JP6513461B2 - Transdermal preparation of brexpiprazole - Google Patents

Description

  The present invention relates to a transdermally absorbable preparation of brexpiprazole.

  Schizophrenia (schizophrenia, schizophrenia) is a type of intrinsic psychosis that mainly develops in adolescence, follows a chronic course, and is gradually disorganizing the personality, some of which lead to mental deterioration. In addition to positive symptoms such as hallucinations and delusion often seen at the early stage of onset, there are negative symptoms with lack of energy and spirit, and cognitive symptoms with problems with concentration and learning. Furthermore, there are depression symptoms and anxiety as similar symptoms.

  Although the drug treatment is taken exclusively for treatment of this schizophrenia, medication is required for a long period, and even if it cures once, there is a large risk of recurrence if the medication is stopped, and drug administration will be continued indefinitely There is a need. Therefore, side effects due to drug administration become a problem, and from such a viewpoint, drugs that can be administered for a long time without side effects are desired.

  As drugs for treating schizophrenia, various drugs classified as psychotropic drugs, for example, phenothiazine derivatives such as chlorpromazine and methoxypromazine; chlorprotikirone having a similar structure to phenothiazine, flupentixol and the like There are thioxanthine derivatives, benzamide derivatives such as sulpiride and sultopride, thienodiazepine derivatives such as crothiazem and etizolam, etc. Furthermore, many drugs such as haloperidol, butyrophenone derivatives such as triperidol, diphenylbutylamine derivatives such as pimozide, etc. are used. However, side effects such as extrapyramidal syndrome, insomnia, etc. are often problematic in the treatment of schizophrenia as described above.

ブレクスピプラゾール（特許文献１）は、一日の投薬量が数ｍｇという少用量で効果を奏することを特徴とする統合失調症の治療のための経口剤として、日本、米国、欧州において臨床開発が進められている。 In recent years, brexpiprazole has attracted attention as a new therapeutic drug for schizophrenia.

Brexpiprazole (Patent Document 1) is clinically developed in Japan, the US and Europe as an oral agent for the treatment of schizophrenia characterized in that the daily dosage is effective at a small dose of several mg. Is in progress.

However, patients with schizophrenia who have advanced symptoms often have difficulty in taking therapeutic agents. Also, for severe schizophrenic patients, forgetting to drink is often a problem. Therefore, applying Brexpiprazole to patients as a percutaneous absorption preparation avoids the difficulty of taking it and administers the drug continuously for a long period of time in patients with advanced symptoms, and also the problem of forgetting to drink It can be avoided and is considered particularly useful.
On the other hand, there has been no report on a percutaneous absorption preparation of brexpiprazole.

JP, 2006-316052, A

  It is necessary to dissolve brexpiprazole in the base of the percutaneous absorption preparation in order to apply it to a transdermal absorption preparation used by adhering brexpiprazole to the skin. However, it is clear from the results of the present inventors' investigation that brexpiprazole is particularly difficult to dissolve poorly and it is difficult to dissolve brexpiprazole in a base and simultaneously achieve high drug flux. The Therefore, the present invention aims to dissolve brexpiprazole in the base of the transdermally absorbable preparation and at the same time to achieve a high drug flux.

  As a result of intensive investigations, the present inventors have now found that, when Brexpiprazole is combined with a specific additive, it dissolves Brexpiprazole in the base of the percutaneous absorption preparation and at the same time achieves a high drug flux. I found it to be possible. The present invention is based on such findings.

According to the present invention, the following invention can be provided.
(1) An adhesive layer comprising brexpiprazole or a salt thereof, at least one additive selected from the group consisting of lactic acid, oleic acid, isostearic acid, benzyl alcohol and N-methylpyrrolidone, and an adhesive base A transdermally absorbable preparation comprising.
(2) The percutaneously absorbable preparation according to (1), wherein the mass ratio of brexpiprazole or a salt thereof to the additive is 1: 2 to 1: 5.
(3) The percutaneously absorbable preparation according to (1) or (2), wherein the additive is lactic acid and / or benzyl alcohol.
(4) The percutaneously absorbable preparation according to any one of (1) to (3), wherein the additive is lactic acid.
(5) The percutaneously absorbable preparation according to (4), wherein the content of lactic acid in the adhesive layer is 4% by mass or more.
(6) The percutaneously absorbable preparation according to any one of (1) to (5), wherein the adhesive base is a (meth) acrylate copolymer.
(7) The composition according to any one of (1) to (6) for the treatment of schizophrenia.

  According to the present invention, it becomes possible to dissolve brexpiprazole in the base of a percutaneous absorption preparation and simultaneously achieve a high drug flux.

1 illustrates one embodiment of a transdermally absorbable preparation according to the present invention. The result of the in vitro hairless mouse skin permeation test in Experiment 2 is shown.

