WO2018117125A1 - Transdermal preparation - Google Patents

Abstract

A transdermal preparation which contains a phenylpiperazine derivative, an organic acid, an ester solvent, an organic sulfoxide, a thermoplastic resin and a tackifying agent. This transdermal preparation is configured such that the content of the organic sulfoxide is from 2% by mass to 35% by mass relative to the total amount of the transdermal preparation.

Description

Transdermal formulation

This disclosure relates to transdermal formulations.

Phenyl piperazine derivatives are widely used as antipsychotic drugs. Phenylpiperazine derivatives are specifically antipsychotics that are effective in improving schizophrenia, manic symptoms in bipolar disorder, or depression or depression, specifically, for example, schizophrenia drugs, Used as a depressant, anxiolytic, etc.

Examples of the phenylpiperazine derivative include aripiprazole, brexpiprazole, and the like. Among them, aripiprazole, which is one of the phenylpiperazine derivatives, is used as a schizophrenia drug (see Japanese Patent No. 2608788).
Japanese Patent No. 2608788 describes phenylpiperazine derivatives as active ingredients. However, the administration method for schizophrenia drugs described in Japanese Patent No. 2608788 is limited to oral administration, injection, and suppository studies.

It may be difficult to orally administer drugs regularly to those who have developed schizophrenia, manic symptoms in bipolar disorder, or depression or depression. Therefore, in recent years, a dosage form for transdermally absorbing a phenylpiperazine derivative has been studied instead of oral administration. If it is a transdermal preparation, it has the advantage that it can be easily administered by a therapist or a caregiver to an application target of schizophrenia and it can be easily confirmed that the transdermal preparation exists on the skin. . Among these, a patch that is held on the skin for a long time and allows an appropriate amount of the drug to continuously penetrate into the skin is desired.

However, phenylpiperazine derivatives have a relatively large molecular weight and are difficult to be transdermally formulated, and various attempts have been made to apply them as transdermal formulations.

For example, 0.5 mole to 5 moles of an aromatic sulfonic acid, an aliphatic sulfonic acid, an aromatic carboxylic acid or an aliphatic carboxylic acid is contained per mole of aripiprazole, and aripiprazole is converted into an organic acid salt. As an external preparation composition having good percutaneous absorbability contained in a pharmaceutical system has been proposed (see International Publication No. 2010/146872).

In addition, as a preparation capable of percutaneously absorbing an active ingredient at a high concentration, a transdermal preparation containing at least one selected from organic sulfoxide, a fatty acid ester and a fatty acid with respect to the active ingredient has been proposed (International Publication No. 1). 2007/16766).

On the other hand, various preparation techniques as a patch have been studied. For example, on a support, a thermoplastic elastomer, a liquid component exceeding 300 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer, aripiprazole, and organic A patch having an adhesive layer containing an acid is disclosed, and it is described that the adhesive layer can contain a tackifier in an amount of 10% by weight or less (see JP-A-2015-98440).

The external preparation composition described in WO2010 / 146872 can absorb aripiprazole percutaneously. However, after the external preparation composition is percutaneously absorbed, the solvent coexisting with aripiprazole diffuses rapidly into the skin, and a therapeutically effective concentration of aripiprazole is supplied continuously over a long period of time. It turns out that it can be difficult to do.
International Publication No. 2007/16766 describes various compounds in parallel for organic sulfoxides, fatty acid esters and fatty acids that are effective for transdermal absorption. However, no particular attention is paid to the phenylpiperazine derivative as an active ingredient after percutaneous absorption, and no investigation has been made regarding the transdermal absorption effect and durability of the phenylpiperazine derivative.

According to the invention described in JP-A-2015-98440, it is said that a patch excellent in skin penetration and transdermal absorbability of aripiprazole can be obtained. However, since the adhesive layer in the patch described in JP-A-2015-98440 contains a lot of liquid components, the adhesive layer is easily deformed by an external force, and it is difficult to stably hold it on the skin. There is a problem that handling property is low when an adhesive layer is formed on the agent. In addition, as described in International Publication No. 2010/14672, after the external preparation composition is percutaneously absorbed, the solvent coexisting with aripiprazole quickly diffuses into the skin, and a therapeutically effective concentration of aripiprazole is obtained. It may be difficult to supply continuously for a certain period of time over a long period of time. Furthermore, in Japanese Patent Application Laid-Open No. 2015-98440, no investigation is made regarding the sustainability of phenylpiperazine derivatives as active ingredients after percutaneous absorption.

The problem to be solved by one embodiment of the present invention is that it has adhesiveness, is stably held on the skin, has good transdermal absorbability of an active ingredient phenylpiperazine derivative, and is in vivo. The object is to provide a transdermal preparation capable of maintaining the supply concentration and supply time of an active ingredient at an appropriate level.

Means for solving the above problems include the following embodiments.
[1] A phenylpiperazine derivative, an organic acid, an ester solvent, an organic sulfoxide, a thermoplastic resin, and a tackifier, and the content of the organic sulfoxide is 2% by mass with respect to the total amount of the transdermal preparation. A transdermal preparation of ~ 35% by weight.
[2] The transdermal preparation according to [1], wherein the phenylpiperazine derivative is at least one selected from aripiprazole and brexpiprazole.
[3] The transdermal formulation according to [1] or [2], wherein the thermoplastic resin contains at least one selected from thermoplastic elastomers.

[4] In any one of [1] to [3], the organic acid is contained in an amount of 10 to 25 parts by mass with respect to a total content of 100 parts by mass of the organic acid, the ester solvent, and the organic sulfoxide. The transdermal preparation described.
[5] Any one of [1] to [4] containing 30 to 75 parts by mass of an ester solvent with respect to 100 parts by mass of the total content of the organic acid, the ester solvent and the organic sulfoxide. The transdermal preparation described in 1.
[6] The total content of organic acid, ester solvent and organic sulfoxide is 35 to 100 parts by mass with respect to 100 parts by mass of the total content of thermoplastic resin and tackifier [1] to [5 ] The transdermal formulation as described in any one of.

[7] The transdermal preparation according to any one of [1] to [3], comprising two or more organic acids.
[8] The transdermal preparation according to [7], wherein the organic acid is contained in an amount of 10 to 75 parts by mass with respect to 100 parts by mass of the total content of the organic acid, the ester solvent, and the organic sulfoxide.
[9] The percutaneous body according to [7] or [8], wherein 10 to 60 parts by mass of the ester solvent is contained per 100 parts by mass of the total content of the organic acid, the ester solvent, and the organic sulfoxide. Formulation.
[10] The total content of organic acid, ester solvent and organic sulfoxide is 35 to 210 parts by mass with respect to 100 parts by mass of the total content of thermoplastic resin and tackifier [7] to [9 ] The transdermal formulation as described in any one of.

[11] The transdermal preparation according to any one of [1] to [10], further comprising liquid paraffin.
[12] The transdermal preparation according to any one of [1] to [11], which contains at least one selected from petroleum resin-based tackifiers and rosin-based tackifiers as a tackifier.
[13] The transdermal formulation according to any one of [1] to [12], wherein the content of the phenylpiperazine derivative is 0.3% by mass to 15% by mass with respect to the total amount of the transdermal formulation.

According to one embodiment of the present invention, adhesiveness is maintained stably on the skin, the transdermal absorbability of the active ingredient phenylpiperazine derivative is good, and the active ingredient is supplied to the living body. It is possible to provide a transdermal preparation capable of maintaining the concentration and supply time at an appropriate level.

Hereinafter, examples of specific embodiments of the present invention will be described in detail. However, the following embodiments are merely examples, and the present invention is not limited to the following descriptions, and may be appropriately changed within the scope of the object of the present invention. Can be added.

In the present specification, a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
Furthermore, in the present specification, the amount of each component contained in the composition means the total amount of the plurality of substances unless specifically stated otherwise, when the composition includes a plurality of substances corresponding to each component.
In the numerical ranges described stepwise in the present specification, the upper limit value or lower limit value described in a numerical range may be replaced with the upper limit value or lower limit value of the numerical range described in other steps. . Further, in the numerical ranges described in this specification, the upper limit value or the lower limit value described in a certain numerical range may be replaced with the values shown in the examples.
In the present specification, a combination of preferred embodiments is a more preferred embodiment.
In the present specification, “(meth) acryl” means at least one of acryl and methacryl.

The transdermal preparation of the present disclosure (hereinafter sometimes referred to as a transdermal preparation) includes a phenylpiperazine derivative, an organic acid, an ester solvent, an organic sulfoxide, and a thermoplastic resin (hereinafter referred to as a specific resin). And a tackifier, and the content of the organic sulfoxide is 2% by mass to 35% by mass with respect to the total amount of the transdermal preparation.
The transdermal preparation contains a pressure-sensitive adhesive composition containing a specific resin and a tackifier, and a liquid component containing a phenylpiperazine derivative, an organic acid, an ester solvent, and an organic sulfoxide, which are active ingredients. Has a uniform formulation form.

