positive integer). The number of carbon atoms in the alkyl group of the alkyl (meth)acrylate is preferably 1 to 16, more preferably 1 to 14, more preferably 2 to 12, and particularly preferably 2 to 10.

Examples of alkyl (meth)acrylates include methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, hexyl (meth)acrylate, n-octyl (meth)acrylate, isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, tridecyl (meth)acrylate, hexadecyl (meth)acrylate, cyclododecyl (meth)acrylate, and cyclohexyl (meth)acrylate. Of these, preferred alkyl (meth)acrylates are ethyl (meth)acrylate, n-octyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate. Alkyl (meth)acrylates may be used alone or in combination of two or more.

The content of alkyl (meth)acrylate in the vinyl monomer that does not contain a functional group having affinity for blonanserin is preferably 80% by mass or more, more preferably 90% by mass or more, and particularly preferably 100% by mass. In other words, it is particularly preferable that the vinyl monomer that does not contain a functional group having affinity for blonanserin is composed only of alkyl (meth)acrylate.

The content of the vinyl monomer component not containing a functional group having affinity for blonanserin in the acrylic polymer (A) is preferably 95% by mass or less, more preferably 93% by mass or less, and particularly preferably 91% by mass or less. The content of the vinyl monomer component not containing a functional group having affinity for blonanserin in the acrylic polymer (A) is preferably 60% by mass or more, more preferably 65% by mass or more, and particularly preferably 70% by mass or more. By setting the content of the vinyl monomer component not containing a functional group having affinity for blonanserin to 95% by mass or less, it is possible to include a sufficient amount of N-vinyl-2-pyrrolidone component in the acrylic polymer (A). By setting the content of the vinyl monomer component not containing a functional group having affinity for blonanserin to 60% by mass or more, it is possible to set the cohesive force of the adhesive layer to a moderate range and improve the adhesive force of the adhesive layer.

When the acrylic polymer (A) is a copolymer of N-vinyl-2-pyrrolidone and a vinyl monomer that does not contain a functional group that has affinity for blonanserin, the total content of the N-vinyl-2-pyrrolidone component and the vinyl monomer component that does not contain a functional group that has affinity for blonanserin in the copolymer is preferably 70% by mass or more, more preferably 80% by mass or more, more preferably 90% by mass or more, more preferably 95% by mass or more, more preferably more than 99% by mass, and particularly preferably 100% by mass. By setting the total content of the N-vinyl-2-pyrrolidone component and the vinyl monomer component that does not contain a functional group that has affinity for blonanserin to 70% by mass or more, a patch that is excellent in both transdermal absorbability of blonanserin and adhesive strength can be obtained.

The polymerization method for the acrylic polymer (A) may be a conventionally known method. For example, the above-mentioned monomers may be polymerized in the presence of a polymerization initiator. Specifically, a predetermined amount of monomer, polymerization initiator, and polymerization solvent are supplied to a reactor and heated at a temperature of 60 to 80°C for 4 to 48 hours to radically polymerize the monomers.

Examples of the polymerization initiator include azobis-based polymerization initiators such as 2,2'-azobisisobutyronitrile (AIBN), 1,1'-azobis(cyclohexane-1-carbonitrile), and 2,2'-azobis-(2,4'-dimethylvaleronitrile); and peroxide-based polymerization initiators such as benzoyl peroxide (BPO), lauroyl peroxide (LPO), and di-tert-butyl peroxide. Examples of the polymerization solvent include ethyl acetate, cyclohexane, and toluene. Furthermore, it is preferable to carry out the polymerization reaction under a nitrogen gas atmosphere.

The acrylic polymer (A) may be crosslinked. Examples of the crosslinking method for the acrylic polymer (A) include a chemical crosslinking method using an organic peroxide, a crosslinking assistant, or a crosslinking agent, and a physical crosslinking method using ionizing radiation. Examples of ionizing radiation include electron beams, α-rays, β-rays, and γ-rays.

Organic peroxides include benzoyl peroxide, acetyl peroxide, decanoyl peroxide, lauroyl peroxide, dicumyl peroxide, di-t-butyl peroxide, t-butyl peroxybenzoate, t-butyl peroxy-2-ethylhexanoate, cumene hydroperoxide, and t-butyl hydroperoxide.

