WO2017057541A1 - Préparation d'absorption transdermique - Google Patents

Préparation d'absorption transdermique Download PDF

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WO2017057541A1
WO2017057541A1 PCT/JP2016/078768 JP2016078768W WO2017057541A1 WO 2017057541 A1 WO2017057541 A1 WO 2017057541A1 JP 2016078768 W JP2016078768 W JP 2016078768W WO 2017057541 A1 WO2017057541 A1 WO 2017057541A1
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Prior art keywords
acid
drug
riociguat
containing layer
preparation
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PCT/JP2016/078768
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English (en)
Japanese (ja)
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加藤　卓也
傑 石川
山根　教郎
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王子ホールディングス株式会社
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Priority claimed from JP2015203480A external-priority patent/JP6459148B2/ja
Application filed by 王子ホールディングス株式会社 filed Critical 王子ホールディングス株式会社
Publication of WO2017057541A1 publication Critical patent/WO2017057541A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention relates to a percutaneous absorption preparation containing riociguat as an active ingredient.
  • Pulmonary hypertension is defined as the mean pulmonary arterial pressure (mean PAP) of 25 mmHg or more, but the cause 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 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). 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 via different binding sites even in the absence of NO stimulation. Has one mechanism.
  • As a sGC stimulator Riociguat addresses NO deficiency by restoring the NO-sGC-cGMP pathway and consequently promotes cGMP production and dilates the pulmonary artery (Non-patent Document 1).
  • Non-Patent Document 1 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.
  • 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 medication adherence by reducing the number of administrations (from 3 times / day to once / 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 that can exert 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).
  • CTEPH chronic thromboembolic pulmonary hypertension
  • PAH pulmonary arterial pulmonary hypertension
  • 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.
  • a percutaneous absorption type preparation containing [2] The transdermal preparation according to [1], wherein the drug-containing layer contains an adhesive.
  • the pressure-sensitive adhesive contains at least one of an acrylic resin or a rubber resin as a main component.
  • 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.
  • 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.
  • a method for treating or preventing chronic thromboembolic pulmonary hypertension or pulmonary arterial pulmonary hypertension wherein the transdermal absorption preparation according to any one of [1] to [7] is applied to the subject's skin
  • said method comprises transdermally administering to the subject an effective amount of riociguat.
  • the percutaneously absorbable preparation according to any one of [1] to [7] for the treatment or prevention of chronic thromboembolic pulmonary hypertension or pulmonary arterial pulmonary hypertension.
  • the present invention it is easy to maintain the blood concentration of riociguat at a level that does not cause side effects by making riociguat into a transdermal absorption preparation. 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 3 times / day for 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.
  • 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.
  • the transdermally absorbable 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. 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.
  • a matrix-type patch preparation is preferable.
  • the matrix-type patch preparation will be described as an example, but the present invention is not limited thereto.
  • 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.
  • CTEPH chronic thromboembolic pulmonary hypertension
  • Preferredary arterial hypertension is one of the clinical classifications of pulmonary hypertension (PH), and is a pathological condition in which pulmonary vascular resistance increases due to stenosis of pulmonary arterioles and blood pressure in pulmonary arteries increases.
  • CTEPH chronic thromboembolic pulmonary hypertension
  • PAH pulmonary arterial pulmonary hypertension
  • CTEPH chronic thromboocclusive pulmonary hypertension
  • PAH pulmonary arterial hypertension
  • 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 (be
  • 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.
  • a solvate for example, a hydrate, preferably a hemihydrate
  • the content of riociguat in the transdermally absorbable preparation of the present invention is an effective amount for the prevention or treatment of the target disease (for example, CTEPH or PAH).
  • 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.
  • it is preferably 0.5 to 40% by weight, more preferably 0.5 to 30% by weight, more preferably 1 to 25% by weight with respect to the drug-containing layer (ie, based on the total weight of the drug-containing layer; the same shall apply hereinafter). Is more preferable.
  • the blood concentration of Riociguat effective for the prevention or treatment of the target disease can be the same as that of the oral drug of Riociguat.
  • the skin permeation rate of riociguat 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.
