WO2021166987A1 - 経皮吸収製剤 - Google Patents
経皮吸収製剤 Download PDFInfo
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- WO2021166987A1 WO2021166987A1 PCT/JP2021/006052 JP2021006052W WO2021166987A1 WO 2021166987 A1 WO2021166987 A1 WO 2021166987A1 JP 2021006052 W JP2021006052 W JP 2021006052W WO 2021166987 A1 WO2021166987 A1 WO 2021166987A1
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- 238000009864 tensile test Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
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- 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
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- 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
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- 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
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- 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
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- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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Definitions
- the present invention relates to a transdermal pharmaceutical product containing tandospirone or a pharmaceutically acceptable salt thereof.
- heptandicarboxyimide (Generic name "tandospirone") is a selective serotonin 1A receptor agonist, and tandospirone citrate tablets (trade name: Cedir (registered trademark) tablets) are commercially available as anxiolytics in Japan.
- Patent Documents 1 to 3 disclose transdermal preparations containing tandospirone.
- the present invention provides a tandospirone-containing transdermal preparation having improved skin permeability of tandospirone and excellent storage stability of the preparation.
- the present inventors have found that the addition of tandospirone improves the skin permeability of tandospirone, and as a result, the amount of tandospirone-containing transdermal absorption preparation to be applied or sprayed is small. It has made it possible to reduce the formulation area. It was also found that the combined use of a specific additive (iii) with levulinic acid produces a synergistic effect in improving the skin permeability of tandospirone. As a result of further diligent studies, the present inventors have obtained a percutaneous absorption preparation with good stability while maintaining the improvement of skin permeability of tandospirone by blending a specific additive (iv). I found that it was possible. The present invention is also excellent in this respect.
- the present invention is as follows.
- a percutaneous absorption preparation having a percutaneous absorption layer wherein the percutaneous absorption layer is (i) Tandospirone or its pharmaceutically acceptable salt, and (ii) A transdermal preparation characterized by containing levulinic acid or a pharmaceutically acceptable salt thereof (hereinafter, may also be referred to as "the transdermal preparation of the present invention”).
- the transdermal preparation according to the above [1] which is a form of a patch preparation (hereinafter, may be referred to as "the patch preparation of the present invention”).
- transdermal preparation according to the above [1] or [2], which further contains (iii) one or more additives selected from the group consisting of polyhydric alcohol fatty acid esters and fatty acid amides.
- (ii) is levulinic acid.
- (ii) is levulinic acid.
- (iv) contains 2,6-di-tert-butyl-4-methylphenol.
- transdermal preparation according to any one of [5] to [8] above, wherein (iv) contains 2,6-di-tert-butyl-4-methylphenol and sodium thiosulfate.
- (iii) contains a polyhydric alcohol fatty acid ester.
- (iii) contains a propylene glycol fatty acid ester.
- transdermal pharmaceutical product according to any one of the above [1] to [14], wherein the content of (ii) in 100% by weight of the transdermal absorption layer is 3 to 10% by weight.
- the content of 2,6-di-tert-butyl-4-methylphenol in (iv) in 100% by weight of the transdermal absorption layer is 0.001 to 10% by weight, and the above [5] to [17]. ].
- the transdermal preparation according to any one of.
- transdermal preparation according to any one of [5] to [20] above, wherein the content of propyl gallate in (iv) in 100% by weight of the transdermal absorption layer is 0.001 to 7% by weight. .. [22] The transdermal preparation according to any one of the above [3] to [21], wherein the content of the polyhydric alcohol fatty acid ester of (iii) in 100% by weight of the transdermal absorption layer is 1 to 20% by weight. .. [23] The transdermal preparation according to any one of the above [2] to [22], wherein the transdermal preparation is a patch preparation and the transdermal absorption layer is an adhesive layer.
- the pressure-sensitive adhesive layer contains an acrylic polymer, and the total weight ratio of the acrylic polymer and the organic liquid component in the pressure-sensitive adhesive layer is 1: 2.33 to 1: 0.25.
- Percutaneous absorption preparation according to. [25] (i) selected from the group consisting of tandospirone or a pharmaceutically acceptable salt thereof, and an aprotic polar solvent, an organic acid (excluding levulinic acid and acetic acid), a nonionic surfactant and a higher alcohol ester.
- a transdermal pharmaceutical product characterized by containing a seed or two or more kinds of additives.
- a transdermal absorption preparation comprising one or more additives selected from the group consisting of sodium sulfite and sodium hydrogen sulfite.
- a composition for stabilizing a drug comprising (i) tandospirone or a pharmaceutically acceptable salt thereof, and (ii) levulinic acid or a pharmaceutically acceptable salt thereof.
- tandospirone or its pharmaceutically acceptable salt which contains (ii) levulinic acid or a pharmaceutically acceptable salt thereof, and (iii) a polyhydric alcohol fatty acid ester or fatty acid amide. Composition to make.
- tandospirone in a pharmaceutical product or a pharmaceutically acceptable salt thereof has excellent skin permeability, and when used, a transdermal tandospirone-containing transdermal substance capable of maintaining a sufficient blood concentration for exerting the medicinal effect of tandospirone can be exhibited.
- Absorbent formulations can be provided. Further, it is possible to provide a transdermal preparation containing tandospirone, which has good storage stability against heat, humidity and light of tandospirone or a pharmaceutically acceptable salt thereof in the preparation, and is easy to manufacture and quality control. ..
- the dosage form of the transdermal preparation is not particularly limited as long as it is a dosage form conventionally used as an external preparation.
- the dosage form described in the 17th revised Japanese Pharmacy can be mentioned, preferably an ointment, a cream, a gel, a gel-like cream, a spray (for example, an external aerosol, a pump spray), and the like.
- It is an external liquid agent (liniment agent and lotion agent) and a patch preparation, more preferably an ointment or a patch preparation, and further preferably a patch preparation.
- the patched formulation means all the formulations that are attached to the skin.
- the shape of the patched formulation is not limited, and may be, for example, a tape shape, a sheet shape, or the like.
- Specific examples of the patch preparation include tape preparations, patch preparations, pap preparations, plaster preparations and the like.
- the patch-like structure has a sheet-like structure consisting of a support, an adhesive layer, and a release film (liner).
- a support a non-woven fabric, a knit, a plastic film or the like is used.
- the pressure-sensitive adhesive layer is a main component containing an active ingredient and a pressure-sensitive adhesive and having an appropriate adhesive strength.
- the release film is a coating that protects the sticking surface of the pressure-sensitive adhesive layer before use, and polypropylene, polyethylene, cellophane, polyester, release paper, or the like is used.
- the pressure-sensitive adhesive layer is stored in a structure sandwiched between a support and a release film, and the release film is peeled off and the surface to which the pressure-sensitive adhesive layer is attached is attached to the skin for use.
- the transdermal absorption layer in the present invention means a composition of a portion that comes into direct contact with the skin.
- the percutaneous absorption preparation is an ointment, a cream, a gel, a gel cream, a lotion, a spray, an aerosol or a liniment
- the transdermal absorption layer is the preparation composition itself.
- the transdermal absorption layer contains (i) tandospirone or a pharmaceutically acceptable salt thereof.
- additives ii), (iii), (iv), (v) and / or other additives can be included.
- the percutaneous absorption preparation is a patch preparation
- the percutaneous absorption layer means an adhesive layer.
- the pressure-sensitive adhesive layer contains (i) tandospirone or a pharmaceutically acceptable salt thereof, and a pressure-sensitive adhesive base.
- additives ii), (iii), (iv), (v) and / or other additives can be included.
- Compound A It is a compound represented by (hereinafter, also referred to as “Compound A”) and is a selective serotonin 1A receptor agonist.
- Tandospirone citrate is commercially available as an anxiolytic (Cedil® Tablets).
- the active ingredient drug of the present invention may be compound A (tandospirone free base) or a pharmaceutically acceptable salt thereof.
- Pharmaceutically acceptable salts include, for example, formate, acetate, propionate, succinate, lactate, malate, adipate, citrate, tartrate, methanesulfonate, fumal. Salts with organic acids such as acid salts, maleates, p-toluene sulfonates, ascorbates; salts with inorganic acids such as hydrochlorides, hydrogen bromides, sulfates, nitrates, phosphates, etc. Can be mentioned. Further, the compound A or a pharmaceutically acceptable salt thereof may be either a solvate (eg, a hydrate, an ethanol solvate, a propylene glycol solvate) or a non-solvate.
- the above-mentioned compound A or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in JP-A-58-126856 or a method similar thereto.
- the produced compound A or a pharmaceutically acceptable salt thereof may be appropriately ground by a commonly used method.
- the content of "Compound A or a pharmaceutically acceptable salt thereof" contained in the transdermal preparation of the present invention is not particularly limited because it needs to be set according to the age, symptoms, etc. of the patient to be administered.
- compound A free base of tandospirone
- it is usually about 0.1 to about 30% by weight, preferably about 0.1 to about 20% by weight, based on 100% by weight of the transdermal absorption layer. More preferably, it is about 0.1 to about 15% by weight.
- the transdermal preparation is a patch preparation, it is usually about 0.1 to about 30% by weight in 100% by weight of the pressure-sensitive adhesive layer, and preferably about 0.1 by weight, although it depends on the area of the patch preparation.
- converted to compound A means that when compound A is in the form of a salt or compound A has water of crystallization, the amount equivalent to the salt or water of crystallization is the weight of compound A. It shall not be included in. In other words, it means that the salt of compound A or its hydrate is calculated by replacing it with the weight of compound A (free base non-hydrate) having an equimolar value thereof.
- the levulinic acid used in the present invention is an organic acid classified as keto acid.
- the levulinic acid used in the present invention is the levulinic acid free acid (ie, levulinic acid itself), and the additive (ii) used in the present invention is the levulinic acid free acid (ie, levulinic acid itself). It may be provided as a pharmaceutically acceptable salt thereof.
- the pharmaceutically acceptable salt include alkali metal salts such as sodium salt and potassium salt.
- a commercially available product may be used as it is, or the pharmaceutically acceptable salt prepared from levulinic acid according to a method known per se is used. May be good.
- As the (ii) levulinic acid used in the present invention or a pharmaceutically acceptable salt thereof levulinic acid is preferable.
- the drug that is, compound A or a pharmaceutically acceptable salt thereof
- the effect of promoting skin permeability of the compound A is not sufficiently obtained, or that compound A or a part of a pharmaceutically acceptable salt thereof tends to be in a crystalline state during production or storage.
- the content of levulinic acid or a pharmaceutically acceptable salt thereof in the transdermal absorption layer is too large, the skin irritation tends to increase.
- the content of levulinic acid or a pharmaceutically acceptable salt thereof in the transdermal absorption layer is 0.1 in 100% by weight of the transdermal absorption layer in terms of levulinic acid (free acid of levulinic acid). It is preferably from 20% by weight, more preferably from 0.5 to 15% by weight, even more preferably from 1 to 10% by weight, and most preferably from 3 to 8% by weight. From the viewpoint of promoting skin permeability of the drug, it is preferably 0.5% by weight or more, more preferably 1% by weight or more, and further preferably 3% by weight or more. From the viewpoint of skin irritation, 15% by weight or less is preferable, and 10% by weight or less is more preferable.
- the content of levulinic acid or a pharmaceutically acceptable salt thereof in the transdermal absorption layer is converted into levulinic acid (free acid of levulinic acid) in 100% by weight of the transdermal absorption layer.
- the lower limit can be 0.1% by weight, 0.5% by weight, 1% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, and the upper limit value is 20% by weight. , 15% by weight, 10% by weight, 8% by weight, 7% by weight.
- “converted to levulinic acid” means that when levulinic acid is in the form of a salt, the salt equivalent amount is not included in the weight of levulinic acid. In other words, it means that the salt of levulinic acid is calculated by replacing it with the weight of levulinic acid (free acid) in the same mole.
- the content of levulinic acid or its pharmaceutically acceptable salt in 100% by weight of the "transdermal absorption layer” is the levulinic acid in the "adhesive layer” or its pharmaceutical. It can be read as the allowable salt content.
- the additive (iii) used in the present invention can be selected from the group consisting of polyhydric alcohol fatty acid esters and fatty acid amides.
- one or more selected from polyhydric alcohol fatty acid esters can be used.
- the polyhydric alcohol fatty acid ester include polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, glycerin fatty acid ester, propylene glycol fatty acid ester and the like.
- glycerin fatty acid ester, propylene glycol fatty acid ester, and diethylene glycol fatty acid ester are preferable, glycerin fatty acid ester and propylene glycol fatty acid ester are more preferable, and propylene glycol fatty acid ester is particularly preferable.
- the fatty acid amide include lauric acid diethanolamide and coconut oil fatty acid N-methylethanolamide.
- Examples of the glycerin fatty acid ester include glycerol tricaprylate, glycerol caplate, glycerol triacetate, glyceryl monocaprelate, glyceryl caprilate, glyceryl oleate, glyceryl stearate, glycerol monolinoleate, glycerol monooleate, and glycerol stearate. And so on.
- Examples of the propylene glycol fatty acid ester include propylene glycol dicaplate, propylene glycol dilaurate, propylene glycol monolaurate, and propylene glycol monocaprilate (preferably propylene glycol monolaurate and propylene glycol monocaprelate). ).
- the polyhydric alcohol fatty acid ester can be used alone or in combination of two or more.
- the content of the polyhydric alcohol fatty acid ester or fatty acid amide in the transdermal absorption layer is not particularly limited, but is preferably 1 to 20% by weight in 100% by weight of the transdermal absorption layer.
- the content of the polyhydric alcohol fatty acid ester or fatty acid amide in the transdermal absorption layer is more preferably 1 to 15% by weight in 100% by weight of the transdermal absorption layer.
- the content of the polyhydric alcohol fatty acid ester or fatty acid amide in the percutaneous absorption layer is 1% by weight, 1.5% by weight, or 3% by weight as the lower limit value in 100% by weight of the percutaneous absorption layer. %, 5% by weight, and as the upper limit values, 20% by weight, 18% by weight, 15% by weight, and 13% by weight can be mentioned.
- the content of the polyhydric alcohol fatty acid ester or fatty acid amide in 100% by weight of the "transdermal absorption layer” is that of the polyhydric alcohol fatty acid ester or fatty acid amide in the "adhesive layer". It can be read as content.
- additive group A The additive component composed of (ii) levulinic acid and (iii) polyhydric alcohol fatty acid ester or fatty acid amide used in the present invention is hereinafter referred to as "additive group A”.
- additive (iv) used in the present invention (hereinafter, also referred to as “additive B group”) is 2,6-di-tert-butyl-4-methylphenol, sodium thiosulfite, 2-. It can be selected from the group consisting of mercaptobenzoimidazole, propyl phosphate, ⁇ -tocopherol, sodium sulfite and sodium hydrogen sulfite.
- Additive Group B is preferably selected from 2,6-di-tert-butyl-4-methylphenol, sodium thiosulfate and 2-mercaptobenzimidazole, and more preferably 2,6-di-tert-butyl.
- the stabilizing effect of compound A in the formulation or a pharmaceutically acceptable salt thereof can be obtained by adding only one additive contained in the additive B group, but it is selected from the additive B group 2 It can also be obtained by adding a combination of additives of more than one species.
