WO2015125969A1 - Transdermal preparation comprising triptan-type medicine - Google Patents

Transdermal preparation comprising triptan-type medicine Download PDF

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WO2015125969A1
WO2015125969A1 PCT/JP2015/055223 JP2015055223W WO2015125969A1 WO 2015125969 A1 WO2015125969 A1 WO 2015125969A1 JP 2015055223 W JP2015055223 W JP 2015055223W WO 2015125969 A1 WO2015125969 A1 WO 2015125969A1
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phosphatidylcholine
liquid
triptan
propylene glycol
drug
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French (fr)
Japanese (ja)
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山崎　啓子
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株式会社メドレックス
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents

Definitions

  • the present invention relates to a transdermal preparation of a triptan-based drug.
  • the present invention relates to a liquid composition containing a triptan drug and phosphatidylcholine.
  • Triptan drugs are used for the treatment of migraine, and oral preparations, nasal preparations, injections and the like are available.
  • oral preparations such as tablets are most widely used, but it is often difficult to take oral preparations due to nausea and vomiting associated with migraine.
  • a transdermal preparation is expected and studied as a dosage form that can be reliably administered even in such a case (for example, Patent Document 1).
  • a transdermal preparation represented by a patch takes time to achieve a sufficient blood concentration, the preparation should be applied to the skin.
  • a percutaneous absorption preparation that can quickly absorb a drug in a short time.
  • An object of the present invention is to provide a percutaneous absorption preparation capable of rapidly transdermally absorbing a triptan-based drug.
  • the inventors have The present inventors have found that the above problems can be solved by a solution containing a triptan-based drug, phosphatidylcholine, and propylene glycol, and completed the present invention.
  • the gist of the present invention is as follows.
  • a liquid-type patch preparation comprising a porous resin body impregnated with a transdermal solution containing a triptan-based drug or a salt thereof, phosphatidylcholine, and propylene glycol, and not containing a hydrophobic solvent.
  • the transdermal absorption liquid is a colloid dispersion in which a triptan drug or a salt thereof is colloidally dispersed in propylene glycol or a propylene glycol-containing liquid in the presence of phosphatidylcholine.
  • the percutaneous absorption type liquid preparation of the present invention is excellent in skin permeability of a triptan-based drug, and achieves a sufficient blood concentration in a short time after application to the skin.
  • the transdermal absorption liquid preparation of the present invention has a greatly reduced decrease in the content of triptan drugs even after long-term storage, and provides a preparation excellent in storage stability.
  • the liquid patch preparation of the present invention has both rapid transdermal absorbability of drugs and good handleability.
  • FIG. 1 is a graph showing the results of a rat skin permeation test of the transdermal absorption liquid preparations prepared in Example 2, Example 4 and Comparative Example 3.
  • FIG. 2 is a photograph showing an example of the liquid patch of the present invention.
  • FIG. 3 is a graph showing the results of a rat blood concentration evaluation test of the transdermal solution prepared in Example 2.
  • the percutaneous absorption type liquid preparation of the present invention contains a triptan type drug or a salt thereof, phosphatidylcholine, and propylene glycol.
  • it is a colloidal dispersion in which a triptan drug or a salt thereof and phosphatidylcholine are colloidally dispersed in propylene glycol or a propylene glycol-containing liquid.
  • the “propylene glycol-containing liquid” refers to propylene glycol in which a solubilizing agent such as water and / or a hydrophilic solvent is dissolved and mixed, as described in detail below.
  • colloidal dispersion liquid refers to a liquid that exhibits a clear Tyndall phenomenon when irradiated with a red laser beam.
  • the average particle size of the dispersoid (colloid particles) in the colloidal dispersion of the present invention is 0.05 to 0.5 ⁇ m, preferably 0.05 to 0.2 ⁇ m, and around 0.1 ⁇ m (0. 04-0.15 ⁇ m), which has the mode of particle diameter.
  • Triptan drugs is a general term for migraine treatments having a tryptamine skeleton, and specifically includes sumatriptan, rizatriptan, naratriptan, eletriptan, zolmitriptan, almotriptan, flovatriptan, abi A triptan etc. can be illustrated.
  • the “salt of triptan drug” is not particularly limited, and examples thereof include succinate, benzoate, tartrate, maleate, mesylate, hydrochloride, hydrobromide and the like.
  • the “triptan drug” sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan are preferable, and the improvement in skin permeability is particularly remarkable, so that rizatriptan and sumatriptan are particularly preferable. preferable.
  • the content of triptans can be selected from the range of usually 1 to 20% by weight, preferably 5 to 15% by weight.
  • Phosphatidylcholine is a general term for compounds represented by the formula (I), and is usually provided as a mixture of different types and combinations of R 1 and R 2 .
  • R 1 and R 2 are the same or different and represent a C 12-22 hydrocarbon group
  • unsaturated phosphatidylcholine in which at least one of R 1 and R 2 is an unsaturated hydrocarbon group can be used.
  • R 1 and R 2 may contain saturated hydrocarbon groups such as palmityl group (16: 0) and stearyl group (18: 0), but unsaturated phosphatidylcholine which can be used in the present invention has such saturated carbonization.
  • the hydrogen group content is less than 80%, preferably less than 70%, more preferably less than 60%, and particularly preferably less than 50%.
  • the unsaturated hydrocarbon group include a paremitrayl group (16: 1), an oleyl group (18: 1), a linoleyl group (18: 2), and a linolenyl group (18: 3).
  • the unsaturated phosphatidylcholine preferably has a content of unsaturated hydrocarbon groups having 18 carbon atoms such as an oleyl group, a linoleyl group, and a linolenyl group of 20% or more, more preferably 30% or more, and particularly preferably. Is 40% or more.
  • unsaturated phosphatidylcholine is used, a stable colloidal dispersion excellent in skin permeability can be prepared.
  • the unsaturated phosphatidylcholine a high-purity phosphatidylcholine which is naturally derived from soybean lecithin, egg yolk lecithin and the like and has a phosphatidylcholine content of 95% or more can be preferably used.
  • phosphatidylcholine that has been chemically and / or biologically modified such as hydrogenated phosphatidylcholine that has been subjected to hydrogenation treatment or lysophosphatidylcholine obtained by enzymatic treatment, a stable colloidal dispersion may not be obtained. It is not preferable.
  • a phosphatidylcholine that has been chemically and / or biologically modified such as a partially hydrogenated natural lecithin, has a high degree of unsaturation and high purity phosphatidylcholine (for example, the iodine value is 20 or more, Lysolecithin content of less than 10%) can be used as the “unsaturated phosphatidylcholine” of the present invention.
  • the iodine value is 20 or more, Lysolecithin content of less than 10%
  • the effect of improving transdermal absorbability of the drug is inferior.
  • the content of phosphatidylcholine is usually selected from 0.1 to 5% by weight, preferably 0.2 to 3% by weight, more preferably 0.3 to 2.0% by weight, particularly preferably 0.3 to 1.5% by weight. % By weight. If the phosphatidylcholine content is less than 0.1% by weight, a stable colloidal dispersion may not be formed, which is not preferable. Even when phosphatidylcholine is added in excess of 5% by weight, the skin permeability is not improved depending on the increase in the phosphatidylcholine content.
