JP2017066123A - Percutaneous absorption type formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide novel means for administration of riociguat, which can make riociguat exhibit excellent pharmacological effect, while avoiding side effect which may be caused by oral administration.SOLUTION: The present invention provides a percutaneous absorption type formulation comprising a support and a medicine-containing layer, the medicine-containing layer comprising as an active ingredient riociguat, and hydroxy acid or phosphoric acid.SELECTED DRAWING: None

Description

  The present invention relates to a percutaneous absorption preparation containing riociguat as an active ingredient.

  Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mean PAP) of 25 mmHg or more, but the cause of the disease is extremely diverse, and the natural history of PH varies greatly depending on the underlying disease. It is said that there is. Chronic thromboembolic pulmonary hypertension (CTEPH) is classified in the fourth group of the WHO clinical classification of pulmonary hypertension, and pulmonary arterial hypertension (PAH) is classified in the first group of the same class. In the same manner as above, the disease progresses with increasing pulmonary vascular resistance, worsening shortness of breath and causing a right heart failure.

  Riociguat (Methyl N- (4,6-Diamino-2- {1-[(2-fluorophenyl) methyl] -1H-pyrazo [3,4-b] pyridin-3-yl} pyrimidin-5-yl) -N -Methylcarbamate; methyl 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5-pyrimidinyl (methyl) carbamate) is Bayer This is a pyrimidinylcarbamate compound discovered by the company, a new class of drugs called soluble guanylate cyclase (sGC) stimulants (Patent Document 1). Riociguat has the chemical structure of the following chemical formula (I), and a drug containing Riociguat (Adempath (registered trademark) tablets) is approved as a 3 times / day oral drug for the treatment of CTEPH and PAH Has been. sGC is a receptor for nitric oxide (NO), and when NO binds to sGC, this enzyme promotes the production of cyclic guanosine monophosphate (cGMP), which is a signal molecule. cGMP plays an important role in regulating vasodilation, proliferation, fibrosis, and inflammation, and is also involved in smooth muscle relaxation. The pathological condition of PH is accompanied by endothelial dysfunction and impaired synthesis of NO, resulting in insufficient stimulation to sGC. Riociguat has the effect of increasing the reactivity of sGC to endogenous NO by stabilizing NO-sGC binding, and the effect of directly stimulating sGC through different binding sites even in the absence of stimulation by NO. Has one mechanism. As a sGC stimulator, Riociguat copes with NO deficiency by restoring the NO-sGC-cGMP pathway, and consequently promotes cGMP production and dilates the pulmonary artery (Non-patent Document 1).

  Riociguato significantly improved 6-minute walking distance, pulmonary vascular resistance, and pulmonary artery mean pressure in the international phase III study of CTEPH patients compared to placebo, and 6-minute walking distance in the long-term study. Improvement was maintained. On the other hand, in the international joint Phase III study (placebo-controlled double-blind comparative study for patients with chronic thrombo-occlusive hypertension and placebo-controlled double-blind comparative study for patients with pulmonary arterial hypertension) Side effects (including abnormal laboratory values) were observed in 304 (62.0%) of 490 cases (including 30 Japanese) who received Riociguat. Major side effects include 93 headaches (19.0%), 72 cases (14.7%) of dyspepsia, 65 cases (13.3%) of floating vertigo, 43 cases (8.8%) of hypotension (approved) Has been reported (Non-Patent Document 1). As a characteristic of Riociguat, there is a clear correlation between blood concentration and hemodynamics, and it has been shown that not only pulmonary vascular resistance but also systemic vascular resistance is simultaneously reduced (Non-patent Document 1). These side effects are presumed to appear in areas where the blood concentration of Riociguat is high. In addition, regarding dyspepsia, it is speculated that in pharmacological studies in mice, enterotoxicosis and chronic inflammation accompanied by mucosal degeneration and regeneration will occur due to decreased gastrointestinal motility due to the smooth muscle relaxation effect of riociguat (Non-patent Document 2), which is considered to be a side effect associated with oral administration. In addition, since Riociguat is administered 3 times a day, there is a problem of medication adherence reduction such as forgetting to drink.

Japanese Patent No. 4455321

Adempas (R) Tablet Interview Form (February 2015 Revised 4th Edition: Bayer Yakuhin Co., Ltd.) Adempas lock deliberation result report (December 10, 2013)

  It is desirable to further reduce the frequency of side effects such as headache, dyspepsia, dizziness and hypotension associated with the administration of Riociguat. These side effects are presumed to be due to the effect of dilating the blood vessels of Riociguat, and the risk of side effects is high in the region with high blood concentrations of Riociguat, that is, the highest plasma concentration (Cmax) in oral administration. Guessed. Furthermore, dyspepsia is presumed to be a chronic inflammation caused by a decrease in motility of the digestive tract due to the smooth muscle relaxing action of riociguat, and is considered to be a side effect associated with oral administration. Therefore, it is considered that the above-mentioned side effects can be suppressed if an excessive increase in blood concentration can be suppressed by making riociguat into a transdermal absorption preparation. Furthermore, from the viewpoint of improving the adherence adherence by reducing the number of administration (3 times / 1 day → 1 time / 1 day to several days), the preparation of riociguat percutaneously absorbable is effective.

  An object of the present invention is to provide a novel means for administering riociguat capable of exhibiting excellent pharmacological effects while avoiding side effects that may occur with oral administration. Another object of the present invention is to provide a novel preventive or therapeutic means for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial pulmonary hypertension (PAH).

As a result of intensive research to achieve the above-mentioned object, the present inventors have found that riociguat, which has been orally administered conventionally, can be administered as a transdermal absorption-type preparation, and further, the skin permeation rate of riociguato It has been found that by appropriately controlling the amount of riociguat, the amount of riociguat effective for the prevention or treatment of CTEPH and PAH can be absorbed transdermally, and the blood concentration of riociguat can be maintained above a certain level.
The present inventors have further studied based on these findings and have completed the present invention.
That is, the present invention is as follows.

[1] A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer comprises:
a) riociguat; and b) at least one acid selected from hydroxy acids or phosphoric acids;
A percutaneous absorption type preparation containing
[2] The transdermal preparation according to [1], wherein the drug-containing layer contains an adhesive.
[3] The transdermal preparation according to [2], wherein the pressure-sensitive adhesive contains at least one of an acrylic resin or a rubber resin as a main component.
[4] The transdermal preparation according to any one of [1] to [3], wherein the drug-containing layer contains an absorption enhancer.
[5] The absorption accelerator is selected from aliphatic alcohols having 10 to 22 carbon atoms, fatty acids having 10 to 22 carbon atoms, polyoxyethylene alkyl ethers having 10 to 22 carbon atoms, fatty acid alkanolamides, and esters. The percutaneously absorbable preparation according to [4], which is at least one selected from the above.
[6] The transdermal absorption preparation according to any one of [1] to [5], wherein the drug-containing layer contains silicic anhydride.
[7] The percutaneously absorbable preparation according to any one of [1] to [6], further comprising a release liner, wherein the support, the drug-containing layer, and the release liner are laminated in this order.
[8] A method for producing a transdermal absorption preparation described in [1] above,
Preparing a mixture comprising at least one acid selected from riociguat, hydroxy acid or phosphoric acid, and optionally other ingredients (eg, adhesive, absorption enhancer, silicic anhydride, etc.);
The production method comprising applying or spreading the mixture on a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer.