- the combination of 2,6-di-tert-butyl-4-methylphenol and two or more selected from sodium thiosulfate and 2-mercaptobenzimidazole has a synergistic stabilizing effect on compound A in the formulation.
- the stabilizing effect means an effect of improving the stability (storage stability) of the compound A in the transdermal preparation of the present invention with respect to heat, humidity and / or light, and for example, during the production of the preparation.
- the product is heated at 40 ° C., 50 ° C. and 60 ° C. for a certain period of time, when it is humidified for a certain period of time (25 ° C. 60% RH, 40 ° C. 75% RH condition, etc.), or when it is exposed to light for a certain period of time.
- Examples thereof include an effect of suppressing a decrease in the content of compound A, an effect of suppressing the formation of related substances, an effect of suppressing discoloration of the pharmaceutical product, and the like.
- the content of the additive of the additive B group in the transdermal absorption layer is preferably 0.001 to 10% by weight in 100% by weight of the transdermal absorption layer.
- the content of 2,6-di-tert-butyl-4-methylphenol is usually 0.001 to 10% by weight, preferably 0.005 to 10% by weight, and 0, based on 100% by weight of the transdermal absorption layer.
- the content of sodium thiosulfate is usually 0.001 to 7% by weight, preferably 0.001 to 5% by weight, more preferably 0.001 to 3% by weight, and 0, based on 100% by weight of the transdermal absorption layer. .001 to 2% by weight is more preferable.
- the content of 2-mercaptobenzimidazole is usually 0.001 to 5% by weight, preferably 0.05 to 5% by weight, more preferably 0.1 to 5% by weight, based on 100% by weight of the transdermal absorption layer. ..
- the content of propyl gallate is preferably 0.001 to 7% by weight, more preferably 0.001 to 5% by weight, based on 100% by weight of the transdermal absorption layer.
- the total content of two or more kinds of additives selected from the additive B group is 0.002 to 15% by weight in 100% by weight of the transdermal absorption layer. %, More preferably 0.005 to 10% by weight.
- the total content when 2,6-di-tert-butyl-4-methylphenol and sodium thiosulfate are contained is preferably 0.002 to 10% by weight, preferably 0.002 to 10% by weight, based on 100% by weight of the transdermal absorption layer. 8% by weight is more preferable.
- the total content of 2,6-di-tert-butyl-4-methylphenol and 2-mercaptobenzimidazole is preferably 0.05 to 10% by weight based on 100% by weight of the transdermal absorption layer.
- the content ratio of the combination of these additives is preferably 1: 0.001 to 1: 1000 in terms of weight ratio. , 1: 0.005 to 1: 500, more preferably 1: 0.01 to 1:50.
- the content ratio of 2,6-di-tert-butyl-4-methylphenol and 2-mercaptobenzimidazole is preferably 1: 0.01 to 1: 500, preferably 1: 0.1 to 1: 500 by weight. 100 is more preferable, and 1: 0.5 to 1:50 is even more preferable.
- the content of the additive B group in 100% by weight of the "transdermal absorption layer” can be read as the content of the additive B group in the "adhesive layer”.
- the pressure-sensitive adhesive layer preferably contains an organic liquid component from the viewpoint of making the pressure-sensitive adhesive layer more flexible and reducing physical skin irritation at the time of sticking and / or peeling.
- the total content of the pressure-sensitive adhesive base and the organic liquid component in the pressure-sensitive adhesive layer is contained.
- the amount ratio is a weight ratio (adhesive base: weight% ratio of the total of organic liquid components), preferably 1: 2.33 to 1: 0.25, and more preferably 1: 2 from the viewpoint of manufacturability. It is .33 to 1: 0.66.
- the adhesive base and the organic liquid The total content ratio of the components is more preferably 1: 1.86 to 1: 0.66, and more preferably 1: 1.86 to 1: 1 from the viewpoint of skin irritation. ..
- the total content of the acrylic polymer and the organic liquid component in the pressure-sensitive adhesive layer is contained.
- the amount ratio is a weight ratio (acrylic polymer: weight% ratio of the total of the organic liquid components), and is preferably 1: 2.33 to 1: 0.25.
- the total content ratio (% by weight ratio) of the acrylic polymer and the organic liquid component in the pressure-sensitive adhesive layer is preferably 1: 1.86 to 1: 0.66.
- the total weight of the organic liquid components is “liquid”, “liquid (partially precipitated)", “liquid”, “oily” or “soft paste” in the range of 25 ° C. ⁇ 5 ° C. as described later. It means the total weight of the components corresponding to "state”.
- Organic liquid components including specific examples described later are calculated as organic liquid components.
- the organic liquid component in the present invention is an organic substance that is itself liquid at room temperature (25 ° C.), exhibits an action of plasticizing the pressure-sensitive adhesive layer, and is compatible with the pressure-sensitive polymer constituting the above-mentioned pressure-sensitive adhesive.
- liquid means that it can be used as a liquid by appropriately warming it to the extent that the quality is not impaired in the formulation. It is used in the sense of including the ones that have been used. For example, in the description of a specific additive (commercially available product) described later, “Liquid”, “liquid”, “liquid (partially precipitated)", “liquid”, “oil” within the range of 25 ° C ⁇ 5 ° C. "” Or “soft paste” is included in the “liquid” herein.
- organic liquid component examples include, for example, isopropyl myristate, ethyl laurate, isopropyl palmitate, ethyl oleate, isostearyl laurate, isotridecyl myristate, octyl palmitate, diisopropyl adipate, cetyl lactate.
- Fatty acid ester of fatty acid and monovalent alcohol having 1 to 18 carbon atoms (hereinafter, also abbreviated as "C8 to 18 (12 to 16) -C1 to 18 fatty acid ester”); glycerin fatty acid ester, propylene glycol fatty acid ester, Fatty acid ester of fatty acid having 8 to 18 carbon atoms such as polyethylene glycol fatty acid ester and sucrose fatty acid ester and polyhydric alcohol having 1 to 18 carbon atoms; fatty acid such as lauric acid diethanolamide and palm oil fatty acid N-methylethanolamide.
- fatty acids eg, capric acid (octanoic acid, C8), caproic acid, pelargonic acid (nonanoic acid, C9), acetic acid, propionic acid, isobutyric acid, levulinic acid, lactic acid, oleic acid, etc.
- alkylsulfonic acid methane
- Organic acids such as sulfonic acid, ethanesulfonic acid, polyoxyethylene ether sulfonic acid); glycols such as ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, 1,3-propanediol, polypropylene glycol; olive oil, castor oil , Oils and fats such as coconut oil, sesame oil, squalane; organic solvents such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, oleyl alcohol, lauri
- the organic liquid component can be used alone or in combination of two or more.
- the organic liquid component in the present invention preferably contains C8-18 (12-16) -C1-18 fatty acid ester, and particularly preferably contains isopropyl myristate or isopropyl palmitate.
- the pressure-sensitive adhesive layer can be crosslinked.
- the cross-linking treatment is not particularly limited, and includes chemical cross-linking treatment (cross-linking treatment using a cross-linking agent, etc.) and physical cross-linking treatment (cross-linking treatment by electron beam irradiation such as ⁇ -rays, ultraviolet irradiation, etc.). It can be done by a method commonly used in the technical field.
- the pressure-sensitive adhesive layer becomes a so-called gel-like pressure-sensitive adhesive layer, and has appropriate adhesiveness and cohesive force while giving a soft feeling to the skin.
- the stability of Compound A or a pharmaceutically acceptable salt thereof during the manufacturing process or storage of the formulation is lowered. It becomes easier (that is, the amount of related substances produced tends to increase).
- the stability of compound A or a pharmaceutically acceptable salt thereof is improved by blending the above-mentioned additive B group in the crosslinked acrylic polymer.
- a cross-linking agent is not particularly limited as long as it is a cross-linking agent whose formation of cross-linking is not inhibited by compound A or a pharmaceutically acceptable salt thereof, and is, for example, a peroxide (for example, benzoyl peroxide (BPO)).
- a peroxide for example, benzoyl peroxide (BPO)
- Etc. isocyanate compounds
- organic metal compounds eg, zirconium, zinc, zinc acetate, etc.
- metal alcoholates eg, tetraethyl titanate, tetraisopropyl titanate, aluminum isoprepyrate, aluminum sec-butyrate, etc.
- metal chelate compounds eg, tetraethyl titanate, tetraisopropyl titanate, etc.
- metal chelate compounds eg, tetraethyl titanate, tetraisopropyl titanate, aluminum sec-butyrate, etc.
- the cross-linking agent contained in the pressure-sensitive adhesive layer the decrease in the cohesive force of the pressure-sensitive adhesive layer is reduced in the state where the patch formulation of the present invention is applied to human skin, and the pressure-sensitive adhesive layer is cohesively broken when the pressure-sensitive adhesive layer is peeled off.
- a metal chelate compound is preferable from the viewpoint of being less likely to occur.
- the cross-linking agent may be used alone or in combination of two or more.
- the amount of the cross-linking agent when the pressure-sensitive adhesive layer is chemically cross-linked with a cross-linking agent varies depending on the type of the cross-linking agent and the adhesive polymer, but is usually preferably in 100% by weight of the pressure-sensitive adhesive layer. It is 0.01 to 10% by weight, more preferably 0.05 to 5% by weight. If the amount of the cross-linking agent is less than 0.01% by weight with respect to 100% by weight of the pressure-sensitive adhesive layer, sufficient cohesive force cannot be imparted to the pressure-sensitive adhesive layer because the number of cross-linking points is too small, and the patch is applied from the skin. When peeling off, adhesive residue or strong skin irritation due to cohesive destruction may occur.
- the chemical cross-linking treatment can be carried out, for example, by adding a cross-linking agent to the pressure-sensitive adhesive layer and then heating and storing the cross-linking agent to a temperature higher than the cross-linking reaction temperature, that is, a aging step. Is appropriately selected depending on the type of cross-linking agent, but is preferably 60 to 90 ° C, more preferably 60 to 80 ° C.
- the heating time is preferably 12 to 96 hours, more preferably 24 to 72 hours.
- the aprotic polar solvent is not particularly limited, but can be selected from, for example, N-methyl-2-pyrrolidone, dimethylacetamide, dimethyllaurylamide and the like.
- the nonionic surfactant is not particularly limited, but can be selected from, for example, lauromacrogol, sorbitan monolaurate, polysorbate 80, polysorbate 20 and the like.
- the organic acid (excluding levulinic acid and acetic acid) is not particularly limited as long as it is other than levulinic acid and acetic acid, and examples thereof include fatty acids, aromatic carboxylic acids, alkylsulfonic acids, and cholic acid derivatives.
- examples of fatty acids include propionic acid, citric acid, isobutyric acid, caproic acid, caprylic acid, lactic acid, maleic acid, oleic acid, pyruvic acid, oxalic acid, succinic acid, tartaric acid and the like.
- examples of the aromatic carboxylic acid include phthalic acid, salicylic acid, benzoic acid and acetylsalicylic acid, and examples of the alkyl sulfonic acid include methanesulfonic acid, ethanesulfonic acid, propylsulfonic acid, butanesulfonic acid and polyoxy.
- Examples thereof include ethylene alkyl ether sulfonic acid, and examples of the cole acid derivative include dehydrocholic acid and the like.
- Organic acids (excluding levulinic acid and acetic acid) are preferably fatty acids, particularly preferably oleic acid.
- the higher alcohol ester is not particularly limited, but can be selected from, for example, diisopropyl adipate, oleyl oleate, diethyl sebacate, and the like.
- the content of the aprotic polar solvent in the transdermal absorption layer is preferably 0.1 to 20% by weight, more preferably 0.5 to 15% by weight, and 1 to 10% by weight in 100% by weight of the transdermal absorption layer. % Is more preferable.
- the content of the nonionic surfactant in the transdermal absorption layer is preferably 0.1 to 20% by weight, more preferably 0.5 to 15% by weight, and 1 to 10% by weight in 100% by weight of the transdermal absorption layer. % By weight is even more preferred.
- the content of organic acids (excluding levulinic acid and acetic acid) in the transdermal absorption layer is preferably 0.1 to 30% by weight, more preferably 0.1 to 25% by weight, based on 100% by weight of the transdermal absorption layer. , 0.1 to 20% by weight, more preferably 0.1 to 15% by weight. In another aspect, 0.3 to 20% by weight is preferable, and 0.3 to 10% by weight is more preferable.
- the oleic acid in the transdermal absorption layer prevents or attaches a part of Compound A or a pharmaceutically acceptable salt thereof to a crystalline state during production or storage. It can also be expected to have the effect of reducing skin irritation at the time.
- Oleic acid can be contained in a high proportion in the transdermal absorption layer.
- the content of oleic acid in the transdermal absorption layer is preferably 0.1 to 30% by weight, more preferably 0.1 to 25% by weight, based on 100% by weight of the transdermal absorption layer. 3 to 20% by weight is more preferable.
- the content of oleic acid in the percutaneous absorption layer is 0.1% by weight, 0.3% by weight, 0.5% by weight, 1% by weight, 1% by weight as the lower limit value in 100% by weight of the percutaneous absorption layer. 5.5% by weight, 2% by weight, and 3% by weight can be mentioned, and the upper limit values can be 30% by weight, 25% by weight, 20% by weight, 15% by weight, and 10% by weight.
- the organic acid is oleic acid
- the content ratio of levulinic acid to oleic acid in the transdermal absorption layer is preferably 1:20 to 20: 1, more preferably 1:10 to 15: 1, and 1: 5. ⁇ 10: 1 is more preferable.
- the content of the higher alcohol ester in the transdermal absorption layer is preferably 0.1 to 30% by weight, more preferably 0.5 to 20% by weight, and 1 to 15% by weight in 100% by weight of the transdermal absorption layer. % Is more preferable.
- the base of the ointment is not particularly limited, but for example, fats and oils, waxes (waxes), paraffin, petrolatum, lanolin, lanolin hydrolyzed, lanolin alcohol and the like.
- An oily base such as hydrocarbons or a water-soluble base such as macrogol can be used.
- the percutaneous absorption layer in the percutaneous absorption preparation of the present invention requires other pharmaceutically acceptable additives used in the production of the transdermal absorption preparation, unless otherwise specified. It may be blended accordingly.
- examples of such components include, but are not limited to, fragrances, colorants, fillers, thickeners, pH adjusters, emulsifiers, suspending agents and the like.
- the pressure-sensitive adhesive layer in the patch formulation of the present invention is formed on at least one side of the support and contains at least (i) Compound A or a pharmaceutically acceptable salt thereof and a pressure-sensitive adhesive base.
- the pressure-sensitive adhesive layer preferably further contains (ii) levulinic acid or a pharmaceutically acceptable salt thereof.
- the pressure-sensitive adhesive layer further comprises (iii) a polyhydric alcohol fatty acid ester or fatty acid amide, and / or (iv) 2,6-di-tert-butyl-4-methylphenol, sodium thiosulfite, 2-mercaptobenzoimidazole, It may contain one or more additives selected from the group consisting of propyl ester ester, ⁇ -tocopherol, sodium sulfite and sodium hydrogen sulfite.