  • 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 ⁇ g / cm 2 / hour, preferably 0.2 to 30 ⁇ g / cm 2 / hour, and more preferably 0.4 to 30 ⁇ g / cm 2 / hour. It is particularly preferably 0.8 to 30 ⁇ g / cm 2 / hour. If the skin permeation rate is 0.1 ⁇ g / cm 2 / hour or more, a sufficient blood concentration can be obtained. If the skin permeation rate is 30 ⁇ g / cm 2 / hour or less, the blood concentration is not too high, which is preferable from the viewpoint of safety. 2.
  • 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, ⁇ -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.
  • At least one acid selected from hydroxy acids or phosphoric acids is preferably a C 2-8 hydroxy acid or phosphoric acid, and glycolic acid, lactic acid, citric acid, salicylic acid, mandelic acid, or phosphoric acid is preferred. More preferred is lactic acid.
  • the content of the acid selected from hydroxy acid or phosphoric acid is not particularly limited as long as it can achieve a sufficient skin permeation rate of riociguat, but it is preferably 120 to 400 parts by mass with respect to 100 parts by mass of riociguat, 140 to 400 parts by mass is more preferable, and 170 to 300 parts by mass is even more preferable.
  • the content of an acid selected from hydroxy acid or phosphoric acid with respect to the drug-containing layer is preferably 0.6 to 60% by mass, more preferably 0.7 to 50% by mass, and even more preferably 1.7 to 50% by mass.
  • an acid selected from hydroxy acid or phosphoric acid 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.
  • 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.
  • 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.
  • 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 monocap
  • 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 further preferably 0.2 to 25% by mass with respect to the drug-containing layer.
  • 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.
  • 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.
  • acrylic resins include (meth) acrylic acid esters represented by monomer units such as 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate, and the like. Examples thereof include a polymer or copolymer containing at least one kind.
  • 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 acid 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 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: made by Hen
  • rubber resins examples 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.
  • SIS styrene-isoprene-styrene block copolymer
  • SBS styrene-butadiene-styrene block copolymer
  • SBR styrene-butadiene rubber
  • PIB polyisobutylene
  • silicone resins include polymers having an organopolysiloxane skeleton and derivatives thereof, and specific examples include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, and diphenylsiloxane.
  • a commercially available silicone resin such as BIO-PSA series (manufactured by Dow Corning) may also be used.
  • 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.
  • the adhesive is a rubber-based resin
  • the content of the adhesive is preferably 5 to 98.9% by mass, more preferably 10 to 98.8% by mass, and more preferably 15 to 97.3% by mass with respect to the drug-containing layer. % Is more preferable.
  • the content of the adhesive is preferably 15 to 98.9% by mass, more preferably 18 to 98.8% by mass, and more preferably 20 to 97.3% by mass with respect to the drug-containing layer. % Is more preferable.
  • the adhesive is a silicone resin, it is preferably 15 to 98.9% by mass, more preferably 18 to 98.8% by mass, and further preferably 20 to 97.3% by mass with respect to the drug-containing layer. 5.
  • the drug-containing layer may further contain a tackifier to improve the adhesive strength.
  • tackifier examples 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.
  • rosin derivatives such as rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin,
  • 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.
  • 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 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 further preferable.
  • an acrylic resin is used as the adhesive, it 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.
  • a silicone resin is used as the adhesive, it is preferably 0 to 30% by mass, more preferably 0 to 20% by mass, and still more preferably 0 to 10% by mass with respect to the drug-containing layer. 6.
  • 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.
  • petroleum oils eg, paraffinic process oil, naphthenic process oil, aromatic process oil, liquid paraffin, etc.
  • squalane equalene
  • vegetable oils eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil, etc.
  • silicone oil eg, dibasic acid ester (eg, dibutyl phthalate,
  • plasticizer you may use suitably what is marketed, such as the Moresco white series (made by Moresco), the high call series (made by Kaneda).
  • 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.
  • a rubber-based resin is used as the adhesive, it is preferably 0 to 70% by mass, more preferably 0 to 60% by mass, and further preferably 0 to 40% by mass with respect to the drug-containing layer.