  According to the present invention, by making riociguat into a transdermal absorption preparation, it becomes easy to maintain the blood concentration of riociguat at a level causing no side effects. Therefore, it is possible to avoid side effects (headache, indigestion, dizziness, hypotension, etc.) that are presumed to be caused by the blood concentration peak and that are caused by a decrease in gastrointestinal motility due to smooth muscle relaxation. If signs of side effects are observed, the administration can be stopped immediately by peeling the transdermal preparation from the skin immediately. In addition, what was administered three times / day in oral administration can be maintained in blood concentration by transdermal preparation, and can be administered once / day to several days. Therefore, improvement in medication adherence can be expected. In addition, according to the present invention, an effective amount of riociguat for the treatment or prevention of CTEPH and PAH is transdermally absorbed, and it becomes easy to maintain the blood concentration of riociguato above a certain level. And prevention or treatment of PAH can be performed.

An example of the manufacturing flow of the transdermally absorbable preparation of the present invention is shown. The result of the in vitro skin permeability test of Test Example 3 is shown. The result of the in vivo skin permeability test of Test Example 4 is shown.

  In the present invention, the transdermal preparation refers to a parenteral preparation in which an active ingredient is absorbed through the skin and delivered to the bloodstream. The transdermally absorbable preparation of the present invention is a patch having a support and a drug-containing layer, and examples thereof include a tape, a poultice, and a plaster.

  The transdermally absorbable preparation of the present invention may be a matrix-type patch preparation containing an adhesive in the drug-containing layer, and a controlled-release membrane and skin for adjusting the transdermal absorption of the drug on the skin-applied side of the drug-containing layer It may also be a reservoir-type patch preparation further having an adhesive layer for sticking to the skin. With such a structure, riociguat can be efficiently transdermally absorbed.

  From the viewpoint of formulation design and ease of production, a matrix-type patch preparation is preferable. Hereinafter, the matrix-type patch preparation will be described as an example, but the present invention is not limited thereto.

  In this specification, “comprising” or “including” also includes the meaning of “consisting essentially of” or “consisting solely of”.

<Drug-containing layer>
1. Active ingredient In the transdermally absorbable preparation of the present invention, the drug-containing layer contains riociguat as an active ingredient. Riociguat is believed to dilate the pulmonary artery by stimulating sGC and promoting cGMP production. Diseases that can be treated or prevented by the transdermally absorbable preparation of the present invention include, but are not limited to, pulmonary hypertension such as chronic thromboocclusive pulmonary hypertension (CTEPH) and pulmonary arterial pulmonary hypertension (PAH). Not.

In the present specification, “chronic thromboembolic pulmonary hypertension (CTEPH)” is one of the clinical classifications of pulmonary hypertension (PH), and the pulmonary artery is blocked by an organized thrombus, and pulmonary blood flow distribution and pulmonary circulation dynamics. This is a pathological condition that has been fixed for over 6 months.
“Pulmonary arterial hypertension (PAH)” is one of the clinical classifications of pulmonary hypertension (PH), and is a pathological condition in which pulmonary arterial stenosis increases pulmonary vascular resistance and increases pulmonary artery blood pressure.

  Prevention or treatment of chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial pulmonary hypertension (PAH) refers to chronic thromboocclusive pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH) in a subject such as a human. ) Onset delay, suppression, treatment of pathological condition after onset, delay or suppression of recurrence after onset.

  In the present invention, riociguat may be a free form or a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; and organic acid salts such as formate, acetate, Trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipate, sorbate , Lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, isostearate , Succinate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), benzenesulfonate (besylate) and the like. . Riociguat or a pharmaceutically acceptable salt thereof may form a co-crystal or a solvate (for example, a hydrate, preferably a hemihydrate), either alone or in combination of two or more May be used in appropriate combination. In the present invention, it is preferable to use a free form of riociguat that has already been established for usefulness in oral administration.

  The content of riociguat in the transdermal preparation of the present invention is an effective amount for the prevention or treatment of the target disease (for example, CTEPH or PAH). Here, the effective amount can achieve a blood concentration of riociguat effective for preventing or treating a target disease (for example, CTEPH or PAH) when the transdermally absorbable preparation of the present invention is applied to the skin of a living body. Amount. Such content can be appropriately adjusted based on information on pharmacokinetics of oral administration, and may vary depending on the administration subject, disease, symptoms, and the like. For example, 0.5-40 mass% is preferable with respect to the drug-containing layer (that is, based on the total mass of the drug-containing layer; the same applies hereinafter), more preferably 0.5-30 mass%, more preferably 1-25 mass% Is more preferable.

  The blood concentration of Riociguat effective for the prevention or treatment of the target disease (for example, CTEPH or PAH) can be the same as that of the oral drug of Riociguat.

  In the transdermal preparation of the present invention, by adjusting the skin permeation rate of riociguat, a blood concentration effective for the prevention or treatment of the target disease (for example, CTEPH or PAH) can be achieved. The skin permeation rate can be adjusted by any means such as adjusting the content of riociguat in the drug-containing layer, or adding an absorption promoter described later to the drug-containing layer. In addition, in this invention, the skin permeation | transmission speed | rate of riociguato means the value measured by the in vitro skin permeability test described in the below-mentioned Example.

The skin permeation rate of riociguat is usually 0.1 to 30 μg / cm ² / hour, preferably 0.2 to 30 μg / cm ² / hour, more preferably 0.4 to 30 μg / cm ² / hour. Yes, particularly preferably 0.8 to 30 μg / cm ² / hour. If the skin permeation rate is 0.1 μg / cm ² / hour or more, a sufficient blood concentration can be obtained. If the skin permeation rate is 30 μg / cm ² / hour or less, the blood concentration is not too high, which is preferable from the viewpoint of safety.

