JP2016199521A - Brexpiprazole percutaneous absorption preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a brexpiprazole percutaneous absorption preparation that has brexpiprazole dissolved in a base agent and also achieves high medical flux.SOLUTION: The percutaneous absorption preparation comprises an adhesive layer comprising brexpiprazole, 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 agent.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a transdermal absorption preparation of brexpiprazole.

  Schizophrenia is a type of endogenous psychosis that develops mainly in adolescence, has a chronic course, and gradually dismantles personalities, some of which lead to mental devastation. Symptoms include positive symptoms such as hallucinations and delusions that are common in the early stages of the onset, negative symptoms lacking energy and motivation, and cognitive symptoms that have problems with concentration and learning. In addition, there are depression and anxiety as related symptoms.

  Treatment of this schizophrenia is exclusively drug therapy, but it requires medication over a long period of time, and even if it is cured, there is a high risk of recurrence once the medication is stopped, and drug administration will continue indefinitely There is a need. Therefore, side effects due to drug administration become a problem, and from such a viewpoint, a drug that can be administered for a long time without side effects is desired.

  As a therapeutic drug for schizophrenia, various drugs classified as psychotropic drugs, for example, phenothiazine derivatives such as chlorpromazine and methoxypromazine; There are many drugs such as thioxanthine derivatives, benzamide derivatives such as sulpiride and sultopride, thienodiazepine derivatives such as clothiazem and etizolam, butyrophenone derivatives such as haloperidol and triperidol, and diphenylbutylamine derivatives such as pimozide. However, side effects such as extrapyramidal syndrome, insomnia, etc. are often problematic in the therapeutic agents for 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 agent for schizophrenia.

Blexpiprazole (Patent Document 1) is an oral agent for the treatment of schizophrenia, which is effective at a small daily dosage of several mg, and is clinically developed in Japan, the United States and Europe. Is underway.

However, schizophrenic patients with advanced symptoms often have difficulty in taking therapeutic drugs themselves. For patients with severe schizophrenia, forgetting to drink is often a problem. Therefore, the application of brexpiprazole as a transdermally absorbable preparation to patients is difficult for patients with advanced symptoms, avoiding difficulty in taking the drug continuously for a long time, and also forgetting to drink It can be avoided and is considered particularly useful.
On the other hand, there has been no report on a transdermal absorption preparation of brexpiprazole.

JP 2006-316052 A

  In order to apply to a transdermal absorption preparation in which brexpiprazole is adhered to the skin, it is necessary to dissolve brexpiprazole in the base of the transdermal absorption preparation. However, brexpiprazole is particularly poorly soluble, and it has become clear from the results of our studies that it is difficult to dissolve brexpiprazole in the base and at the same time achieve a high drug flux. It was. Accordingly, an object of the present invention is to dissolve brexpiprazole in the base of a transdermally absorbable preparation and at the same time achieve a high drug flux.

  As a result of intensive studies, the present inventors have recently achieved a high drug flux by combining brexpiprazole with a specific additive and dissolving brexpiprazole in the base of a transdermal preparation. I found out. The present invention is based on such knowledge.

According to the present invention, the following inventions 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 transdermally absorbable preparation according to (1), wherein a mass ratio of brexpiprazole or a salt thereof and the additive is 1: 2 to 1: 5.
(3) The percutaneous absorption preparation according to (1) or (2), wherein the additive is lactic acid and / or benzyl alcohol.
(4) The transdermally absorbable preparation according to any one of (1) to (3), wherein the additive is lactic acid.
(5) The transdermally absorbable preparation according to (4), wherein the content of lactic acid in the adhesive layer is 4% by mass or more.
(6) The transdermally 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, brexpiprazole can be dissolved in the base of a transdermal absorption preparation, and at the same time, a high drug flux can be achieved.

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

Detailed description of the invention

Transdermally absorbable preparation The transdermally 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 comprising. It is surprising that when brexpiprazole and the above additives are used in combination, brexpiprazole can be dissolved in the base of the transdermally absorbable preparation and at the same time a high drug flux can be achieved.

  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, and mesylate. .

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

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

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%.
Moreover, the lower limit of the content of the additive of the present invention is not particularly limited, but is preferably 4% by mass, and more preferably 8% by mass. Setting the lower limit of the additive content in this way is particularly preferable when lactic acid and benzyl alcohol are used as the additive.

  In addition, when lactic acid is added to the transdermally absorbable preparation of the present invention, the content of lactic acid is not particularly limited, but is 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 use either of them. Setting the content of lactic acid in this manner is particularly preferable for suppressing skin irritation.

  The base of the present invention is preferably an adhesive base, more preferably a (meth) acrylate copolymer, considering that it is applied to the skin.

Monomers suitable for the preparation of the (meth) acrylate copolymers of the present invention are not limited thereto, but 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 a mixture of these monomers. These monomers are preferably an acrylic acid or esters of methacrylic acid comprising another linear without functional groups, branched-chain or cyclic aliphatic C ₁ -C ₁₂ substituent.