Since the transdermal formulation of the present disclosure includes an adhesive composition containing a specific resin and a tackifier, the transdermal preparation has adhesiveness and has a self-supporting property that is stably retained on the skin.
Here, the self-supporting property means a property that, when a transdermal preparation is applied on the skin, it can maintain the shape at the time of application for a desired period of time to be retained on the skin. The self-supporting property is, for example, that when a transdermal preparation is applied on a resin film to form a uniform layer having a thickness of 1 mm and the appearance is observed after 1 hour at room temperature, the shape at the time of application is It can be confirmed by visually observing that it is maintained. On the other hand, in a gel-like preparation having a low viscosity, it is visually confirmed that the layer thickness changes or the peripheral edge flows after 1 hour. It is determined that such a preparation whose shape at the time of application changes with the passage of time has no self-supporting property.

Note that “the shape at the time of application is maintained” means, for example, immediately after forming a uniform layer having a thickness of 1 mm as described above (initial state) and after 1 hour at room temperature (after time) ) Indicates a case where at least one of the following conditions (1) and (2) is satisfied.
(1) Layer thickness direction change rate = | (initial layer thickness−time-lapse layer thickness) | × 100 / initial layer thickness ≦ 40 (%)
(2) Layer area change rate = | (area of initial layer−area of layer after time) | × 100 / area of initial layer ≦ 130 (%)
In the above measurement, the “layer thickness” employs an average value of measured values of arbitrary five points in the measurement target region. The “layer area” means an area calculated from the projection of the formed layer.

When the transdermal preparation containing the aforementioned pressure-sensitive adhesive composition and liquid component is applied to the skin, the liquid component containing the active ingredient held in the pressure-sensitive adhesive composition gradually permeates the skin.
In a transdermal preparation containing a pressure-sensitive adhesive composition and a liquid component, the organic sulfoxide contained in the liquid component and the tackifier contained in the pressure-sensitive adhesive composition form an appropriate interaction to form a liquid component. Is believed to be stably retained in the formulation. That is, when the content of the organic sulfoxide is 2% by mass to 35% by mass with respect to the total amount of the transdermal preparation, the miscibility between the pressure-sensitive adhesive composition and the liquid component is improved, and a uniform preparation can be obtained. .
Furthermore, the transdermal preparation has a good transdermal absorbability of the phenylpiperazine derivative, which is an active ingredient held in the adhesive composition, and an appropriate supply concentration and supply time of the active ingredient in the living body. Can be maintained within a certain range.
In the present specification, “supplying an active ingredient into a living body” refers to supplying the active ingredient subcutaneously, preferably into the blood.

Although the action of the transdermal preparation of the present disclosure is not clear, it is estimated as follows.
Phenylpiperazine derivatives are known to have a longer blood half-life when taken into the body than other drugs. From the viewpoint of maintaining the drug effect, the phenylpiperazine derivative is desired to maintain a sufficient concentration in the blood to ensure its effectiveness.
Certain organic acids are known to have high solubility of phenylpiperazine derivatives. According to the techniques described in Patent Documents 1 to 4, the combined use of a predetermined organic acid and another solvent is studied. It has been done. However, when the permeation rate of the coexisting solvent is higher than that of the organic acid, only the coexisting solvent penetrates deep into the skin first, and even if the organic acid remains, the solubility of the phenylpiperazine derivative It is difficult to maintain the value within a proper range for a proper time. Therefore, it is difficult for the known technique to continuously supply the necessary active ingredient concentration for the required time, in vivo, specifically subcutaneously, preferably into the blood.

In addition, when a liquid component containing the aforementioned phenylpiperazine derivative is mixed in a matrix formed of the pressure-sensitive adhesive composition, the affinity between the component contained in the pressure-sensitive adhesive composition and the liquid component is extremely good. Therefore, it becomes a preparation with good uniformity and film forming property. However, when the affinity between the component contained in the pressure-sensitive adhesive composition and the liquid component is extremely good, the release of the liquid component containing the phenylpiperazine derivative contained in the matrix may be inhibited. On the other hand, when the affinity between the component contained in the pressure-sensitive adhesive composition and the liquid component is too low, separation of the component contained in the pressure-sensitive adhesive composition and the liquid component, or precipitation of the active component, etc. May occur.

In the transdermal preparation of the present disclosure, the matrix formed of the pressure-sensitive adhesive composition contains a thermoplastic resin, and further contains a tackifier, so that components contained in the liquid component (for example, organic sulfoxide and tackifier) ) And the matrix form an appropriate interaction, so that the liquid component can be stably held in the matrix. Therefore, the liquid component containing the phenylpiperazine derivative which is an active ingredient is retained in the matrix, but each component contained in the liquid component is chemically or electrostatically different from the thermoplastic resin contained in the adhesive composition. It is difficult to form an interaction, and the release property of the liquid component is good while being a uniform preparation.
For this reason, when the preparation is brought into contact with the skin, the liquid component moves to the skin having a higher affinity with the liquid component than the matrix formed by the adhesive composition, and the concentration gradient generated between the matrix and the skin also occurs. Together, the liquid component is thought to penetrate quickly through the skin.
Further, since the preparation contains a tackifier, when the preparation is brought into contact with the skin, it is stably held on the skin due to the self-adhesiveness caused by the tackifier, and the specific resin has a self-supporting property. Therefore, the transdermal preparation is stably held on the skin following the unevenness of the skin surface. For this reason, it is considered that the penetration of the liquid component into the skin is performed stably for a long time.

When the liquid component contains a specific amount of an ester solvent in addition to the phenylpiperazine derivative, the permeability of the three components of the phenylpiperazine derivative, organic sulfoxide and organic acid to the skin is improved.
A mixed solvent of an organic acid and an organic sulfoxide that has penetrated into the skin has good solubility of the phenylpiperazine derivative, and the phenylpiperazine derivative exists in the solution in the form of an organic acid salt by dissolution. For this reason, precipitation of the phenyl piperazine derivative is suppressed, and the penetration into the living body is improved.

The organic sulfoxide coexists with the organic acid, so that the high solubility of the phenylpiperazine derivative is maintained in the resulting mixed solvent. In the body, preferably in the blood, the necessary active ingredient concentration will last for the required time. This is presumably because the permeation rate of organic sulfoxide into the skin is not too fast, for example, as in known amide solvents, but is relatively slow, and the permeation rate is in an appropriate range.
Moreover, the supply concentration and supply time of the active ingredient in the living body can be maintained at an appropriate level by the composition of the liquid component. Therefore, the amount of the active ingredient penetrating into the skin in the initial stage is smaller than in the case of applying a certain amount of the formulation directly to the skin, such as an ointment, but the liquid component containing the active ingredient as described above. Therefore, it is considered that supply of an appropriate amount of the active ingredient can be continued for a long time.
Note that the present disclosure is not limited to the above estimation mechanism.

Hereinafter, each component contained in the transdermal preparation will be described in detail.
(1) Liquid component containing phenylpiperazine derivative First, a liquid component containing a phenylpiperazine derivative as an active ingredient will be described.

[Phenyl piperazine derivatives]
The transdermal formulation of the present disclosure contains a phenyl piperazine derivative as an active ingredient.
The phenyl piperazine derivative that can be used in the transdermal preparation is not particularly limited as long as it is effective for the treatment of schizophrenia and the like.
The phenylpiperazine derivative preferably has a molecular weight of 300 or more, and more preferably has a molecular weight of 400 or more.
Although there is no restriction | limiting in particular in the upper limit of molecular weight, From a soluble viewpoint to the solvent to coexist, molecular weight can be 600 or less.

The phenyl piperazine derivative used suitably in this indication is illustrated with molecular weight. The numerical value in () after each compound name represents the molecular weight of the compound written together.
Examples of phenylpiperazine derivatives having a molecular weight of 300 or more include aripiprazole (molecular weight: 448.38), brexpiprazole (433), etoperidone (414.37), nefazodone (506.46), trazodone (371.8), Virazodone (441.52) and the like can be mentioned.
Among these, as the phenylpiperazine derivative, the phenylpiperazine derivative is preferably at least one selected from aripiprazole (hereinafter sometimes referred to as ARP) and brexpiprazole (hereinafter sometimes referred to as BRP).

The phenylpiperazine derivative contained in the transdermal preparation may be one type or two or more types.
The content of the phenylpiperazine derivative with respect to the total amount of the transdermal preparation is preferably 0.3% by mass or more from the viewpoint of the effect.
The content of the phenylpiperazine derivative with respect to the total amount of the transdermal preparation is preferably 0.3% by mass to 15% by mass, more preferably 0.5% by mass to 15% by mass, and 1% by mass to 15% by mass. % Is more preferable, 5% by mass to 15% by mass is particularly preferable, and 6% by mass to 13% by mass is most preferable.
When the content of the phenylpiperazine derivative is within the above-mentioned range, when a transdermal preparation is applied to the skin, the phenylpiperazine derivative is administered subcutaneously, preferably in blood, at an effective concentration at which a medicinal effect can be obtained for a desired time. It can be expected to maintain.
The content of the phenylpiperazine derivative can be measured by high performance liquid chromatography (hereinafter sometimes referred to as HPLC). As the HPLC measuring apparatus to be used, an apparatus as described in detail in the following examples can be used.