  • the solution of the present invention in which triptans and phosphatidylcholine are colloidally dispersed in propylene glycol or propylene glycol is excellent in storage stability and skin permeability. However, if it further contains alkanolamine as an absorption enhancer, the drug penetrates the skin. Sexually improves.
  • alkanolamine primary, secondary, or tertiary alkanolamine having 2 to 12 carbon atoms can be used. Of these, secondary or tertiary alkanolamines are preferred, and tertiary alkanolamines are particularly preferred. Specific examples include diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. Triethanolamine is particularly preferable because of its excellent skin permeation promoting effect.
  • the alkanolamine content is appropriately selected from the range of 0.1 to 10% by weight, preferably 1 to 10% by weight, particularly preferably 3 to 5% by weight.
  • the alkanolamine content is within the above range, an increase in the skin permeability of the drug is recognized as the alkanolamine content increases. Even if the alkanolamine content exceeds 10% by weight, the alkanolamine content is increased. Dependence on skin permeability is not improved.
  • the colloidal dispersion of the present invention is produced by mixing a triptan-based drug dissolved in propylene glycol and phosphatidylcholine dissolved in propylene glycol.
  • a solubilizing agent such as water and polyethylene glycol can be added to form a propylene glycol-containing liquid, and the triptan-based drug can be dissolved in the propylene glycol-containing liquid.
  • the addition amount of the solubilizing agent is selected from a range in which the content of propylene glycol in the propylene glycol-containing liquid is 50% by weight or more, preferably 60% by weight or more, and particularly preferably 65% by weight or more. When the amount of the solubilizing agent is large and the content of propylene glycol is small, a stable colloid expressing good drug skin permeability may not be formed, which is not preferable.
  • the propylene glycol-containing liquid may further contain a hydrophilic solvent miscible with propylene glycol as necessary.
  • a hydrophilic solvent miscible with propylene glycol as necessary.
  • Specific examples include polyhydric alcohols such as glycerin and 1,3-butanediol.
  • the content of such a hydrophilic solvent is less than 10% by weight of the propylene glycol-containing liquid.
  • polyhydric alcohols such as glycerin and butanediol
  • the use of these polyhydric alcohols as a substitute for propylene glycol is not suitable for the colloidal liquid of the present invention.
  • phosphatidylcholine when phosphatidylcholine is added to glycerin, liquid turbidity and aggregation of phosphatidylcholine on the liquid surface are observed, and phosphatidylcholine alone tends to form an associated colloid. Furthermore, after drug addition, it tends to gel.
  • 1,3-butanediol is used, phosphatidylcholine is completely dissolved as a molecule as in the case of propylene glycol.
  • aggregation and precipitation occur in a short time after addition of the drug, unlike in the case of propylene glycol. Tend.
  • the liquid agent of the present invention does not contain a hydrophobic solvent.
  • the “hydrophobic solvent” is an oily solvent that does not dissolve in propylene glycol at an arbitrary ratio.
  • hydrocarbons such as liquid paraffin and squalene; higher fatty acids such as oleic acid, lauric acid, myristic acid, palmitic acid and stearic acid; higher alcohols such as cetyl alcohol, stearyl alcohol and myristyl alcohol;
  • fatty acid esters such as isopropyl myristate, isopropyl palmitate, and butyl stearate; and vegetable oils such as olive oil, camellia oil, and jojoba oil.
  • the colloidal dispersion of the present invention contains propylene glycol in an amount of 60% by weight or more, and is composed only of components that are soluble in propylene glycol or a propylene glycol-containing liquid.
  • Additives that can be added include fragrances, antioxidants, preservatives, colorants, buffers, pH adjusters, and the like.
  • fragrances include ethanol and orange essence.
  • antioxidant include tocopherol acetate, sodium edetate, erythorbic acid, 1,3-butylene glycol, sodium pyrosulfite and the like.
  • preservative include sorbic acid and taurine.
  • pH regulator include organic acids such as citric acid, acetic acid and tartaric acid; and inorganic acids such as phosphoric acid and hydrochloric acid.
  • an ultraviolet absorber or an antibacterial agent can be added according to the purpose.
  • the colloidal dispersion of the present invention can be produced by mixing a triptan-based drug dissolved in propylene glycol or a propylene glycol-containing liquid and phosphatidylcholine dissolved in propylene glycol or a propylene glycol-containing liquid.
  • a triptan-based drug dissolved in propylene glycol or a propylene glycol-containing liquid
  • phosphatidylcholine dissolved in propylene glycol or a propylene glycol-containing liquid.
  • the solution becomes a true solution, and a particle diameter of 10 nm or more is not observed.
  • the Tyndall phenomenon is not observed in any of these triptan-based drug solutions and phosphatidylcholine solutions.
  • a colloidal dispersion exhibiting a Tyndall phenomenon is obtained, and the mode value of the particle diameter is observed around 100 nm.
  • a solution (solution I) in which a triptan drug is dissolved in propylene glycol or a propylene glycol-containing liquid, and phosphatidyl choline dissolved in propylene glycol or a propylene glycol-containing liquid As a method of mixing a dissolved triptan drug and a dissolved phosphatidyl choline, a solution (solution I) in which a triptan drug is dissolved in propylene glycol or a propylene glycol-containing liquid, and phosphatidyl choline dissolved in propylene glycol or a propylene glycol-containing liquid.
  • Each of the prepared solutions (liquid II) is prepared, and the liquid I and liquid II are mixed; the phosphatidylcholine is added to the liquid I and mixed; the method of adding a triptan-based drug to the liquid II; and propylene glycol or propylene
  • a method of simultaneously adding a triptan-based drug and phosphatidylcholine to the glycol liquid can be exemplified and is not particularly limited.
  • the method of preparing each of liquid I and liquid II and mixing them is excellent in that it can be confirmed with certainty that the triptan-based drug and phosphatidylcholine are in a dissolved state.
  • a stable colloidal dispersion having an average particle diameter of 50 to 500 nm can be obtained by mixing and stirring a dissolved triptan drug and a dissolved phosphatidylcholine.
  • Alkanolamine and other additives can be added at any time.
  • the method for applying the solution of the present invention to the skin is not particularly limited, and examples thereof include a method of applying or spraying the solution, and a method of attaching an appropriate carrier carrying the solution on the skin.
  • the liquid patch preparation in which the carrier is impregnated with the percutaneous absorption type liquid preparation of the present invention does not impair the excellent percutaneous absorption characteristics of the liquid preparation, and the dose can be easily set.
  • a porous resin sheet having a fine pore structure with a pore diameter of about 10 to 150 ⁇ m can be used.
  • the resin constituting the porous resin sheet include polyurethane, polyethylene, polypropylene, polystyrene, polyvinyl acetate, polyethylene terephthalate, and ethylene-vinyl acetate copolymer.
  • a porous resin sheet made of polyurethane, that is, a foamed urethane sheet is preferable from the viewpoints of versatility and handling.