  • an acrylic resin is used as the adhesive, it is preferably 0 to 50% by mass, more preferably 0 to 40% by mass, and still more preferably 0 to 30% by mass with respect to the drug-containing layer.
  • the anhydrous silicic acid drug-containing layer may further contain anhydrous silicic acid.
  • 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 (BET method) of silicic anhydride is not particularly limited, but is preferably 20 to 400 m 2 / g, more preferably 50 to 350 m 2 / g.
  • the content of silicic 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 strength as a transdermal preparation and adhesive strength. Preferably, 0.2 to 8% by mass is more preferable.
  • 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 adjuster 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, and improving the safety to the skin.
  • 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.
  • 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.
  • antioxidants examples include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like.
  • colorant examples 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 thereof include sodium oxide, talc, copper chlorophyllin sodium, green leaf extract powder, d-borneol, octyldodecyl myristate, methylene blue, ammonium manganese phosphate, and rose oil.
  • ultraviolet absorbers examples 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.
  • silicate eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate Sodium
  • magnesium hydroxide eg, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.
  • preservatives examples include ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.
  • the total content of other optional components is preferably 0 to 10% by mass, more preferably 0 to 5% by mass with respect to the drug-containing layer.
  • 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 to 140 cm 2 , preferably 2 to 100 cm 2 , more preferably 4 to 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 transdermally absorbable preparation of the present invention can be appropriately adjusted according to the type of 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 ⁇ m, preferably 30 to 200 ⁇ m, more preferably 30 ⁇ m to 150 ⁇ m.
  • One embodiment of the drug-containing layer in the transdermal preparation of the present invention includes one containing an acid selected from riociguat and hydroxy acid or phosphoric acid (see [1] above).
  • 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.
  • an acid selected from riociguat, hydroxy acid or phosphoric acid and an adhesive are preferably contained.
  • an adhesive what contains an acrylic resin as a main component is preferable.
  • the acrylic resin a polymer or copolymer containing at least one (meth) acrylic acid ester is preferable.
  • those containing a rubber-based resin as a main component are also preferable.
  • SIS is particularly preferable as the rubber-based resin.
  • 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
  • the content of adhesive is 10 to 98.%. It is preferably 9% by mass.
  • an acid selected from riociguat, hydroxy acid or phosphoric acid, an adhesive and an absorption accelerator.
  • an adhesive what contains an acrylic resin as a main component is preferable.
  • the acrylic resin a polymer or copolymer containing at least one (meth) acrylic acid ester is preferable.
  • those containing a rubber-based resin as a main component are also preferable.
  • SIS is particularly preferable as the rubber-based resin.
  • Absorption accelerators are selected from the group consisting of 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. At least one selected is preferred.
  • 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
  • the content of adhesive is 10 to 98.%. It is preferable that the content of the absorption accelerator is 8% by mass and 0.1 to 30% by mass.
  • 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.
  • the transdermally absorbable preparation of the present invention may further have a release liner.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the content of the organic solvent in the coating solution is not particularly limited, and is, for example, 30 to 90% by mass, preferably 40 to 80% by mass with respect to the entire coating solution.
  • 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.
  • 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.
  • 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.
  • a percutaneously absorbable preparation can be produced by pasting a support.
  • a transdermal preparation may be produced by laminating a release liner.
  • 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.
  • Riociguat 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.
  • it can be applied to the upper arm, abdomen, chest, neck, waist back, buttocks or legs. Can be pasted.
  • the transdermal administration of the transdermal preparation of the present invention to a subject may be combined with the administration of a pharmaceutical composition containing a pharmaceutical ingredient other than riociguat, if necessary.
  • the administration form may be simultaneous administration or administration with a time difference
  • the pharmaceutical composition may be intravenous, intraperitoneal, subcutaneous and intramuscular, oral, topical or transmucosal. It can be administered by various routes including:
  • 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.
  • 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.
  • 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 has the following blending ratio Derivatives (manufactured by Arakawa Chemical Co., Ltd.) and Haicol M-352 (liquid paraffin, Kaneda) were dissolved in toluene to obtain a 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
  • 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.
  • 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).
  • Quintac 3570C styrene-isoprene-styrene block copolymer, manufactured by Nippon Zeon Co., Ltd.