[Organic acid]
The organic acid contained in the transdermal preparation is not particularly limited. In particular, the organic acid preferably functions as a solvent for a phenylpiperazine derivative (hereinafter sometimes referred to as an active ingredient).
By containing the organic acid, the solubility of the active ingredient in the transdermal preparation is further improved. Furthermore, even after the percutaneous preparation penetrates subcutaneously, the precipitation of crystals is suppressed in the body, and the active ingredient can be continuously present at an effective concentration over a long period of time.
Examples of the organic acid include a substituted aliphatic carboxylic acid or aromatic carboxylic acid having at least one selected from a hydroxyl group, an alkoxy group, an acyl group, a carbonyl group, and a carboxyl group as a substituent.
Among the above-described substituents introduced into the aliphatic carboxylic acid or aromatic carboxylic acid, a hydroxyl group is preferable from the viewpoint of better solubility of the active ingredient.

Hereinafter, examples of the aliphatic carboxylic acid and the aromatic carboxylic acid into which the above-described substituent can be introduced will be given.
The aliphatic carboxylic acid may be either an aliphatic monocarboxylic acid or an aliphatic dicarboxylic acid.
Examples of the aliphatic monocarboxylic acid include short-chain aliphatic monocarboxylic acids having 2 to 7 carbon atoms, medium-chain aliphatic monocarboxylic acids having 8 to 11 carbon atoms, and long-chain aliphatic monocarboxylic acids having 12 or more carbon atoms. Can be mentioned.
Examples of the short-chain aliphatic monocarboxylic acid having 2 to 7 carbon atoms include acetic acid, butyric acid, hexanoic acid, and cyclohexanecarboxylic acid. Examples of the medium chain aliphatic monocarboxylic acid having 8 to 11 carbon atoms include caprylic acid and capric acid. Examples of the long chain aliphatic monocarboxylic acid having 12 or more carbon atoms include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid and the like.

Examples of the aliphatic dicarboxylic acid include sebacic acid, adipic acid, malic acid, maleic acid, fumaric acid and the like.

Examples of the aromatic carboxylic acid include benzoic acid and cinnamic acid.
Examples of the aromatic carboxylic acid having a substituent include p-hydroxybenzoic acid, salicylic acid, and acetylsalicylic acid.
Among these, the inclusion of the aliphatic monocarboxylic acid having the above-described substituent is preferable from the viewpoint of further improving the penetration of the active ingredient into the skin.

It is more preferable that the aliphatic monocarboxylic acid used as the organic acid includes the above-described short-chain aliphatic monocarboxylic acid having 2 to 7 carbon atoms having a substituent. Specific examples of the aliphatic monocarboxylic acid include glycolic acid, lactic acid, methoxyacetic acid, mandelic acid, levulinic acid, and 3-hydroxybutyric acid. From the viewpoint of solubility of the active ingredient, biocompatibility, etc., short-chain aliphatic monocarboxylic acids having 2 to 7 carbon atoms having a hydroxyl group as a substituent are more preferable, and lactic acid and glycolic acid are more preferable.

The transdermal preparation may contain only one organic acid or two or more organic acids.
As 1st Embodiment, the aspect in which a transdermal formulation contains only 1 type of organic acids is mentioned.
Moreover, as a preferable combination of organic acids in the case where the transdermal preparation contains two or more kinds of organic acids, second and third embodiments described later may be mentioned.

Hereinafter, preferable combinations of organic acids when the transdermal preparation contains two or more organic acids will be described.
As a second embodiment, from the viewpoint of further improving the penetration of the active ingredient into the skin,
A short-chain aliphatic monocarboxylic acid having 2 to 7 carbon atoms having a substituent as the first aliphatic monocarboxylic acid,
And a second aliphatic monocarboxylic acid selected from at least one of the aforementioned medium-chain aliphatic monocarboxylic acid having 8 to 11 carbon atoms or the long-chain saturated aliphatic monocarboxylic acid having 12 or more carbon atoms described above. The combination containing is preferably mentioned.

When the first aliphatic monocarboxylic acid includes a short-chain aliphatic monocarboxylic acid having 2 to 7 carbon atoms having a substituent, the preferred range and specific examples are as described above.

When the second aliphatic monocarboxylic acid contains a medium chain fatty acid having 8 to 11 carbon atoms, a medium chain fatty acid monocarboxylic acid having 10 to 11 carbon atoms is preferable.
When the second aliphatic monocarboxylic acid includes a long-chain saturated aliphatic monocarboxylic acid having 12 or more carbon atoms, a long-chain saturated aliphatic monocarboxylic acid having 12 to 17 carbon atoms is preferable, and has 12 to 14 carbon atoms. Long chain saturated aliphatic monocarboxylic acids are more preferred.
The second aliphatic monocarboxylic acid may or may not have a substituent. Especially, the compound which has a substituent is preferable from a viewpoint of improving the permeability to the skin of an active ingredient more. Examples of the substituent include a hydroxyl group, an alkoxy group, an acyl group, a carbonyl group, and a carboxyl group, and among them, a compound having a hydroxyl group, a carbonyl group, or a carboxyl group is preferable.

As a third embodiment, from the viewpoint of further improving the penetration of the active ingredient into the skin, a short-chain aliphatic monocarboxylic acid having 2 to 7 carbon atoms having a substituent as the first aliphatic monocarboxylic acid. It is preferable that a long-chain unsaturated aliphatic monocarboxylic acid having 14 or more carbon atoms is included as the second aliphatic monocarboxylic acid.

When the first aliphatic monocarboxylic acid includes a short-chain aliphatic monocarboxylic acid having 2 to 7 carbon atoms having a substituent, the preferred range and specific examples are as described above.

When a long-chain unsaturated aliphatic monocarboxylic acid having 14 or more carbon atoms is included as the second aliphatic monocarboxylic acid, a long-chain unsaturated aliphatic monocarboxylic acid having 14 to 40 carbon atoms is preferable, and 18 to 40 carbon atoms is preferable. Long-chain unsaturated aliphatic monocarboxylic acids are more preferable, and long-chain unsaturated aliphatic monocarboxylic acids having 18 to 30 carbon atoms are more preferable. The unsaturated bond of the long-chain unsaturated aliphatic monocarboxylic acid having 14 or more carbon atoms means a double bond or a triple bond existing in the carbon chain. The number of unsaturated bonds should just be one or more, and although there is no restriction | limiting in particular in an upper limit, For example, it can be 10 or less.
The second aliphatic monocarboxylic acid may or may not have a substituent, but a compound having a substituent is preferable from the viewpoint of further enhancing the penetration of the active ingredient into the skin. Examples of the substituent include a hydroxyl group, an alkoxy group, an acyl group, a carbonyl group, and a carboxyl group, and among them, a compound having a hydroxyl group, a carbonyl group, or a carboxyl group is preferable.

The content of the first aliphatic monocarboxylic acid relative to the total amount of the transdermal preparation is preferably 3.0% by mass or more, and more preferably 3.5% by mass or more. The upper limit is preferably 30% by mass or less and more preferably 20% by mass or less from the viewpoint of compatibility in the transdermal preparation.
The content of the second aliphatic monocarboxylic acid relative to the total amount of the transdermal preparation is preferably 0.5% by mass or more, and more preferably 1.0% by mass or more. The upper limit is preferably 20% by mass or less, more preferably 15% by mass or less, still more preferably 7.0% by mass or less, and even more preferably 5.0% by mass or less from the viewpoint of compatibility with the transdermal preparation. .
From the viewpoint of enhancing the penetration of the active ingredient into the skin, the first aliphatic monocarboxylic acid is contained in an amount of 10% by mass to 20% by mass and the second aliphatic monocarboxylic acid is contained in an amount of 2.0% by mass to 5. It is preferable to contain 0 mass%.

By containing an organic acid, an ester solvent described in detail below, and a specific amount of organic sulfoxide as a solvent for the active ingredient contained in the transdermal preparation, the solubility and stability of the active ingredient are as described above. Properties, absorption rate in percutaneous absorption, release from a matrix containing a specific resin material, and the like are preferable ranges.
From the viewpoint of compatibility of the transdermal preparation, the organic acid is preferably contained in an amount of 3 parts by mass or more, preferably 5 parts by mass or more, based on 100 parts by mass of the total content of the organic acid, the ester solvent, and the organic sulfoxide. Is preferred.
Although there is no restriction | limiting in particular in content of organic acid, For example, it can be 25 mass parts or less, and 20 mass parts or less are preferable.

The content of the organic acid is suitable, for example, when the transdermal preparation contains one organic acid.
In addition, when the transdermal preparation contains two or more organic acids as in the second embodiment and the third embodiment described above, the upper limit of the content of the organic acid is, for example, 75 parts by mass or less. 70 parts by mass or less is preferable.