2. Acid In the percutaneous absorption type preparation of the present invention, at least one acid selected from hydroxy acid or phosphoric acid is contained in the drug-containing layer in order to improve the skin permeation rate of riociguat. Hydroxy acids include glycolic acid, lactic acid, citric acid, isocitric acid, tartaric acid, 3-hydroxypropionic acid, tartronic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, citramalic acid , Isocitric acid, leucine acid, mevalonic acid, pantoic acid, linoleic acid, linonelaidic acid, cerebronic acid, quinic acid, shikimic acid, gluconic acid, salicylic acid, mandelic acid and the like. Among these, at least one acid selected from hydroxy acid or phosphoric acid is preferably a hydroxy acid or phosphoric acid having 2 to 8 carbon atoms, such as glycolic acid, lactic acid, citric acid, salicylic acid, mandelic acid, or phosphoric acid. More preferred is lactic acid. The content of the acid selected from hydroxy acid or phosphoric acid is not particularly limited as long as a sufficient skin permeation rate of riociguat can be achieved, but is preferably 120 to 400 parts by mass with respect to 100 parts by mass of riociguat, 140 to 400 mass parts is more preferable, and 170-300 mass parts is further more preferable. As for content of the acid chosen from hydroxy acid or phosphoric acid to a medicine content layer, 0.6-60 mass% is preferred, 0.7-50 mass% is more preferred, and 1.7-50 mass% is still more preferred. By containing an acid selected from hydroxy acid or phosphoric acid, the solubility of riociguat is increased, and the skin permeability of riociguat is improved. In particular, when the content of an acid selected from hydroxy acid or phosphoric acid is within the above range, the effect of improving skin permeability becomes more prominent than when the content is outside the above range.

3. The absorption enhancer drug-containing layer may further contain an absorption enhancer for improving the skin permeability of riociguat. The absorption enhancer may be any compound that has been recognized to promote skin permeation in transdermal administration. For example, acetic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, sorbine Fatty acids such as acids, oleic acid, linoleic acid, linolenic acid, isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, hexadecyl isostearate, hexyl laurate, decyl oleate, oleyl oleate, diisopropyl adipate, diethyl sebacate , Diisopropyl sebacate, medium chain fatty acid triglyceride, tri (caprylic / capric) glycerin, glyceryl monooleate, propylene glycol monocaprylate, propylene glycol monocaprate, monolaurate Esters such as pyrene glycol, propylene glycol monopalmitate, propylene glycol monostearate, propylene glycol monooleate, propylene glycol monobehenate, propylene glycol dicaprate, triacetin, ethyl lactate, triethyl citrate; sorbitan monolaurate, monoolein Sorbitan fatty acid esters such as acid sorbitan; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate; polyethylene monooleate Glycol: Polyethylene glycol monostearate, polyethylene glycol monopalmitate , Polyoxyethylene fatty acid esters such as polyethylene glycol monolaurate; oxalic acid, fumaric acid, succinic acid, glutaric acid, adipic acid, pimelic acid, sebacic acid, benzoic acid, nicotinic acid, methanesulfonic acid, benzenesulfonic acid, Organic acids such as toluenesulfonic acid and saccharin or salts thereof; aliphatic or aromatic alcohols such as decanol, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, hexyldecanol, octyldodecanol, benzyl alcohol, or Ethers thereof; polyhydric alcohols having 3 to 8 carbon atoms (for example, propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin, dipropylene glycol) , Octanediol, etc.); phenol ethers such as polyoxyethylene nonylphenyl ether and polyoxyethylene octylphenyl ether; castor oil or hydrogenated castor oil; ionic interfaces such as oleoyl sarcosine, lauryldimethylaminoacetic acid betaine, sodium lauryl sulfate Activator; C10-22 polyoxyethylene alkyl ether (for example, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene behenyl ether, etc.); dimethyl Nonionic surfactants such as laurylamine oxide; lauric acid diethanolamide, palmitic acid diethanolamide, stearic acid diethanolamide Fatty acid alkanolamides such as oleic acid diethanolamide and lauric acid monoisopropanolamide; alkylmethyl sulfoxides such as dimethyl sulfoxide and decylmethyl sulfoxide; 2-pyrrolidone, N-methyl-2-pyrrolidone, N -Pyrrolidones such as ethyl-2-pyrrolidone; Azacycloalkanes such as 1-dodecylazacycloheptan-2-one and 1-geranylazacycloheptan-2-one; Terpenes such as menthol, camphor and limonene Can be mentioned. Of these, esters, aliphatic alcohols having 10 to 22 carbon atoms, fatty acids having 10 to 22 carbon atoms, polyoxyethylene alkyl ethers having 10 to 22 carbon atoms, and fatty acid alkanolamides are preferable. An absorption accelerator can be used individually by 1 type or in combination of 2 or more types.

  The content of the absorption accelerator is preferably 0.1 to 30% by mass, more preferably 0.1 to 25% by mass, and still more preferably 0.2 to 25% by mass with respect to the drug-containing layer.

4. The adhesive drug-containing layer may contain an adhesive. Examples of the pressure-sensitive adhesive contained in the drug-containing layer include those containing acrylic resins, rubber resins, silicone resins, and the like.

  The pressure-sensitive adhesive preferably contains at least one selected from the group consisting of acrylic resins, rubber resins and silicone resins as a main component, and at least selected from the group consisting of acrylic resins and rubber resins. What contains 1 type as a main component is more preferable. Here, the “main component” means usually 70% by mass or more, further 80% by mass or more, further 90% by mass or more, and particularly 100% by mass with respect to the total mass of the pressure-sensitive adhesive.

  As an acrylic resin, for example, (meth) acrylic acid ester represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like is used as a monomer unit. Examples thereof include a polymer or copolymer containing at least one kind. Specifically, for example, acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, 2-ethylexyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid-1 , 6-hexane glycol copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid Examples thereof include a dodecyl copolymer solution, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and an acrylic resin alkanolamine solution. DURO-TAK (registered trademark) acrylic adhesive series (DURO TAK 87-900A, DURO TAK 87-9301, DURO TAK 87-4098, DURO TAK 387-2510, DURO TAK 87-2510, DURO TAK 387-2287, DURO TAK 87-2287, DURO TAK 87-4287, DURO TAK 387-2516, DURO TAK 87-2516, DURO TAK 87-2074, DURO TAK 387-235A, DURO TAK 387-2353, DURO TAK 87-2353, DURO TAK 87-2852, DURO TAK 387-2051, DURO TAK 87-2051, DURO TAK 387-2052, DURO TAK 87-2052, DURO TAK 387-2054, DURO TAK 87-2054, DURO TAK 87-2194, DURO TAK 87- 2196: manufactured by Henkel), GELVA series (GELVA GMS 3083, GELVA GMS 3253, GELVA GMS 788, GELVA GMS 9073: manufactured by Henkel), MAS-683, MAS-811, MASCOS10, MAS11D1 (manufactured by Cosmed Pharmaceutical) Commercially available acrylic resins may be used.