- the thickness of the pressure-sensitive adhesive layer is not particularly limited as long as it is not extremely thick, but is preferably 20 to 600 ⁇ m, more preferably 30 to 300 ⁇ m, and even more preferably 50 to 200 ⁇ m.
- additives used in the production of the patch formulation are blended as necessary in the pressure-sensitive adhesive layer of the patch formulation of the present invention, unless there is a particular problem. May be good.
- Such components are not particularly limited, and examples thereof include fragrances, colorants, fillers, thickeners, and the like.
- the fragrance is not particularly limited, and examples thereof include dl-menthol, orange oil, mentha oil, lemon oil, and rose oil.
- the thickener is not particularly limited, and examples thereof include carboxymethyl cellulose, carrageenan, pectin, poly (N-vinylacetamide), and N-vinylacetamide / sodium acrylate copolymer.
- the pH adjusting agent is not particularly limited, and examples thereof include citric acid hydrate, glycine, acetic acid, tartaric acid, sodium hydrogencarbonate, and lactic acid.
- the emulsifier is not particularly limited, and examples thereof include oleyl alcohol, hydroxypropyl cellulose, propylene glycol, and propylene glycol fatty acid ester.
- the suspending agent is not particularly limited, and examples thereof include carmellose sodium, glycerin fatty acid ester, and polyoxyethylene hydrogenated castor oil 60.
- the patch formulation of the present invention includes a support and an adhesive layer formed on at least one side of the support. That is, the support has a first surface and a second surface of the sheet-like structure, and forms an adhesive layer on at least the first surface. If necessary, the release sheet may be provided on the surface of the pressure-sensitive adhesive layer opposite to the support side.
- the shape of the patched formulation may be an arbitrary shape, a single-wafer shape, or a roll-shaped roll.
- the formulation of the pressure-sensitive adhesive layer is not particularly limited, but as the pressure-sensitive adhesive base, for example, an acrylic polymer, a rubber-based polymer, a silicone-based polymer, or the like can be used. In addition, these polymers can be used alone or in combination of two or more.
- an acrylic polymer having a unit of (meth) acrylic acid alkyl ester as a main constituent unit is preferable.
- the acrylic polymer containing the (meth) acrylic acid alkyl ester as a main constituent unit include the (meth) acrylic acid alkyl ester from the viewpoints of adhesion to human skin, drug solubility in preparation of a preparation, and the like.
- Acrylic polymers are preferred.
- (meth) acrylic means both “acrylic” and “methacryl”.
- the alkyl group is a linear, branched or cyclic alkyl group having 1 to 18 carbon atoms (for example, methyl, ethyl, n-propyl).
- the alkyl group has a linear, branched or cyclic alkyl group having 4 to 8 carbon atoms.
- Alkyl groups eg n-butyl, isobutyl, ester-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, 3-methylpentyl, n-heptyl, cycloheptyl, n-octyl , 2-Ethylhexyl, cyclooctyl, etc.) are more preferred, and among them, (meth) acrylic acid alkyl esters having an alkyl group of n-butyl, 2-ethylhexyl or cyclohexyl are even more preferable.
- Particularly preferable specific examples of the (meth) acrylic acid alkyl ester (first monomer component) are, for example, butyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, cyclohexyl acrylate and methacrylic acid. Cyclohexyl acrylate can be mentioned, with 2-ethylhexyl acrylate being the most preferred.
- the (meth) acrylic acid alkyl ester (first monomer component) can be used alone or in combination of two or more.
- the functional group capable of participating in the cross-linking reaction is, for example, a vinyl monomer such as a hydroxy group, a carboxy group, or a vinyl group.
- a vinyl monomer in which the functional group capable of participating in the cross-linking reaction is a hydroxy group or a carboxy group is preferable.
- Specific examples of the vinyl monomer (second monomer component) include (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester, (meth) acrylic acid, itaconic acid, maleic acid, and maleic anhydride.
- the vinyl monomer (second monomer component) can be used alone or in combination of two or more.
- the other monomer (third monomer component) mainly adjusts the cohesive force of the pressure-sensitive adhesive layer and the solubility and / or release property of the drug (compound A or a pharmaceutically acceptable salt thereof).
- the other monomer (third monomer component) include vinyl esters such as vinyl acetate and vinyl propionate; vinyl ethers such as methyl vinyl ether and ethyl vinyl ether; N-vinyl-2-pyrrolidone, N-vinylcaprolactam and the like.
- Vinylamides alkoxy group-containing monomers such as (meth) acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid tetrahydrofurfuryl ester; hydroxypropyl (meth) acrylate, ⁇ -hydroxymethyl acrylate (The hydroxy group-containing monomer is used as a third monomer component and does not participate in the cross-linking reaction.); (Meta) acrylamide, dimethyl (meth) acrylamide, N-butyl (meth) acrylamide, etc.
- N-methylol (meth) acrylamide and other (meth) acrylic acid derivatives N-methylol (meth) acrylamide and other (meth) acrylic acid derivatives; (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid tert-butylaminoethyl (Meta) Acrylic Acid Aminoalkyl Esters such as Esters; (Meta) Acrylic Acid Monomer Ethylene Glycol Ester, (Meta) Acrylic Acid Monomer Diethylene Glycol Ester, (Meta) Acrylic Acid Monomer Polyethylene Glycol Ester, (Meta) Acrylic Acid Monomer Polypropylene Glycol (Meta) acrylic acid alkoxyalkylene glycol esters such as esters; (meth) acrylonitrile; sulfos such as styrene sulfonic acid, allyl sulfonic acid, sulfopropyl (meth)
- Monomers having a group examples thereof include vinyl group-containing monomers such as vinyl piperidone, vinyl pyrimidine, vinyl piperazine, vinyl pyrrole, vinyl imidazole, vinyl oxazole, and vinyl morpholine. Of these, vinyl esters (eg, vinyl acetate) and vinylamides (eg, N-vinyl-2-pyrrolidone) are preferable.
- the other monomer (third monomer component) may be used alone or in combination of two or more.
- the acrylic polymer in the patch formulation of the present invention is a copolymer of a (meth) acrylic acid alkyl ester (first monomer component) and a vinyl monomer having a functional group capable of participating in a cross-linking reaction (second monomer component).
- the copolymerization ratio (first monomer component / second monomer component) is preferably 85 to 99% by weight / 1 to 15% by weight, more preferably 90 to 99% by weight / 1 to 10% by weight.
- the acrylic polymer in the patch formulation of the present invention includes a (meth) acrylic acid alkyl ester (first monomer component), a vinyl monomer having a functional group capable of participating in a cross-linking reaction (second monomer component), and other components.
- first monomer component a vinyl monomer having a functional group capable of participating in a cross-linking reaction
- second monomer component a vinyl monomer having a functional group capable of participating in a cross-linking reaction
- the copolymerization ratio is 35 to 94% by weight / 1 to 15% by weight.
- % / 5 to 50% by weight is preferable, and 50 to 89% by weight / 1 to 10% by weight / 10 to 40% by weight is more preferable.
- the polymerization reaction using each of the monomer components may be carried out by a method known per se, and is not particularly limited.
- the monomer is subjected to a polymerization initiator (for example, ethyl peroxide) in a solvent (for example, ethyl acetate).
- a polymerization initiator for example, ethyl peroxide
- a solvent for example, ethyl acetate
- examples thereof include a method of reacting at 50 to 70 ° C. for 5 to 48 hours in the presence of benzoyl, azobisisobutyronitrile, etc.).
- acrylic polymer in the patch formulation of the present invention examples include 2-ethylhexyl acrylate / acrylic acid / N-vinyl-2-pyrrolidone copolymer and 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate.
- Ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / acrylic acid copolymer and the like are preferable, and 2-ethylhexyl acrylate / acrylic acid / N-vinyl-2-pyrrolidone copolymer is particularly preferable. preferable.
- the glass transition temperature of the acrylic polymer in the patch formulation of the present invention varies depending on the copolymerization composition, but is preferably -100 to -10 ° C, more preferably -100 to -10 ° C, from the viewpoint of adhesiveness as the patch formulation. , ⁇ 90 to ⁇ 20 ° C.
- the glass transition temperature is a value measured by a differential scanning calorimeter.
- Examples of the rubber-based polymer in the patch formulation of the present invention include styrene-isoprene-styrene block copolymer, isoprene rubber, polyisobutylene, styrene-butadiene-styrene block copolymer, and styrene-ethylene / butylene-styrene block copolymer weight. Examples thereof include coalescence, styrene-ethylene / propylene-styrene block copolymer, styrene-butadiene rubber and the like.
- styrene-isoprene-styrene block copolymer and polyisobutylene are preferable, and styrene-isoprene-styrene block copolymer is more preferable.
- the rubber-based polymer may be used alone or in combination of two or more.
- silicone-based polymer in the patch formulation of the present invention examples include those containing polyorganosiloxane as a main component, such as silicone rubber, dimethylsiloxane base, diphenylsiloxane base, and polydimethylsiloxane, and a tackifier such as MQ resin. Can be used.
- the silicone-based polymer may be used alone or in combination of two or more.
- the content of the pressure-sensitive base in the pressure-sensitive adhesive layer is preferably 30 to 80% by weight, more preferably 40 to 70% by weight, based on 100% by weight of the pressure-sensitive adhesive layer. ..
- the surface of the pressure-sensitive adhesive layer opposite to the support side is preferably laminated with a release liner until the formulation is actually used.
- the release liner is not particularly limited, and a known release liner can be used. Specifically, for example, a release liner in which a release treatment agent layer made of a release treatment agent is formed on the surface of a base material for a release liner, a plastic film itself having high peelability, and a surface of a base material for a release liner. Examples thereof include a peeling liner having a structure in which a peeling layer is formed of a highly peelable plastic film material. The peeling surface of the release liner may be only one side of the base material or may be both sides.
- the release treatment agent is not particularly limited, and for example, a release agent such as a long-chain alkyl group-containing polymer, a silicone-based polymer (silicone-based release agent), or a fluoropolymer (fluorine-based release agent).
- a release agent such as a long-chain alkyl group-containing polymer, a silicone-based polymer (silicone-based release agent), or a fluoropolymer (fluorine-based release agent).
- a plastic film such as a polyethylene terephthalate (PET) film, a polyimide film, a polypropylene film, a polyethylene film, a polycarbonate film, a polyester (excluding PET) film, or a metal deposited on these films.
- PET polyethylene terephthalate
- Metal-deposited plastic film papers such as Japanese paper, Western paper, kraft paper, glassin paper, and high-quality paper
- base material made of fibrous material such as non-woven fabric and cloth
- an ethylene- ⁇ -olefin copolymer such as polyethylene (low density polyethylene, linear low density polyethylene, etc.), polypropylene, ethylene-propylene copolymer and the like.
- a polyolefin-based film made of a polyolefin-based resin composed of a mixture thereof; a film made by Teflon (registered trademark) or the like can be used.
- the release layer formed on the surface of the release liner substrate can be formed by laminating or coating the highly removable plastic film material on the release liner substrate.
- the thickness (overall thickness) of the release liner is not particularly limited, but is usually 200 ⁇ m or less, preferably 25 to 100 ⁇ m.
- the skin adhesiveness of the patched product of the present invention can be evaluated by using a test method such as a tack force test, a tensile test, and a peeling test (JIS Z 0237: 2009, JIS K 6854).
- a test method such as a tack force test, a tensile test, and a peeling test (JIS Z 0237: 2009, JIS K 6854).
- JIS Z 0237: 2009, JIS K 6854 a peeling test
- the patch formulation of the present invention is peeled off from the liner and evaluated as a sensory test in which the thumb is pressed against the plaster surface to peel off, it is preferable that the patch has an appropriate adhesiveness when the thumb is peeled off.
- the patched product of the present invention is attached to the normal skin on the back of a rabbit, 24 hours after administration (30 minutes after release of obstruction and removal of sample), and further after administration.
- the observation score is preferably 2 or less according to the criteria of the Draize method.
- observation score (total of erythema and crust formation + edema formation) / number of observation points)
- the transdermal preparation of the present invention can be produced by a known method using a pharmaceutically acceptable additive.
- the method for producing the ointment of the present invention is not particularly limited, and the ointment can be produced by a generally known method. For example, it can be manufactured by the following manufacturing method.
- Ointment base, compound A or pharmaceutically acceptable salt thereof, additive group A and additive group B are added to a suitable solvent together with other additives as necessary and mixed thoroughly until uniform. And form a semi-solid ointment.
- suitable solvent include water, glycerin, propylene glycol, polyethylene glycol, 1,3-butylene glycol, ethanol, isopropanol and the like.
- an oil-based ointment usually, an oil-based base such as oils and fats, waxes and hydrocarbons such as paraffin is heated and melted, and compound A or a pharmaceutically acceptable salt thereof, Additives A group and additive B group can be added, mixed to dissolve or disperse, and mixed and kneaded until the whole becomes homogeneous.
- a water-soluble ointment a water-soluble base such as macrogol is usually heated and thawed, and compound A or a pharmaceutically acceptable salt thereof, additive A group, and additive B group are produced. Can be produced by adding, mixing and kneading until the whole becomes homogeneous.
- compound A or a pharmaceutically acceptable salt thereof is added with lebric acid or a pharmaceutically acceptable salt thereof, and additive group B, if necessary, an organic liquid component or other addition.
- higher alcohols such as setanol and stearyl alcohol, higher fatty acids such as myristic acid, lauric acid, palmitic acid, stearic acid and linoleic acid or their esters, waxes such as purified lanolin and whale wax, sorbitan fatty acid esters and sho
- a surfactant such as a sugar fatty acid ester, hydrophilic vaseline, liquid paraffin, hydrocarbons such as plastibase, etc.
- the method for producing the patch formulation of the present invention is not particularly limited, but for example, it can be produced by the following production method.
- Adhesive base containing acrylic polymer, compound A or pharmaceutically acceptable salt thereof, levulinic acid or pharmaceutically acceptable salt thereof, and additive group B, if necessary, organic liquid component or other Add with additives to the appropriate solvent and mix well until uniform.
- the solvent include ethyl acetate, toluene, hexane, 2-propanol, methanol, ethanol, water and the like. Then, when a cross-linking agent is blended, the cross-linking agent is further added to this mixed solution and mixed sufficiently. At this time, if necessary, a solvent may be added together with the cross-linking agent and mixed.
- the obtained mixed solution is applied to one side of the support or the peeled surface of the peeling liner and dried to form an adhesive layer.
- the coating can be carried out by, for example, casting, printing, or other techniques known to those skilled in the art.
- a release liner or a support is attached to the pressure-sensitive adhesive layer to form a laminated body.
- it is usually left at 60 to 90 ° C., preferably 60 to 70 ° C. for 24 to 48 hours to promote the cross-linking reaction.
- the dose of the transdermal preparation of the present invention varies depending on the age, body weight, symptom, etc. of the patient, but is usually 0.1 to 500 mg per day, preferably 0.1 to 500 mg, as a compound A equivalent value for adults. It is 1 to 100 mg, more preferably 2 to 50 mg, still more preferably 2 to 35 mg.
- the size of the patch preparation of the present invention is usually 2 to 100 cm 2 , preferably 2 to 70 cm 2 , and more preferably 4 to 50 cm 2 .