Examples of cross-linking aids include divinylbenzene, trimethylolpropane trimethacrylate, trimethylolpropane triacrylate, 1,6-hexanediol di(meth)acrylate, 1,9-nonanediol di(meth)acrylate, trimellitic acid triallyl ester, triethylene glycol diacrylate, tetraethylene glycol diacrylate, cyanoethyl acrylate, and bis(4-acryloxypolyethoxyphenyl)propane.

Examples of crosslinking agents include isocyanate compounds (e.g., tetramethylene diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, xylylene diisocyanate, tolylene diisocyanate, 4,4-diphenylmethane diisocyanate, trimer adduct of trimethylolpropane and hexamethylene diisocyanate, etc.); aziridine compounds (e.g., 2,2-bishydroxymethylbutanol-tris[3-(1-aziridinyl)propionic acid], 4,4-bis(ethyleneiminocarbonylamino)diphenylmethane, etc.); organometallic compounds (e.g., zirconium and zinc alaninate, zinc acetate, ammonium zinc glycine, titanium compounds, etc.); metal alcoholates (e.g., tetraethyl titanate, tetraisopropyl titanate, aluminum isopropylate, aluminum sec-butylate, etc.); and metal chelate compounds (e.g., dipropoxybis(acetylacetonate)titanium, tetraoctylene glycol titanium, aluminum isopropylate, ethyl acetoacetate aluminum diisopropylate, aluminum tris(ethyl acetoacetate), aluminum tris(acetylacetonate), etc.).

When crosslinking the acrylic polymer (A) by a chemical crosslinking method, the acrylic polymer (A) can be crosslinked by heating the acrylic polymer (A) to a temperature at which the crosslinking reaction proceeds in the presence of an organic peroxide, a crosslinking aid, or a crosslinking agent. When a crosslinking aid is used, the monomer of the acrylic polymer (A), the polymerization initiator, and the polymerization solvent, as well as the crosslinking aid, can be supplied to the reactor during the polymerization of the acrylic polymer (A) described above, and radical polymerization can be performed to obtain an acrylic polymer (A) crosslinked by the crosslinking aid.

As described above, the acrylic polymer (A) may be crosslinked. However, if the acrylic polymer (A) is crosslinked, the cohesive force of the adhesive layer may increase excessively, suppressing the diffusion and migration of blonanserin in the adhesive layer, which may reduce the transdermal absorbability of blonanserin. In addition, if an organic peroxide, crosslinking aid, or crosslinking agent added with the intention of crosslinking remains in the adhesive layer, the organic peroxide, crosslinking aid, or crosslinking agent may interact with the organic acid, which may prevent the organic acid from functioning as a dissolving agent for blonanserin, which may reduce the transdermal absorbability of blonanserin. Therefore, it is preferable that the acrylic polymer (A) is not crosslinked.

When the acrylic polymer (A) contained in the adhesive layer is not crosslinked, the gel fraction of the adhesive layer is preferably 1% by mass or less, more preferably 0.5% by mass or less, more preferably 0.1% by mass or less, more preferably 0.05% by mass or less, and particularly preferably 0% by mass.

The gel fraction of the adhesive layer is a value measured as follows: the mass [ _W0 (g)] of the adhesive layer is measured, this is immersed in xylene at 120°C for 24 hours, the insoluble matter is filtered through a 200 mesh wire screen, the residue on the wire screen is vacuum dried, the mass [ _W1 (g)] of the dried residue is measured, and the gel fraction of the adhesive layer is calculated according to the following formula.
Gel fraction (mass %)=(W ₁ /W ₀ )×100

The content of the acrylic polymer (A) in the acrylic adhesive is preferably 80% by mass or more, more preferably 90% by mass or more, and particularly preferably 100% by mass. In other words, it is particularly preferable that the acrylic adhesive consists only of the acrylic polymer (A). By making the content of the acrylic polymer (A) 80% by mass or more, it is possible to provide a patch having excellent adhesive strength and transdermal absorbability of blonanserin.