  Examples of rubber resins include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, and polyisobutylene (PIB). ), Polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, preferably SIS. Also, commercially available rubber resins such as the Quintac (registered trademark) series (Quintac 3570C, etc .: manufactured by Nippon Zeon Co., Ltd.), the Clayton D polymer series (Clayton Polymer Japan Co., Ltd.), and the JSR SIS / TR series (JSR Life Science Co., Ltd.) are used. May be.

  Examples of the silicone-based resin include polymers having an organopolysiloxane skeleton and derivatives thereof. Specific examples include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, and diphenylsiloxane. Commercially available silicone resins such as BIO-PSA series (Dow Corning) may also be used.

  As the pressure-sensitive adhesive contained in the drug-containing layer of the transdermally absorbable preparation of the present invention, one of the acrylic resin, rubber resin, and silicone resin described above is used alone, or two or more kinds are combined. Can be used. More preferred are acrylic or rubber resins.

  The amount of the adhesive contained in the drug-containing layer is adjusted in consideration of the formation of the drug-containing layer, sufficient skin permeability of riociguat, and the like. The content of the pressure-sensitive adhesive is usually 10 to 98.9% by mass, preferably 15 to 98.8% by mass with respect to the drug-containing layer. When the pressure-sensitive adhesive is a rubber-based resin, the content of the pressure-sensitive adhesive is preferably 5 to 98.9% by mass, more preferably 10 to 98.8% by mass with respect to the drug-containing layer. % Is more preferable. When the pressure-sensitive adhesive is an acrylic resin, the content of the pressure-sensitive adhesive is preferably 15 to 98.9% by mass, more preferably 18 to 98.8% by mass with respect to the drug-containing layer, and 20 to 97.3% by mass. % Is more preferable. When the pressure-sensitive adhesive is a silicone-based resin, the content is preferably 15 to 98.9% by mass, more preferably 18 to 98.8% by mass, and still more preferably 20 to 97.3% by mass with respect to the drug-containing layer.

5. Tackifier The drug-containing layer may further contain a tackifier to improve the adhesive strength. Examples of the tackifier include rosin derivatives such as rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, aliphatic Saturated hydrocarbon resin, aliphatic hydrocarbon resin, maleic resin, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose , Polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, polyvinyl alcohol and the like. In addition, as the tackifier, commercially available products such as Alcon series (Arakawa Chemical Co., Ltd.), Pine Crystal series (Arakawa Chemical Co., Ltd.), Clearon series (Yasuhara Chemical Co., Ltd.), YS Resin Series (Yasuhara Chemical Co., Ltd.), etc. You may use suitably. In particular, when the rubber-based resin is used as an adhesive, it is preferable to use a glycerin ester of hydrogenated rosin, an alicyclic saturated hydrocarbon resin, a terpene resin, or an aliphatic saturated hydrocarbon resin as a tackifier. A tackifier can be used individually by 1 type or in combination of 2 or more types.

  The content of the tackifier is preferably 5 to 70% by mass, preferably 5 to 60% by mass with respect to the drug-containing layer when a rubber-based resin is used as the adhesive in consideration of sufficient adhesive strength as a patch. % Is more preferable, and 10 to 50% by mass is more preferable. When using acrylic resin as an adhesive, 0-40 mass% is preferable with respect to a drug content layer, 0-30 mass% is more preferable, and 0-20 mass% is further more preferable. When using a silicone resin as an adhesive, 0-30 mass% is preferable with respect to a drug content layer, 0-20 mass% is more preferable, and 0-10 mass% is further more preferable.

6. Plasticizer The drug-containing layer may further contain a plasticizer. Plasticizers include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, liquid paraffin, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil, etc.), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), diethylene glycol, polyethylene glycol, salicylic acid glycol, crotamiton, etc. It is done. Moreover, as a plasticizer, you may use suitably what is marketed, such as the Moresco white series (made by Moresco), the high call series (made by Kaneda). In particular, when the rubber-based resin is used as an adhesive, liquid paraffin is preferably used as a plasticizer. A plasticizer can be used individually by 1 type or in combination of 2 or more types.

  The content of the plasticizer is adjusted in consideration of sufficient permeability of riociguat and maintenance of sufficient cohesion as a transdermal preparation. When using rubber-type resin as an adhesive, 0-70 mass% is preferable with respect to a drug content layer, 0-60 mass% is more preferable, 0-40 mass% is further more preferable. When using acrylic resin as an adhesive, 0-50 mass% is preferable with respect to a drug content layer, 0-40 mass% is more preferable, and 0-30 mass% is further more preferable. In the case of using a silicone-based resin as the adhesive, the total amount is preferably 0 to 40% by mass, more preferably 0 to 30% by mass, and further preferably 0 to 20% by mass with respect to the drug-containing layer.

7). The anhydrous silicic acid drug-containing layer may further contain anhydrous silicic acid. Examples of silicic anhydride include those in which the surface of the fine particles is not treated at all (hydrophilicity), and the surface of which is subjected to lipophilic treatment. The primary particle diameter of silicic anhydride is not particularly limited, but is preferably 5 to 100 nm, and more preferably 7 to 50 nm. The specific surface area of the silicic anhydride (BET method) is not particularly limited, is preferably a 20 to 400 m ² / g, it is more preferred 50~350m ² / g.

  The content of silicic acid anhydride is 0.1 to 10% by mass with respect to the drug-containing layer in consideration of sufficient permeability of riociguat, maintenance of sufficient cohesive force as a transdermal preparation and adhesive strength. Preferably, 0.2-8 mass% is more preferable.

8. Other optional component drug-containing layer further contains a known additive such as a pH adjuster, a crosslinking agent, an antioxidant, a colorant, an ultraviolet absorber, a filler, or an antiseptic, as necessary. May be.

  The pH adjusting agent can be used to adjust the pH of the drug-containing layer for the purpose of improving the solubility, stability and skin permeability of riociguat, improving the safety to the skin, and the like. The pH adjusting agent may be any compound as long as it is an acid or base or a salt thereof that is usually used for pH adjustment in the pharmaceutical field. For example, hydrochloric acid, sulfuric acid, succinic acid, acetic acid, methanesulfonic acid, edetate Acid, aqueous ammonia, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, meglumine, trometamol, glycine, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium citrate, acetic acid Sodium, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, etc. are mentioned.

  Examples of crosslinking agents include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. Is mentioned. Among these, an isocyanate compound or a blocked isocyanate compound is preferable.

  Examples of the antioxidant include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like.

  Examples of the colorant include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, water Examples include sodium oxide, talc, sodium copper chlorophyllin, green leaf extract powder, d-borneol, octyldodecyl myristate, methylene blue, ammonium manganese phosphate, and rose oil.