- the patch formulation of the present invention is usually reattached at a frequency of 3 times / day to once / week, preferably once / day to once / week, and more preferably once / day.
- Compound A or a pharmaceutically acceptable salt thereof should be used in combination with another drug (hereinafter, also referred to as "combination drug") as long as its efficacy is not impaired. Can be done. At this time, the administration time is not limited, and these may be administered to the administration subject at the same time or may be administered at different times. It can also be administered as a single preparation containing Compound A or a pharmaceutically acceptable salt thereof in combination with a combination drug.
- Combination drugs include, for example, levodopa or existing Parkinson's disease therapeutic agents.
- Parkinson's disease therapeutic agents include, for example, dopamine agonists (eg, bromocryptin, pergolide, talipexol, cabergolin, pramipexosol, ropinilol, rotigotine, etc.), monoamine oxidase B (MAOB) inhibitors (eg, eg).
- dopamine agonists eg, bromocryptin, pergolide, talipexol, cabergolin, pramipexosol, ropinilol, rotigotine, etc.
- MAOB monoamine oxidase B
- Selegiline, rasagiline, safinamide), catechol-O-methyltransferase (COMT) inhibitors eg entacapone
- anticholinergic agents eg biperidene, trihexy
- thiaprid droxydopa, carbidopa, zonisamide, etc., but are not limited thereto.
- acrylic polymer A In an inert gas atmosphere, 55 parts of 2-ethylhexyl acrylate, 40 parts of N-vinyl-2-pyrrolidone, 5 parts of N- (2-hydroxyethyl) acrylamide and 0.2 parts of azobisisobutyronitrile are contained in ethyl acetate. A solution of an acrylic polymer (acrylic polymer A) was prepared by solution polymerization at 60 ° C.
- acrylic polymer B Under an inert gas atmosphere, 75 parts of 2-ethylhexyl acrylate, 22 parts of N-vinyl-2-pyrrolidone, 3 parts of acrylic acid and 0.2 part of azobisisobutyronitrile are solution-polymerized in ethyl acetate at 60 ° C. As a result, a solution of acrylic polymer (acrylic polymer B) was prepared.
- Test Example 2 Solution skin permeability test
- the skin from which the miniature pig was removed was attached to a skin permeation experimental cell (effective area 3 mm ⁇ , receptor liquid volume 1.25 mL) so that the dermis layer side became the receptor layer, and 5 ⁇ L of a saturated solution of compound A in various additives was added to the receptor liquid.
- a 24-hour skin permeability test was performed under the condition of a temperature of 32 ⁇ 1 ° C.
- a degassed PBS (-) solution phosphate buffered saline
- the receptor solution was sampled, and the concentration of the permeated compound A was quantified by high performance liquid chromatography (ODS column, UV detector).
- IPM isopropyl myristate
- PGMC propylene glycol monocaprelate
- the obtained coating liquid is dried on the surface of the release liner, which is a 75 ⁇ m-thick polyethylene terephthalate (hereinafter referred to as “PET”) film that has been peeled with a silicone-based release agent.
- PET polyethylene terephthalate
- the plaster was applied so that the thickness of the plaster was about 150 ⁇ m, and dried to form an adhesive layer.
- the adhesive surface of the formed pressure-sensitive adhesive layer was bonded to the non-woven fabric side of the laminated film of the PET film as a support and the PET non-woven fabric to prepare a laminated body, and the patch formulation of Example 1 was obtained.
- the above base concentration (% by weight) is a value obtained by subtracting the weight (g) of ethyl acetate from the weight (g) of the coating liquid and dividing the weight (g) by the weight (g) of the coating liquid. Is multiplied by 100 (% by weight).
- Example 2 A patch formulation of Example 2 was obtained in the same manner as in Example 1 except that the IPM was 17.5 parts and the levulinic acid was 7.5 parts.
- Example 3 A patch formulation of Example 3 was obtained in the same manner as in Example 1 except that the IPM was 15.0 parts and the levulinic acid was 10.0 parts.
- Example 4 Acrylic polymer C (MAS683, Cosmedy Pharmaceutical) 60.0 parts, compound A 5.0 parts, IPM 30.0 parts, levulinic acid 5.0 parts are dissolved in an appropriate amount of ethyl acetate and added to make it uniform. The coating liquid was obtained by thoroughly mixing and stirring until. The obtained coating liquid was applied to a support, which is a PET film, so that the thickness of the plaster after drying was about 100 ⁇ m, and dried to form an adhesive layer. Then, the formed pressure-sensitive adhesive layer was attached to a release liner to obtain a patched formulation of Example 4.
- a support which is a PET film
- Example 5 A patch formulation of Example 5 was obtained in the same manner as in Example 4 except that the IPM was 25.0 parts and the levulinic acid was 10.0 parts.
- Example 6 Acrylic polymer C 50.0 parts, IPM 15.0 parts, levulinic acid 10.0 parts, 2,6-di-tert-butyl-4-methylphenol 5.0 parts added, and sodium thiosulfate (anhydride).
- the patch formulation of Example 6 was obtained in the same manner as in Example 4 except that 5.0 parts were dissolved in an appropriate amount of water for injection and added.
- Example 6a IPM 12.5 parts, oleic acid 1.5 parts, propylene glycol monolaurate (hereinafter referred to as "PGML”) 10.0 parts, lauromacrogol 5.0 parts, 2,6-di-tert- A patch formulation of Example 6a was obtained in the same manner as in Example 4 except that 1.0 part of butyl-4-methylphenol was added.
- PGML propylene glycol monolaurate
- Example 6b A patch formulation of Example 6b was obtained in the same manner as in Example 6a except that the IPM was 9.0 parts and the oleic acid was 5.0 parts.
- Comparative Example 1 A patch formulation of Comparative Example 1 was obtained in the same manner as in Example 1 except that 5.0 parts of lactic acid was used without using levulinic acid.
- Comparative Example 2 A patch formulation of Comparative Example 2 was obtained in the same manner as in Comparative Example 1 except that the IPM was 17.5 parts and the lactic acid was 7.5 parts.
- Comparative Example 3 A patch formulation of Comparative Example 3 was obtained in the same manner as in Comparative Example 1 except that 15.0 parts of IPM and 10.0 parts of lactic acid were used.
- Comparative Example 4 A patch formulation of Comparative Example 4 was obtained in the same manner as in Example 4 except that levulinic acid was not used and the IPM was 35.0 parts.
- Comparative Example 5 A patch formulation of Comparative Example 5 was obtained in the same manner as in Example 4 except that 5.0 parts of acetic acid was added without using levulinic acid.
- Comparative Example 6 A patch formulation of Comparative Example 6 was obtained in the same manner as in Comparative Example 5 except that 5.0 parts of lactic acid was added without using acetic acid.
- Comparative Example 6a A patch formulation of Comparative Example 6a was obtained in the same manner as in Comparative Example 4 except that the IPM was 34.0 parts and 1.0 part of 2,6-di-tert-butyl-4-methylphenol was added.
- Test Example 3 Skin permeability test 1-flow cell method-
- the patch is attached to the stratum corneum side of the skin from which the hairless mouse has been removed, and attached to the skin permeation experimental flow cell (effective area 6 mm ⁇ ) so that the dermis layer side becomes the receptor layer, the flow flow rate is 2.5 mL / h, and the receptor liquid temperature is 32.
- a skin permeation experiment was performed for 24 hours under the condition of ⁇ 1 ° C.
- a degassed PBS (-) solution phosphate buffered saline) was used as the receptor solution.
- the receptor solution was sampled over time, and the concentration of the permeated compound A was quantified by high performance liquid chromatography (ODS column, UV detector).
- Test Example 4 Skin permeability test 2-plate method-
- the patch is attached to the stratum corneum side of the skin from which the hairless mouse has been removed, and attached to a skin permeation experimental plate cell (effective area 8 mm ⁇ , receptor fluid volume 1.4 mL) so that the dermis layer side is the receptor layer, and the receptor fluid temperature is 32.
- a skin permeation experiment was performed for 24 hours under the condition of ⁇ 1 ° C.
- a degassed PBS (-) solution phosphate buffered saline
- the receptor solution was sampled, and the concentration of the permeated compound A was quantified by high performance liquid chromatography (ODS column, UV detector).
- Example 7 Except for the fact that the acrylic polymer A was 50.0 parts, the compound A was 20.0 parts, the IPM was 25.0 parts, and the levulinic acid was 5.0 parts, and the plaster thickness was about 100 ⁇ m without using PGMC. Obtained the patch formulation of Example 7 in the same manner as in Example 1.
- Example 8 A patch formulation of Example 8 was obtained in the same manner as in Example 1 except that the IPM was 20.0 parts, 5.0 parts of PGMC was added, and the plaster was coated so that the thickness of the plaster was about 100 ⁇ m.
- Comparative Example 7 A patch formulation of Comparative Example 7 was obtained in the same manner as in Example 1 except that PGMC and levulinic acid were not used, the IPM was 30.0 parts, and the plaster thickness was about 100 ⁇ m.
- Comparative Example 8 A patch formulation of Comparative Example 8 was obtained in the same manner as in Example 1 except that the IPM was 25.0 parts and the plaster thickness was about 100 ⁇ m without using levulinic acid.
- Acrylic polymer B 45.0 parts, compound A 5.5 parts, IPM 31.7 parts, PGML 10.0 parts, levulinic acid 5.0 parts, lauromacrogol 1.5 parts, 2,6-di-toluene Sufficiently dissolve 1.0 part of -butyl-4-methylphenol and 0.08 part of sodium thiosulfate (as anhydride) dissolved in an appropriate amount of water for injection in an appropriate amount of ethyl acetate and toluene until the solution becomes uniform.
- sodium thiosulfate as anhydride
- a cross-linking agent 0.1 part of aluminum ethyl acetoacetate diisopropyrate (hereinafter referred to as "ALCH") was dissolved in an appropriate amount of ethyl acetate and acetylacetone and added, and the mixture was sufficiently added until the mixture became uniform. Mixing and stirring were carried out to obtain a coating solution.
- the obtained coating liquid was coated and dried in the same manner as in Example 1 except that the thickness of the plaster was about 100 ⁇ m to form an adhesive layer, which was then bonded to the support to form a laminate. Made. Then, the mixture was allowed to stand at 70 ° C. for 48 hours to prepare a crosslinked pressure-sensitive adhesive layer, and a patch formulation of Example 9 was obtained.
- Example 10 Without using 2,6-di-tert-butyl-4-methylphenol and sodium thiosulfate, 42.1 parts of acrylic polymer B, 8.0 parts of compound A, 33.1 parts of IPM, 7.5 parts of PGML. , Lauro macrogol 4.0 parts and ALCH 0.4 parts were obtained in the same manner as in Example 9 except that the patch formulation of Example 10 was obtained.
- Example 11 A patch formulation of Example 11 was obtained in the same manner as in Example 10 except that 34.9 parts of acrylic polymer B, 26.9 parts of IPM, 14.9 parts of PGML, and 10.0 parts of lauromacrogol were prepared. ..
- Example 12 Without using 2,6-di-tert-butyl-4-methylphenol and sodium thiosulfate, 39.6 parts of acrylic polymer B, 5.0 parts of compound A, 35.0 parts of IPM, 10.0 parts of PGML The patch formulation of Example 12 was obtained in the same manner as in Example 9 except that 5.0 parts of levulinic acid, 5.0 parts of lauromacrogol and 0.4 parts of ALCH were prepared.
- Example 12a Acrylic polymer B 45.0 parts, IPM 33.7 parts, ALCH 0.1 parts, 2,6-di-tert-butyl-4-methylphenol 1.0 parts, thio A patch formulation of Example 12a was obtained in the same manner as in Example 12 except that 0.13 part of sodium sulfate (as an anhydride) was added.
- Example 13 Acrylic polymer B 45.0 parts, compound A 5.5 parts, IPM 33.2 parts, PGML 10.0 parts, levulinic acid 5.0 parts, ALCH 0.1 parts, without using lauromacrogol. Attachment of Example 13 in the same manner as in Example 12 except that 1.0 part of 2,6-di-tert-butyl-4-methylphenol and 0.08 part of sodium thiosulfate (as anhydride) were added. The formulation was obtained.
- Example 13a A patch formulation of Example 13a was obtained in the same manner as in Example 13 except that 32.2 parts of IPM, 6.0 parts of levulinic acid, and 0.13 parts of sodium thiosulfate (as anhydride) were used.
- Example 13b A patch formulation of Example 13b was obtained in the same manner as in Example 13a except that the IPM was 31.2 parts and the levulinic acid was 7.0 parts.
- Example 14 Acrylic polymer B 49.9 parts, compound A 6.5 parts, IPM 23.5 parts, PGML 10.0 parts, levulinic acid 3.0 parts, lauromacrogol 7.0 parts, ALCH 0.1 parts A patch formulation of Example 14 was obtained in the same manner as in Example 12 except for the above.
- Example 15 Performed without using PGML and lauromacrogol, except that the acrylic polymer B was 36.9 parts, the compound A was 8.0 parts, the IPM was 49.8 parts, the levulinic acid was 5.0 parts, and the ALCH was 0.4 parts.
- a patch formulation of Example 15 was obtained in the same manner as in Example 12.
- Comparative Example 9 Same as Example 10 except that PGML, levulinic acid and lauromacrogol were not used, and the acrylic polymer B was 49.9 parts, the compound A was 5.0 parts, the IPM was 45.0 parts, and the ALCH was 0.1 parts. Then, the patch formulation of Comparative Example 9 was obtained.
- Comparative Example 10 A patch formulation of Comparative Example 10 was obtained in the same manner as in Comparative Example 9 except that the acrylic polymer B was 49.8 parts, the compound A was 8.0 parts, the IPM was 41.8 parts, and the ALCH was 0.4 parts.
- Comparative Example 11 Acrylic polymer B 34.9 parts, compound A 2.0 parts, IPM 42.8 parts, PGML 14.9 parts, levulinic acid 5.0 parts, ALCH 0.4 parts were used without using lauromacrogol. A patch formulation of Comparative Example 11 was obtained in the same manner as in Example 12 except for the above.
- Example 16 To 4.0 parts of Compound A, 10.0 parts of PGML, 5.0 parts of lauromacrogol, and 5.0 parts of levulinic acid were added and mixed and dissolved, and gelled hydrocarbon (Hicol Gel (registered trademark), Kaneda) was added. (Co., Ltd.) 76.0 parts were added and mixed and kneaded so as to be uniform to obtain the ointment of Example 16.
- Gelled hydrocarbon Hicol Gel (registered trademark), Kaneda
- Example 17 Conducted in the same manner as in Example 16 except that 15.0 parts of IPM was added to make 5.0 parts of compound A and 60.0 parts of gelled hydrocarbon (Hicol Gel (registered trademark), Kaneda Co., Ltd.). The ointment of Example 17 was obtained.
- Example 17a Implemented except that 20.0 parts of oleic acid was added to make 8.0 parts of compound A, 7.0 parts of levulinic acid, and 50.0 parts of gelled hydrocarbon (Hicol Gel (registered trademark), Kaneda Co., Ltd.). The ointment of Example 17a was obtained in the same manner as in Example 16.