The content of the organic acid in the transdermal preparation can be measured by a known method.
For example, the content when the organic acid is lactic acid can be measured by ion chromatography. For the measurement of ion chromatography, for example, Thermo Fisher Scientific Co., Ltd .: Dionex (registered trademark) ICS-2000 can be used. Using 1 mM KOH as the eluent, ion chromatography can be measured using a diluted solution obtained by diluting the prepared transdermal preparation.
Further, even when the transdermal preparation contains a second organic acid in addition to lactic acid, it can be measured by the same measurement method, and ion chromatography is performed according to the characteristics of the organic acid to be measured. The content can be measured using a gas chromatography mass spectrometer (GC-MS) or the like. Moreover, these measuring devices may be used in combination.
For example, as in the second embodiment or the third embodiment described above, an organic acid having a long-chain saturated aliphatic structure / an organic acid having an unsaturated aliphatic structure (long-chain saturated fat having 12 or more carbon atoms) Organic monocarboxylic acid, long-chain unsaturated aliphatic monocarboxylic acid having 14 or more carbon atoms, etc.) It is preferable to measure with a graphy mass spectrometer.
As ion chromatography, for example, Thermo Fisher Scientific Co., Ltd .: Dionex (registered trademark) ICS-2000 can be used. Further, as GC-MS, for example, GCMS-QP2010 manufactured by Shimadzu Corporation can be used.

[Ester solvent]
By including an ester-based solvent in the transdermal preparation, the penetration of the active ingredient in the transdermal preparation, the organic acid that is a coexisting solvent, and the organic sulfoxide into the skin is further improved, and the solvent partitionability in the skin is further improved. Can be good.
Examples of the ester solvent include aliphatic dicarboxylic acid alkyl esters, and specific examples include triacetin, diethyl sebacate, diisopropyl adipate, diisopropyl sebacate, isopropyl palmitate, isopropyl myristate, and the like. . Among ester solvents, diethyl sebacate, diisopropyl adipate, and the like are preferable, and diethyl sebacate is more preferable, from the viewpoint of better penetration of active ingredients into the skin.

A transdermal formulation may contain only 1 type of ester solvents, and may contain 2 or more types.
The content of the ester solvent in the transdermal preparation is an ester with respect to 100 parts by mass of the total content of the organic acid, the ester solvent and the organic sulfoxide from the viewpoint of further improving the permeability to the skin and the solvent partitioning property. The content of the system solvent is preferably 3 parts by mass or more, more preferably 5 parts by mass or more, further preferably 15 parts by mass or more, and even more preferably 30 parts by mass or more.
Since the sustained release property of the transdermal preparation obtained by changing the content of the ester solvent can be appropriately adjusted, the upper limit is not particularly limited, but can be contained, for example, at 75 parts by mass or less. , Preferably 60 parts by mass or less, and more preferably 50 parts by mass or less.
The content of the ester solvent described above is suitable, for example, when the transdermal preparation contains one organic acid.

In addition, for example, when the transdermal preparation contains two or more organic acids as in the second embodiment and the third embodiment described above, it is said that the permeability to the skin and the solvent partitionability are further improved. From the viewpoint, it is preferable to contain 3 parts by mass or more of the ester solvent, more preferably 5 parts by mass or more, with respect to 100 parts by mass of the total content of the organic acid, the ester solvent, and the organic sulfoxide. It is more preferable to contain at least part.
Since the sustained release property of the transdermal preparation obtained by changing the content of the ester solvent can be appropriately adjusted, the upper limit is not particularly limited, but can be contained, for example, at 60 parts by mass or less. The content is preferably 50 parts by mass or less, more preferably 40 parts by mass or less, and still more preferably 30 parts by mass or less.

The content of the ester solvent in the transdermal preparation can be measured by a known method.
For example, the ester solvent content can be measured with a gas chromatograph mass spectrometer (GC-MS). As the GC-MS, for example, GCMS-QP2010 manufactured by Shimadzu Corporation can be used. Measurement can be performed by diluting the prepared transdermal preparation with ethanol or the like.

[Organic sulfoxide]
The transdermal preparation contains 2% to 35% by weight of organic sulfoxide with respect to the total amount of the transdermal preparation. When the content of the organic sulfoxide is in the above-described range, the release of the liquid component including the active ingredient from the matrix containing the specific resin material contained in the transdermal preparation is improved, and the active ingredient is dissolved in the liquid component. And the permeability in the skin is maintained at an appropriate rate. Therefore, it is presumed and preferable that the active ingredient in the transdermal preparation can be continuously supplied to the skin, further subcutaneously, preferably into the blood for the required time.
In this embodiment, examples of the organic sulfoxide include compounds represented by the following general formula (I), sulfolane, dimethyl sulfone and the like.

The compound represented by formula (I) will be described.

In general formula (I), R ¹ and R ² each independently represents a monovalent organic group. R ¹ and R ² may combine with each other to form a ring structure.
Examples of the organic group in R ¹ and R ² include an alkyl group and an aryl group. From the viewpoint that the solubility of the active ingredient becomes better and the permeation rate is controlled in a more appropriate range, the number of carbon atoms is 1. Alkyl groups of ˜5 are preferred.
Among the compounds represented by the general formula (I), dimethyl sulfoxide (hereinafter sometimes referred to as DMSO) in which both R ¹ and R ² are methyl groups is more preferable.

As the organic sulfoxide in this embodiment, one or more selected from dimethyl sulfoxide, sulfolane, and dimethyl sulfone are preferable, and dimethyl sulfoxide is more preferable.

The transdermal preparation may contain only one kind of organic sulfoxide or two or more kinds.
The content of the organic sulfoxide with respect to the total amount of the transdermal preparation is 2 to 35% by mass. From the viewpoint of improving the self-supporting property of the transdermal preparation, it is preferably 30% by mass or less, more preferably 25% by mass or less, further preferably 23% by mass or less, and 21% by mass. Even more preferably:
On the other hand, the lower limit of the content is not particularly limited. For example, when the transdermal preparation contains only one organic acid as in the first embodiment described above, the content of the organic sulfoxide is 2% by mass. 4 mass% or more is preferable, 5 mass% or more is more preferable, and 7 mass% or more is further preferable. In addition, for example, when the transdermal preparation contains two or more organic acids as in the second and third aspects described above, two or more different organic acids and organic sulfoxides are used as the active ingredient solvent. Will work. Therefore, compared to the first embodiment containing only one organic acid, the organic sulfoxide content functions effectively even if it is smaller, and the organic sulfoxide content is 1% by mass or more. 2 mass% or more is preferable, and 4 mass% or more is more preferable.
By setting the content of the organic sulfoxide within the above range, a transdermal preparation having an appropriate self-supporting property can be obtained. Therefore, a transdermal preparation can be made into a preparation excellent in production suitability. In addition, by using a transdermal preparation, appropriate blood dynamics of the active ingredient can be maintained over a long period of time.

Considering that organic sulfoxide functions as the main solvent of the active ingredient, it is possible to maintain the solubility of the active ingredient and the permeability of the active ingredient in a more appropriate range. The content of the organic sulfoxide is preferably 25 parts by mass or more, and more preferably 30 parts by mass or more with respect to 100 parts by mass of the total content. On the other hand, the upper limit is preferably 55 parts by mass or less, and more preferably 50 parts by mass or less. In addition, the preferable content ratio of the organic sulfoxide with respect to the total content of the organic acid, the ester solvent, and the organic sulfoxide as described above is suitable, for example, when the transdermal preparation contains only one organic acid.

Also, for example, when the transdermal preparation contains two or more organic acids, the organic sulfoxide functions as a solvent for the active ingredient. Therefore, in terms of maintaining the solubility of the active ingredient and the permeability of the active ingredient in a more appropriate range, not only the content relative to the total amount of the above-mentioned transdermal preparation, but also the relative content ratio as a solvent, Compared to the first embodiment containing only one organic acid, the organic sulfoxide content in the case of containing two or more organic acids tends to function effectively even if it is less. From such a viewpoint, the content of the organic sulfoxide is preferably 10 parts by mass or more and 15 parts by mass or more with respect to 100 parts by mass of the total content of the organic acid, the ester solvent and the organic sulfoxide. Is more preferable. On the other hand, the upper limit of the content of organic sulfoxide is preferably 35 parts by mass or less, and more preferably 30 parts by mass or less.

The measuring method of content of organic sulfoxide is not specifically limited, It can implement by a well-known method.
The content of organic sulfoxide can be measured by, for example, a gas chromatograph mass spectrometer (GC-MS). As the GC-MS, for example, GCMS-QP2010 manufactured by Shimadzu Corporation can be used. Measurement can be performed by using ethanol or the like as a diluent and diluting the prepared transdermal preparation with ethanol or the like.

(Content ratio of solvent of active ingredient in liquid component)
In the liquid component containing the active ingredient, the organic acid is 10 parts by mass to 25 parts by mass and the ester solvent is 30 parts by mass with respect to a total content of 100 parts by mass of the organic acid, the ester solvent, and the organic sulfoxide. It is preferable to contain 75 parts by mass and 25 to 55 parts by mass of organic sulfoxide.