  Examples of the ultraviolet absorber include amino acid compounds, benzophenone compounds, cinnamic acid derivatives, cyanoacrylate derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, and the like. Can be mentioned.

  Fillers include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium bicarbonate, silicate (eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate Sodium), magnesium hydroxide, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.

  Examples of the preservative include ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.

  0-10 mass% is preferable with respect to a drug content layer, and, as for the total content of other arbitrary components, 0-5 mass% is more preferable.

The area of the drug-containing layer in the transdermally absorbable preparation of the present invention can be appropriately adjusted according to the content of riociguat and / or the skin permeation rate. Typically, it is in the range of 2-140 cm ² , preferably 2-100 cm ² , more preferably 4-50 cm ² . The shape is not particularly limited, and may be a square, a rectangle, a circle, an ellipse, or the like.

  The thickness of the drug-containing layer in the percutaneous absorption-type preparation of the present invention can be appropriately adjusted according to the type of pressure-sensitive adhesive, the content of riociguat and / or the skin permeation rate, and is not particularly limited. Typically, it is in the range of 20 to 300 μm, preferably 30 to 200 μm, more preferably 30 μm to 150 μm.

One embodiment of the drug-containing layer in the transdermally absorbable preparation of the present invention includes one containing an acid selected from liociguat and hydroxy acid or phosphoric acid (see [1] above).
It is preferable that the content of riociguat is 0.5 to 40% by mass and the content of an acid selected from hydroxy acid or phosphoric acid is 0.6 to 60% by mass with respect to the drug-containing layer.

As a more preferable aspect of the drug-containing layer in the transdermal preparation of the present invention, it is preferable to contain an acid selected from riociguat, hydroxy acid or phosphoric acid and an adhesive. As an adhesive, what contains an acrylic resin as a main component is preferable. As the acrylic resin, a polymer or copolymer containing at least one (meth) acrylic acid ester is preferable.
As an adhesive, what contains a rubber-type resin as a main component is also preferable. SIS is particularly preferable as the rubber-based resin.
With respect to the drug-containing layer, the content of riociguat is 0.5 to 40% by mass, the content of acid selected from hydroxy acid or phosphoric acid is 0.6 to 50% by mass, and the content of adhesive is 10 to 98.%. It is preferably 9% by mass.

As a more preferable embodiment of the drug-containing layer in the transdermal preparation of the present invention, an acid selected from riociguat, hydroxy acid or phosphoric acid, an adhesive and an absorption accelerator are preferably contained. As an adhesive, what contains an acrylic resin as a main component is preferable. As the acrylic resin, a polymer or copolymer containing at least one (meth) acrylic acid ester is preferable.
As an adhesive, what contains a rubber-type resin as a main component is also preferable. SIS is particularly preferable as the rubber-based resin.
As an absorption promoter, from the group consisting of C10-22 aliphatic alcohols, C10-22 fatty acids, C10-22 polyoxyethylene alkyl ethers, fatty acid alkanolamides, esters At least one selected is preferred.
With respect to the drug-containing layer, the content of riociguat is 0.5 to 40% by mass, the content of acid selected from hydroxy acid or phosphoric acid is 0.6 to 50% by mass, and the content of adhesive is 10 to 98.%. The content of 8% by mass and the absorption accelerator is preferably 0.1 to 30% by mass.

<Support>
As the support in the transdermal preparation of the present invention, a drug-impermeable, stretchable or non-stretchable support can be used. Such a support is not particularly limited as long as it is usually used in the field of pharmaceuticals. For example, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), Examples thereof include synthetic resin films or sheets such as nylon and polyurethane, or laminates, porous bodies, foams, and films in which aluminum is vapor-deposited. In order to obtain good anchoring properties with the adhesive layer, paper, woven fabric, nonwoven fabric, or a laminate of these and a film can also be used as the support.

<Release liner>
The transdermally absorbable preparation of the present invention may further have a release liner. In this case, the release liner is laminated on the surface of the drug-containing layer laminated on the support opposite to the surface in contact with the support, and protects the drug-containing layer until the transdermal preparation is applied to the skin. can do. The release liner is not particularly limited as long as it is impervious to at least riociguat in the drug-containing layer. For example, a film made of a polymer material such as polyethylene, polypropylene, polyester, polyethylene terephthalate, and aluminum is vapor-deposited on the film. And those obtained by applying silicone oil or the like on paper.

<Manufacture of transdermal preparation>
The transdermally absorbable preparation of the present invention can be produced according to a known method. A mixture containing an acid selected from riociguat, hydroxy acid or phosphoric acid, and other components as necessary is prepared, and this mixture is applied or spread on a release liner to form a drug-containing layer. It can manufacture by sticking a support body together.

  Specifically, an acid selected from the above riociguat, hydroxy acid or phosphoric acid, and other components as necessary, are added to an organic solvent so as to have the above content, and mixed and stirred to prepare a coating solution.

  As the organic solvent, ethyl acetate, hexane, pentane, heptane, toluene, cyclohexane, chloroform, methylene chloride, methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, cyclohexanone, acetone, a mixed solvent thereof or the like can be used. Content of the organic solvent in a coating liquid is not specifically limited, For example, it is 30-90 mass% with respect to the whole coating liquid, Preferably it is 40-80 mass%.

  Next, this coating solution is applied or spread on a release liner, the solvent in the coating solution is evaporated to form a drug-containing layer, and then a support is attached to obtain a transdermal absorption preparation. Can do. Alternatively, a transdermal preparation can be obtained by applying or spreading a coating liquid on a support, evaporating the solvent in the coating liquid to form a drug-containing layer, and then attaching a release liner. . From the viewpoint of ease of production, a method in which a coating solution is applied or spread on a release liner, a solvent in the coating solution is evaporated to form a drug-containing layer, and then a support is bonded together is preferable. Coating or spreading of the coating solution can be performed using a knife coater, comma coater, reverse coater, or die coater. Although an example of a manufacturing flow is shown in FIG. 1, it is not limited to this.

  The percutaneous absorption preparation of the present invention is prepared by heating and melting the acid selected from riociguat, hydroxy acid or phosphoric acid, and other components as necessary, and applying or spreading the melt on a release liner. After the drug-containing layer is formed, a percutaneously absorbable preparation can be produced by pasting a support. After the melt is applied or spread on a support to form a drug-containing layer, a transdermal preparation may be produced by laminating a release liner.

<Administration method>
Prevention or treatment of a target disease (for example, CTEPH or PAH) by the percutaneously absorbable preparation of the present invention is performed by directly applying the percutaneously absorbable preparation of the present invention to the subject's skin and administering riociguat transdermally. It can be carried out. The subject in the present invention is a mammal such as a human, preferably a human.