The content ratio of the acrylic adhesive in the adhesive layer is preferably 45 parts by mass or more, more preferably 50 parts by mass or more, and particularly preferably 55 parts by mass or more, relative to 100 parts by mass of the total amount of blonanserin, organic acid, and acrylic adhesive. The content ratio of the acrylic adhesive in the adhesive layer is preferably 90 parts by mass or less, more preferably 88 parts by mass or less, and particularly preferably 85 parts by mass or less, relative to 100 parts by mass of the total amount of blonanserin, organic acid, and acrylic adhesive. When the content ratio of the acrylic adhesive is 45 parts by mass or more, the adhesive strength of the adhesive layer to the skin can be improved. When the content ratio of the acrylic adhesive is 90 parts by mass or less, a required amount of a drug or other additive can be added to the adhesive layer.

The adhesive layer may contain other additives such as plasticizers, tackifiers, and fillers, provided that they do not affect the skin irritation of the patch.

(Plasticizer)
The adhesive layer may contain a plasticizer. The plasticizer is used to improve the adhesive strength of the adhesive layer. Examples of the plasticizer include esters such as isopropyl myristate, decyl oleate, and isopropyl adipate, monohydric alcohols such as myristyl alcohol, cetanol, octyldodecanol, isostearyl alcohol, and stearyl alcohol, dihydric alcohols such as octanediol, and liquid paraffin. The plasticizer may be used alone or in combination of two or more kinds. When the adhesive layer contains a plasticizer, the content of the plasticizer in the adhesive layer is preferably 5 to 50 parts by mass, more preferably 5 to 45 parts by mass, and particularly preferably 5 to 15 parts by mass, relative to 100 parts by mass of the acrylic adhesive.

(Tackifier)
The adhesive layer may contain a tackifier. Examples of the tackifier include terpene resin, modified terpene resin, hydrogenated terpene resin, terpene phenol resin, rosin, hydrogenated rosin, rosin ester, petroleum resin, coumarone-indene resin, phenol resin, xylene resin, and alicyclic saturated hydrocarbon resin. The tackifier may be used alone or in combination of two or more. When the adhesive layer contains a tackifier, the content of the tackifier in the adhesive layer is preferably 20 to 80 parts by mass, more preferably 30 to 70 parts by mass, based on 100 parts by mass of the acrylic adhesive.

(Filler)
The adhesive layer may contain a filler. The filler is used to adjust the shape retention of the adhesive layer. Examples of the filler include inorganic fillers such as light anhydrous silicic acid, titanium oxide, and zinc oxide; organic metal salts such as calcium carbonate and magnesium stearate; cellulose derivatives such as lactose, crystalline cellulose, ethyl cellulose, and low-substituted hydroxypropyl cellulose; and crosslinked polyvinylpyrrolidone. The filler may be used alone or in combination of two or more. When the adhesive layer contains a filler, the content of the filler in the adhesive layer is preferably 5 parts by mass or less, more preferably 0.1 to 2 parts by mass, based on 100 parts by mass of the acrylic adhesive.

The thickness of the adhesive layer is preferably 20 μm or more, more preferably 30 μm or more, and particularly preferably 50 μm or more. The thickness of the adhesive layer is preferably 200 μm or less, more preferably 150 μm or less, and particularly preferably 120 μm or less. When the thickness of the adhesive layer is 20 μm or more, the amount of drug required to obtain the desired medicinal effect can be contained in the adhesive layer. When the thickness of the adhesive layer is 200 μm or less, strong drying conditions are not required during production to reduce residual solvent in the adhesive layer, so that volatilization or decomposition of the drug in the adhesive layer can be suppressed.

[Support]
In the patch of the present invention, an adhesive layer is laminated and integrated on one side of the support. The support is required to have strength to prevent loss of the drug in the adhesive layer and to impart self-retention to the patch. Examples of such supports include resin films, nonwoven fabrics, woven fabrics, knitted fabrics, and aluminum sheets.

Examples of resins that may be used to form the resin film include cellulose acetate, rayon, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polypropylene, and polyvinylidene chloride. Among these, polyethylene terephthalate is preferred because it prevents loss of the drug from the adhesive layer.

Examples of materials constituting the nonwoven fabric include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-methyl (meth)acrylate copolymer, nylon, polyester, vinylon, SIS copolymer, SEBS copolymer, rayon, cotton, etc., with polyester being preferred. These materials may be used alone or in combination of two or more.