That is, in the transdermal formulation, the balance of the content ratio of each component as a solvent for dissolving the active ingredient contained in the liquid component is as follows. The content ratio of organic acid: ester solvent: organic sulfoxide is 10 to 10 by mass ratio. 25:30 to 75:25 to 55 are preferred.
More specifically, the content ratio of organic acid: ester solvent: organic sulfoxide is, for example, 14:60:26, 15:56:29, 19:44:37, 19:38:43, 14:56:30, 15:33:52, 14:59:28, 16:49:34, 20:33:47, 17:37:47, and the like.
The content ratio of each component as a solvent for dissolving the active ingredient contained in the liquid component is suitable when the transdermal preparation contains only one organic acid as in the first embodiment described above, for example. is there.

Moreover, among them, for example, when the transdermal preparation contains two or more kinds of organic acids as in the second embodiment and the third embodiment described above, in the liquid component containing the active ingredient, the organic acid and , 30 to 75 parts by weight of the organic acid, 10 to 60 parts by weight of the ester solvent, and 10 to 35 parts by weight of the organic sulfoxide with respect to 100 parts by weight of the total content of the ester solvent and the organic sulfoxide. It is preferable to contain a mass part.

That is, in the transdermal formulation, the balance of the content ratio of each component as a solvent for dissolving the active ingredient contained in the liquid component is as follows. The content ratio of organic acid: ester solvent: organic sulfoxide is 10 to 10 by mass ratio. 75: 10-60: 10-35 are preferred.
More specifically, the organic acid: ester solvent: organic sulfoxide content ratio is, for example, 46:30:24, 56:24:20, 56:22:22, 46:30:24, 54:24:22, 62:20:18, 63:19:18, 65:18:17, 67:16:17, 66:14:20, 67:17:16, 66:13:21, 59: 21:20, 59:20:21, etc.

(2) Adhesive composition containing a thermoplastic resin and a tackifier [thermoplastic resin: specific resin]
The specific resin in the transdermal preparation can be plastically deformed along the surface of the skin when applied to the skin, and preferably has physical properties that give the preparation applied to the skin self-supporting properties. The specific resin functions as a main agent that forms a matrix in the preparation.

The specific resin preferably contains at least one thermoplastic resin selected from natural rubber, synthetic rubber, thermoplastic elastomer, acrylic acid polymer, silicone polymer, and the like.
In addition, the thermoplastic resin in this specification includes vulcanized rubber that is a partially vulcanized product of natural rubber.
More specifically, specific resins include natural rubber, isoprene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butylene-styrene block copolymer. Examples thereof include a copolymer, a homopolymer of (meth) acrylic acid alkyl ester, a copolymer of (meth) acrylic acid alkyl ester, polybutene, liquid polyisoprene, and silicone rubber.

The specific resin preferably contains at least one selected from thermoplastic elastomers from the viewpoints of stability, shape followability, and proper mixing with liquid components.
Furthermore, from the viewpoint of easy release of the liquid component including the active ingredient, the specific resin material preferably does not have a polar group in the molecule, and from such a viewpoint, it includes a structural unit derived from styrene. Styrenic block copolymers are preferred.
Thermoplastic elastomers include styrene-based blocks containing structural units derived from styrene such as styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, styrene-ethylene-butylene-styrene block copolymers, and the like. A copolymer is more preferable, and a styrene-isoprene-styrene block copolymer is particularly preferable.
Commercially available products may be used as the specific resin. Examples of commercially available products include SIS5002 (trade name, styrene-isoprene-styrene block copolymer) manufactured by JSR Corporation, Quantac (registered by Nippon Zeon Co., Ltd.). (Trademark) 3421 (trade name, styrene-isoprene-styrene block copolymer).

The transdermal preparation may contain only one kind of thermoplastic resin as a specific resin, or may contain two or more kinds.
The content of the specific resin with respect to the total amount of the transdermal formulation is preferably 15% by mass to 40% by mass, and preferably 20% by mass to 35% from the viewpoint of the stability of the formulation on the skin and the ease of releasing the active ingredient. More preferably, it is more preferably 25% by mass to 30% by mass.

[Tackifier]
There are no particular limitations on the tackifier that can be used in the transdermal preparation, and any known composition can be obtained as long as a composition having a uniform appearance can be obtained when mixed with the specific resin described above to obtain a pressure-sensitive adhesive composition. A tackifier can be appropriately selected and used.
Examples of the tackifier include known petroleum resin-based adhesives, rosin-based tackifiers, and terpene-based tackifiers, and any of them can be used.
Especially, it is preferable that at least 1 sort (s) chosen from a petroleum resin type tackifier and a rosin type tackifier is included as a tackifier.
For example, by using a petroleum resin-based pressure-sensitive adhesive as a tackifier, the release of active ingredients can be made better. Moreover, the sustained release of an active ingredient can be made more favorable by using a rosin-type tackifier as a tackifier.
Accordingly, the tackifier can be selected according to the intended use of the transdermal preparation. For example, when used for applications where the patch is replaced in a short time, a petroleum resin adhesive is used, and when used for an application where the patch is left applied for a long time, rosin-based tackifier is applied. A selection method using an agent is conceivable.
In the case of using a thermoplastic elastomer, particularly a styrene block copolymer, which is a preferred example, as the specific resin, the tackifier is preferably at least one of a rosin tackifier and a petroleum resin tackifier. A petroleum resin-based tackifier is more preferable.
Commercially available tackifiers may be used. Examples of commercially available products include Arakawa Chemical Industries, Ltd., alicyclic saturated hydrocarbon resin Alcon (registered trademark) P series, Arakawa Chemical Industries, Ltd., Rosin derivatives (rosin ester) Pine Crystal (registered trademark) KE series, manufactured by Yasuhara Chemical Co., Ltd., terpene resin (YS resin PX1150N: trade name) and the like.

The transdermal preparation may contain only one type of tackifier or two or more types.
The content of the tackifier based on the total amount of the transdermal preparation is preferably 3% by mass to 40% by mass, more preferably 4% by mass to 35% by mass, from the viewpoint of the stability of the preparation on the skin. More preferred is from 30% by weight.

The content ratio of the tackifier to the specific resin (specific resin content: tackifier content) is preferably in the range of 80:20 to 40:60 on a mass basis, and in the range of 60:40 to 50:50. It is more preferable that When the content ratio of the specific resin and the tackifier is within the above range, precipitation of the active ingredient is suppressed and the release of the active ingredient is improved.

[Other ingredients that can be included in transdermal preparations]
The transdermal formulation contains known additives depending on the dosage form of the transdermal formulation depending on the purpose, as long as the effect is not impaired, in addition to the active ingredients, solvents, specific resin materials and tackifiers already described. be able to.
Other ingredients that can be used in the transdermal formulation include, for example, transdermal absorption enhancers, wetting agents, emollients, skin protectants, bases, surfactants, viscosity modifiers, organic particles, inorganic particles, and buffering agents. , PH adjusting agents, coloring agents, fragrances, crosslinking agents and the like. Moreover, you may contain a well-known stabilizer, an antioxidant, etc. for the purpose of the stability improvement of a formulation.

(Preparation of transdermal preparation)
The transdermal preparation of the present disclosure can be prepared by a conventional method. An example of the preparation method is given below.

(Preparation of liquid components)
An organic sulfoxide, an ester solvent, and an organic acid are weighed in a container and sufficiently mixed to prepare a mixed solvent.
Thereafter, the required amount of the phenylpiperazine derivative is weighed and added to the mixed solvent obtained by the above-described method, and further stirred to be sufficiently dissolved. In this way, a liquid component containing the active ingredient can be obtained. Preparation of the preparation by stirring can be performed at room temperature (25 ° C.).
In the case where the composition of the liquid component includes a solvent having a slow solid dissolution rate such as a phenylpiperazine derivative, one of the following means i) to iii) is carried out when preparing the liquid component. May be.
i) Heating and stirring the liquid component at 40 ° C. to 70 ° C. ii) Promoting dissolution by ultrasonic treatment iii) Performing both heating and stirring and ultrasonic treatment The liquid component subjected to the dissolution promotion treatment is allowed to stand at room temperature for one day, and after standing for one day, no insoluble matter or precipitate is observed, and it is confirmed visually that the active ingredient is dissolved. It is preferable.

(Preparation of adhesive composition)
Apart from the preparation of the liquid component, a pressure-sensitive adhesive composition containing a specific resin material and a tackifier is prepared.
The pressure-sensitive adhesive composition can be prepared by mixing a specific resin material, a tackifier, and an appropriate solvent, stirring, and uniformly dissolving the specific resin material and the tackifier in the solvent.
As the solvent, when a thermoplastic elastomer is used as the specific resin material, it is preferable to use cyclohexane, ethyl acetate, toluene, tetrahydrofuran, methyl ethyl ketone, or the like.
Only 1 type may be used for the solvent in an adhesive composition, and 2 or more types may be mixed and used for it.