  • the liquid-type patch preparation may have a form in which one surface of the porous resin sheet is coated with a liquid-impermeable sheet.
  • FIG. 2 is a photograph showing an example of a liquid-type patch preparation in which one surface of a porous resin sheet is covered with a liquid-impermeable sheet and the periphery is sealed by thermocompression bonding.
  • Example 1 and Examples 2 to 4 containing phosphatidylcholine significantly improved the skin permeability of the triptan-based drug compared with the solutions of Comparative Example 1 and Comparative Examples 2 and 3 not containing phosphatidylcholine.
  • the liquid preparations of Examples 2 and 3 showed further superior skin permeability compared to the liquid preparation of Example 4 by containing triethanolamine.
  • Example 2 In vivo blood concentration evaluation test using rats
  • the liquid preparation prepared in Example 2 was impregnated into urethane foam (thickness: 0.5 mm, area of about 6 cm 2 , discontinuous cell type) to prepare a liquid-type patch.
  • the prepared liquid patch was applied to the back of a rat (5 weeks old, male), and the change in blood concentration of the rat was evaluated according to a conventional method.
  • the change in the blood concentration of Rizatriptan is shown in FIG.
  • the blood concentration of the human was estimated from the blood concentration of the rat by body surface area conversion.
  • the area of application to humans was calculated as 20 cm 2 .
  • the results are shown in Table 2 below.
  • T max when humans are administered 10 mg of Rizatriptan tablets is 1 hour on average
  • C max is 20 ng / mL on average.
  • Example 2 Liquid drug stability evaluation test
  • the solution prepared in Example 2 was stored in an environment of 40 ° C. and 75% humidity, and the content of rizatriptan was evaluated.
  • the results are shown in Table 3 below as a ratio to the initial content.
  • transdermal absorption liquid preparation and liquid patch preparation of the present invention can be used as a transdermal preparation of a triptan drug excellent in skin permeability and storage stability.

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Abstract

The present invention provides: a transdermal liquid preparation which comprises a triptan-type medicine; and a liquid-type adhesive skin patch which is produced by impregnating a resin porous sheet with the transdermal liquid preparation. The transdermal liquid preparation according to the present invention contains a triptan-type medicine or a salt thereof, phosphatidylcholine and propylene glycol, and does not contain a hydrophobic solvent. It is preferred that the transdermal liquid preparation according to the present invention additionally contains an alkanolamine. Examples of the triptan-type medicine include sumatriptan, zolmitriptan, eletriptan, rizatriptan and naratriptan. As the alkanol amine, triethanolamine can be used preferably.

Description

トリプタン系薬剤の経皮吸収型製剤Transdermal preparation of triptan drugs
　本発明は、トリプタン系薬剤の経皮吸収製剤に関する。特に、トリプタン系薬剤とホスファチジルコリンを含む液剤組成物に関する。 The present invention relates to a transdermal preparation of a triptan-based drug. In particular, the present invention relates to a liquid composition containing a triptan drug and phosphatidylcholine.
　トリプタン系薬剤は片頭痛の治療に用いられ、経口製剤、点鼻製剤、注射剤などが入手可能である。これらの中で、錠剤等の経口製剤が最も広く用いられるが、片頭痛に伴う悪心、嘔吐の症状により、経口剤の服用が困難となる場合も少なくない。経皮吸収型製剤は、このような場合でも確実に投与可能な剤型として期待され、検討されている（例えば、特許文献１）。しかし、貼付剤に代表される経皮吸収型製剤は、十分な血中濃度を達成するまでに時間を要するため、製剤を皮膚に適用後。短時間で速やかに薬剤が吸収される経皮吸収型製剤が望まれていた。 Triptan drugs are used for the treatment of migraine, and oral preparations, nasal preparations, injections and the like are available. Among these, oral preparations such as tablets are most widely used, but it is often difficult to take oral preparations due to nausea and vomiting associated with migraine. A transdermal preparation is expected and studied as a dosage form that can be reliably administered even in such a case (for example, Patent Document 1). However, since a transdermal preparation represented by a patch takes time to achieve a sufficient blood concentration, the preparation should be applied to the skin. There has been a demand for a percutaneous absorption preparation that can quickly absorb a drug in a short time.
国際公開第２００７／０９４８７６号International Publication No. 2007/094876
　本発明は、トリプタン系薬剤を速やかに経皮吸収できる　経皮吸収型製剤を提供することを目的とする。 An object of the present invention is to provide a percutaneous absorption preparation capable of rapidly transdermally absorbing a triptan-based drug.
　本発明者らは、
トリプタン系薬剤、ホスファチジルコリン、及びプロピレングリコールを含む液剤により上記課題を解決し得ることを見出し、本発明を完成した。本願発明の要旨は以下のとおりである。 The inventors have
The present inventors have found that the above problems can be solved by a solution containing a triptan-based drug, phosphatidylcholine, and propylene glycol, and completed the present invention. The gist of the present invention is as follows.
１）　トリプタン系薬剤又はその塩、ホスファチジルコリン、及びプロピレングリコールを含み、疎水性溶媒を含まない、経皮吸収型液剤。
２）　トリプタン系薬剤またはその塩が、ホスファチジルコリンの存在下にプロピレングリコール又はプロピレングリコール含有液中でコロイド分散したコロイド分散液である、上記１）に記載の経皮吸収型液剤。
３）　さらに、アルカノールアミンを含む、上記１）又は２）に記載の経皮吸収型液剤。
４）　トリプタン系薬剤が、スマトリプタン、ゾルミトリプタン、エレトリプタン、リザトリプタン、ナラトリプタンから成る群より選択される、上記１）～３）のいずれかに記載の経皮吸収型液剤。
５）　アルカノールアミンが、トリエタノールアミンである、上記３）又は４）に記載の経皮吸収型液剤。
６）　ホスファチジルコリンの含有量が、０．１～５重量％である、上記１）～５）いずれかの項に記載の経皮吸収型液剤。
７）　ホスファチジルコリンが、卵黄ホスファチジルコリン、大豆ホスファチジルコリンの中から一つ以上選択される、上記１）～６）いずれかの項に記載の経皮吸収型液剤。 1) A percutaneous absorption type liquid preparation containing a triptan type drug or a salt thereof, phosphatidylcholine, and propylene glycol and not containing a hydrophobic solvent.
2) The percutaneous absorption type liquid preparation according to 1) above, wherein the triptan type drug or a salt thereof is a colloidal dispersion obtained by colloidal dispersion in propylene glycol or a propylene glycol-containing liquid in the presence of phosphatidylcholine.
3) The percutaneous absorption type liquid preparation according to 1) or 2), further comprising an alkanolamine.
4) The transdermal drug solution according to any one of 1) to 3) above, wherein the triptan drug is selected from the group consisting of sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan.
5) The transdermal absorption liquid preparation according to 3) or 4) above, wherein the alkanolamine is triethanolamine.
6) The transdermal solution according to any one of 1) to 5) above, wherein the content of phosphatidylcholine is 0.1 to 5% by weight.