- Example 18 Implemented except that 25.0 parts of oleic acid was added to make 8.0 parts of compound A, 7.0 parts of levulinic acid, and 45.0 parts of gelled hydrocarbon (Hicol Gel (registered trademark), Kaneda Co., Ltd.). The ointment of Example 18 was obtained in the same manner as in Example 16.
- Example 19 Implemented except that 20.0 parts of oleic acid was added to make 10.0 parts of compound A, 7.0 parts of levulinic acid, and 48.0 parts of gelled hydrocarbon (Hicol Gel (registered trademark), Kaneda Co., Ltd.). The ointment of Example 19 was obtained in the same manner as in Example 16.
- Comparative Example 12 Add 42.0 parts of oleic acid to 8.0 parts of compound A, mix and dissolve, and add 50.0 parts of gelled hydrocarbon (Hicol Gel (registered trademark), Kaneda Co., Ltd.) to make it uniform. As described above, the ointment of Comparative Example 12 was obtained.
- Gelled hydrocarbon Hicol Gel (registered trademark), Kaneda Co., Ltd.
- Comparative Example 13 PGML 10.0%, Lauro Macrogol 5.0 parts added, Compound A 5.0 parts, Oleic acid 25.0 parts, Gelled hydrocarbon (Hicol Gel (registered trademark), Kaneda Co., Ltd.) 55.0 The ointment of Comparative Example 13 was obtained in the same manner as in Example 16 except that the portion was used.
- Example 20 Acrylic polymer B 39.6 parts, compound A 5.0 parts, IPM 35.0 parts, PGML 10.0 parts, levulinic acid 5.0 parts, lauromacrogol 5.0 parts, ALCH 0.4 parts are used. Then, a coating liquid was obtained in the same manner as in Example 9. Dissolve 0.05 part of 2,6-di-tert-butyl-4-methylphenol in an appropriate amount of methanol, add the coating solution obtained above so that the total amount becomes 100 parts, and then the same as in Example 9. Then, the patch formulation of Example 20 was obtained.
- Example 21 Same as Example 20 except that 0.13 part of sodium thiosulfate (as anhydride) was dissolved in an appropriate amount of water for injection and added without using 2,6-di-tert-butyl-4-methylphenol. Then, the patch formulation of Example 21 was obtained.
- Example 22 Add 0.62 part of 2-mercaptobenzimidazole (hereinafter referred to as "2-MBI") dissolved in an appropriate amount of methanol without using 2,6-di-tert-butyl-4-methylphenol. A patch formulation of Example 22 was obtained in the same manner as in Example 20 except for the above.
- 2-MBI 2-mercaptobenzimidazole
- Example 20 in the same manner as in Example 20 except that 0.019 part of propyl gallate was dissolved in an appropriate amount of methanol and added without using 2,6-di-tert-butyl-4-methylphenol. Twenty-three patches were obtained.
- Example 20 in the same manner as in Example 20 except that 0.002 part of ⁇ -tocopherol was dissolved in an appropriate amount of methanol and added without using 2,6-di-tert-butyl-4-methylphenol. Twenty-four patches were obtained.
- Example 25 The same as in Example 20 except that 0.2 part of sodium sulfite (as anhydrous) was dissolved in an appropriate amount of water and added without using 2,6-di-tert-butyl-4-methylphenol. The patch formulation of Example 25 was obtained.
- Example 20 in the same manner as in Example 20 except that 0.3 part of sodium bisulfite was dissolved in an appropriate amount of water and added without using 2,6-di-tert-butyl-4-methylphenol. Twenty-six patches were obtained.
- Example 27 Acrylic polymer B 48.9 parts, compound A 6.5 parts, IPM 23.5 parts, PGML 10.0 parts, levulinic acid 3.0 parts, lauromacrogol 7.0 parts, ALCH 0.1 parts are used. Then, 1.0 part of 2,6-di-tert-butyl-4-methylphenol was dissolved in an appropriate amount of methanol and added to obtain a patch formulation of Example 27 in the same manner as in Example 9.
- Example 28 Except for the fact that 2,6-di-tert-butyl-4-methylphenol was not used, 49.7 parts of acrylic polymer B was used, and 0.2 parts of 2-MBI was dissolved in an appropriate amount of methanol and added. A patch formulation of Example 28 was obtained in the same manner as in Example 27.
- Example 29 The acrylic polymer B is 48.7 parts, 1.0 part of 2,6-di-tert-butyl-4-methylphenol is dissolved in an appropriate amount of methanol, and 0.2 part of sodium thiosulfate (as anhydrous) is an appropriate amount.
- a patch formulation of Example 29 was obtained in the same manner as in Example 27, except that it was dissolved in water and added.
- Example 30 Acrylic polymer B 48.7 parts, except that 1.0 part of 2,6-di-tert-butyl-4-methylphenol and 0.2 parts of 2-MBI were dissolved in an appropriate amount of methanol and added. A patch formulation of Example 30 was obtained in the same manner as in Example 27.
- Example 31 Acrylic polymer B 45.0 parts, compound A 5.5 parts, IPM 33.2 parts, PGML 10.0 parts, levulinic acid 5.0 parts, ALCH 0.1 parts, 2,6-di-tert-butyl
- Example 31 in the same manner as in Example 9 except that 1.0 part of -4-methylphenol was used and 0.08 part of sodium thiosulfate (as an anhydride) was dissolved in an appropriate amount of water and added. The patch formulation of was obtained.
- Example 32 A patch formulation of Example 32 was obtained in the same manner as in Example 31 except that 0.13 part of sodium thiosulfate (as an anhydride) was used.
- Example 33 A patch formulation of Example 33 was obtained in the same manner as in Example 31 except that the IPM was 31.7 parts and 1.5 parts of Lauromacrogol was added.
- Example 34 A patch formulation of Example 34 was obtained in the same manner as in Example 32, except that the IPM was 31.7 parts and 1.5 parts of Lauromacrogol was added.
- Comparative Example 14 Acrylic polymer B 39.6 parts, compound A 5.0 parts, IPM 35.0 parts, PGML 10.0 parts, levulinic acid 5.0 parts, lauromacrogol 5.0 parts, ALCH 0.4 parts are used. Then, the patch formulation of Comparative Example 14 was obtained in the same manner as in Example 9.
- Example 15 Comparison was carried out in the same manner as in Example 20 except that 0.013 part of L-ascorbyl palmitate was dissolved in an appropriate amount of methanol and added without using 2,6-di-tert-butyl-4-methylphenol. The patch formulation of Example 15 was obtained.
- Comparative Example 16 Comparative Example in the same manner as in Example 20 except that 0.1 part of L-ascorbic acid was dissolved in an appropriate amount of methanol and added without using 2,6-di-tert-butyl-4-methylphenol. 16 patches were obtained.
- Comparative Example 17 A patch formulation of Comparative Example 17 was obtained in the same manner as in Example 27, except that 2,6-di-tert-butyl-4-methylphenol was not used and 49.9 parts of acrylic polymer B was used. ..
- Test Example 5 Pharmaceutical stability test
- a pharmaceutical sample containing various stabilizers is stored under harsh conditions (60 ° C. for 2 weeks or 50 ° C. for 1 month), and the stability of the pharmaceutical product is determined by the change in the content of compound A in the pharmaceutical product due to storage and the color difference of the pharmaceutical product.
- it was stored under light exposure conditions total illuminance 53000 lx ⁇ h, illuminance 2000 lx, irradiation time 26.5 h
- the content of compound A was measured by the following method.
- transdermal preparation containing tandospirone, which has excellent skin permeability by containing levulinic acid and can maintain a sufficient blood concentration for exerting the medicinal effect of tandospirone when used. can.
- tandospirone-containing transdermal preparation patch preparation
- tandospirone which is an active ingredient drug. can.
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Abstract
Description
本発明者らは、さらに鋭意検討を加えた結果、特定の添加剤(iv)を配合することによって、タンドスピロンの皮膚透過性の向上を維持しつつ、安定性が良好な経皮吸収製剤が得られることを見出した。本発明は、この点においても優れる。
[1]
経皮吸収層を有する経皮吸収製剤であって、該経皮吸収層が、
(i)タンドスピロン又はその薬学的に許容される塩、及び
(ii)レブリン酸又はその薬学的に許容される塩
を含有することを特徴とする経皮吸収製剤(以下、「本発明の経皮吸収製剤」と称することもある。)。
[2]
貼付製剤の形態である、上記[1]に記載の経皮吸収製剤(以下、「本発明の貼付製剤」と称することもある。)。
[3]
さらに(iii)多価アルコール脂肪酸エステル及び脂肪酸アミドからなる群から選択される1種又は2種以上の添加剤を含有する、上記[1]又は[2]に記載の経皮吸収製剤。
[4]
さらに前記経皮吸収層が、オレイン酸を含有する、上記[1]~[3]のいずれかに記載の経皮吸収製剤。
[5]