The pressure-sensitive adhesive composition may contain a known additive depending on the purpose.
For example, a surfactant such as polyoxyethylene alkyl ether may be included for the purpose of improving the surface area of the coating.
The pressure-sensitive adhesive composition can contain a viscosity modifier such as a thickener or a softener. When the pressure-sensitive adhesive composition contains a softening agent, it is possible to improve handling properties, sticking properties, and the like of the pressure-sensitive adhesive composition. By including the softening agent, the pressure-sensitive adhesive composition becomes soft, the followability to the unevenness of the fine skin surface is improved, and the adhesion and the sticking property are considered to be further improved.
As the softening agent, known components having biocompatibility can be used without particular limitation. Examples of the softener include oily components such as mineral oil, neutral oil, liquid paraffin, polybutene, linseed oil, octyl palmitate, squalene, squalane, silicone oil, and isobutyl myristate.
Mineral oil is a hydrocarbon, which is a liquid oil from which solid hydrocarbons have been removed, obtained by heating a crude oil to about 300 ° C. or higher, performing fractional distillation, and cooling a distillation fraction. The mineral oil is preferably a mineral oil that is liquid in the range of 30 ° C. to 37 ° C., and is solid at a lower temperature, that is, a temperature of less than 20 ° C., and more preferably a mineral oil having a melting point of 30 ° C. to 35 ° C.
Examples of the neutral oil include palm oil, rapeseed oil, soybean oil and the like as vegetable oil.

Among these, preferred examples of the oil component that can be used as a softener include petroleum softeners such as liquid paraffin, process oil, and low molecular weight polybutene, and fatty acid softeners such as coconut oil and castor oil.
When the pressure-sensitive adhesive composition contains liquid paraffin as a softening agent, the content of liquid paraffin is 1 mass with respect to the total amount of the pressure-sensitive adhesive composition from the viewpoint of skin permeability of the active ingredient and peelability of the transdermal preparation. % To 25% by mass is preferable, and 2% to 25% by mass is more preferable.

Furthermore, for the purpose of controlling the tackiness of the tape or the like, the pressure-sensitive adhesive composition may contain a filler such as zinc oxide, titanium oxide, calcium carbonate, silicic acid or the like, if necessary.

Next, the liquid component obtained as described above and the pressure-sensitive adhesive composition are mixed and sufficiently stirred to obtain a precursor liquid for a transdermal preparation (hereinafter referred to as a preparation preparation precursor liquid). be able to.
As will be described later, a transdermal preparation can be obtained by removing the solvent contained in the preparation preparation precursor liquid. That is, in the obtained transdermal preparation, the above-mentioned solvent for dissolving the specific resin used for the preparation of the adhesive composition hardly remains, and even if it remains, it is 0.5% relative to the total amount of the transdermal preparation. Less than mass%. Here, the solvent to be removed refers to the aforementioned solvent used for preparing the pressure-sensitive adhesive composition for the purpose of dissolving the specific resin or the like. In addition, the ester solvent contained in a liquid component is not included in the solvent here.

When mixing the pressure-sensitive adhesive composition and the liquid component when preparing the precursor liquid for preparation of the preparation, the organic acid, the ester solvent and the organic are used with respect to 100 parts by mass of the total content of the thermoplastic resin and the tackifier. The total content with sulfoxide is preferably as follows.
When the transdermal preparation contains only one organic acid, the total content of the organic acid, the ester solvent and the organic sulfoxide is 35 parts by mass to 100 parts by mass of the total content of the thermoplastic resin and the tackifier. The amount is preferably 100 parts by mass, and more preferably 55 parts by mass to 100 parts by mass.
When the transdermal preparation contains two or more organic acids, the total content of the organic acid, the ester solvent and the organic sulfoxide is 35 parts by mass to 100 parts by mass of the thermoplastic resin and the tackifier. It is preferable that it is 210 mass parts.
When the mixing ratio of the total content of the thermoplastic resin and the tackifier in the pressure-sensitive adhesive composition and the total content of the organic acid, the ester solvent, and the organic sulfoxide in the liquid component is within the above range, it is uniform. It becomes easy to obtain a skin preparation, and the release property of the liquid component containing the active ingredient from the obtained transdermal preparation becomes better.
When a transdermal formulation contains other components, it can be contained in the formulation by a conventional method at a stage suitable for each component.

The form of the transdermal preparation includes a form of a patch having a layer composed of the above-mentioned transdermal preparation on the support, a form of a coating that directly applies the transdermal preparation to the skin, and a sheet-like material such as a nonwoven fabric. Examples include a form in which a transdermal preparation is applied and the application side of the transdermal preparation is brought into contact with the skin.
As a method for producing a patch, for example, the preparation preparation precursor liquid obtained as described above is applied on a support to form a preparation preparation precursor liquid layer, and heated to prepare the preparation. And a method of obtaining a patch having a layer composed of a transdermal preparation on a support by removing the solvent used for dissolving the specific resin material and the like contained in the precursor liquid layer. The transdermal preparation layer in the obtained transdermal preparation as a patch has tackiness because it contains a tackifier, and is stably held on the skin when the patch is applied to the skin.
The patch having a support that is one embodiment of the transdermal preparation of the present disclosure includes a haptic agent, a patch agent, and a tape agent.

In addition, as a method for producing a transdermal preparation in the form of a coating agent, a liquid component and a pressure-sensitive adhesive composition are mixed to prepare a precursor liquid for preparation of the preparation, mixed while heating, and a pressure-sensitive adhesive composition By removing the solvent contained in the product, it is possible to obtain a transdermal preparation as a coating agent having adhesiveness.
The obtained transdermal preparation as a coating agent can be applied to the surface of a sheet such as a nonwoven fabric or a woven fabric and applied to the skin or directly applied to a desired region on the skin. . The transdermal preparation applied on the skin adheres to the skin according to the shape of the skin surface and is stably held.
When applied directly on the skin, the transdermal preparation has adhesiveness on the side opposite to the skin side, so the area where the transdermal preparation is applied should be covered with a breathable nonwoven fabric or woven fabric. You can also. Moreover, as already stated, it can also apply | coat to sheets, such as a nonwoven fabric, and can also be made to contact skin.
A sheet-like material such as a non-woven fabric or a woven fabric used for coating the application region of the transdermal preparation can take any shape such as a rectangle and a circle, and a bandage.
When the precursor liquid for preparation preparation is heated to remove the solvent contained in the aforementioned pressure-sensitive adhesive composition, it is removed until the content of the solvent in the obtained transdermal preparation is 0.5% by mass or less. That is, it is preferable from the viewpoint of biocompatibility to remove 99.5% by mass or more of the solvent contained.
The method for measuring the amount of solvent removed was the same as the method for measuring the content of dimethyl sulfoxide described in the examples below, and the product obtained by heating and drying the precursor liquid for preparation of the preparation was subjected to gas chromatography. Analysis can be performed using a graphy mass spectrometer (GC-MS). Details of measurement conditions and the like are as described in the examples.

(Transdermal absorbability of phenylpiperazine derivatives in transdermal formulations)
The transdermal preparation is excellent in transdermal absorbability of the phenylpiperazine derivative, which is an active ingredient, and the phenylpiperazine derivative can be continuously administered, so that excellent drug efficacy can be maintained for a desired time.
One of the methods for evaluating transdermal absorbability is a known skin permeability evaluation method.
The skin permeability of the transdermal preparation of the present disclosure is evaluated by the in vitro skin permeation test method described in the following examples.
In addition, the skin permeability evaluated by a known skin permeability experiment method is synonymous with the transdermal absorbability of the transdermal preparation in this specification.

In vivo skin permeation experiments that can evaluate transdermal formulations include skin pharmacokinetic tests, biological tests, residual dose tests, kinetic tests, clinical tests, animal tests and exposure dose tests. Can be mentioned.

<Use of transdermal preparation>
The transdermal preparation of the present disclosure is used by being applied to or applied to the skin of an application subject.
That is, the use of the transdermal preparation involves applying the transdermal preparation described above on the skin to the side having the transdermal preparation applied to the skin, or applying the aforementioned transdermal preparation directly to the skin. including.

In general, the transdermal formulation of the present disclosure, which is a patch having a transdermal formulation layer formed on a support, is applied to the skin in order to allow a desired amount of the active ingredient to penetrate into the skin over time. Used.
Examples of the support used for the patch include a resin film having air permeability, a nonwoven fabric, a cloth, and a film having no air permeability.
When the above-mentioned transdermal preparation is placed on one side of the support to form a patch, the side on which the transdermal preparation is placed becomes the surface that adheres to the skin. When the transdermal preparation is applied to the surface that adheres to the skin, as described above, since it contains the specific resin material and the tackifier, it has surface adhesiveness and can be stably fixed to the skin.

In addition, when a transdermal preparation is applied on the skin, the surface of the application area of the transdermal preparation is protected by wrapping the application area of the preparation with a breathable bandage or covering with a non-woven fabric. Can be used.
When a transdermal preparation is applied on the skin and covered with a separate material such as a nonwoven fabric to protect the application area of the preparation, a separate bandage, non-woven fabric, etc. should have adhesiveness, stretchability, etc. It may be used. In addition, when using a separate bandage or nonwoven fabric that does not have adhesiveness, stretchability, etc., the separate body can be fixed and applied with an adhesive tape, bandage stopper, or the like.

Dose amount of phenylpiperazine derivative contained in the transdermal preparation, that is, the mass of the transdermal preparation layer in the case of a patch having a support, the area of the patch, or the application amount when applied to the skin The number of administrations per day can be appropriately selected according to the purpose.
That is, the amount and the number of times that a necessary amount of phenylpiperazine derivative can be absorbed into the skin are selected for the application target person.