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

  In the present invention, as long as the sufficiently high drug skin permeability and sufficiently high physical properties of the percutaneously absorbable preparation of the present invention are not impaired, carboxyl groups derived from side reactions such as contamination of impurities and thermal degradation, 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 having substantially no carboxyl group and hydroxyl group, and particularly preferably 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid. It is an acid dodecyl copolymer.

  In addition to the above additives, pharmaceutically acceptable components such as absorption accelerators, plasticizers, lubricants, excipients and the like 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 diester Examples include caprylate, oleyl oleate, isopropyl palmitate, oleyl alcohol, isostearyl alcohol, propylene glycol, polyethylene glycol 400, and propylene carbonate.

  In addition, the thickness of the adhesive layer in the present invention is appropriately determined by those skilled in the art in consideration of the drug amount and the like, and can be, for example, 40 to 100 μm.

The adhesive layer of the transdermally absorbable preparation according to the present invention may be used as it is as a transdermally absorbable preparation, but can be constituted by appropriately including a support and a cover in addition to the adhesive layer.
FIG. 1 is a cross-sectional view showing an embodiment of a transdermally absorbable preparation according to the present invention.
In FIG. 1, the percutaneous absorption preparation 1 according to the present invention comprises, in order from the skin side, an adhesive layer 2 composed of an adhesive layer 2 and a support 3 arranged on the skin contact surface. 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, nonwoven fabric, PET (polyethylene terephthalate), polyurethane, polyester, polyethylene, and composite materials thereof.
Moreover, the material of a cover is not specifically limited, The material similar to a support body can be used.

Production method A preferred production method of the transdermally absorbable preparation according to the present invention is as follows.
First, the constituent 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 constituent components in the solvent. Next, this mixed solution is used as a plaster solution and applied onto a liner. Next, the plaster solution is dried at about 60 to 120 ° C. to obtain an adhesive layer. If desired, a support is laminated thereon to obtain a transdermally absorbable preparation.
When the cover is attached to the transdermal 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 transdermal absorption preparation are prepared. 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 transdermally absorbable preparation according to the present invention can be preferably used as a therapeutic agent for schizophrenia, an adjuvant therapeutic agent for major depression, a therapeutic agent for Alzheimer type dementia, or a therapeutic agent for attention deficit / hyperactivity disorder.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.

Test example 1
The solubility of brexpiprazole in 100 g of various additives was measured by kneading brexpiprazole and the additive in a mortar for 15 minutes and measuring the concentration of brexpiprazole in the filtrate by HPLC after filtration. The results are shown in Table 1.

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

Test example 2
2-1 Preparation of transdermal absorption preparation
Example 1
Blexpiprazole (10 mass%), lactic acid (4 mass%), benzyl alcohol (4 mass%) and other additives (25 mass%; sorbitan monolaurate (5 mass%), propylene glycol monolaurate (10 mass%) %) And diethyl sebacate (10% by mass)), and these were mixed and dissolved in a 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer solution (57% by mass after drying), A plaster solution was obtained.

The plaster 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 .
Next, a support (Scotchpak ^(trademark) 9732, manufactured by 3M) was laminated on one side opposite to the liner of the drug-containing layer (adhesive layer) to obtain the percutaneous absorption preparation of Example 1.

Example 2
Blexpiprazole (10% by mass), lactic acid (5% 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)), these were mixed, and dissolved in 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer solution (56% by mass after drying), A plaster solution was obtained.
Using the obtained plaster solution, the percutaneously absorbable preparation of Example 2 was obtained by the same production method as Example 1.

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

2-2: In vitro hairless mouse skin permeation test (24 hours)
A flow-through cell in which the percutaneous absorption preparations (application area: 4.5 cm ² ) of Examples 1 and 2 were applied to the stratum corneum side of the hairless mouse skin, and hot water was circulated so that the skin surface was about 32 ° C. 5 cm ² ). A 40% PEG400 aqueous solution was used as the receiver solution, and the receiver solution was sampled at a rate of 5 mL / hr every 24 hours for up to 24 hours. For the sampling solution, the amount of drug was measured by HPLC, the permeation rate per hour was calculated, and the average value ± standard error every 2 hours of flux per unit area (μg / cm ² / hr) was determined.

  The result is shown in FIG. Both of the transdermally absorbable preparations of Examples 1 and 2 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 ½ or less of the transdermally absorbable preparations of Examples 1 and 2. .

Claims (7)

  It comprises 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. , Transdermal absorption preparation.   The transdermally absorbable preparation according to claim 1, wherein a mass ratio of brexpiprazole or a salt thereof and the additive is 1: 2 to 1: 5.   The transdermally absorbable preparation according to claim 1 or 2, wherein the additive is lactic acid and / or benzyl alcohol.   The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the additive is lactic acid.   The transdermally absorbable preparation according to claim 4, wherein the content of lactic acid in the adhesive layer is 4% by mass or more.   The transdermally absorbable preparation according to any one of claims 1 to 5, wherein the adhesive base is a (meth) acrylate copolymer.   The transdermally absorbable preparation according to any one of claims 1 to 6, for treating schizophrenia.

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