さらに(iv)2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム、2-メルカプトベンゾイミダゾール、没食子酸プロピル、α-トコフェロール、亜硫酸ナトリウム及び亜硫酸水素ナトリウムからなる群から選択される1種又は2種以上の添加剤を含有する、上記[1]~[4]のいずれかに記載の経皮吸収製剤。
[6]
(i)が、タンドスピロンである、上記[1]~[5]のいずれかに記載の経皮吸収製剤。
[7]
(ii)が、レブリン酸である、上記[1]~[6]のいずれかに記載の経皮吸収製剤。
[8]
(iv)が、2,6-ジ-tert-ブチル-4-メチルフェノールを含む、上記[5]~[7]のいずれかに記載の経皮吸収製剤。
[9]
(iv)が、2,6-ジ-tert-ブチル-4-メチルフェノール及びチオ硫酸ナトリウムを含む、上記[5]~[8]のいずれかに記載の経皮吸収製剤。
[10]
(iii)が、多価アルコール脂肪酸エステルを含有する、上記[3]~[9]のいずれかに記載の経皮吸収製剤。
[11]
(iii)が、プロピレングリコール脂肪酸エステルを含有する、上記[3]~[10]のいずれかに記載の経皮吸収製剤。
[12]
前記経皮吸収製剤が、さらに(v)1価アルコール脂肪酸エステルを含有する、上記[1]~[11]のいずれかに記載の経皮吸収製剤。
[13]
前記(v)1価アルコール脂肪酸エステルが、ミリスチン酸イソプロピル及び/又はパルミチン酸イソプロピルである、上記[12]に記載の経皮吸収製剤。
[14]
前記経皮吸収層100重量%中の(i)の含有量が、0.1~30重量%である、上記[1]~[13]のいずれかに記載の経皮吸収製剤。
[15]
前記経皮吸収層100重量%中の(ii)の含有量が、0.1~20重量%である、上記[1]~[14]のいずれかに記載の経皮吸収製剤。
[16]
前記経皮吸収層100重量%中の(ii)の含有量が、3~10重量%である、上記[1]~[14]のいずれか一項に記載の経皮吸収製剤。
[17]
前記経皮吸収層100重量%中の(ii)の含有量が、6~7重量%である、上記[1]~[14]のいずれか一項に記載の経皮吸収製剤。
[18]
前記経皮吸収層100重量%中の(iv)の2,6-ジ-tert-ブチル-4-メチルフェノールの含有量が、0.001~10重量%である、上記[5]~[17]のいずれかに記載の経皮吸収製剤。
[19]
前記経皮吸収層100重量%中の(iv)のチオ硫酸ナトリウムの含有量が、無水物として0.001~7重量%である、上記[5]~[18]のいずれかに記載の経皮吸収製剤。
[20]
前記経皮吸収層100重量%中の(iv)の2-メルカプトベンゾイミダゾールの含有量が、0.001~5重量%である、上記[5]~[19]のいずれかに記載の経皮吸収製剤。
[21]
前記経皮吸収層100重量%中の(iv)の没食子酸プロピルの含有量が、0.001~7重量%である、上記[5]~[20]のいずれかに記載の経皮吸収製剤。
[22]
前記経皮吸収層100重量%中の(iii)の多価アルコール脂肪酸エステルの含有量が、1~20重量%である、上記[3]~[21]のいずれかに記載の経皮吸収製剤。
[23]
前記経皮吸収製剤が、貼付製剤であり、経皮吸収層が、粘着剤層である、上記[2]~[22]のいずれかに記載の経皮吸収製剤。
[24]
前記粘着剤層が、アクリル系ポリマーを含み、該粘着剤層中のアクリル系ポリマーと有機液状成分の合計の重量比が、1:2.33~1:0.25である、上記[23]に記載の経皮吸収製剤。
[25]
(i)タンドスピロン又はその薬学的に許容される塩、並びに非プロトン性極性溶媒、有機酸(レブリン酸及び酢酸を除く)、非イオン性界面活性剤及び高級アルコールエステルからなる群から選択される1種又は2種以上の添加剤を含有することを特徴とする経皮吸収製剤。
[26]
有機酸が、オレイン酸である、上記[25]に記載の経皮吸収製剤。
[27]
(i)タンドスピロン又はその薬学的に許容される塩、並びに(iv)2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム、2-メルカプトベンゾイミダゾール、没食子酸プロピル、α-トコフェロール、亜硫酸ナトリウム及び亜硫酸水素ナトリウムからなる群から選択される1種又は2種以上の添加剤を含有することを特徴とする経皮吸収製剤。
[28]
2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム、2-メルカプトベンゾイミダゾール、没食子酸プロピル、α-トコフェロール、亜硫酸ナトリウム及び亜硫酸水素ナトリウムからなる群から選択される少なくとも1つの成分を含む、(i)タンドスピロン又はその薬学的に許容される塩、及び(ii)レブリン酸又はその薬学的に許容される塩を含む医薬を安定化するための組成物。
[29]
(ii)レブリン酸又はその薬学的に許容される塩、及び(iii)多価アルコール脂肪酸エステル又は脂肪酸アミドを含有する、(i)タンドスピロン又はその薬学的に許容される塩の皮膚透過性を向上させるための組成物。
経皮吸収製剤が貼付製剤の場合、経皮吸収層は粘着剤層を意味する。該粘着剤層には、(i)タンドスピロン又はその薬学的に許容される塩、及び粘着基剤を含有する。さらに、添加剤(ii)、(iii)、(iv)、(v)及び/又はその他の添加剤を含有することができる。
(i)本発明の経皮吸収製剤に含まれる有効成分薬物である、(1R,2S,3R,4S)-N-[4-[4-(ピリミジン-2-イル)ピペラジン-1-イル]ブチル]-2,3-ビシクロ[2.2.1]ヘプタンジカルボキシイミド(一般名「タンドスピロン」)は、下記式:
経皮吸収製剤が貼付製剤の場合は、粘着剤層100重量%中、通常、約0.1~約30重量%程度であり、好ましくは、貼付製剤の面積にもよるが、約0.1~約20重量%程度、より好ましくは、約0.1~約15重量%程度である。さらに好ましくは、1~10重量%、さらにより好ましくは、2~8重量%である。
ここで、「化合物Aに換算して」とは、化合物Aが塩の形態をとっている場合、又は化合物Aが結晶水を有する場合に、当該塩又は結晶水相当量は、化合物Aの重量には含めないものとする。言い換えれば、化合物Aの塩又はその水和物について、それと等モルの化合物A(遊離塩基非水和物)の重量に置き換えて計算することを意味する。
本発明で使用されるレブリン酸は、ケト酸に分類される有機酸である。本発明で使用されるレブリン酸は、レブリン酸の遊離酸(すなわち、レブリン酸自体)であり、本発明で使用される添加剤(ii)は、レブリン酸の遊離酸(すなわち、レブリン酸自体)であってもよいし、その薬学的に許容される塩として提供されてもよい。薬学的に許容される塩としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩等が挙げられる。レブリン酸又はその薬学的に許容される塩としては、市販品をそのまま使用してもよいし、自体公知の方法に従い、レブリン酸から調製された、その薬学的に許容される塩を使用してもよい。本発明で使用される(ii)レブリン酸又はその薬学的に許容される塩としては、レブリン酸が好ましい。
ここで、「レブリン酸に換算して」とは、レブリン酸が塩の形態をとっている場合に、当該塩相当量は、レブリン酸の重量には含めないものとする。言い換えれば、レブリン酸の塩について、それと等モルのレブリン酸(遊離酸)の重量に置き換えて計算することを意味する。
本発明において使用される添加剤(iii)は、多価アルコール脂肪酸エステル及び脂肪酸アミドからなる群から選択することができる。好ましくは、多価アルコール脂肪酸エステルから選択される1種又は2種以上を使用することができる。
多価アルコール脂肪酸エステルとしては、例えば、ポリオキシエチレンソルビタン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、グリセリン脂肪酸エステル、プロピレングリコール脂肪酸エステル等が挙げられる。これらの中でも、グリセリン脂肪酸エステル、プロピレングリコール脂肪酸エステル、ジエチレングリコール脂肪酸エステルが好ましく、グリセリン脂肪酸エステル及びプロピレングリコール脂肪酸エステルがより好ましく、プロピレングリコール脂肪酸エステルが特に好ましい。
脂肪酸アミドとしては、例えば、ラウリン酸ジエタノールアミド、ヤシ油脂肪酸N-メチルエタノールアミド等が挙げられる。
具体的には、経皮吸収層中の多価アルコール脂肪酸エステル又は脂肪酸アミドの含有量は、経皮吸収層100重量%中、下限値としては、1重量%、1.5重量%、3重量%、5重量%を挙げることができ、上限値としては、20重量%、18重量%、15重量%、13重量%を挙げることができる。
本発明において使用される添加剤(iv)(以下、「添加剤B群」と称することもある。)は、2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム、2-メルカプトベンゾイミダゾール、没食子酸プロピル、α-トコフェロール、亜硫酸ナトリウム及び亜硫酸水素ナトリウムからなる群から選択することができる。添加剤B群は、好ましくは、2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム及び2-メルカプトベンゾイミダゾールから選択され、より好ましくは、2,6-ジ-tert-ブチル-4-メチルフェノール及びチオ硫酸ナトリウムから選択される。
また、製剤中の化合物A又はその薬学的に許容される塩の安定化効果は、添加剤B群に含まれる添加剤1種のみの添加でも得られるが、添加剤B群から選択される2種以上の添加剤を組合せて添加しても得られる。特に、2,6-ジ-tert-ブチル-4-メチルフェノールと、チオ硫酸ナトリウム及び2-メルカプトベンゾイミダゾールから選択される2種以上の組合せは、製剤中の化合物Aの相乗的な安定化効果が得られるため好ましい。ここで、安定化効果とは、本発明の経皮吸収製剤中の化合物Aの熱、湿度及び/又は光に対する安定性(保存安定性)を向上させる効果を意味し、例えば、製剤の製造中或いは保管時に、40℃、50℃及び60℃で一定時間加温された時、一定時間加湿された時(25℃60%RH、40℃75%RH条件等)、一定時間曝光された時の化合物Aの含量低下を抑制する効果、類縁物質の生成を抑制する効果、製剤の変色を抑制する効果等が挙げられる。
これらの添加剤の組合せの含有比率として、2,6-ジ-tert-ブチル-4-メチルフェノール及びチオ硫酸ナトリウムの含有量比は、重量比で、1:0.001~1:1000が好ましく、1:0.005~1:500がより好ましく、1:0.01~1:50がさらに好ましい。2,6-ジ-tert-ブチル-4-メチルフェノール及び2-メルカプトベンゾイミダゾールの含有量比は、重量比で、1:0.01~1:500が好ましく、1:0.1~1:100がより好ましく、1:0.5~1:50がさらに好ましい。
本発明の貼付製剤において、粘着剤層をより柔軟化し、貼付時及び/又は剥離時の物理的な皮膚刺激を低減する観点から、粘着剤層には、有機液状成分を含有することが好ましい。
本発明の貼付製剤においては、粘着剤層に架橋処理を施すことができる。当該架橋処理は、特に限定されず、化学的架橋処理(架橋剤を用いた架橋処理等)及び物理的架橋処理(γ線のような電子線照射や紫外線照射による架橋処理等)等の、当技術分野で一般的に行われている手法により行うことができる。当該架橋処理により粘着剤層は、いわゆるゲル状態の粘着剤層となり、皮膚にソフト感を与えつつ、適度な接着性と凝集力を有するものとなる。本発明の貼付製剤において、粘着剤層に化学的架橋処理又は物理的架橋処理を行うと、製剤の製造工程中又は保管中における化合物A又はその薬学的に許容される塩の安定性が低下しやすくなる(すなわち、類縁物質の生成量が増加する傾向になる)。本発明においては、架橋処理がなされたアクリル系ポリマー中に上記添加剤B群を配合することにより、化合物A又はその薬学的に許容される塩の安定性を向上させることが確認された。
また、非イオン性界面活性剤は、特に限定されないが、例えば、ラウロマクロゴール、モノラウリン酸ソルビタン、ポリソルベート80、ポリソルベート20等から選択することができる。
有機酸(レブリン酸及び酢酸を除く)は、レブリン酸及び酢酸以外であれば特に限定されないが、脂肪酸、芳香族カルボン酸、アルキルスルホン酸、コール酸誘導体等が挙げられる。具体的には、脂肪酸としては、例えば、プロピオン酸、クエン酸、イソ酪酸、カプロン酸、カプリル酸、乳酸、マレイン酸、オレイン酸、ピルビン酸、シュウ酸、コハク酸、酒石酸等が挙げられる。芳香族カルボン酸としては、例えば、フタル酸、サリチル酸、安息香酸及びアセチルサリチル酸等が挙げられ、アルキルスルホン酸としては、例えば、メタンスルホン酸、エタンスルホン酸、プロピルスルホン酸、ブタンスルホン酸、ポリオキシエチレンアルキルエーテルスルホン酸等が挙げられ、コール酸誘導体としては、例えば、デヒドロコール酸等が挙げられる。有機酸(レブリン酸及び酢酸を除く)は、好ましくは、脂肪酸であり、特に好ましくは、オレイン酸である。
高級アルコールエステルは、特に限定されないが、例えば、アジピン酸ジイソプロピル、オレイン酸オレイル、セバシン酸ジエチル等から選択することができる。
経皮吸収層中の非プロトン性極性溶媒の含有量は、経皮吸収層100重量%中、0.1~20重量%が好ましく、0.5~15重量%がより好ましく、1~10重量%がさらに好ましい。
経皮吸収層中の非イオン性界面活性剤の含有量は、経皮吸収層100重量%中、0.1~20重量%が好ましく、0.5~15重量%がより好ましく、1~10重量%がさらに好ましい。
経皮吸収層中の有機酸(レブリン酸及び酢酸を除く)の含有量は、経皮吸収層100重量%中、0.1~30重量%が好ましく、0.1~25重量%がより好ましく、0.1~20重量%、0.1~15重量%がさらに好ましい。別の態様としては、0.3~20重量%が好ましく、0.3~10重量%がより好ましい。
本発明の経皮吸収製剤において、経皮吸収層中のオレイン酸は、化合物A又はその薬学的に許容される塩の一部が製造中又は保管中に結晶状態になることを防いだり、貼付時の皮膚刺激を低減する効果も期待できる。オレイン酸は、経皮吸収層中に高い割合で含有することができる。具体的には、経皮吸収層中のオレイン酸の含有量は、経皮吸収層100重量%中、0.1~30重量%が好ましく、0.1~25重量%がより好ましく、0.3~20重量%がさらに好ましい。
経皮吸収層中のオレイン酸の含有量は、経皮吸収層100重量%中、下限値としては、0.1重量%、0.3重量%、0.5重量%、1重量%、1.5重量%、2重量%、3重量%を挙げることができ、上限値としては、30重量%、25重量%、20重量%、15重量%、10重量%を挙げることができる。
上記有機酸がオレイン酸の場合、経皮吸収層中のレブリン酸とオレイン酸の含有量比は、1:20~20:1が好ましく、1:10~15:1がより好ましく、1:5~10:1がさらに好ましい。
また、経皮吸収層中の高級アルコールエステルの含有量は、経皮吸収層100重量%中、0.1~30重量%が好ましく、0.5~20重量%がより好ましく、1~15重量%がさらに好ましい。
これらの添加剤を配合することにより、化合物A又はその薬学的に許容される塩の皮膚透過性を向上することができる。
本発明の経皮吸収製剤が軟膏剤の場合、軟膏剤の基剤としては、特に限定されないが、例えば、油脂類、ロウ類(ミツロウ)、パラフィン、ワセリン、ラノリン、加水ラノリン、ラノリンアルコール等の炭化水素類等の油脂性基剤、又は、マクロゴール等の水溶性基剤を用いることができる。
本発明の経皮吸収製剤における経皮吸収層には、上記各成分の他に、特に支障のない限り、経皮吸収製剤の製造に用いられる薬学的に許容されるその他の添加剤を必要に応じて配合してもよい。このような成分としては、特に限定されないが、例えば、香料、着色剤、充填剤、増粘剤、pH調節剤、乳化剤、懸濁化剤等が挙げられる。
本発明の貼付製剤における粘着剤層は、支持体の少なくとも片面に形成され、少なくとも、(i)化合物A又はその薬学的に許容される塩及び粘着基剤を含有する。粘着剤層は、さらに、 (ii)レブリン酸又はその薬学的に許容される塩を含有することが好ましい。粘着剤層は、さらに、(iii)多価アルコール脂肪酸エステル又は脂肪酸アミド、及び/又は(iv)2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム、2-メルカプトベンゾイミダゾール、没食子酸プロピル、α-トコフェロール、亜硫酸ナトリウム及び亜硫酸水素ナトリウムからなる群から選択される1種又は2種以上の添加剤を含有してもよい。
本発明の貼付製剤は、支持体と、該支持体の少なくとも片面に形成された粘着剤層とを含む。つまり、支持体はシート状構造の第一の面と第二の面とを有し、少なくとも第一の面には粘着剤層を形成する。必要に応じて、粘着剤層の支持体側とは反対側の面に剥離シートを有していてもよい。また、貼付製剤の形状は、任意形状の枚葉型でも、ロール状に巻回したものでもよい。
本発明の貼付製剤において、粘着剤層の処方については、特に限定されないが、粘着基剤としては、例えば、アクリル系ポリマー、ゴム系ポリマー、シリコーン系ポリマー等を用いることができる。また、これらの高分子は、1種又は2種以上を組み合わせて用いることができる。
本発明の貼付製剤において、粘着剤層の支持体側とは反対側の面(皮膚への貼付面)は、製剤を実際に使用するまでは、剥離ライナーが積層されているのが好ましい。当該剥離ライナーとしては、特に制限されず、公知の剥離ライナーを用いることができる。具体的には、例えば、剥離処理剤からなる剥離処理剤層が剥離ライナー用の基材の表面に形成された剥離ライナー、それ自体が剥離性の高いプラスチックフィルム、剥離ライナー用の基材の表面に、前記剥離性の高いプラスチックフィルムの素材による剥離層を形成した構成の剥離ライナー等が挙げられる。当該剥離ライナーの剥離面は、基材の片面のみであってもよく、両面であってもよい。
本発明の貼付製剤の皮膚接着性の評価は、タック力試験、引張試験、剥離試験(JIS Z 0237:2009、JIS K 6854)等の試験法を用いて実施することができる。例えば、タック力試験では、本発明の貼付製剤をライナーから剥離し、親指を膏体面に押し付けて剥がす官能試験として評価したとき、親指を剥がす際に適度な接着性であることが好ましい。
・紅斑と痂皮形成
0:紅斑なし
1:ごく軽度の紅斑
2:明らかな紅斑
3:中~強度の紅斑
4:強い紅斑~痂皮形成
・浮腫形成
0:浮腫なし
1:ごく軽度の浮腫
2:明らかな浮腫