The transdermal preparation of the present disclosure is stably held on the skin, and the active ingredient is gradually released from the matrix containing the specific resin material and the tackifier to the skin. Since it is absorbed through the skin and quickly penetrates into the living body, and the penetration rate into the skin is within the appropriate range, the concentration and time of supplying the active ingredient to the living body (subcutaneously, preferably in blood) are at an appropriate level. Can be maintained at. Therefore, the phenylpiperazine derivative, which is an active ingredient, can be supplied into the body by, for example, continuously permeating the skin for a certain period from the region where the patch is fixed.

<Treatment method>
In another embodiment of the present invention, the above-mentioned transdermal preparation containing a phenylpiperazine derivative as an active ingredient is applied to the skin of an application subject to be treated for schizophrenia or the like, or the skin Also included is a method of treating schizophrenia that comprises applying to the skin.

Hereinafter, the transdermal preparation will be described in detail with reference to examples. However, the present invention is not limited to the following examples.

[Example 1]
[Preparation of coating solution for transdermal preparation]
60% by mass of dimethyl sulfoxide as an organic sulfoxide (sometimes abbreviated as DMSO), 30% by mass of ethyl sebacate as an ester solvent (sometimes abbreviated as DES), and lactic acid as an organic acid (abbreviated as LA) 10% by mass) was weighed into a container and stirred sufficiently to prepare a mixed solvent.
In Tables 1 and 2 below, the solvent content is based on mass.
Thereafter, 11% by mass of aripiprazole, which is a phenylpiperazine derivative, was weighed and added to the mixed solvent obtained by the above-described method, and further stirred to dissolve sufficiently to obtain a liquid component containing the active ingredient. Preparation of the preparation by stirring was performed at room temperature (25 ° C.).
In the obtained liquid component, insoluble matters, precipitates, and the like were not observed by visual observation, and it was confirmed that the active component was uniformly dissolved.

The details of the liquid components described in Tables 1 and 2 are as follows.
・ Aripiprazole (Tokyo Chemical Industry Co., Ltd.)
・ Brexpiprazole (Changzhou Neostar United)
Biotechnology Co. , Ltd)
・ Dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd., for molecular biology)
・ Diethyl sebacate (Nikko Chemicals, NIKKOL (registered trademark) DES-SP)
・ Lactic acid (Merck)

As a separate process, an adhesive composition was prepared.
Styrene-isoprene-styrene block copolymer (SIS5002 (trade name), JSR Co., Ltd.), 50% by mass, a thermoplastic elastomer as a specific resin material, Alcon, an alicyclic saturated hydrocarbon resin as a tackifier (registered) (Trademark) P-100 (Arakawa Chemical Industries, Ltd.) In a container of 50% by mass, a mixed solvent of cyclohexane (Wako Pure Chemical Industries, Ltd.) and ethyl acetate (Wako Pure Chemical Industries, Ltd.) 50% by mass / 50% by mass) to prepare an adhesive composition. In the preparation of the pressure-sensitive adhesive composition, the total amount of the thermoplastic elastomer and the tackifier was 44.4% by mass, dissolved in the above-described mixed solvent, and sufficiently stirred. After preparing a uniform pressure-sensitive adhesive composition, 8 parts by weight of liquid paraffin (Wako Pure Chemical Industries, Ltd.) and 8 parts by weight of poly (polystyrene) are used for the thermoplastic elastomer (based on 100 parts by weight of the component). Oxyethylene lauryl ether (Nikko Chemicals Co., Ltd., NIKKOL (registered trademark) BL-9EX: cosmetic ingredient name: Laureth 9) was added and dissolved with a stir bar.
66.3% by mass of the obtained pressure-sensitive adhesive composition and 33.7% by mass of a liquid component containing an active ingredient were mixed to prepare a homogeneous transdermal preparation solution.
By removing 99.5% by mass or more of the solvent used for the preparation of the pressure-sensitive adhesive composition from the obtained transdermal preparation solution, a transdermal preparation having the composition shown in Table 1 is prepared.

[Preparation of a patch as a transdermal preparation]
The transdermal preparation solution obtained above was applied to one side of a polyethylene terephthalate (PET) film (thickness: 50 μm, Toray Industries, Inc.) as a support in a thickness of 1.0 mm before drying. Then, a coating film of the transdermal preparation solution was formed.
Next, drying treatment was performed with a blast heating dryer (Espec Corp., SPHH-102), and cyclohexane and ethyl acetate, which are solvents contained in the adhesive composition, were volatilized and removed from the coating film of the transdermal preparation solution. . Drying was performed at a temperature of 50 ° C. for 10 minutes, and then the temperature was raised to 80 ° C., and the drying time was adjusted until the DMSO content in the transdermal preparation coating film reached a desired amount.
The total amount of cyclohexane and ethyl acetate remaining in the dried transdermal preparation coating film was 0.5% by mass or less.

[Examples 2 to 11, Comparative Example 1]
According to the compositions shown in Tables 1 and 2 below, patches that were transdermal preparations of Examples 2 to 11 and Comparative Example 1 were prepared in the same manner as Example 1.
The liquid components used in any of the transdermal preparations were confirmed by visual observation that insolubles, precipitates and the like were not observed, and the active ingredients were uniformly dissolved.

[Example 12]
[Preparation of coating solution for transdermal preparation]
DMSO 60% by mass as organic sulfoxide, 20% by mass of DES as an ester solvent, and 20% by mass of LA as an organic acid were weighed in a container and sufficiently mixed to prepare a mixed solvent.
Thereafter, 11% by mass of aripiprazole, which is a phenylpiperazine derivative, was weighed and added to the mixed solvent obtained by the above-described method, and further stirred to dissolve sufficiently to obtain a liquid component containing the active ingredient. Preparation of the preparation by stirring was performed at room temperature (25 ° C.).
In the obtained liquid component, insoluble matters, precipitates, and the like were not observed by visual observation, and it was confirmed that the active component was uniformly dissolved.

[Examples 13 to 36]
Patches that were transdermal preparations of Examples 13 to 36 were prepared in the same manner as Example 12 according to the compositions shown in Tables 2 to 3 below.
When two or more organic acids were included, in addition to the single LA in Example 12, a second organic acid was used.
The liquid components used in any of the transdermal preparations were confirmed by visual observation that insolubles, precipitates and the like were not observed, and the active ingredients were uniformly dissolved.
In Tables 2 to 3 below, the solvent content ratios are based on mass.

The detection method of each component in the transdermal preparation coating film after drying, ie, the transdermal preparation layer formed on the support, is as follows.
About the sample before application, the component ratio contained was analyzed using a gas chromatography mass spectrometer (GC-MS) and ion chromatography (anion).
10 mg of the transdermal preparation layer was collected from the patch, which was the subject before application, and dissolved in 10 mL (milliliter) of ethanol for HPLC (Wako Pure Chemical Industries, Ltd.). Dissolution of the transdermal preparation was performed by stirring the solution with a stir bar for 30 minutes and then performing ultrasonic treatment (Branson (registered trademark) tabletop ultrasonic cleaner 2510J-DTH, Nippon Emerson Co., Ltd.) for 30 minutes. Then, each component contained in the transdermal preparation layer was extracted. The extracted liquid was analyzed for the concentration of each component in the extract using the following method.

(Analysis of the concentration of organic acids such as lactic acid)
The concentration of lactic acid was determined by ion chromatography (anion) (Thermo Fisher Scientific Co., Ltd .: Dionex (registered trademark)) using a sample obtained by diluting the aforementioned extract with 1 mM aqueous potassium hydroxide solution 50 times. ) Measurement was performed using ICS-2000).
Suppressor: ASRS-4mm (current value 230mA),
Column: Ion PAC AS11-HC,
Flow rate: 1.5 mL / min,
Injection volume: 25 μL,
Measurement was performed under the condition of column temperature: 35 ° C.

In Tables 4 and 5, the content of the second organic acid used in combination with lactic acid in Examples 16, 17, and 19 to 36 is a numerical value of the amount of each fatty acid used in the preparation of the transdermal preparation. ing. This is because each organic acid used has a high boiling point, and the preparation method of the transdermal preparation described above, for example, there is almost no variation in the content of the organic acid due to volatilization in the drying process, and the amount of organic acid charged and the transdermal formulation are transdermal. This is because the organic acid content in the preparation is almost the same.