7) The transdermal solution according to any one of 1) to 6) above, wherein the phosphatidylcholine is selected from at least one of egg yolk phosphatidylcholine and soybean phosphatidylcholine.
８）　トリプタン系薬剤又はその塩、ホスファチジルコリン、及びプロピレングリコールを含み、疎水性溶媒を含まない経皮吸収型液剤を、樹脂多孔体に含浸して成る液型貼付製剤。
９）　前記経皮吸収型液剤が、トリプタン系薬剤又はその塩が、ホスファチジルコリンの存在下にプロピレングリコール又はプロピレングリコール含有液中でコロイド分散したコロイド分散液である、上記８）に記載の液型貼付製剤。
１０）　前記経皮吸収型液剤が、さらにアルカノールアミンを含む、請求項９）又は１０）に記載の液型貼付製剤。 8) A liquid-type patch preparation comprising a porous resin body impregnated with a transdermal solution containing a triptan-based drug or a salt thereof, phosphatidylcholine, and propylene glycol, and not containing a hydrophobic solvent.
9) The liquid patch according to 8) above, wherein the transdermal absorption liquid is a colloid dispersion in which a triptan drug or a salt thereof is colloidally dispersed in propylene glycol or a propylene glycol-containing liquid in the presence of phosphatidylcholine. Formulation.
10) The liquid-type patch preparation according to claim 9) or 10), wherein the transdermal absorption-type liquid preparation further contains an alkanolamine.
　本発明の経皮吸収型液剤は、トリプタン系薬剤の皮膚透過性に優れ、皮膚に適用後短時間で十分な血中濃度を達成する。また、本発明の経皮吸収型液剤は、長期保存後もトリプタン系薬剤の含量低下が極めて低減されており、保存安定性に優れた製剤が提供される。 The percutaneous absorption type liquid preparation of the present invention is excellent in skin permeability of a triptan-based drug, and achieves a sufficient blood concentration in a short time after application to the skin. In addition, the transdermal absorption liquid preparation of the present invention has a greatly reduced decrease in the content of triptan drugs even after long-term storage, and provides a preparation excellent in storage stability.
　本発明の液型貼付製剤は、速やかな薬剤の経皮吸収性及び、良好な取扱い性を兼ね備えている。 The liquid patch preparation of the present invention has both rapid transdermal absorbability of drugs and good handleability.
図１は、実施例２、実施例４及び比較例３で調製した経皮吸収型液剤の、ラット皮膚透過試験の結果を示すグラフである。FIG. 1 is a graph showing the results of a rat skin permeation test of the transdermal absorption liquid preparations prepared in Example 2, Example 4 and Comparative Example 3. 図２は、本発明の液型貼付剤の一例を示す写真である。FIG. 2 is a photograph showing an example of the liquid patch of the present invention. 図３は、実施例２で調製した経皮吸収型液剤の、ラット血中濃度評価試験の結果を示すグラフである。FIG. 3 is a graph showing the results of a rat blood concentration evaluation test of the transdermal solution prepared in Example 2.
　本発明の経皮吸収型液剤は、トリプタン系薬剤又はその塩と、ホスファチジルコリンと、プロピレングリコールとを含む。好ましくは、トリプタン系薬剤又はその塩及びホスファチジルコリンが、プロピレングリコール又はプロピレングリコール含有液中にコロイド分散したコロイド分散液となっている。本明細書において、『プロピレングリコール含有液』とは、下記詳述するが、水等の溶解補助剤及び／又は親水性溶媒を溶解混合したプロピレングリコールを示す。 The percutaneous absorption type liquid preparation of the present invention contains a triptan type drug or a salt thereof, phosphatidylcholine, and propylene glycol. Preferably, it is a colloidal dispersion in which a triptan drug or a salt thereof and phosphatidylcholine are colloidally dispersed in propylene glycol or a propylene glycol-containing liquid. In the present specification, the “propylene glycol-containing liquid” refers to propylene glycol in which a solubilizing agent such as water and / or a hydrophilic solvent is dissolved and mixed, as described in detail below.
　本明細書において『コロイド分散液』とは、赤色レーザー光で照射することによって明確なチンダル現象を呈する液体を示す。本発明のコロイド分散液における分散質（コロイド粒子）の平均粒子径は、０．０５～０．５μｍであり、好ましくは０．０５～０．２μｍである、また、０．１μｍ付近（０．０４～０．１５μｍ）に粒子径の最頻値を有する。 In this specification, “colloid dispersion liquid” refers to a liquid that exhibits a clear Tyndall phenomenon when irradiated with a red laser beam. The average particle size of the dispersoid (colloid particles) in the colloidal dispersion of the present invention is 0.05 to 0.5 μm, preferably 0.05 to 0.2 μm, and around 0.1 μm (0. 04-0.15 μm), which has the mode of particle diameter.
　『トリプタン系薬剤』とは、トリプタミン骨格を有する片頭痛治療薬の総称であり、具体的には、スマトリプタン、リザトリプタン、ナラトリプタン、エレトリプタン、ゾルミトリプタン、アルモトリプタン、フロバトリプタン、アビトリプタン等を例示できる。『トリプタン系薬剤の塩』としては、特に制限されないが、コハク酸塩、安息香酸塩、酒石酸塩、マレイン酸塩、メシル酸塩、塩酸塩、臭化水素酸塩等が例示できる。本発明において、『トリプタン系薬剤』としては、スマトリプタン、ゾルミトリプタン、エレトリプタン、リザトリプタン、ナラトリプタンが好ましく、皮膚透過性の向上がとりわけ顕著であることから、リザトリプタン、スマトリプタンが特に好ましい。 “Triptan drugs” is a general term for migraine treatments having a tryptamine skeleton, and specifically includes sumatriptan, rizatriptan, naratriptan, eletriptan, zolmitriptan, almotriptan, flovatriptan, abi A triptan etc. can be illustrated. The “salt of triptan drug” is not particularly limited, and examples thereof include succinate, benzoate, tartrate, maleate, mesylate, hydrochloride, hydrobromide and the like. In the present invention, as the “triptan drug”, sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan are preferable, and the improvement in skin permeability is particularly remarkable, so that rizatriptan and sumatriptan are particularly preferable. preferable.
　トリプタン系薬剤の含有量は、通常、１～２０重量％、好ましくは５～１５重量％の範囲から選択することができる。 The content of triptans can be selected from the range of usually 1 to 20% by weight, preferably 5 to 15% by weight.
　ホスファチジルコリンは、式（Ｉ）で示される化合物の総称であり、通常、Ｒ１及びＲ２の種類及び組み合わせの異なる混合物として提供される。 Phosphatidylcholine is a general term for compounds represented by the formula (I), and is usually provided as a mixture of different types and combinations of R 1 and R 2 .