The support may be a single layer or a laminated sheet in which multiple layers are laminated together. Examples of laminated sheets include a laminated sheet in which a polyethylene terephthalate film is laminated together with a nonwoven fabric or a flexible resin film.

The thickness of the support is not particularly limited, but is preferably 2 μm or more. The thickness of the support is preferably 200 μm or less, and more preferably 2 to 100 μm or less.

[Release liner]
In the patch of the present invention, a release liner may be integrally laminated in a releasable manner on one side of the adhesive layer. The release liner is used to prevent loss of the drug in the adhesive layer and to protect the adhesive layer.

Examples of release liners include paper and resin films. Resins that make up the resin film include polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, etc. It is preferable that the surface of the release liner that faces the adhesive layer is subjected to a release treatment.

[Method of manufacturing patch]
Examples of methods for producing the patch of the present invention include: (1) a method in which an adhesive layer solution containing blonanserin, an organic acid, an acrylic adhesive, and a solvent, and, if necessary, other additives is applied to one side of a support, and then dried to laminate an adhesive layer onto one side of the support, and, if necessary, a release liner is laminated onto the adhesive layer such that the release-treated surface of the release liner faces the adhesive layer; and (2) a method in which the adhesive layer solution is applied to the release-treated surface of a release liner, and then dried to form an adhesive layer on the release liner, and then the support is laminated onto the adhesive layer.

The adhesive layer solution is obtained by uniformly stirring blonanserin, an organic acid, an acrylic adhesive, a solvent, and, if necessary, other additives. Examples of the solvent include toluene, normal hexane, cyclohexane, normal heptane, and ethyl acetate. The solvents may be used alone or in combination of two or more.

As described above, the adhesive layer of the patch of the present invention can exhibit excellent adhesive strength by using the acrylic polymer (A). Therefore, it is preferable to use the patch by directly attaching this adhesive layer to the skin.

The patch of the present invention has the above-mentioned configuration and therefore has excellent transdermal absorption of blonanserin.

The present invention will be described in more detail below using examples, but the present invention is not limited to these.

(Preparation of Acrylic Polymer (A1))
A reaction liquid consisting of monomers containing 75 parts by mass of 2-ethylhexyl methacrylate and 25 parts by mass of N-vinyl-2-pyrrolidone, and 50 parts by mass of ethyl acetate was supplied to a polymerizer, and the inside of the polymerizer was made into a nitrogen atmosphere at 80° C. Then, the monomers were polymerized while adding a polymerization initiator solution obtained by dissolving 1.2 parts by mass of lauroyl peroxide in 30 parts by mass of ethyl acetate and 20 parts by mass of cyclohexane to the reaction liquid over 24 hours, and after the polymerization was completed, ethyl acetate was further added to the reaction liquid to obtain an acrylic polymer solution (A1) having an acrylic polymer (A1) content of 30% by mass.

(Preparation of Acrylic Polymer (A2))
A reaction liquid consisting of monomers containing 40 parts by mass of n-octyl acrylate, 50 parts by mass of ethyl acrylate, and 10 parts by mass of N-vinyl-2-pyrrolidone, and 50 parts by mass of ethyl acetate was supplied to a polymerizer, and the inside of the polymerizer was made into a nitrogen atmosphere at 80° C. Then, the monomers were polymerized while adding a polymerization initiator solution obtained by dissolving 1 part by mass of lauroyl peroxide in 30 parts by mass of ethyl acetate and 20 parts by mass of cyclohexane to the reaction liquid over 24 hours, and after the polymerization was completed, ethyl acetate was further added to the reaction liquid to obtain an acrylic polymer solution (A2) having an acrylic polymer (A2) content of 30% by mass.

(Preparation of Acrylic Polymer (A3))
A reaction liquid consisting of monomers containing 13 parts by mass of dodecyl methacrylate, 78 parts by mass of 2-ethylhexyl methacrylate, and 9 parts by mass of 2-ethylhexyl acrylate, and 50 parts by mass of ethyl acetate was supplied to a polymerizer, and the inside of the polymerizer was made into a nitrogen atmosphere at 80° C. Then, the monomers were polymerized while adding a polymerization initiator solution obtained by dissolving 0.5 parts by mass of benzoyl peroxide in 10 parts by mass of ethyl acetate and 10 parts by mass of cyclohexane to the reaction liquid over 24 hours, and after the polymerization was completed, ethyl acetate was further added to the reaction liquid to obtain an acrylic polymer solution (A3) having an acrylic polymer (A3) content of 30% by mass.