3:中等度の浮腫
4:強度の浮腫
本発明の経皮吸収製剤は、薬学的に許容される添加剤を用いて、公知の方法で製造することができる。
本発明の軟膏剤の製造方法としては、特に限定されるものではなく、一般的に知られる方法により製造することができる。例えば、以下の製造方法により製造することができる。
本発明の貼付製剤の製造方法としては、特に限定されるものではないが、例えば、以下の製造方法により製造することができる。
本発明の経皮吸収製剤の投与量は、患者の年齢、体重、症状等により異なるが、通常、成人に対して、化合物A換算値として、1日あたり通常、0.1~500mg、好ましくは、1~100mg、より好ましくは、2~50mg、さらに好ましくは、2~35mgである。
本発明の経皮吸収製剤が、貼付製剤の場合、本発明の貼付製剤のサイズは、通常、2~100cm2、好ましくは、2~70cm2、より好ましくは、4~50cm2である。本発明の貼付製剤は、通常、3回/日~1回/週、好ましくは、1回/日~1回/週、より好ましくは、1回/日の頻度で貼り変えられる。
本発明の経皮吸収製剤において、化合物A又はその薬学的に許容される塩は、その薬効を損なわない限り、他の薬剤(以下、「併用薬」と称することもある。)と併用することができる。この際、投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。また、化合物A又はその薬学的に許容される塩と併用薬とを組み合わせて含有する単一の製剤として投与することもできる。併用薬としては、例えば、レボドパ又は既存のパーキンソン病治療薬が挙げられる。既存のパーキンソン病治療薬の具体例としては、例えば、ドパミンアゴニスト(例えば、ブロモクリプチン、ペルゴリド、タリペキソール、カベルゴリン、プラミペキソール、ロピニロール、ロチゴチン(rotigotine)等)、モノアミン酸化酵素B(MAOB)阻害薬(例えば、セレギリン、ラサギリン(rasagiline)、サフィナミド(Safinamide))、カテコール-O-メチル基転移酵素(COMT)阻害薬(例えば、エンタカポン)、アマンタジン、アポモルヒネ、イストラデフィリン、抗コリン薬(例えば、ビペリデン、トリヘキシフェニジル、プロフェナミン、マザチコール)、チアプリド、ドロキシドパ、カルビドパ、ゾニサミド等を挙げることができるが、これらに限定されない。
不活性ガス雰囲気下、アクリル酸2-エチルヘキシル55部、N-ビニル-2-ピロリドン40部、N-(2-ヒドロキシエチル)アクリルアミド5部及びアゾビスイソブチロニトリル0.2部を酢酸エチル中60℃にて溶液重合させることにより、アクリル系ポリマー(アクリル系ポリマーA)の溶液を調製した。
不活性ガス雰囲気下、アクリル酸2-エチルヘキシル75部、N-ビニル-2-ピロリドン22部、アクリル酸3部及びアゾビスイソブチロニトリル0.2部を酢酸エチル中60℃にて溶液重合させることにより、アクリル系ポリマー(アクリル系ポリマーB)の溶液を調製した。
貼付製剤(テープ剤)中の化合物Aの含量を増加させるためには、薬物溶解度が高い添加剤を添加することが好ましいため、HLB値が異なる種々の添加剤を用いて、化合物Aの飽和溶解度測定を行った結果を表1に示した。また、表1において飽和溶解度の高かった添加剤(すなわち、乳酸、レブリン酸及びオレイン酸)について、種々の他の添加剤を組み合わせた液剤を調製し、各液剤について、化合物Aの皮膚透過量を測定した結果を表2に示した。
バイアル瓶に各種添加剤を量り取り、化合物Aをそれ以上溶解しなくなるまで添加し、室温で一晩撹拌後、0.45μmのPTFEフィルターを用いてろ過し、ろ液中の化合物Aの濃度を高速液体クロマトグラフィー(ODSカラム、UV検出器)にて定量した。ただし、化合物Aの濃度が20%を超えた時点で、化合物Aの添加を中止した。
ミニブタ摘出皮膚を皮膚透過実験用セル(有効面積3mmφ、レセプター液量1.25mL)に真皮層側がレセプター層になるように装着し、各種添加剤における化合物Aの飽和溶液5μLを添加し、レセプター液温が32±1℃の条件で、24時間皮膚透過性試験を行った。レセプター液として脱気したPBS(-)溶液(リン酸緩衝生理食塩水)を用いた。24時間後にレセプター液のサンプリングを行い、透過した化合物Aの濃度を高速液体クロマトグラフィー(ODSカラム、UV検出器)にて定量した。
(1)No.1~12の乳酸を含む組合せ、No.25~36のオレイン酸を含む組合せと比較して、No.13~24のレブリン酸を含む組合せにおいて、相対的に高い化合物Aの皮膚透過性を示すことが分かった。同等の高い飽和溶解度を示した有機酸(乳酸、レブリン酸又はオレイン酸)の中で、レブリン酸を含む組み合わせにおいて、顕著に優れた化合物Aの皮膚透過性が見られたことは、予期せぬ結果である。
(2)とりわけ、レブリン酸、多価アルコール脂肪酸エステル及び界面活性剤の組合せにおいて、化合物Aの高い皮膚透過性が得られ、その中でも特に、ミリスチン酸イソプロピル、レブリン酸、プロピレングリコール脂肪酸エステル、ラウロマクロゴールの組合せ(No.15及びNo.21)において、化合物Aの高い皮膚透過性が得られることが分かった。
アクリル系ポリマーA 50.0部、化合物A 20.0部、ミリスチン酸イソプロピル(以下、「IPM」と称す。) 20.0部、プロピレングリコールモノカプリレート(以下、「PGMC」と称す。) 5.0部、レブリン酸 5.0部を、適量の酢酸エチル及びトルエンに溶解して溶液が均一になるまで十分に混合し、トルエンでベース濃度が20重量%に調整し、均一になるまで十分に混合撹拌を行って塗工液を得た。得られた塗工液を、シリコーン系剥離剤にて剥離処理を施した厚さ75μmポリエチレンテレフタレート(以下、「PET」と称す)製フィルムである剥離ライナーの剥離処理を施した面に、乾燥後の膏体厚が約150μmとなるように塗工し、乾燥し、粘着剤層を形成した。そして、形成した粘着剤層の粘着面を支持体であるPETフィルムとPET不織布との積層フィルムの不織布側に貼り合わせて積層体を作製し、実施例1の貼付製剤を得た。
なお、上記のベース濃度(重量%)とは、塗工液の重量(g)から酢酸エチルの重量(g)を引いた重量(g)を、塗工液の重量(g)で除した値に100を乗じた値(重量%)である。
IPM 17.5部、レブリン酸 7.5部としたこと以外は実施例1と同様にして、実施例2の貼付製剤を得た。
IPM 15.0部、レブリン酸 10.0部としたこと以外は実施例1と同様にして、実施例3の貼付製剤を得た。
アクリル系ポリマーC(MAS683、コスメディ製薬) 60.0部、化合物A 5.0部、IPM 30.0部、レブリン酸 5.0部を、適量の酢酸エチルに溶解して加え、均一になるまで十分に混合撹拌を行って塗工液を得た。得られた塗工液を、PET製フィルムである支持体に、乾燥後の膏体厚が約100μmとなるように塗工し、乾燥し、粘着剤層を形成した。そして、形成した粘着剤層を剥離ライナーに貼り合わせ、実施例4の貼付製剤を得た。
IPM 25.0部、レブリン酸 10.0部としたこと以外は実施例4と同様にして、実施例5の貼付製剤を得た。
アクリルポリマーC 50.0部、IPM 15.0部、レブリン酸 10.0部とし、2,6-ジ-tert-ブチル-4-メチルフェノール 5.0部を加え、さらにチオ硫酸ナトリウム(無水物として) 5.0部を適量の注射用水に溶解して加えたこと以外は実施例4と同様にして、実施例6の貼付製剤を得た。
IPM 12.5部とし、オレイン酸 1.5部、プロピレングリコールモノラウレート(以下、「PGML」と称す。) 10.0部、ラウロマクロゴール 5.0部、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部を加えたこと以外は実施例4と同様にして、実施例6aの貼付製剤を得た。
IPM 9.0部、オレイン酸 5.0部としたこと以外は実施例6aと同様にして、実施例6bの貼付製剤を得た。
レブリン酸を使用せず、乳酸 5.0部とした以外は実施例1と同様にして、比較例1の貼付製剤を得た。
IPM 17.5部、乳酸 7.5部とした以外は比較例1と同様にして、比較例2の貼付製剤を得た。
IPM 15.0部、乳酸 10.0部とした以外は比較例1と同様にして、比較例3の貼付製剤を得た。
レブリン酸を使用せず、IPM 35.0部とした以外は実施例4と同様にして、比較例4の貼付製剤を得た。
レブリン酸を使用せず、酢酸 5.0部を加えたこと以外は実施例4と同様にして、比較例5の貼付製剤を得た。
酢酸を使用せず、乳酸 5.0部を加えたこと以外は比較例5と同様にして、比較例6の貼付製剤を得た。
IPM 34.0部とし、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部を加えたこと以外は比較例4と同様にして、比較例6aの貼付製剤を得た。
上記実施例及び比較例で作製した貼付製剤について、下記の試験を行った。結果は、表3、表4-1及び表4-2に示した。
貼付製剤をヘアレスマウス摘出皮膚の角質層側に貼り付け、皮膚透過実験用フローセル(有効面積6mmφ)に真皮層側がレセプター層になるように装着し、フロー流量2.5mL/h、レセプター液温32±1℃の条件で、24時間皮膚透過実験を行った。レセプター液として、脱気したPBS(-)溶液(リン酸緩衝生理食塩水)を用いた。経時的にレセプター液のサンプリングを行い、透過した化合物Aの濃度を高速液体クロマトグラフィー(ODSカラム、UV検出器)にて定量した。
貼付製剤をヘアレスマウス摘出皮膚の角質層側に貼り付け、皮膚透過実験用プレートセル(有効面積8mmφ、レセプター液量1.4mL)に真皮層側がレセプター層になるように装着し、レセプター液温32±1℃の条件で、24時間皮膚透過実験を行った。レセプター液として、脱気したPBS(-)溶液(リン酸緩衝生理食塩水)を用いた。24時間後にレセプター液のサンプリングを行い、透過した化合物Aの濃度を高速液体クロマトグラフィー(ODSカラム、UV検出器)にて定量した。
(1)粘着剤層に乳酸を含有する比較例1~3と比較して、レブリン酸を含有する実施例1~3においては、化合物Aの皮膚透過性が顕著に向上し、最大透過速度が、45μg/cm2/h以上となることが分かった。
(2)また、比較例1~3において、乳酸含量を増加させると皮膚透過性が低下するのに対して、実施例1~3においては、レブリン酸含量を増加させると添加量依存的に皮膚透過性が向上することが分かった。
(1)粘着剤層に有機酸を含有しない比較例4と比較して、レブリン酸を含有する実施例4~6においては、累積透過量及び最大透過速度が、1.5倍程度向上し、化合物Aの皮膚透過性が向上することが分かった。
(2)一方、酢酸又は乳酸を含有する比較例5、6においては、有機酸を含有しない比較例4と比較して、化合物Aの皮膚透過性の顕著な向上は見られなかった。
(1)レブリン酸、オレイン酸、PGML及びラウロマクロゴールを含有する実施例6a、6bにおいては、有機酸を含有しない比較例6aと比較して化合物Aの皮膚透過性が向上することが分かった。
PGMCを使用せず、アクリル系ポリマーA 50.0部、化合物A 20.0部、IPM 25.0部、レブリン酸 5.0部とし、膏体厚が約100μmとなるよう塗工したこと以外は実施例1と同様にして、実施例7の貼付製剤を得た。
IPM 20.0部とし、PGMC 5.0部を加え、膏体厚が約100μmとなるよう塗工したこと以外は実施例1と同様にして、実施例8の貼付製剤を得た。
PGMCとレブリン酸を使用せず、IPM 30.0部とし、膏体厚が約100μmとなるよう塗工したこと以外は実施例1と同様にして、比較例7の貼付製剤を得た。
レブリン酸を使用せず、IPM 25.0部とし、膏体厚が約100μmとなるよう塗工したこと以外は実施例1と同様にして、比較例8の貼付製剤を得た。
上記実施例及び比較例で作製した製剤について、試験例3の評価を行った。結果は、表5に示した。
(1)粘着剤層に添加剤A群を含有しない比較例7と比較して、多価アルコール脂肪酸エステルであるPGMCのみを含有する比較例8では、化合物Aの皮膚透過性の向上はほとんど認められなかった。これに対し、レブリン酸を含有する実施例7においては、化合物Aの皮膚透過性の顕著な向上が認められた。さらに、実施例8においては、単独では化合物Aの皮膚透過促進効果をほとんど示さなかったPGMCに、レブリン酸を組み合わせること(添加剤A群とすること)により、相乗的に化合物Aの皮膚透過性が向上することが分かった。
アクリル系ポリマーB 45.0部、化合物A 5.5部、IPM 31.7部、PGML 10.0部、レブリン酸 5.0部、ラウロマクロゴール 1.5部、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部、適量の注射用水に溶解したチオ硫酸ナトリウム(無水物として) 0.08部を、適量の酢酸エチル及びトルエンに溶解して溶液が均一になるまで十分に混合した後、架橋剤として、アルミニウムエチルアセトアセテート ジイソプロピレート(以下、「ALCH」と称す。) 0.1部を、適量の酢酸エチル及びアセチルアセトンに溶解して加え、均一になるまで十分に混合撹拌を行って、塗工液を得た。得られた塗工液を、膏体厚が約100μmとなるようにしたこと以外は実施例1と同様に塗工、乾燥し、粘着剤層を形成し、支持体と貼り合わせて積層体を作製した。その後、70℃で48時間放置し、架橋粘着剤層を調製し、実施例9の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノール及びチオ硫酸ナトリウムを使用せず、アクリル系ポリマーB 42.1部、化合物A 8.0部、IPM 33.1部、PGML 7.5部、ラウロマクロゴール 4.0部、ALCH 0.4部としたこと以外は実施例9と同様にして、実施例10の貼付製剤を得た。
アクリル系ポリマーB 34.9部、IPM 26.9部、PGML 14.9部、ラウロマクロゴール 10.0部としたこと以外は実施例10と同様にして、実施例11の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウムを使用せず、アクリル系ポリマーB 39.6部、化合物A 5.0部、IPM 35.0部、PGML 10.0部、レブリン酸 5.0部、ラウロマクロゴール 5.0部、ALCH 0.4部としたこと以外は実施例9と同様にして、実施例12の貼付製剤を得た。
ラウロマクロゴールを使用せず、アクリル系ポリマーB 45.0部、IPM 33.7部、ALCH 0.1部とし、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部、チオ硫酸ナトリウム(無水物として) 0.13部を加えたこと以外は実施例12と同様にして、実施例12aの貼付製剤を得た。
ラウロマクロゴールを使用せず、アクリル系ポリマーB 45.0部、化合物A 5.5部、IPM 33.2部、PGML 10.0部、レブリン酸 5.0部、ALCH 0.1部とし、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部、チオ硫酸ナトリウム(無水物として) 0.08部を加えたこと以外は実施例12と同様にして、実施例13の貼付製剤を得た。
IPM 32.2部、レブリン酸 6.0部、チオ硫酸ナトリウム(無水物として) 0.13部としたこと以外は実施例13と同様にして、実施例13aの貼付製剤を得た。
IPM 31.2部、レブリン酸 7.0部としたこと以外は実施例13aと同様にして、実施例13bの貼付製剤を得た。
アクリル系ポリマーB 49.9部、化合物A 6.5部、IPM 23.5部、PGML 10.0部、レブリン酸 3.0部、ラウロマクロゴール 7.0部、ALCH 0.1部としたこと以外は実施例12と同様にして、実施例14の貼付製剤を得た。
PGML及びラウロマクロゴールを使用せず、アクリル系ポリマーB 36.9部、化合物A 8.0部、IPM 49.8部、レブリン酸 5.0部、ALCH 0.4部としたこと以外は実施例12と同様にして、実施例15の貼付製剤を得た。
PGML、レブリン酸及びラウロマクロゴールを使用せず、アクリル系ポリマーB 49.9部、化合物A 5.0部、IPM 45.0部、ALCH 0.1部としたこと以外は実施例10と同様にして、比較例9の貼付製剤を得た。
アクリル系ポリマーB 49.8部、化合物A 8.0部、IPM 41.8部、ALCH 0.4部としたこと以外は比較例9と同様にして比較例10の貼付製剤を得た。
ラウロマクロゴールを使用せず、アクリル系ポリマーB 34.9部、化合物A 2.0部、IPM 42.8部、PGML 14.9部、レブリン酸 5.0部、ALCH 0.4部としたこと以外は実施例12と同様にして、比較例11の貼付製剤を得た。
上記実施例及び比較例で作製した製剤について試験例3の評価を行った。結果は表6及び7に示した。
化合物A 4.0部に、PGML 10.0部、ラウロマクロゴール 5.0部、レブリン酸 5.0部を添加して混合溶解し、ゲル化炭化水素(ハイコールジェル(登録商標)、カネダ株式会社) 76.0部を添加して、均一になるように混和練合して実施例16の軟膏剤を得た。
IPM 15.0部を加え、化合物A 5.0部、ゲル化炭化水素(ハイコールジェル(登録商標)、カネダ株式会社) 60.0部としたこと以外は実施例16と同様にして、実施例17の軟膏剤を得た。
オレイン酸 20.0部を加え、化合物A 8.0部、レブリン酸 7.0部、ゲル化炭化水素(ハイコールジェル(登録商標)、カネダ株式会社) 50.0部としたこと以外は実施例16と同様にして、実施例17aの軟膏剤を得た。
オレイン酸 25.0部を加え、化合物A 8.0部、レブリン酸 7.0部、ゲル化炭化水素(ハイコールジェル(登録商標)、カネダ株式会社) 45.0部としたこと以外は実施例16と同様にして、実施例18の軟膏剤を得た。
オレイン酸 20.0部を加え、化合物A 10.0部、レブリン酸 7.0部、ゲル化炭化水素(ハイコールジェル(登録商標)、カネダ株式会社) 48.0部としたこと以外は実施例16と同様にして、実施例19の軟膏剤を得た。
化合物A 8.0部にオレイン酸 42.0部を添加して混合溶解し、ゲル化炭化水素(ハイコールジェル(登録商標)、カネダ株式会社) 50.0部を添加して、均一になるように混和練合して比較例12の軟膏剤を得た。