Figure JPOXMLDOC01-appb-C000001
 （式中、Ｒ１及びＲ２は同一又は異なって、Ｃ１２－２２炭化水素基を示す）
Figure JPOXMLDOC01-appb-C000001
 (Wherein R 1 and R 2 are the same or different and represent a C 12-22 hydrocarbon group)
　　本発明では、Ｒ１、Ｒ２の少なくとも一方が、不飽和炭化水素基である、不飽和ホスファチジルコリンを用いることができる。Ｒ１、Ｒ２としてパルミチル基（１６：０）、ステアリル基（１８：０）等の飽和炭化水素基を含んでいてもよいが、本発明で使用できる不飽和ホスファチジルコリンは、このような飽和炭化水素基の含有率が８０％未満、好ましくは７０％未満、さらに好ましくは６０％未満、特に好ましくは５０％未満である。不飽和炭化水素基としては、パレミトレイル基（１６：１）、オレイル基（１８：１）、リノレイル基（１８：２）、リノレニル基（１８：３）を例示できる。本発明において不飽和ホスファチジルコリンは、オレイル基、リノレイル基、リノレニル基等の炭素数１８である不飽和炭化水素基の含有率が２０％以上であるのが好ましく、さらに好ましくは３０％以上、特に好ましくは４０％以上である。不飽和ホスファチジルコリンを用いると、皮膚透過性に優れた安定なコロイド分散液を調製することができる。 In the present invention, unsaturated phosphatidylcholine in which at least one of R 1 and R 2 is an unsaturated hydrocarbon group can be used. R 1 and R 2 may contain saturated hydrocarbon groups such as palmityl group (16: 0) and stearyl group (18: 0), but unsaturated phosphatidylcholine which can be used in the present invention has such saturated carbonization. The hydrogen group content is less than 80%, preferably less than 70%, more preferably less than 60%, and particularly preferably less than 50%. Examples of the unsaturated hydrocarbon group include a paremitrayl group (16: 1), an oleyl group (18: 1), a linoleyl group (18: 2), and a linolenyl group (18: 3). In the present invention, the unsaturated phosphatidylcholine preferably has a content of unsaturated hydrocarbon groups having 18 carbon atoms such as an oleyl group, a linoleyl group, and a linolenyl group of 20% or more, more preferably 30% or more, and particularly preferably. Is 40% or more. When unsaturated phosphatidylcholine is used, a stable colloidal dispersion excellent in skin permeability can be prepared.
　本発明では、不飽和ホスファチジルコリンとして、大豆レシチン、卵黄レシチン等の天然由来であり、ホスファチジルコリンの含有量が９５％以上である高純度のホスファチジルコリンを好ましく使用できる。水素添加処理を行った水素化ホスファチジルコリンや、酵素処理等により得られるリゾホスファチジルコリン等の化学的及び／又は生物学的修飾がなされたホスファチジルコリンを用いると、安定なコロイド分散液が得られない場合があり、好ましくない。ただし、天然由来レシチンの部分水添物等、化学的及び／又は生物学的修飾がなされたホスファチジルコリンであっても、不飽和度の高い、高純度ホスファチジルコリン（例えば、ヨウ素価が２０以上であり、リゾレシチンの含有量が１０％未満である）は、本発明の『不飽和ホスファチジルコリン』として用い得る。コロイドが形成されない場合には、薬物の経皮吸収性向上効果が劣る。 In the present invention, as the unsaturated phosphatidylcholine, a high-purity phosphatidylcholine which is naturally derived from soybean lecithin, egg yolk lecithin and the like and has a phosphatidylcholine content of 95% or more can be preferably used. When using phosphatidylcholine that has been chemically and / or biologically modified, such as hydrogenated phosphatidylcholine that has been subjected to hydrogenation treatment or lysophosphatidylcholine obtained by enzymatic treatment, a stable colloidal dispersion may not be obtained. It is not preferable. However, even a phosphatidylcholine that has been chemically and / or biologically modified, such as a partially hydrogenated natural lecithin, has a high degree of unsaturation and high purity phosphatidylcholine (for example, the iodine value is 20 or more, Lysolecithin content of less than 10%) can be used as the “unsaturated phosphatidylcholine” of the present invention. When no colloid is formed, the effect of improving transdermal absorbability of the drug is inferior.
　ホスファチジルコリンの含量は通常、０．１～５重量％から選択され、好ましくは０．２～３重量％、さらに好ましくは０．３～２．０重量％、特に好ましくは０．３～１．５重量％である。ホスファチジルコリンの含量が０．１重量％未満であると、安定なコロイド分散液が形成されない場合があり、好ましくない。５重量％を超えてホスファチジルコリンを添加しても、ホスファチジルコリン含量の増加に依存する皮膚透過性の向上はみられない。 The content of phosphatidylcholine is usually selected from 0.1 to 5% by weight, preferably 0.2 to 3% by weight, more preferably 0.3 to 2.0% by weight, particularly preferably 0.3 to 1.5% by weight. % By weight. If the phosphatidylcholine content is less than 0.1% by weight, a stable colloidal dispersion may not be formed, which is not preferable. Even when phosphatidylcholine is added in excess of 5% by weight, the skin permeability is not improved depending on the increase in the phosphatidylcholine content.
　トリプタン系薬剤とホスファチジルコリンがプロピレングリコール又はプロピレングリコール中にコロイド分散した本発明の液剤は、保存安定性及び皮膚透過性に優れているが、吸収促進剤としてアルカノールアミンをさらに含有すると、薬物の皮膚透過性が飛躍的に向上する。アルカノールアミンとしては、炭素数２～１２の１級、２級、又は３級のアルカノールアミンを使用することができる。これらの中で、２級又は３級アルカノールアミンが好ましく、３級のアルカノールアミンが特に好ましい。具体的には、例えば、ジエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、トリイソプロパノールアミンを挙げることができる。皮膚透過促進効果が優れていることから、トリエタノールアミンが特に好ましい。 The solution of the present invention in which triptans and phosphatidylcholine are colloidally dispersed in propylene glycol or propylene glycol is excellent in storage stability and skin permeability. However, if it further contains alkanolamine as an absorption enhancer, the drug penetrates the skin. Sexually improves. As the alkanolamine, primary, secondary, or tertiary alkanolamine having 2 to 12 carbon atoms can be used. Of these, secondary or tertiary alkanolamines are preferred, and tertiary alkanolamines are particularly preferred. Specific examples include diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. Triethanolamine is particularly preferable because of its excellent skin permeation promoting effect.
　アルカノールアミンの含量は０．１～１０重量％、好ましくは１～１０重量％、特に好ましくは３～５重量％の範囲から適宜選択される。アルカノールアミンの含有量が上記範囲内ではアルカノールアミンの含有量の増加に伴って薬剤の皮膚透過性の向上が認められるが、１０重量％を超えてアルカノールアミンを添加しても、アルカノールアミン添加量に依存した皮膚透過性の向上は認められない。 The alkanolamine content is appropriately selected from the range of 0.1 to 10% by weight, preferably 1 to 10% by weight, particularly preferably 3 to 5% by weight. When the alkanolamine content is within the above range, an increase in the skin permeability of the drug is recognized as the alkanolamine content increases. Even if the alkanolamine content exceeds 10% by weight, the alkanolamine content is increased. Dependence on skin permeability is not improved.