(Examples 1 to 4 and Comparative Examples 1 to 2)
Free base-type blonanserin, lactic acid, levulinic acid, isopropyl myristate, acrylic polymer (A1), acrylic polymer (A2), and acrylic polymer (A3) were blended in amounts shown in Table 1 for the adhesive layer, respectively, and ethyl acetate was added to give a solids concentration of 30% by mass, followed by mixing until uniform to prepare an adhesive layer solution.

Next, a 38 μm thick polyethylene terephthalate film that had been treated with a silicone release agent was prepared as a release liner, and the adhesive layer solution was applied to the silicone release-treated surface of the polyethylene terephthalate film and dried at 60°C for 30 minutes to produce a laminate in which an 80 μm thick adhesive layer was formed on the silicone release-treated surface of the polyethylene terephthalate film.

A polyethylene terephthalate film with a thickness of 25 μm was prepared as a support, and one side of the support was placed opposite the adhesive layer of the laminate, and the adhesive layer of the laminate was laminated and integrated with the support to produce a patch. The gel fraction of the adhesive layer is shown in Table 1.

In addition, in the patch of Comparative Example 2, immediately after production, a liquid component thought to be levulinic acid excessively seeped onto the surface of the adhesive layer, reducing the adhesive strength of the adhesive layer, making it impossible to laminate the adhesive layer of the laminate to the support, and thus making it impossible to produce the patch.

(Comparative Example 3)
A commercially available patch (trade name "Lonasen Tape 40 mg", manufactured by Sumitomo Dainippon Pharma Co., Ltd.) was prepared. This patch was manufactured by the following method.

Under an inert gas atmosphere, 75 parts by mass of 2-ethylhexyl acrylate, 22 parts by mass of N-vinyl-2-pyrrolidone, 3 parts by mass of acrylic acid, and 0.2 parts by mass of azobisisobutyronitrile were solution polymerized in ethyl acetate at 60°C to obtain an acrylic polymer (A4).

55.94 parts by mass of acrylic polymer (A4), 6.46 parts by mass of free base type blonanserin, 17.77 parts by mass of isopropyl myristate, 14.54 parts by mass of sesame oil, 0.97 parts by mass of 2,6-di-tert-butyl-4-methylphenol (BHT), 1.26 parts by mass of magnesium aluminometasilicate (Neusilin (trade name) type: UFL2, manufactured by Fuji Chemical Industry Co., Ltd.), were mixed thoroughly with an appropriate amount of ethyl acetate until homogeneous, and then 0.06 parts by mass of trifunctional isocyanate as a crosslinking agent was added. A 75 μm-thick polyethylene terephthalate film that had been subjected to a silicone release treatment was prepared as a release liner, and the obtained adhesive layer solution was applied to the silicone release-treated surface of the release liner and dried to form an adhesive layer. The adhesive surface of the formed adhesive layer was then bonded to a 3.5 μm-thick polyethylene terephthalate film and a 12 g/m-area weight polyethylene terephthalate film. The laminate was prepared by laminating the polyethylene terephthalate nonwoven fabric of ² to the nonwoven fabric side of the support. Then, the laminate was left at 70°C for 48 hours, and the acrylic polymer (A4) in the adhesive layer was crosslinked by a crosslinking agent. After leaving, the release liner of the laminate was peeled off, and the adhesive layer was allowed to contain lactic acid so that the final content of lactic acid was 3 parts by mass relative to 97 parts by mass of the adhesive layer. Then, the same release liner as the release liner was prepared separately, and the silicone release-treated surface of this release liner was laminated to the adhesive layer so that it faced each other, thereby preparing a patch. The thickness of the adhesive layer was 80 μm. The gel fraction of the adhesive layer is shown in Table 1.

(Performance evaluation of patches)
The patches of Examples 1 to 4 and Comparative Examples 1 and 3 were evaluated for transdermal absorbency, storage stability, and adhesive strength according to the following procedures.