  When Riociguat is transdermally administered by the transdermally absorbable preparation of the present invention, the inclusion of Riociguat in the drug-containing layer so as to achieve a blood concentration effective for prevention or treatment of the target disease (for example, CTEPH or PAH) The percutaneously absorbable preparation of the present invention is applied to the skin after appropriately adjusting the amount and / or skin permeation rate, the area of the drug-containing layer and / or the thickness of the drug-containing layer, and the like.

  The percutaneous absorption type preparation of the present invention may be applied to the skin of any part of the body as long as it can be applied. For example, it can be applied to the upper arm, abdomen, chest, neck, waist back, buttocks or legs. Can be pasted.

  Transdermal administration to the subject of the transdermally absorbable preparation of the present invention may be combined with administration of a pharmaceutical composition containing a pharmaceutical ingredient other than riociguat, if necessary. In this case, the administration form may be simultaneous administration or administration with a time difference, and the pharmaceutical composition may be intravenous, intraperitoneal, subcutaneous and intramuscular, oral, topical or transmucosal. It can be administered by various routes including: In addition, a pharmaceutical composition containing a pharmaceutical ingredient other than riociguat is administered to a subject by an administration route usually used for the pharmaceutical ingredient. Examples of pharmaceutical components other than Riociguat include, but are not limited to, CTEPH therapeutic agents other than Riociguat, PAH therapeutic agents, antithrombotic agents, and the like.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited to a following example. Moreover, in each Example,% is mass% unless there is particular notice.

(Manufacture of percutaneous absorption preparation containing riociguat)
Example 1
-Preparation of rubber-based resin composition (1) Quintac 3570C (styrene-isoprene-styrene block copolymer, manufactured by Nippon Zeon Co., Ltd.), Pine Crystal KE-311 (ultra-light rosin) so that the solid content becomes the following blending ratio Derivatives, manufactured by Arakawa Chemical Industry Co., Ltd.) and Haicol M-352 (liquid paraffin, manufactured by Kaneda Co., Ltd.) were dissolved in toluene to obtain a rubber-based resin composition (1).
Ingredient name Mixing ratio Quantac3570C (manufactured by Nippon Zeon) 34%
Pine Crystal KE-311 (Arakawa Chemical Industries) 34%
High call M-352 (manufactured by Kaneda) 17%

・ Manufacture of percutaneously absorbable preparations: Riociguat as an active ingredient, lactic acid (made by Musashino Chemical Laboratories) as a hydroxy acid, and rubber-based resin composition as an adhesive so that the solid content after coating and drying is as follows. After mixing and stirring (1) in an appropriate amount of toluene, a coating solution was obtained.
Ingredient name Composition ratio Riociguat 5%
Lactic acid (Musashino Chemical Laboratory Co., Ltd.) 10%
Rubber resin composition (1) 85%

  The coating solution was applied on a release film (75 μm single-sided silicon-treated PET film, film binder 75E-0010 BD: manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent was about 50 μm, and dried. A support (25 μm PET film, Lumirror T-60: manufactured by Toray Industries, Inc.) was bonded to produce a transdermal absorption preparation.

Example 2
Riociguat as an active ingredient, lactic acid as a hydroxy acid (manufactured by Musashino Chemical Laboratory Co., Ltd.), lauric acid diethanolamide (manufactured by Wako Pure Chemical Industries, Ltd.) as an absorption accelerator, so that the solid content after coating and drying has the following blending ratio A percutaneously absorbable preparation was produced in the same manner as in Example 1 except that the rubber-based resin composition (1) as an adhesive was mixed and stirred in an appropriate amount of toluene and then a coating solution was obtained.
Ingredient name Composition ratio Riociguat 5%
Lactic acid (Musashino Chemical Laboratory Co., Ltd.) 10%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 5%
Rubber resin composition (1) 80%

Examples 3-4
The transdermal preparations of Examples 3 to 4 were produced in the same manner as in Example 2 except that the hydroxy acid or phosphoric acid was changed to the compounds shown in Table 1.

Example 5
-Preparation of rubber-based resin composition (2) Quintac 3570C (styrene-isoprene-styrene block copolymer, manufactured by Nippon Zeon Co., Ltd.), Pine Crystal KE-311 (ultra-light rosin) so that the solid content has the following blending ratio Derivative, manufactured by Arakawa Chemical Industries, Ltd.) was dissolved in toluene to obtain a rubber-based resin composition (2).
Ingredient name Mixing ratio Quintac 3570C (made by Nippon Zeon) 20%
Pine Crystal KE-311 (Arakawa Chemical Industries) 40%

・ Manufacture of percutaneous absorption type preparations: Riociguat as active ingredient, lactic acid (made by Musashino Chemical Laboratories) as an active ingredient, and lauric acid diethanolamide as an absorption accelerator so that the solid content after coating and drying is as follows. (Wako Pure Chemical Industries, Ltd.) and oleyl alcohol (Croda), Aerosil 200 (manufactured by Nippon Aerosil Co., Ltd.) as silicic acid, and rubber-based resin composition (2) as an adhesive after mixing and stirring in an appropriate amount of toluene A percutaneous absorption type preparation was produced in the same manner as in Example 1 except that the coating solution was obtained.
Ingredient name Composition ratio Riociguat 10%
Lactic acid (Musashino Chemical Laboratory) 12.5%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 5%
Oleyl alcohol (Croda) 10%
Aerosil200 (Nippon Aerosil Co., Ltd.) 2.5%
Rubber resin composition (2) 60%

Examples 6-9
The transdermal preparations of Examples 6 to 9 were produced in the same manner as in Example 5 except that the mixing ratio of lactic acid and the rubber-based resin composition was changed to the mixing ratio shown in Table 1.

Examples 10-23
Transdermal absorption preparations of Examples 10 to 23 were produced in the same manner as in Example 8, except that the absorption accelerator was changed to the compounds shown in Tables 1, 2 and 3.