　下記詳述するが、本発明のコロイド分散液は、プロピレングリコールに溶解状態のトリプタン系薬剤と、プロピレングリコールに溶解状態のホスファチジルコリンとを混合することにより製造する。プロピレングリコールには、水、ポリエチレングリコール等の溶解補助剤を添加してプロピレングリコール含有液とし、このプロピレングリコール含有液にトリプタン系薬剤を溶解することもできる。溶解補助剤の添加量は、プロピレングリコール含有液中のプロピレングリコールの含有量が５０重量％以上、好ましくは６０重量％以上、特に好ましくは６５重量％以上となる範囲から選択される。溶解補助剤の量が多く、プロピレングリコールの含有量が少ないと、良好な薬物皮膚透過性を発現する安定なコロイドが形成されない場合があり、好ましくない。 As will be described in detail below, the colloidal dispersion of the present invention is produced by mixing a triptan-based drug dissolved in propylene glycol and phosphatidylcholine dissolved in propylene glycol. To propylene glycol, a solubilizing agent such as water and polyethylene glycol can be added to form a propylene glycol-containing liquid, and the triptan-based drug can be dissolved in the propylene glycol-containing liquid. The addition amount of the solubilizing agent is selected from a range in which the content of propylene glycol in the propylene glycol-containing liquid is 50% by weight or more, preferably 60% by weight or more, and particularly preferably 65% by weight or more. When the amount of the solubilizing agent is large and the content of propylene glycol is small, a stable colloid expressing good drug skin permeability may not be formed, which is not preferable.
　プロピレングリコール含有液には、必要に応じてプロピレングリコールと混和する親水性溶媒をさらに含むこともできる。具体的には、例えば、グリセリン、１，３－ブタンジオール等の多価アルコールを挙げることができる。このような親水性溶媒の含有量は、プロピレングリコール含有液の１０重量％未満である。 The propylene glycol-containing liquid may further contain a hydrophilic solvent miscible with propylene glycol as necessary. Specific examples include polyhydric alcohols such as glycerin and 1,3-butanediol. The content of such a hydrophilic solvent is less than 10% by weight of the propylene glycol-containing liquid.
　グリセリン、ブタンジオール等の多価アルコールをプロピレングリコールに少量添加してもよいが、これらの多価アルコールをプロピレングリコールの代替として使用することは本発明のコロイド液には適切ではない。例えば、グリセリンにホスファチジルコリンを添加すると、液の白濁及び液表面へのホスファチジルコリンの集合が認められ、ホスファチジルコリン単独で会合コロイドを形成する傾向がある。さらに薬物添加後は、ゲル化する傾向にある。また、1，３－ブタンジオールを使用した場合には、ホスファチジルコリンはプロピレングリコールの場合と同様に分子として完全溶解するが、薬物添加後、プロピレングリコールの場合とは異なり短時間で凝集・沈殿が生じる傾向がある。 Although a small amount of polyhydric alcohols such as glycerin and butanediol may be added to propylene glycol, the use of these polyhydric alcohols as a substitute for propylene glycol is not suitable for the colloidal liquid of the present invention. For example, when phosphatidylcholine is added to glycerin, liquid turbidity and aggregation of phosphatidylcholine on the liquid surface are observed, and phosphatidylcholine alone tends to form an associated colloid. Furthermore, after drug addition, it tends to gel. When 1,3-butanediol is used, phosphatidylcholine is completely dissolved as a molecule as in the case of propylene glycol. However, aggregation and precipitation occur in a short time after addition of the drug, unlike in the case of propylene glycol. Tend.
　本発明の液剤は、疎水性溶媒を含まない。本明細書において『疎水性溶媒』とは、プロピレングリコールに任意の割合で溶解しない油性の溶媒である。具体的には例えば、流動パラフィン、スクアレン等の炭化水素類；オレイン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸等の高級脂肪酸類；セチルアルコール、ステアリルアルコール、ミリスチルアルコール等の高級アルコール類；ミリスチン酸イソプロピル、パルミチン酸イソプロピル、ステアリン酸ブチル等の脂肪酸エステル類；オリーブ油、ツバキ油、ホホバ油等の植物油類を例示することができる。 The liquid agent of the present invention does not contain a hydrophobic solvent. In the present specification, the “hydrophobic solvent” is an oily solvent that does not dissolve in propylene glycol at an arbitrary ratio. Specifically, for example, hydrocarbons such as liquid paraffin and squalene; higher fatty acids such as oleic acid, lauric acid, myristic acid, palmitic acid and stearic acid; higher alcohols such as cetyl alcohol, stearyl alcohol and myristyl alcohol; Examples include fatty acid esters such as isopropyl myristate, isopropyl palmitate, and butyl stearate; and vegetable oils such as olive oil, camellia oil, and jojoba oil.
　本発明のコロイド分散液は、プロピレングリコールを６０重量％以上含み、プロピレングリコール又はプロピレングリコール含有液に可溶な成分のみにより構成されている。 The colloidal dispersion of the present invention contains propylene glycol in an amount of 60% by weight or more, and is composed only of components that are soluble in propylene glycol or a propylene glycol-containing liquid.
　本発明のコロイド分散液に対して、必要に応じて外用剤や化粧料に使用する各種添加剤を追加することができる。追加可能な添加剤としては、香料や抗酸化剤、防腐剤、着色剤、緩衝剤、ｐＨ調整剤等を挙げることができる。香料としては、エタノール、オレンジエッセンス等を例示できる。抗酸化剤としては、酢酸トコフェロール、エデト酸ナトリウム、エリソルビン酸、１，３－ブチレングリコール、ピロ亜硫酸ナトリウム等を例示できる。防腐剤としては、ソルビン酸、タウリン等を例示できる。ｐＨ調節剤としては、クエン酸、酢酸、酒石酸等の有機酸；リン酸、塩酸等の無機酸を例示できる。更には、紫外線吸収剤や抗菌剤を目的に応じて添加することができる。 Various additives used for external preparations and cosmetics can be added to the colloidal dispersion of the present invention as necessary. Additives that can be added include fragrances, antioxidants, preservatives, colorants, buffers, pH adjusters, and the like. Examples of the fragrances include ethanol and orange essence. Examples of the antioxidant include tocopherol acetate, sodium edetate, erythorbic acid, 1,3-butylene glycol, sodium pyrosulfite and the like. Examples of the preservative include sorbic acid and taurine. Examples of the pH regulator include organic acids such as citric acid, acetic acid and tartaric acid; and inorganic acids such as phosphoric acid and hydrochloric acid. Furthermore, an ultraviolet absorber or an antibacterial agent can be added according to the purpose.