(Transdermal absorption)
Five flat square test pieces with an area of 3 ^cm2 were punched out from the patch. The adhesive layer of each of the three test pieces was dissolved in tetrahydrofuran, and the amount of free base blonanserin was measured using HPLC (high performance liquid chromatography), and the arithmetic mean value was taken as the amount of free base blonanserin (μg/ ^cm2 ) before the test. The release liner was peeled off from the remaining two test pieces to expose the adhesive layer entirely, and each test piece was attached to the back of a rat whose back had been shaved for 24 hours. After peeling off the test piece from the rat's back, each adhesive layer was dissolved in tetrahydrofuran, and the amount of free base blonanserin was measured using HPLC, and the arithmetic mean value was taken as the amount of free base blonanserin (μg/ ^cm2 ) after the test. The amount of free base Blonanserin after the test was subtracted from the amount of free base Blonanserin before the test to obtain the percutaneous absorption amount (μg/cm ² ), which is shown in Table 1.

(Storage stability)
Immediately after the preparation of the patch, a planar square test piece with an area of 3 ^cm2 was punched out from the patch. Next, the release liner was peeled off from the test piece, and the surface of the adhesive layer was observed at a magnification of 40 times using a polarizing microscope, and a photograph was taken. The obtained photograph was observed to observe the state of precipitation of crystals of free base form of Blonanserin. When the entire amount of free base form of Blonanserin was dissolved and there was no precipitation of crystals of free base form of Blonanserin, it was rated as "absent", and when there was precipitation of crystals of free base form of Blonanserin, it was rated as "present". The results are shown in the "storage stability" column of "immediately after preparation" in Table 1.

Next, the test specimen was sealed in a packaging material with an inner surface of polyacrylonitrile, and then stored in an atmosphere at a temperature of 40°C for 24 hours, then in an atmosphere at a temperature of 4°C for 24 hours, and then further stored in an atmosphere at a temperature of 25°C for 24 hours. After storage, the test specimen was removed and the same observation site as immediately after production was promptly observed at a magnification of 40x using a polarizing microscope, photographed, and the photographs obtained were observed to observe the state of precipitation of crystals of free base blonanserin. When the entire amount of free base blonanserin was dissolved and no precipitation of crystals of free base blonanserin occurred, it was rated as "absent," and when precipitation of crystals of free base blonanserin occurred, it was rated as "present." The results are shown in the "After storage" column of "Storage stability" in Table 1.

In addition, when crystals with a diameter of 1 μm or more were observed in the evaluation of storage stability, it was determined that crystals of free base blonanserin had precipitated. The crystal diameter refers to the diameter of the smallest circle that can surround the crystal on a photograph.

(Adhesion test)
A test piece (25 mm wide x 40 mm long) was cut out from the patch. The release liner was peeled off from the test piece to expose the adhesive layer, and the peel adhesion (N/cm) of the adhesive layer was measured in accordance with the "180° peel adhesion test" in "3.1 Peel adhesion test" of "6.13 Adhesive strength test" of the general test method of the 17th revised Japanese Pharmacopoeia, and the peel adhesion was taken as the adhesive strength of the patch. The results are shown in Table 1.

As described above, the present invention can provide a patch that has excellent transdermal absorbability of blonanserin.

Claims (3)

A support and an adhesive layer laminated and integrated on one surface of the support,
The adhesive layer is
Blonanserin,
an organic acid including at least one of lactic acid and levulinic acid ;
an acrylic pressure-sensitive adhesive comprising an acrylic polymer (A) which contains 5% by mass or more of an N-vinyl-2-pyrrolidone component and does not contain a functional group having affinity for the above-mentioned blonanserin, or, if it contains a functional group having affinity for the above-mentioned blonanserin, the content of a monomer component containing the functional group having affinity for the above-mentioned blonanserin is less than 1% by mass;
Contains
A patch, wherein the functional group having affinity for blonanserin is a carboxy group, a sulfonic acid group, or a phosphate group represented by the following chemical formula (1) :
The patch according to claim 1, characterized in that the organic acid comprises levulinic acid . The patch according to claim 1 or 2, characterized in that the molar ratio of the organic acid to blonanserin [(moles of organic acid)/(moles of blonanserin)] is 1 or more and 15 or less.