  • pine crystal KE-311 ultra-light rosin
  • 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.
  • 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
  • oleyl alcohol manufactured by Croda
  • Aerosil 200 manufactured by Nippon Aerosil Co., Ltd.
  • DURO TAK87-4098 non-functional acrylic resin, manufactured by Henkel
  • 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
  • oleyl alcohol manufactured by Croda
  • Aerosil200 manufactured by Nippon Aerosil Co., Ltd.
  • DURO TAK387-2287 hydroxy group-containing acrylic resin, manufactured by Henkel
  • Example 34 A support (25 ⁇ m PET film, Lumirror T-60: manufactured by Toray Industries, Inc.) was bonded, and further heat-treated at 60 ° C. for 48 hours to produce a transdermal absorption preparation of Example 34.
  • 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.
  • 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.
  • 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 applying the percutaneous absorption preparations of Examples and Comparative Examples to the stratum corneum 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 installed in a vertical diffusion cell (trade name: Palm Cell Vertical TP-6: manufactured by Beadrex) with the warm water of the water circulated on the outer periphery 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.
  • 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 mm ⁇ ) 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).
  • 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 ⁇ m 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 Co., Ltd.) circulated in the cell was attached so that the skin basement membrane was on the receiver side.
  • a vertical diffusion cell trade name: Palm Cell Vertical TP-6: manufactured by Beadrex Co., Ltd.
  • Member White Cross Co., Ltd.
  • Tagader Roll manufactured by 3M Healthcare Co., Ltd.
  • non-woven adhesive bandage Silky Tech, ALCARE Co., Ltd.
  • transdermal absorption-type preparation containing riociguat that can avoid side effects that may occur with oral administration.
  • 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.

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Abstract

La présente invention concerne une préparation d'absorption transdermique comprenant un support et une couche contenant un médicament, la couche contenant le médicament comprenant du riociguat à titre de principe actif, et un hydroxyacide ou acide phosphorique.
PCT/JP2016/078768 2015-09-29 2016-09-29 Préparation d'absorption transdermique WO2017057541A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210369769A1 (en) * 2018-11-02 2021-12-02 Dyve Biosciences, Inc. Management of risk of cation overload and electrolyte imbalance with topically applied buffers

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08225448A (ja) * 1995-02-23 1996-09-03 Sekisui Chem Co Ltd 局所麻酔用経皮吸収テープ
JPH09110681A (ja) * 1995-10-16 1997-04-28 Sekisui Chem Co Ltd 貼付剤
JP2007511605A (ja) * 2003-11-18 2007-05-10 スリーエム イノベイティブ プロパティズ カンパニー オランザピン含有経皮薬物送達組成物
WO2014105480A1 (fr) * 2012-12-28 2014-07-03 Teikoku Pharma Usa, Inc. Compositions de buprénorphine à libération transdermique prolongée et leurs méthodes d'utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08225448A (ja) * 1995-02-23 1996-09-03 Sekisui Chem Co Ltd 局所麻酔用経皮吸収テープ
JPH09110681A (ja) * 1995-10-16 1997-04-28 Sekisui Chem Co Ltd 貼付剤
JP2007511605A (ja) * 2003-11-18 2007-05-10 スリーエム イノベイティブ プロパティズ カンパニー オランザピン含有経皮薬物送達組成物
WO2014105480A1 (fr) * 2012-12-28 2014-07-03 Teikoku Pharma Usa, Inc. Compositions de buprénorphine à libération transdermique prolongée et leurs méthodes d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Shin Iyakuhin no 'Shiyojo no Chui' no Kaisetsu", April 2014 (2014-04-01), pages 1 - 25, Retrieved from the Internet <URL:http://www.adempas.jp/static/pdf/doctor/careful.pdf> [retrieved on 20161215] *
BONDERMAN, DIANA ET AL.: "Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction:A phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study", CIRCULATION, vol. 128, no. 5, 2013, pages 502 - 511, XP055375814, ISSN: 0009-7322 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210369769A1 (en) * 2018-11-02 2021-12-02 Dyve Biosciences, Inc. Management of risk of cation overload and electrolyte imbalance with topically applied buffers

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