　本発明のコロイド分散液は、プロピレングリコール又はプロピレングリコール含有液に溶解状態のトリプタン系薬剤と、プロピレングリコール又はプロピレングリコール含有液に溶解状態のホスファチジルコリンを混合することにより製造することができる。トリプタン系薬剤、又はホスファチジルコリンのいずれか一方のみを溶解した場合は、真の溶液となり、１０ｎｍ以上の粒子径は観測されない。また、これらのトリプタン系薬剤溶液、ホスファチジルコリン溶液のいずれにもチンダル現象は観察されない。ところが、溶解状態のトリプタン系薬剤と溶解状態のホスファチジルコリンとを混合すると、チンダル現象を示すコロイド分散液となり、粒子径の最頻値は１００ｎｍ付近に観測される。 The colloidal dispersion of the present invention can be produced by mixing a triptan-based drug dissolved in propylene glycol or a propylene glycol-containing liquid and phosphatidylcholine dissolved in propylene glycol or a propylene glycol-containing liquid. When only one of the triptans and phosphatidylcholine is dissolved, the solution becomes a true solution, and a particle diameter of 10 nm or more is not observed. In addition, the Tyndall phenomenon is not observed in any of these triptan-based drug solutions and phosphatidylcholine solutions. However, when a dissolved triptan drug and a dissolved phosphatidylcholine are mixed, a colloidal dispersion exhibiting a Tyndall phenomenon is obtained, and the mode value of the particle diameter is observed around 100 nm.
　溶解状態のトリプタン系薬剤と溶解状態のホスファチジルコリンを混合する方法としては、プロピレングリコール又はプロピレングリコール含有液にトリプタン系薬剤を溶解した溶液（Ｉ液）及び、プロピレングリコール又はプロピレングリコール含有液にホスファチジルコリンを溶解した溶液（ＩＩ液）を各々調製し、Ｉ液とＩＩ液とを混合する方法；上記Ｉ液にホスファチジルコリンを添加混合する方法；上記ＩＩ液にトリプタン系薬剤を添加混合する方法；プロピレングリコール又はプロピレングリコール液にトリプタン系薬剤及びホスファチジルコリンを同時に添加する方法などが例示でき、特に制限されない。Ｉ液及びＩＩ液を各々調製し、両者を混合する方法は、トリプタン系薬剤及びホスファチジルコリンが溶解状態にあることを確実に確認できる点で優れている。溶解状態のトリプタン系薬剤と、溶解状態のホスファチジルコリンとを混合し、撹拌することにより、５０～５００ｎｍに平均粒子径を有する安定なコロイド分散液が得られる。 As a method of mixing a dissolved triptan drug and a dissolved phosphatidyl choline, a solution (solution I) in which a triptan drug is dissolved in propylene glycol or a propylene glycol-containing liquid, and phosphatidyl choline dissolved in propylene glycol or a propylene glycol-containing liquid. Each of the prepared solutions (liquid II) is prepared, and the liquid I and liquid II are mixed; the phosphatidylcholine is added to the liquid I and mixed; the method of adding a triptan-based drug to the liquid II; and propylene glycol or propylene A method of simultaneously adding a triptan-based drug and phosphatidylcholine to the glycol liquid can be exemplified and is not particularly limited. The method of preparing each of liquid I and liquid II and mixing them is excellent in that it can be confirmed with certainty that the triptan-based drug and phosphatidylcholine are in a dissolved state. A stable colloidal dispersion having an average particle diameter of 50 to 500 nm can be obtained by mixing and stirring a dissolved triptan drug and a dissolved phosphatidylcholine.
　アルカノールアミン及び他の添加剤は、任意の時点で添加することができる。 Alkanolamine and other additives can be added at any time.
　本発明の液剤を皮膚に適応する方法は特に制限されず、液剤を塗布又は噴霧する方法、液剤を担持させた適宜な担持体を皮膚上に貼付する方法などが例示できる。 The method for applying the solution of the present invention to the skin is not particularly limited, and examples thereof include a method of applying or spraying the solution, and a method of attaching an appropriate carrier carrying the solution on the skin.
　担持体に本発明の経皮吸収型液剤を含浸させた液型貼付製剤は、液剤の優れた経皮吸収特性を損なわず、用量設定も容易である。 The liquid patch preparation in which the carrier is impregnated with the percutaneous absorption type liquid preparation of the present invention does not impair the excellent percutaneous absorption characteristics of the liquid preparation, and the dose can be easily set.
　上記担持体としては、孔径約１０～１５０μｍの微細孔構造を有する樹脂多孔体シートを用いることができる。上記樹脂多孔体シートを構成する樹脂としては、ポリウレタン、ポリエチレン、ポリプロピレン、ポリスチレン、ポリ酢酸ビニル、ポリエチレンテレフタレート、エチレン‐酢酸ビニル共重合体等を例示できる。これらの中で、ポリウレタンから成る樹脂多孔体シート、すなわち、発泡ウレタンシートが汎用性、取扱い性等の点から好ましい。 As the carrier, a porous resin sheet having a fine pore structure with a pore diameter of about 10 to 150 μm can be used. Examples of the resin constituting the porous resin sheet include polyurethane, polyethylene, polypropylene, polystyrene, polyvinyl acetate, polyethylene terephthalate, and ethylene-vinyl acetate copolymer. Among these, a porous resin sheet made of polyurethane, that is, a foamed urethane sheet is preferable from the viewpoints of versatility and handling.
　上記液型貼付製剤は、樹脂多孔体シートの一方の面を液剤不透過性のシートで被覆した形態としてもよい。図２は、樹脂多孔体シートの一方の面を液剤不透過性シートで被覆し、周囲を熱圧着により封止した液型貼付製剤の一例を示す写真である。 The liquid-type patch preparation may have a form in which one surface of the porous resin sheet is coated with a liquid-impermeable sheet. FIG. 2 is a photograph showing an example of a liquid-type patch preparation in which one surface of a porous resin sheet is covered with a liquid-impermeable sheet and the periphery is sealed by thermocompression bonding.
　以下、実施例により本発明を具体的に説明するが、本発明はこれら実施例により何ら限定されるものではない。 Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.
（トリプタン系薬剤を含む経皮吸収型液剤の調製）
　下表１に示す組成で液剤を調製した。得られた液剤について、フランツセルを用いてトリプタン系薬剤の皮膚透過性を評価した。試験に用いた皮膚は６週齢ヘアレスラット（雄）腹部摘出皮膚であり、レセプター溶液は（水：エタノール＝９：１）溶液であった。６時間後の累積皮膚透過量を表１に併せて示す。実施例２及び４、並びに比較例３で調製した液剤の累積皮膚透過量の推移を図１に示す。 (Preparation of transdermal drug containing triptans)
Solutions were prepared with the compositions shown in Table 1 below. About the obtained liquid agent, the skin permeability of the triptan type | system | group chemical | medical agent was evaluated using Franz cell. The skin used for the test was 6-week-old hairless rat (male) abdominal excised skin, and the receptor solution was a (water: ethanol = 9: 1) solution. The cumulative skin permeation amount after 6 hours is also shown in Table 1. The transition of the cumulative skin permeation amount of the solutions prepared in Examples 2 and 4 and Comparative Example 3 is shown in FIG.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　ホスファチジルコリンを含む実施例１及び実施例２乃至４の液剤は、ホスファチジルコリンを含まない比較例１並びに比較例２及び３の液剤に比べて、トリプタン系薬剤の皮膚透過性が飛躍的に向上した。特に、実施例２及び３の液剤は、トリエタノールアミンを含むことにより実施例４の液剤に比べてさらに優れた皮膚透過性を示した。 The solution of Example 1 and Examples 2 to 4 containing phosphatidylcholine significantly improved the skin permeability of the triptan-based drug compared with the solutions of Comparative Example 1 and Comparative Examples 2 and 3 not containing phosphatidylcholine. In particular, the liquid preparations of Examples 2 and 3 showed further superior skin permeability compared to the liquid preparation of Example 4 by containing triethanolamine.