Detailed Description of the Invention

Transdermal Absorbent Preparation The percutaneously absorbable preparation of the present invention comprises brexpiprazole or a salt thereof and at least one additive selected from the group consisting of lactic acid, oleic acid, isostearic acid, benzyl alcohol and N-methylpyrrolidone. It is characterized by including. It is a surprising fact that brexpiprazole can be dissolved in the base of a transdermally absorbable preparation while simultaneously achieving a high drug flux when used in combination with the above additives.

  In addition, the salt of brexpiprazole is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include hydrochloride, tartrate, hydrobromide, citrate or mesylate, etc. .

  The content of brexpiprazole or a salt thereof in the percutaneously absorbable preparation of the present invention is not particularly limited, but is preferably 1% by mass to 20% by mass, and more preferably 5% by mass to 15% by mass.

  The mass ratio of brexpiprazole or a salt thereof to the additive in the percutaneous absorption preparation of the present invention is not particularly limited, but is preferably 1: 2 to 1: 5, more preferably 1: 3. ~ 1: 5.

  Further, the additive of the present invention is not particularly limited, but is preferably lactic acid and / or benzyl alcohol, more preferably lactic acid. The use of such additives is preferred to achieve a high drug flux for brexpiprazole.

Although the upper limit of the content of the additive in the adhesive layer of the present invention is not particularly limited,
Preferably it is 50 mass%, More preferably, it is 40 mass%.
The lower limit of the content of the above-mentioned additive of the present invention is not particularly limited, but is preferably 4% by mass, more preferably 8% by mass. Thus, setting the lower limit of the content of the additive is particularly preferable when using lactic acid and benzyl alcohol as the additive.

  Moreover, when adding lactic acid to the percutaneous absorption preparation of the present invention, the content of lactic acid is not particularly limited, but 3% by mass to 5% by mass, 3% by mass to 4% by mass or 4% by mass to 5% by mass It is preferable to set it as either of. It is particularly preferable to set the content of lactic acid in this way to suppress skin irritation.

  The base of the present invention is preferably an adhesive base, more preferably a (meth) acrylate copolymer, in consideration of application to the skin.

Suitable monomers for the preparation of the (meth) acrylate copolymers according to the invention are, but not limited to, in particular n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate Ethyl methacrylate, methyl acrylate, methyl methacrylate, t-butyl acrylate, s-butyl acrylate, t-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate, isopropyl methacrylate, dodecyl acrylate, Dodecyl methacrylate and mixtures of these monomers. These monomers are preferably esters of acrylic or methacrylic acid containing linear, branched or cyclic aliphatic C ₁ -C ₁₂ substituents without further functional groups.

  Vinyl acetate can also be used as a comonomer for the preparation of (meth) acrylate copolymers with at least one of these monomers. In the production process of the acrylate copolymer or the methacrylate copolymer, a small amount of a monomer having a carboxyl group or a hydroxyl group may be present as an impurity in the raw material monomer, or a side reaction such as thermal degradation may occur during polymerization. In some cases, carboxyl groups or hydroxyl groups derived from impurities may be introduced into the acrylic or methacrylic polymer to be used.

  In the present invention, carboxyl groups derived from side reactions such as mixing of impurities and thermal degradation are used unless the skin permeability of the drug of the present invention having a sufficiently high permeability and the physical properties of the formulation are sufficiently high. A hydroxyl group may be contained in the (meth) acrylate copolymer. However, it is preferable to use a (meth) acrylate copolymer in which carboxyl groups and hydroxyl groups are reduced as much as possible. Therefore, the adhesive base of the present invention is preferably a (meth) acrylate copolymer substantially having no carboxyl group and no hydroxyl group, and particularly preferably 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, and the like. It is an acid dodecyl copolymer.

  In addition to the above additives, pharmaceutically acceptable components such as an absorption accelerator, a plasticizer, a lubricant, and an excipient can be appropriately added to the adhesive layer of the present invention. Such pharmaceutically acceptable ingredients include, but are not limited to, sorbitan monolaurate, propylene glycol monolaurate, diethyl sebacate, diisopropyl adipate, isopropyl myristate, propylene glycol monocaprylate, propylene glycol di- Examples include caprylate, oleyl oleate, isopropyl palmitate, oleyl alcohol, isostearyl alcohol, propylene glycol, polyethylene glycol 400, propylene carbonate and the like.

  The thickness of the adhesive layer in the present invention can be appropriately determined by, for example, 40 to 100 μm, although it can be appropriately determined by the person skilled in the art in consideration of the amount of drug and the like.

The adhesive layer of the percutaneously absorbable preparation according to the present invention may be used as it is as a percutaneously absorbable preparation, but may be constituted appropriately including a support and a cover in addition to the adhesive layer.
FIG. 1 is a cross-sectional view of an embodiment of a transdermally absorbable preparation according to the present invention.
In FIG. 1, the percutaneously absorbable preparation 1 according to the present invention is, in order from the skin side, an adherent layer 2 and an adhesive layer 2 composed of a support 3 disposed on the skin contact surface. It can adhere to the skin.

The support may be stretchable or non-stretchable. The specific material constituting the support is not particularly limited, and examples thereof include woven fabric, non-woven fabric, PET (polyethylene terephthalate), polyurethane, polyester, polyethylene or composite materials thereof.
Further, the material of the cover is not particularly limited, and the same material as the support can be used.