Example 24
Riociguat as an active ingredient, lactic acid as a hydroxy acid (made by Musashino Chemical Laboratories), lauric acid diethanolamide (made by Wako Pure Chemical Industries) as an absorption accelerator so that the solid content after coating and drying has the following blending ratio Except that oleyl alcohol (made by Croda), Aerosil 200 (made by Nippon Aerosil Co., Ltd.) as silicic acid, and rubber-based resin composition (2) as an adhesive were mixed and stirred in an appropriate amount of toluene, and then a coating solution was obtained. A percutaneous absorption type preparation was produced in the same manner as in Example 1.
Ingredient name Mixing ratio Riociguat 15%
Lactic acid (Musashino Chemical Laboratory Co., Ltd.) 30%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 5%
Oleyl alcohol (Croda) 10%
Aerosil 200 (Nippon Aerosil Co., Ltd.) 2.5%
Rubber resin composition (2) 37.5%

Example 25
Riociguat as an active ingredient, lactic acid as a hydroxy acid (made by Musashino Chemical Laboratories), lauric acid diethanolamide (made by Wako Pure Chemical Industries) as an absorption accelerator so that the solid content after coating and drying has the following blending ratio After mixing and stirring oleyl alcohol (manufactured by Croda), Aerosil 200 (manufactured by Nippon Aerosil Co., Ltd.) as silicic acid, and DURO TAK87-4098 (non-functional acrylic resin, manufactured by Henkel) as a pressure-sensitive adhesive, A transdermal absorption preparation was produced in the same manner as in Example 1 except that the coating solution was obtained.
Ingredient name Composition ratio Riociguat 10%
Lactic acid (Musashino Chemical Laboratory) 20%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 5%
Oleyl alcohol (Croda) 10%
Aerosil200 (Nippon Aerosil Co., Ltd.) 2.5%
DURO TAK87-4098 (Henkel) 52.5%

Examples 26-28
The percutaneous absorption type preparations of Examples 26 to 28 were produced in the same manner as in Example 25 except that the hydroxy acid was changed to the compounds shown in Table 3.

Example 29
Riociguat as an active ingredient, lactic acid as a hydroxy acid (made by Musashino Chemical Laboratories), lauric acid diethanolamide (made by Wako Pure Chemical Industries) as an absorption accelerator so that the solid content after coating and drying has the following blending ratio After mixing and stirring oleyl alcohol (manufactured by Croda), Aerosil 200 (manufactured by Nippon Aerosil Co., Ltd.) as silicic acid, and DURO TAK87-4098 (non-functional acrylic resin, manufactured by Henkel) as a pressure-sensitive adhesive, A transdermal absorption preparation was produced in the same manner as in Example 1 except that the coating solution was obtained.
Ingredient name Mixing ratio Riociguat 15%
Lactic acid (Musashino Chemical Laboratory Co., Ltd.) 30%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 5%
Oleyl alcohol (Croda) 10%
Aerosil200 (Nippon Aerosil Co., Ltd.) 2.5%
DURO TAK87-4098 (manufactured by Henkel) 37.5%

Example 30
A percutaneous absorption type preparation of Example 30 was produced in the same manner as in Example 29 except that the blending ratio of riociguat, lactic acid and adhesive was changed to the blending ratio shown in Table 3.

Example 31
In Example 25, the percutaneously absorbable preparation of Example 31 was produced in the same manner as in Example 25 except that oleyl alcohol was replaced with oleic acid.

Example 32
In Example 25, the percutaneously absorbable preparation of Example 32 was prepared in the same manner as in Example 25 except that DURO TAK87-4098 was replaced with DURO TAK387-2516 (hydroxy group-containing acrylic resin, manufactured by Henkel). Manufactured.

Example 33
In Example 32, the percutaneously absorbable preparation of Example 33 was produced in the same manner as in Example 25 except that oleyl alcohol was replaced with oleic acid.

Example 34
Riociguat as an active ingredient, lactic acid as a hydroxy acid (made by Musashino Chemical Laboratories), lauric acid diethanolamide (made by Wako Pure Chemical Industries) as an absorption accelerator so that the solid content after coating and drying has the following blending ratio After mixing and stirring oleyl alcohol (manufactured by Croda), Aerosil 200 as silicic anhydride (manufactured by Nippon Aerosil Co., Ltd.), and DURO TAK387-2287 (hydroxy group-containing acrylic resin, manufactured by Henkel Co., Ltd.) as an adhesive. Furthermore, after adding polyisocyanate (Coronate HL, manufactured by Tosoh Corporation) as a crosslinking agent after diluting with an appropriate amount of ethyl acetate, and mixing and stirring, a coating solution was obtained.
Ingredient name Composition ratio Riociguat 10%
Lactic acid (Musashino Chemical Laboratory) 20%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 5%
Oleyl alcohol (Croda) 10%
Aerosil200 (Nippon Aerosil Co., Ltd.) 2.5%
DURO TAK387-2287 (made by Henkel) 52.4%
Coronate HL (manufactured by Tosoh Corporation) 0.1%

  The coating solution was applied on a release film (75 μm single-sided silicon-treated PET film, film binder 75E-0010 BD: manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent was about 50 μm, and dried. A support (25 μm PET film, Lumirror T-60: manufactured by Toray Industries, Inc.) was bonded, and further heat-treated at 60 ° C. for 48 hours, whereby a transdermal absorption preparation of Example 34 was produced.

Example 35
In Example 34, the percutaneously absorbable preparation of Example 35 was produced in the same manner as in Example 34 except that oleyl alcohol was replaced with oleic acid.

Example 36
In Example 31, a coating solution of Example 36 was obtained in the same manner as in Example 31 except that the mixing ratio of oleic acid, Aerosil 200 and the pressure-sensitive adhesive was changed to the mixing ratio shown in Table 4.

The coating solution is applied on a release film (75 μm single-sided silicon-treated PET film, film binder 75E-0010 BD: manufactured by Fujimori Kogyo Co., Ltd.) so that the coating amount after evaporation of the solvent is about 8 mg / cm ² and dried. After that, it was bonded to the nonwoven fabric side of a support (PET film / PET nonwoven fabric laminate, EH-1212: manufactured by Japan Vilene Co., Ltd.) to produce the percutaneous absorption preparation of Example 36.

Example 37
In Example 36, the percutaneously absorbable preparation of Example 37 was produced in the same manner as in Example 36 except that the blending ratio of lactic acid and oleic acid was changed to the blending ratio shown in Table 4.

Comparative Example 1
In Example 1, a percutaneous absorption type preparation was produced in the same manner as in Example 1 except that the blending ratio of the rubber-based resin composition (1) was 95% instead of 85%, and lactic acid was not used. .

Comparative Examples 2-3
In Example 2, a transdermal preparation was produced in the same manner as in Example 2 except that the acid shown in Table 4 was used instead of lactic acid.

Test Example 1 In vitro skin permeability test (hairless mouse)
After pasting the percutaneous absorption preparations of Examples and Comparative Examples on the horny layer side of 7-week-old male Hos: HR-1 hairless mouse isolated skin (Labskin, manufactured by Hoshino Experimental Animal Breeding Co., Ltd.), 32 ° C. Was attached to a vertical diffusion cell (trade name: Palm Cell Vertical TP-6: manufactured by Beadrex Co., Ltd.) in which the warm water was circulated in the outer peripheral portion so that the skin basement membrane was on the receiver side. The receiver cell was filled with a 40% polyethylene glycol 400 aqueous solution, the receiver solution was sampled over time, and the amount of riociguat in the receiver solution was measured by the HPLC method. From the measurement results, the cumulative permeation amount of riociguat at 24 hours after the start of the test was calculated, and the skin permeation rate was calculated (average value of n = 3). The obtained results are shown in Tables 1 to 4.