（ラットを用いたイン・ビボ（ｉｎ　ｖｉｖｏ）血中濃度評価試験）
　実施例２で調製した液剤を、ウレタンフォーム（厚み：０．５ｍｍ、面積約６ｃｍ２、不連続気泡タイプ）に含浸させて液型貼付剤を作製した。作製した液型貼付剤をラット（５週齢、雄）の背部に貼付してラットの血中濃度の推移を常法に従って評価した。リザトリプタンの血中濃度の推移を図３に示す。 (In vivo blood concentration evaluation test using rats)
The liquid preparation prepared in Example 2 was impregnated into urethane foam (thickness: 0.5 mm, area of about 6 cm 2 , discontinuous cell type) to prepare a liquid-type patch. The prepared liquid patch was applied to the back of a rat (5 weeks old, male), and the change in blood concentration of the rat was evaluated according to a conventional method. The change in the blood concentration of Rizatriptan is shown in FIG.
　上記ラットの血中濃度から体表面積換算によりヒトの血中濃度を予測した。ヒトへの貼付面積は２０ｃｍ２として算出した。結果を下表２に示す。 The blood concentration of the human was estimated from the blood concentration of the rat by body surface area conversion. The area of application to humans was calculated as 20 cm 2 . The results are shown in Table 2 below.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　文献情報（リザトリプタン安息香酸塩、医薬品インタビューフォーム）によると、ヒトにリザトリプタン錠１０ｍｇ投与時のＴｍａｘは平均１時間、Ｃｍａｘは平均２０ｎｇ／ｍＬである。本発明の液型貼付剤を用いてリザトリプタンをヒトに経皮投与した場合、３時間以内に血中濃度は最大となり、しかも、治療上十分な血中濃度を達成するものと予測された。また、液型貼付剤を貼付したラット皮膚に紅斑等の副作用は一切認められなかった。 According to literature information (risatriptan benzoate, pharmaceutical interview form), T max when humans are administered 10 mg of Rizatriptan tablets is 1 hour on average, and C max is 20 ng / mL on average. When risatriptan was transdermally administered to humans using the liquid patch of the present invention, the blood concentration was maximized within 3 hours, and it was predicted to achieve a therapeutically sufficient blood concentration. In addition, no side effects such as erythema were observed on the rat skin to which the liquid patch was applied.
（液剤の安定性評価試験）
　実施例２で調製した液剤を、４０℃、湿度７５％環境下に保存し、リザトリプタンの含量を評価した。結果を初期含量との比率として下表３に示す。 (Liquid drug stability evaluation test)
The solution prepared in Example 2 was stored in an environment of 40 ° C. and 75% humidity, and the content of rizatriptan was evaluated. The results are shown in Table 3 below as a ratio to the initial content.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　リザトリプタンの含量低下は認められなかった。 No decrease in Rizatriptan content was observed.
　本発明の経皮吸収型液剤及び液型貼付製剤は、皮膚透過性及び保存安定性に優れたトリプタン系薬剤の経皮投与型製剤として利用することができる。

  The transdermal absorption liquid preparation and liquid patch preparation of the present invention can be used as a transdermal preparation of a triptan drug excellent in skin permeability and storage stability.

Claims (10)

  1. 　トリプタン系薬剤又はその塩、ホスファチジルコリン、及びプロピレングリコールを含み、疎水性溶媒を含まない、経皮吸収型液剤。 A transdermal absorption liquid containing a triptan type drug or a salt thereof, phosphatidylcholine, and propylene glycol and not containing a hydrophobic solvent.
  2. 　トリプタン系薬剤又はその塩が、ホスファチジルコリンの存在下にプロピレングリコール又はプロピレングリコール含有液中でコロイド分散したコロイド分散液である、請求項１に記載の経皮吸収型液剤。 The percutaneous absorption type liquid preparation according to claim 1, wherein the triptan type drug or a salt thereof is a colloidal dispersion obtained by colloidal dispersion in propylene glycol or a propylene glycol-containing liquid in the presence of phosphatidylcholine.
  3. 　さらに、アルカノールアミンを含む、請求項１又は２に記載の経皮吸収型液剤。 The percutaneous absorption type liquid preparation according to claim 1 or 2, further comprising an alkanolamine.
  4. 　トリプタン系薬剤が、スマトリプタン、ゾルミトリプタン、エレトリプタン、リザトリプタン、ナラトリプタンから成る群より選択される、請求項１～３いずれかの項に記載の経皮吸収型液剤。 The transdermal absorption liquid preparation according to any one of claims 1 to 3, wherein the triptan-based drug is selected from the group consisting of sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan.
  5. 　アルカノールアミンが、トリエタノールアミンである、請求項３又は４に記載の経皮吸収型液剤。 The transdermal absorption liquid preparation according to claim 3 or 4, wherein the alkanolamine is triethanolamine.
  6. 　ホスファチジルコリンの含有量が、０．１～５重量％である、請求項１～５いずれかの項に記載の経皮吸収型液剤。 The transdermal absorption liquid preparation according to any one of claims 1 to 5, wherein the content of phosphatidylcholine is 0.1 to 5% by weight.
  7. 　ホスファチジルコリンが、卵黄ホスファチジルコリン、大豆ホスファチジルコリンの中から１つ以上選択される、請求項１～６いずれかの項に記載の経皮吸収型液剤。 The transdermal absorption liquid preparation according to any one of claims 1 to 6, wherein the phosphatidylcholine is selected from at least one of egg yolk phosphatidylcholine and soybean phosphatidylcholine.
  8. 　トリプタン系薬剤又はその塩、ホスファチジルコリン、及びプロピレングリコールを含み、疎水性溶媒を含まない経皮吸収型液剤を、樹脂多孔体に含浸して成る液型貼付製剤。 A liquid-type patch preparation comprising a porous resin body impregnated with a transdermal absorption liquid containing a triptan-based drug or a salt thereof, phosphatidylcholine, and propylene glycol and not containing a hydrophobic solvent.
  9. 　前記経皮吸収型液剤が、トリプタン系薬剤又はその塩が、ホスファチジルコリンの存在下にプロピレングリコール又はプロピレングリコール含有液中でコロイド分散した経皮吸収型コロイド分散液である、請求項８に記載の液型貼付製剤。 9. The liquid according to claim 8, wherein the transdermal absorption liquid is a transdermal absorption colloid dispersion in which a triptan drug or a salt thereof is colloidally dispersed in propylene glycol or a propylene glycol-containing liquid in the presence of phosphatidylcholine. Mold patch preparation.
  10. 　前記経皮吸収型液剤が、さらにアルカノールアミンを含む、請求項９又は１０に記載の液型貼付製剤。

          The liquid patch preparation according to claim 9 or 10, wherein the transdermal absorption liquid preparation further contains an alkanolamine.

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