Production Method A preferred method for producing the percutaneously absorbable preparation according to the present invention is as follows.
First, the components of the pressure-sensitive adhesive layer according to the present invention are appropriately mixed in a solvent to prepare a mixed solution containing the components in the solvent. Next, this mixture is used as a paste solution and applied onto a liner. Next, the plaster solution is dried at about 60 to 120 ° C. to obtain an adhesive layer, and if necessary, a support is laminated thereon to obtain a percutaneous absorption preparation.
In addition, when the cover is attached to the percutaneous absorption preparation, for example, a cover having an adhesive layer disposed on one side is prepared, and one side of the cover on the adhesive layer side and one side of the support side of the percutaneous absorption preparation You may stick together.

  Examples of the solvent used in preparing the adhesive layer in the above production method include acetone, ethyl acetate, butyl acetate, toluene, n-hexane, n-heptane, tetrahydrofuran, dimethylformamide, methanol, ethanol and the like. .

  The percutaneously absorbable preparation according to the present invention can be preferably used as a therapeutic agent for treating schizophrenia, a therapeutic agent for treating major depression, a therapeutic agent for Alzheimer's disease, a therapeutic agent for attention deficit / hyperactivity disorder.

  EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

Test Example 1
The solubility of 100 parts of brexpiprazole in various additives was measured by kneading the brekspiprazole and additives for 15 minutes in a mortar, filtering and measuring the concentration of brexpiprazole in the filtrate by HPLC. The results are shown in Table 1.

  As shown in Table 1, when lactic acid, oleic acid, isostearic acid, benzyl alcohol or N-methyl pyrrolidone was used, brexpiprazole showed high solubility.

Test example 2
2-1: Preparation of transdermally absorbable preparation
Example 1
Brexpiprazole (10% by mass), lactic acid (4% by mass), benzyl alcohol (4% by mass) and other additives (25% by mass; sorbitan monolaurate (5% by mass), propylene glycol monolaurate (10% by mass) %) And diethyl sebacate (10% by mass) are prepared, mixed, dissolved in 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate copolymer fluid (57% by mass after drying), A plaster solution was obtained.

The above-mentioned paste solution was applied onto a polyethylene terephthalate liner and dried at 80 ° C. for 15 minutes to obtain an adhesive layer. The amount of the adhesive layer after drying was adjusted to 80 g / m ² .
Then, the liner opposite one surface to the support of the drug-containing layer (adhesive layer) and (Scotchpak ^(TM) manufactured by 9732,) was laminated to obtain a percutaneous absorption preparation of Example 1.

Example 2
Brexpiprazole (10 wt%), lactic acid (5 wt%), benzyl alcohol (4 wt%) and other additives (25 wt%; sorbitan monolaurate (5 wt%), propylene glycol monolaurate (10 wt%) %) And diethyl sebacate (10% by mass) are prepared, mixed, and dissolved in 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate copolymer fluid (56% by mass after drying), A plaster solution was obtained.
The percutaneous absorption preparation of Example 2 was obtained by the same production method as Example 1 using the obtained paste solution.

Comparative Example When lactic acid and benzyl alcohol were removed from the formulation of the adhesive layer of Example 1, the drug did not dissolve, and the percutaneously absorbable preparation of Comparative Example could not be manufactured.

2-2: in vitro hairless mouse skin permeation test (24 hours)
A flow-through cell in which each of the percutaneous absorption preparations of Example 1 and 2 (application area 4.5 cm ² ) was attached to the stratum corneum side of hairless mouse skin, and warm water was circulated so that the skin surface became about 32 ° C ( It was set to 5 cm ² ). A 40% aqueous solution of PEG 400 was used as a receiver solution, and sampling of the receiver solution was performed at a rate of 5 mL / hr every two hours for up to 24 hours. The amount of drug was measured by HPLC for the sampling solution, the permeation rate per hour was calculated, and the mean value ± standard error of the flux per unit area (μg / cm ² / hr) every two hours was determined.

  The results are shown in FIG. The percutaneously absorbable preparations of Examples 1 and 2 both achieved high flux at 24 hours.

  When the content of lactic acid was 3% by mass, the maximum flux and the flux at 22 hours from the start of the test were both 1/2 or less of the percutaneous absorption preparations of Examples 1 and 2 .

Claims (3)

Ri Na contain blurring click spin pantoprazole or a salt thereof, lactic acid, an adhesive layer containing benzyl alcohol and (meth) acrylate copolymer,
The percutaneously absorbable preparation whose content of lactic acid in the adhesive layer is 4% by mass or more . The monomer constituting the (meth) acrylate copolymer is n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate, t-butyl acrylate, A monomer selected from s-butyl acrylate, t-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate, isopropyl methacrylate, dodecyl acrylate and dodecyl methacrylate. The percutaneous absorption preparation as described in.   The percutaneously absorbable preparation according to claim 1 or 2, for the treatment of schizophrenia.

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