(Analysis of diethyl sebacate concentration)
The diethyl sebacate concentration was analyzed using a gas chromatography mass spectrometer (GC-MS) (GCMS-QP2010, manufactured by Shimadzu Corporation). The extract solution was used as the measurement target of the measurement sample.
Column: DB-WAX (length 30 m, inner diameter 0.25 mm, film thickness 0.25 μm) (Agilent Technology Co., Ltd.)
Injection volume: 1 μL
Vaporization chamber temperature: 250 ° C
Column temperature: 60 ° C
Ionization method: EI (Electron ionization)
Ionization voltage: 70V

(Analysis of DMSO concentration)
The DMSO concentration was analyzed using a gas chromatography mass spectrometer (GC-MS) (GCMS-QP2010, manufactured by Shimadzu Corporation). The extract solution was used as the measurement target of the measurement sample.
Column: DB-624 (length 60 m, inner diameter 0.32 mm, film thickness 1.8 μm) (Agilent Technology Co., Ltd.)
Injection volume: 1 μL
Vaporization chamber temperature: 250 ° C
Column temperature: 40 ° C
Ionization method: EI (Electron ionization)
Ionization voltage: 70V

[Evaluation of transdermal preparation 1]
The skin permeability of the transdermal preparations of Examples 1 to 11 and Comparative Example 1 was evaluated by the following method.
Using a Franz diffusion cell (permeation area: 1 cm ² , receptor liquid volume: 8 mL) at a test temperature of 32 ° C., a transdermal absorbability evaluation test was performed under the following conditions.
The skin of the abdomen of 8-week-old SPF (Specific Pathogen Free) rat was used as a membrane.
As the receptor solution, polyethylene glycol 400: PBS pH 7.4 (6: 4) was used.
The concentration of the active ingredient to be permeated was measured using high performance liquid chromatography (HPLC: LC-10 system, Shimadzu Corporation).
The above-described commercially available rat abdominal excised skin is sandwiched between vertical diffusion cells (effective diffusion area: 1 cm ² ), and the transdermal preparation as the subject is applied to the stratum corneum at the mass shown in the table, and the skin is already applied to the dermis side. The receptor fluid described above was applied.
Here, the mass of the subject is measured before being applied to the stratum corneum side of the vertical diffusion cell, and a plurality of samples are stacked in a desired number of masses, and there is a support except for the outermost subject. The PET film was removed and lamination was performed.
300 μL of the receptor fluid was sampled at 3 hours, 6 hours, 21 hours and 24 hours after the start of the experiment, and the concentration of aripiprazole (ARP) or brexpiprazole (BRP) eluted through the skin was determined. Measured by the above-mentioned HPLC, the accumulated permeation amount of ARP or BRP at each time was measured. The results are also shown in Tables 1 and 2 below.
The measurement was performed three times, and Tables 1 and 2 list individual measured values and average values.
The measurement time is an example, and the time for sampling and measuring the receptor fluid is appropriately determined according to the purpose.

In Tables 1 and 2, “-” means that the component is not contained. Moreover, each component may be described with an abbreviation.
That is, the styrene-isoprene-styrene block copolymer is described as “SIS5002,” the petroleum resin as the tackifier is “Arcon P-100”, and the surfactant is described as “Laureth 9”.
In addition, Tables 1 and 2 show the content ratio (mass ratio (%)) of the liquid component to the total solid content (content of SIS 5002 + content of Alcon P-100) of the pressure-sensitive adhesive composition in the preparation.

From the results of Tables 1 and 2, the transdermal preparations of Examples 1 to 11 all had good skin permeability (transdermal absorbability) of ARP and BRP as active ingredients. In particular, skin permeability was particularly good when the DMSO content was in the range of 10 to 15% by mass.
From these results, it is understood that the patch, which is the transdermal preparation of each example, maintained the supply of a predetermined amount of the active ingredient subcutaneously by the skin permeation of the active ingredient for at least 24 hours.
On the other hand, in Comparative Example 1 in which the content of DMSO, which is an organic sulfoxide, is too small, sufficient skin permeability of the active ingredient was not obtained.

[Evaluation of transdermal preparation 2]
In Examples 12 to 36, skin permeability was evaluated in the same manner as in Evaluation 1 of the transdermal preparation described above. However, for Examples 18 to 20, the membrane (skin sample) was changed from rat abdominal excised skin to human skin (Biopredic International, frozen human abdominated skinned, Transkin (registered trademark), TRA002). Other than that, it was evaluated by the same method as Evaluation 1 of the transdermal preparation. The results are shown in Tables 3-7.

From the results of Tables 3 to 7, the transdermal preparations of Examples 13 to 36 all had good skin permeability (percutaneous absorption) of ARP and BRP which are active ingredients. Among these, the transdermal preparations of Examples 16, 17, and 19 to 36 using lactic acid that is the first organic acid and a second organic acid different from lactic acid in comparison with Example 18 In addition, the skin permeability (transdermal absorbability) of ARP, which is an active ingredient, was further improved. This is considered to be because the penetration of the active ingredient into the skin could be further improved by the action of the fatty acid used in combination with the first organic acid on the stratum corneum as the second organic acid. From these results, it can be seen that when two or more kinds of organic acids are used, a transdermal preparation capable of expecting drug penetration in a smaller area can be prepared.

[Example 37 to Example 41]
According to the composition shown in Table 8 below, patches that were transdermal preparations of Examples 37 to 41 were prepared in the same manner as in Example 1.
The liquid components used in any of the transdermal preparations were confirmed by visual observation that insolubles, precipitates and the like were not observed, and the active ingredients were uniformly dissolved.
In addition, the content ratio of the solvent in the following Table 8 is based on mass.

“-” In Table 8 means that the component is not contained. Moreover, each component may be described with an abbreviation. “SIS5002,” “Arcon P-100,” and “Laureth 9” are as described above. Rosin resin as a tackifier (Arakawa Chemical Industries, Ltd., rosin ester Pine Crystal (registered trademark) KE-100) was described as “Pine Crystal KE-100”.
In addition, Table 8 shows the content ratio (mass ratio (%)) of the liquid component with respect to the total solid content of the adhesive composition in the preparation (content of SIS 5002 + content of Alcon P-100).

Evaluation of the obtained adhesive composition was performed in the same manner as in Example 1. The results are shown in Table 8 below.

From the results shown in Table 8, the transdermal preparations of Examples 37 to 41 all had good skin permeability (transdermal absorbability) of ARP as an active ingredient.
In comparison with Example 37 and Example 27, even when the transdermal preparation of Example 37 contains a large amount of liquid paraffin, the skin of ARP as an active ingredient is different from the transdermal preparation of Example 27. The permeability (percutaneous absorption) was almost the same. From this, it can be seen that by adjusting the content of liquid paraffin, it is possible to widely adjust the adhesive strength, flexibility, etc. of the transdermal preparation according to the application without changing the skin permeability.
In addition, even when a rosin resin was used in place of petroleum resin as the tackifier of Example 41, it was found that good penetration of the active ingredient into the skin was obtained, and drug penetration could be expected. It can be seen that a skin preparation can be prepared.

The disclosures of Japanese Patent Application 2016-245703 filed on December 19, 2016 and Japanese Patent 2017-100402 filed on May 19, 2017 are incorporated herein by reference.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually stated to be incorporated by reference, Incorporated herein by reference.

Claims (13)

1. Containing a phenylpiperazine derivative, an organic acid, an ester solvent, an organic sulfoxide, a thermoplastic resin, and a tackifier,
   A transdermal preparation having an organic sulfoxide content of 2% to 35% by mass relative to the total amount of the transdermal preparation.
2. The transdermal preparation according to claim 1, wherein the phenylpiperazine derivative is at least one selected from aripiprazole and brexpiprazole.
3. The transdermal preparation according to claim 1 or 2, wherein the thermoplastic resin contains at least one selected from thermoplastic elastomers.
4. The meridian according to any one of claims 1 to 3, wherein the organic acid is contained in an amount of 10 to 25 parts by mass with respect to 100 parts by mass of the total content of the organic acid, the ester solvent and the organic sulfoxide. Skin preparation.
5. The ester solvent according to any one of claims 1 to 4, wherein the ester solvent is contained in an amount of 30 to 75 parts by mass with respect to a total content of 100 parts by mass of the organic acid, the ester solvent, and the organic sulfoxide. Transdermal formulation.
6. The total content of the organic acid, the ester solvent and the organic sulfoxide with respect to 100 parts by mass of the total content of the thermoplastic resin and the tackifier is 35 parts by mass to 100 parts by mass. 2. A transdermal preparation according to item 1.
7. The transdermal preparation according to any one of claims 1 to 3, comprising two or more organic acids.
8. The transdermal preparation according to claim 7, comprising 10 parts by mass to 75 parts by mass of the organic acid with respect to 100 parts by mass of the total content of the organic acid, the ester solvent, and the organic sulfoxide.
9. The transdermal preparation according to claim 7 or 8, which contains 10 to 60 parts by mass of an ester solvent relative to 100 parts by mass of the total content of the organic acid, the ester solvent and the organic sulfoxide.
10. The total content of the organic acid, the ester solvent and the organic sulfoxide with respect to 100 parts by mass of the total amount of the thermoplastic resin and the tackifier is 35 parts by mass to 210 parts by mass. 2. A transdermal preparation according to item 1.
11. The transdermal preparation according to any one of claims 1 to 10, further comprising liquid paraffin.
12. The transdermal preparation according to any one of claims 1 to 11, comprising at least one selected from petroleum resin-based tackifiers and rosin-based tackifiers as tackifiers.
13. The transdermal preparation according to any one of claims 1 to 12, wherein the content of the phenylpiperazine derivative is 0.3% by mass to 15% by mass with respect to the total amount of the transdermal formulation.