<HPLC measurement conditions>
Apparatus: ACQUITY UPLC H-Class system (manufactured by Waters)
Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 50 mm (manufactured by Waters)
Column temperature: 40 ° C
Flow rate: 0.5mL / min
Detection wavelength: 235 nm
Mobile phase: 0.1% trifluoroacetic acid aqueous solution / acetonitrile mixture

Reference example 1
In Example 8, a percutaneous absorption type preparation was produced in the same manner as in Example 8 except that Riociguat was not used.

Reference example 2
In Example 36, a percutaneous absorption type preparation was produced in the same manner as in Example 36 except that riociguato was not used.

Test Example 2 Guinea pig skin primary irritation test A 6-week-old Hartley male guinea pig was used. The day before administration, the left and right torso parts of the guinea pig are shaved and shaved to a size of about 3 × 7 cm. On the next day of hair cutting, the percutaneous absorption preparations (15 mmφ) of Example 8, Example 36, Reference Example 1 and Reference Example 2 were affixed to the back, and fixed with an adhesive foam pad M (manufactured by 3M Healthcare). After an ethylene film tape (Keeppore A, manufactured by Nichiban Co., Ltd.) is wound around the body, it is fixed with Silky Tech (ALCARE, No. 5). 24 hours after administration, each patch was removed, and the applied site was wiped with absorbent cotton moistened with acetone. The skin reaction was observed 24, 48 and 72 hours after administration, and the skin irritation index (PI) was calculated with reference to the Draize criteria (1959) shown in Table 4 to determine the skin. Irritation was evaluated. For each test substance, a score by individual at 24, 48 and 72 hours after administration was calculated and divided by the number of observations (three times). I. I. (Individual PI) was calculated. Individual P.M. I. I. Values were summed, and the average value was calculated as P.I. I. I. It was.

  The results are shown in Table 6. The evaluation of irritation is based on P.I. I. When I. is 0, it is “non-irritant”, when it is greater than 0 and less than 2, it is “lightly irritant”, when it is 2 or more and less than 5, it is “moderately irritant”; . Statistical processing was not performed during the evaluation.

  As is apparent from Table 6, the skin irritation of the transdermal preparations of Example 8 and Example 36 was mild.

Test Example 3 In vitro skin permeability test (human skin)
After applying the percutaneous absorption preparations produced in Example 25 and Example 30 to the stratum corneum side of human skin (obtained from Caucasian, KAC) treated to about 400 μm with a dermatome, hot water at 32 ° C. was added to the outer periphery. A vertical diffusion cell (trade name: Palm Cell Vertical TP-6: manufactured by Beadrex) was attached so that the skin basement membrane was on the receiver side. The receiver cell was filled with a 40% polyethylene glycol 400 aqueous solution, the receiver solution was sampled over time, and the amount of riociguat in the receiver solution was measured by the HPLC method. From the measurement results, the cumulative permeation amount of riociguat at 24 hours after the start of the test was calculated, and the skin permeation rate was calculated (average value of n = 3). The obtained results are shown in FIG.

  As is clear from FIG. 2, the transdermally absorbable preparation of the present invention showed high skin permeability even in human skin.

Test Example 4 In vivo skin permeability test The back skin of 7-week-old male SD rats (Charles River, n = 6) was shaved with an electric clipper. The transdermal preparation (10 cm ² ) produced in Example 36 was applied to the back, and member (White Cross Co., Ltd.), Tagader Roll (manufactured by 3M Healthcare Co., Ltd.), non-woven adhesive bandage (Silky Tech, ALCARE Co., Ltd.) Was wound and pasted for 24 hours, and the preparation was removed after 24 hours. At 0.5, 1, 3, 6, 12, 20 and 24 hours after application, blood was collected from the subclavian vein under isoflurane inhalation anesthesia (about 0.35 mL), and the blood was transferred to a polypropylene container. Plasma was separated from the obtained blood by a centrifuge (4 ° C., 1000 g). The plasma obtained using Oasis was subjected to solid phase extraction, and the plasma concentration (ng / mL) of riociguat at each time was measured using LC / MS / MS, and the average value of 6 samples was calculated. Riociguat was quantified by LC / MS method. The result is shown in FIG.
<LC / MS / MS measurement conditions>
Apparatus: ACQUITY UPLC H-Class system (manufactured by Waters)
Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 50 mm (manufactured by Waters)
Detector: Xevo G2-S Q-Tof (manufactured by Waters)
Detection condition: Resolution / Positive, m / z = 423.17
Flow rate: About 0.4mL / min
Mobile phase: mixed solution of 0.1% formic acid aqueous solution and 0.1% formic acid-acetonitrile solution

  As is apparent from FIG. 3, when the transdermal preparation of the present invention is applied to rats, riociguat is continuously absorbed through the skin, and the plasma concentration is maintained above a certain level for 24 hours. It was confirmed that

  ADVANTAGE OF THE INVENTION According to this invention, the percutaneous absorption type formulation containing a riociguat which can avoid the side effect which may arise with oral administration is provided. The transdermally absorbable preparation of the present invention can provide a novel administration means effective in preventing or treating chronic thrombotic pulmonary hypertension and pulmonary arterial hypertension with high adherence and few side effects.

Claims (7)

A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer is
a) riociguat; and b) at least one acid selected from hydroxy acids or phosphoric acids;
A percutaneous absorption type preparation containing   The transdermally absorbable preparation according to claim 1, wherein the drug-containing layer contains an adhesive.   The transdermal preparation according to claim 2, wherein the pressure-sensitive adhesive contains at least one of an acrylic resin or a rubber resin as a main component.   The transdermal preparation according to any one of claims 1 to 3, wherein the drug-containing layer contains an absorption enhancer.   The absorption accelerator is at least one selected from aliphatic alcohols having 10 to 22 carbon atoms, fatty acids having 10 to 22 carbon atoms, polyoxyethylene alkyl ethers having 10 to 22 carbon atoms, fatty acid alkanolamides, and esters. The transdermally absorbable preparation according to claim 4, which is a seed.   The transdermal preparation according to any one of claims 1 to 5, wherein the drug-containing layer contains silicic anhydride.   The transdermal absorption preparation according to any one of claims 1 to 6, further comprising a release liner, wherein the support, the drug-containing layer, and the release liner are laminated in this order.

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