PGML 10.0%、ラウロマクロゴール 5.0部を加え、化合物A 5.0部、オレイン酸 25.0部、ゲル化炭化水素(ハイコールジェル(登録商標)、カネダ株式会社) 55.0部としたこと以外は実施例16と同様にして、比較例13の軟膏剤を得た。
上記実施例及び比較例で作製した製剤について、有効面積10.25mmφ、ドナーサンプル200μLとして、試験例4の評価を行った。結果は、表8に示した。
(1)添加剤A群を含有しない比較例9及び10と比較して、添加剤A群を含有する実施例9~11では、累積透過量及び最大透過速度が向上し、化合物Aの皮膚透過性において顕著な向上が認められた。
(2)添加剤A群であるプロピレングリコール脂肪酸エステルは、7.5~14.9重量%の添加量において、化合物Aの良好な皮膚透過性を示すことが分かった。
(3)界面活性剤であるラウロマクロゴールは、1.5~10.0重量%の添加量において、化合物Aの良好な皮膚透過性を示すことが分かった。
(4)添加剤A群を含有する実施例10及び11において、良好なタック力を示すことが分かった。
(1)化合物Aの含量が2.0重量%である比較例11と比較して、化合物Aの含量を5.0重量%以上とした実施例12~15において、累積透過量及び最大透過速度が向上し、化合物Aの皮膚透過性が向上することが分かった。
(2)実施例14によれば、添加剤A群であるレブリン酸の含量が3.0重量%以上の条件において、化合物Aの皮膚透過性の向上効果が認められることが分かった。
(3)比較例11において、良好なタック力が得られなかった。一方で、添加剤A群を含有する実施例15において、良好なタック力を示すことが分かった。
(1)添加剤A群を含有しない比較例12と比較して、添加剤A群を含有する実施例16~19では、累積透過量及び最大透過速度が向上し、化合物Aの皮膚透過性において顕著な向上が認められた。
(2)また、実施例17aと比較して実施例18では、累積透過量及び最大透過速度が向上し、レブリン酸と併用するオレイン酸含量を増加させることで、化合物Aの皮膚透過性が向上することが分かった。
(3)レブリン酸を含有しない比較例13では、比較例12と比較して累積透過量及び最大透過速度のわずかな向上しか認められなかった。
アクリル系ポリマーB 39.6部、化合物A 5.0部、IPM 35.0部、PGML 10.0部、レブリン酸 5.0部、ラウロマクロゴール 5.0部、ALCH 0.4部を使用し、実施例9と同様にして、塗工液を得た。2,6-ジ-tert-ブチル-4-メチルフェノール 0.05部を適量のメタノールに溶解し、全量が100部となるよう先に得た塗工液を加えた後、実施例9と同様にして、実施例20の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、チオ硫酸ナトリウム(無水物として) 0.13部を適量の注射用水に溶解して加えたこと以外は実施例20と同様にして、実施例21の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、2-メルカプトベンズイミダゾール(以下、「2-MBI」と称す。) 0.62部を、適量のメタノールに溶解して加えたこと以外は実施例20と同様にして、実施例22の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、没食子酸プロピル 0.019部を、適量のメタノールに溶解して加えたこと以外は実施例20と同様にして、実施例23の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、α-トコフェロール 0.002部を、適量のメタノールに溶解して加えたこと以外は実施例20と同様にして、実施例24の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、亜硫酸ナトリウム(無水物として) 0.2部を、適量の水に溶解して加えたこと以外は実施例20と同様にして、実施例25の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、亜硫酸水素ナトリウム 0.3部を、適量の水に溶解して加えたこと以外は実施例20と同様にして、実施例26の貼付製剤を得た。
アクリル系ポリマーB 48.9部、化合物A 6.5部、IPM 23.5部、PGML 10.0部、レブリン酸 3.0部、ラウロマクロゴール 7.0部、ALCH 0.1部を使用し、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部を適量のメタノールに溶解して加え、実施例9と同様にして、実施例27の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、アクリル系ポリマーB 49.7部とし、2-MBI 0.2部を適量のメタノールに溶解して加えたこと以外は、実施例27と同様にして、実施例28の貼付製剤を得た。
アクリル系ポリマーB 48.7部とし、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部を適量のメタノールに溶解し、チオ硫酸ナトリウム(無水物として) 0.2部を適量の水に溶解して加えたこと以外は、実施例27と同様にして、実施例29の貼付製剤を得た。
アクリル系ポリマーB 48.7部とし、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部及び2-MBI 0.2部を適量のメタノールに溶解して加えたこと以外は、実施例27と同様にして、実施例30の貼付製剤を得た。
アクリル系ポリマーB 45.0部、化合物A 5.5部、IPM 33.2部、PGML 10.0部、レブリン酸 5.0部、ALCH 0.1部、2,6-ジ-tert-ブチル-4-メチルフェノール 1.0部を使用し、チオ硫酸ナトリウム(無水物として) 0.08部を適量の水に溶解して加えたこと以外は、実施例9と同様にして、実施例31の貼付製剤を得た。
チオ硫酸ナトリウム(無水物として) 0.13部としたこと以外は、実施例31と同様にして、実施例32の貼付製剤を得た。
IPM 31.7部とし、ラウロマクロゴール 1.5部を加えたこと以外は、実施例31と同様にして、実施例33の貼付製剤を得た。
IPM 31.7部とし、ラウロマクロゴール 1.5部を加えたこと以外は、実施例32と同様にして、実施例34の貼付製剤を得た。
アクリル系ポリマーB 39.6部、化合物A 5.0部、IPM 35.0部、PGML 10.0部、レブリン酸 5.0部、ラウロマクロゴール 5.0部、ALCH 0.4部を使用し、実施例9と同様にして、比較例14の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、パルミチン酸L-アスコルビル 0.013部を適量のメタノールに溶解して加えたこと以外は実施例20と同様にして、比較例15の貼付製剤を得た。
[比較例16]
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、L-アスコルビン酸 0.1部を適量のメタノールに溶解して加えたこと以外は実施例20と同様にして、比較例16の貼付製剤を得た。
2,6-ジ-tert-ブチル-4-メチルフェノールを使用せず、アクリル系ポリマーB 49.9部としたこと以外は、実施例27と同様にして、比較例17の貼付製剤を得た。
上記実施例及び比較例で作製した製剤について、下記の試験を行った。結果は、表10及び11に示した。
種々の安定化剤を含有する製剤サンプルを、苛酷条件(60℃2週間又は50℃1ヶ月)で保存を行い、保存による製剤中の化合物Aの含量の変化と製剤色差から、製剤の安定性を評価した。また、製剤の光に対する安定性を評価するため、曝光条件(総照度53000lx・h、照度2000lx、照射時間26.5h)で保存を行い、製剤中の化合物含量を測定した。化合物Aの含量の測定は、下記の方法で行った。
以下の条件において、HPLCで分析した際の、薬物(化合物A)に相当するピーク面積をHPLCのチャートから面積百分率%で算出した。
移動相A:薄めたリン酸塩緩衝液(0.05mol、pH6.8)
移動相B:HPLC用アセトニトリル
検出器:紫外吸光光度計(測定波長:245nm)
カラム:内径4.6mm、長さ10cmのステンレス管にHPLC用オクタデシルシリル化シリカゲルを充填する(XBridge C18又は同等品)移動相の送液:移動相A及び移動相Bの混合比を表9に示すように変えて濃度勾配制御する
製剤を標準白色板の上に載せ、色彩色差計(CR-400、コニカミノルタ)を用いてb*値を測定した。
(1)粘着剤層に安定化剤として、パルミチン酸L-アスコルビルを含む比較例15では、粘着剤層に安定化剤を含まない比較例14と同様に苛酷条件での保存で化合物Aの含量が低下し、色差の指標であるb*値も増加することが分かった。
(2)粘着剤層に安定化剤として、L-アスコルビン酸を含む比較例16では、粘着剤層に安定化剤を含まない比較例14と比較して化合物Aの含量の低下がやや抑制されたものの、b*値が増加することが分かった。
(3)これに対し、粘着剤層に安定化剤として、2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム、2-MBI、没食子酸プロピル、α-トコフェロール、亜硫酸ナトリウム、又は亜硫酸水素ナトリウムを含む実施例20~26では、苛酷条件での保存下でも、化合物Aの含量の低下が抑制され、b*値の増加も抑制されることが分かった。
(1)粘着剤層に安定化剤を含有しない比較例17では、製剤の熱苛酷条件及び曝光条件での保存下で、化合物Aの含量が低下することが分かった。これに対し、粘着剤層に安定化剤を含有させた実施例27~34では、化合物Aの含量の低下が抑制された。
(2)また、安定化剤である2,6-ジ-tert-ブチル-4-メチルフェノールと、チオ硫酸ナトリウム又は2-MBIの組み合わせにより、製剤の安定性は、顕著に向上することが分かった。
(3)さらに、安定化剤である2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム及び2-MBIを単独又は組み合わせて配合することにより、曝光条件においても、製剤中の化合物Aの安定化効果が維持されることが分かった。
Claims (23)
- 経皮吸収層を有する経皮吸収製剤であって、該経皮吸収層が、
(i)タンドスピロン又はその薬学的に許容される塩、及び
(ii)レブリン酸又はその薬学的に許容される塩
を含有することを特徴とする経皮吸収製剤。 - 貼付製剤の形態である、請求項1に記載の経皮吸収製剤。
- さらに前記経皮吸収層が、(iii)多価アルコール脂肪酸エステル又は脂肪酸アミドを含有する、請求項1又は2に記載の経皮吸収製剤。
- さらに前記経皮吸収層が、オレイン酸を含有する、請求項1~3のいずれか一項に記載の経皮吸収製剤。
- さらに前記経皮吸収層が、(iv)2,6-ジ-tert-ブチル-4-メチルフェノール、チオ硫酸ナトリウム、2-メルカプトベンゾイミダゾール、没食子酸プロピル、α-トコフェロール、亜硫酸ナトリウム及び亜硫酸水素ナトリウムからなる群から選択される1種又は2種以上の添加剤を含有する、請求項1~4のいずれか一項に記載の経皮吸収製剤。
- (i)が、タンドスピロンである、請求項1~5のいずれか一項に記載の経皮吸収製剤。
- (ii)が、レブリン酸である、請求項1~6のいずれか一項に記載の経皮吸収製剤。
- (iv)が、2,6-ジ-tert-ブチル-4-メチルフェノールを含む、請求項5~7のいずれか一項に記載の経皮吸収製剤。
- (iv)が、2,6-ジ-tert-ブチル-4-メチルフェノール及びチオ硫酸ナトリウムを含む、請求項5~8のいずれか一項に記載の経皮吸収製剤。
- (iii)が、プロピレングリコール脂肪酸エステルである、請求項3~9のいずれか一項に記載の経皮吸収製剤。
- 前記プロピレングリコール脂肪酸エステルが、プロピレングリコールモノカプリレート、プロピレングリコールモノラウレート、又はそれらの組合せである、請求項10に記載の経皮吸収製剤。
- 前記経皮吸収層が、さらに1価アルコール脂肪酸エステルを含有する、請求項1~11のいずれか一項に記載の経皮吸収製剤。
- 前記1価アルコール脂肪酸エステルが、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、又はそれらの組合せである、請求項12に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(i)の含有量が、0.1~30重量%である、請求項1~13のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(ii)の含有量が、0.1~20重量%である、請求項1~14のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(ii)の含有量が、3~10重量%である、請求項1~14のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(ii)の含有量が、6~7重量%である、請求項1~14のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(iv)の2,6-ジ-tert-ブチル-4-メチルフェノールの含有量が、0.001~10重量%である、請求項5~17のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(iv)のチオ硫酸ナトリウムの含有量が、無水物として0.001~7重量%である、請求項5~18のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(iv)の2-メルカプトベンゾイミダゾールの含有量が、0.001~5重量%である、請求項5~19のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(iv)の没食子酸プロピルの含有量が、0.001~7重量%である、請求項5~20のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層100重量%中の(iii)の多価アルコール脂肪酸エステルの含有量が、1~20重量%である、請求項3~21のいずれか一項に記載の経皮吸収製剤。
- 前記経皮吸収層が、粘着剤層であって、支持体の少なくとも片面に該粘着剤層を有する、請求項2~22のいずれか一項に記載の経皮吸収製剤。
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JP2020026337A (ja) | 2018-08-10 | 2020-02-20 | トヨタ車体株式会社 | ワーク搬送装置 |
JP2020132798A (ja) | 2019-02-22 | 2020-08-31 | 株式会社日本触媒 | 粘着剤組成物およびガラス用粘着シート |
-
2021
- 2021-02-18 TW TW110105525A patent/TW202140017A/zh unknown
- 2021-02-18 CN CN202180015721.8A patent/CN115087445A/zh active Pending
- 2021-02-18 KR KR1020227031721A patent/KR20220143065A/ko active Search and Examination
- 2021-02-18 CA CA3168199A patent/CA3168199A1/en active Pending
- 2021-02-18 US US17/904,577 patent/US20230091378A1/en active Pending
- 2021-02-18 JP JP2022501956A patent/JPWO2021166987A1/ja active Pending
- 2021-02-18 MX MX2022010192A patent/MX2022010192A/es unknown
- 2021-02-18 AU AU2021223929A patent/AU2021223929A1/en active Pending
- 2021-02-18 WO PCT/JP2021/006052 patent/WO2021166987A1/ja unknown
- 2021-02-18 EP EP21756323.8A patent/EP4108243A4/en active Pending
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See also references of EP4108243A4 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11559525B2 (en) | 2019-04-26 | 2023-01-24 | Sumitomo Pharma Co., Ltd. | Therapeutic drug for dyskinesia |
US11628169B2 (en) | 2020-08-31 | 2023-04-18 | Sumitomo Pharma Co., Ltd. | Therapeutic drug for motor complications in Parkinson's disease |
Also Published As
Publication number | Publication date |
---|---|
CA3168199A1 (en) | 2021-08-26 |
CN115087445A (zh) | 2022-09-20 |
US20230091378A1 (en) | 2023-03-23 |
KR20220143065A (ko) | 2022-10-24 |
AU2021223929A1 (en) | 2022-09-22 |
MX2022010192A (es) | 2022-09-19 |
JPWO2021166987A1 (ja) | 2021-08-26 |
TW202140017A (zh) | 2021-11-01 |
EP4108243A1 (en) | 2022-12-28 |
EP4108243A4 (en) | 2024-04-17 |
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