CN115279350A - Patch containing blonanserin and its preparation method - Google Patents
Patch containing blonanserin and its preparation method Download PDFInfo
- Publication number
- CN115279350A CN115279350A CN202180012756.6A CN202180012756A CN115279350A CN 115279350 A CN115279350 A CN 115279350A CN 202180012756 A CN202180012756 A CN 202180012756A CN 115279350 A CN115279350 A CN 115279350A
- Authority
- CN
- China
- Prior art keywords
- adhesive layer
- acid
- patch
- mass
- adhesive
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XVGOZDAJGBALKS-UHFFFAOYSA-N Blonanserin Chemical compound C1CN(CC)CCN1C1=CC(C=2C=CC(F)=CC=2)=C(CCCCCC2)C2=N1 XVGOZDAJGBALKS-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 229950002871 blonanserin Drugs 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title description 48
- 239000012790 adhesive layer Substances 0.000 claims abstract description 74
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 73
- 239000010410 layer Substances 0.000 claims abstract description 63
- 239000004310 lactic acid Substances 0.000 claims abstract description 36
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 36
- 229920002725 thermoplastic elastomer Polymers 0.000 claims abstract description 27
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 25
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 23
- 230000001070 adhesive effect Effects 0.000 claims description 111
- 239000000853 adhesive Substances 0.000 claims description 110
- -1 aliphatic dicarboxylic acid ester Chemical class 0.000 claims description 60
- 239000000203 mixture Substances 0.000 claims description 50
- 239000007788 liquid Substances 0.000 claims description 35
- 238000004519 manufacturing process Methods 0.000 claims description 33
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 229920002367 Polyisobutene Polymers 0.000 claims description 30
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 claims description 28
- 150000007524 organic acids Chemical class 0.000 claims description 12
- 238000010030 laminating Methods 0.000 claims description 11
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- 239000004820 Pressure-sensitive adhesive Substances 0.000 abstract description 61
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- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
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- 239000000194 fatty acid Substances 0.000 description 16
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- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 5
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- ASGSROHYBOETMM-UHFFFAOYSA-N alpha-monoisostearyl glycerylether Natural products CC(C)CCCCCCCCCCCCCCCCC(=O)OCC(O)CO ASGSROHYBOETMM-UHFFFAOYSA-N 0.000 description 5
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
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- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 3
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
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- 238000005070 sampling Methods 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 150000003377 silicon compounds Chemical class 0.000 description 1
- 239000013464 silicone adhesive Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000010675 spruce oil Substances 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-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
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000000196 viscometry Methods 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Psychiatry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a patch having: a support and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a nonvolatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is more than 0 molar equivalent and 1.5 molar equivalent or less relative to blonanserin contained in the pressure-sensitive adhesive layer; or to a patch having: and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a nonvolatile hydrocarbon oil, and does not contain lactic acid.
Description
Technical Field
The present invention relates to a patch containing blonanserin and a method for producing the same. More specifically, the present invention relates to a blonanserin-containing patch preparation having high skin permeability and a method for producing the same.
Background
In the treatment of schizophrenia, there are problems of relapse (regeneration) and regeneration (reburning) caused by poor administration compliance of a therapeutic drug for schizophrenia (oral preparation). The Lonasen (registered trademark) tape marketed in 2019 in 9 months is a patch preparation containing blonanserin as an active ingredient as a therapeutic agent for schizophrenia, and unlike conventional oral preparations, the tape preparation can be confirmed by visual observation of the administration state, and the administration can be easily managed by caregivers and caregivers, and therefore, is expected to improve the administration compliance.
The formulation technology described in patent documents 1 and 2 was used for the Lonasen (registered trademark) tape. Patent document 1 describes an adhesive patch using an acrylic adhesive as an adhesive base, and discloses the following technique: when lactic acid is added as a permeation enhancer, the permeation amount of blonanserin is dramatically increased in the rat skin permeation test.
Patent document 2 discloses the following technique: by adding lactic acid as an essential component, it is possible to achieve an unprecedented high blonanserin transmission in all adhesive bases of silicone adhesives, rubber adhesives (styrene-isoprene-styrene block copolymers) and acrylic adhesives.
However, the Lonasen (registered trademark) tape has a low drug utilization rate (non-patent document 1), and the size of the preparation must be increased in order to obtain a blood concentration necessary for treatment by percutaneous absorption of a sufficient amount of the drug. Considering that the application site of the Lonasen (registered trademark) tape must be changed every day, the case where the size of the preparation is too large is very inconvenient for the patient, and it can be said that the preparation is very difficult to use.
Therefore, a blonanserin-containing patch having high skin permeability and a method for producing the same are not known at all, and it is highly desired to provide such a blonanserin-containing patch and a method for producing the same.
Documents of the prior art
Patent document
Patent document 1: japanese patent No. 5001271
Patent document 2: japanese patent No. 5837518
Non-patent literature
Non-patent document 1: drug evaluation Form (Pharmaceutical Interview Form) Lonasen (registered trademark) tape (version 1, 6 months, 2019)
Disclosure of Invention
Problems to be solved by the invention
The present invention addresses the above problems and achieves the following objects. That is, an object of the present invention is to provide a blonanserin-containing patch preparation having high skin permeability and a method for producing the same.
Means for solving the problems
As a result of intensive studies to achieve the above object, the present inventors have found that a blonanserin-containing patch having high skin permeability can be provided by a patch comprising: and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a nonvolatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is 1.5 molar equivalents or less relative to blonanserin contained in the pressure-sensitive adhesive layer.
The present invention is based on the above findings of the present inventors, and the following describes a method for solving the above problems. That is to say that the first and second electrodes,
< 1 > a patch having: and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a nonvolatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is more than 0 molar equivalent and 1.5 molar equivalent or less relative to blonanserin contained in the pressure-sensitive adhesive layer.
< 2 > a patch having: the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a nonvolatile hydrocarbon oil, and does not contain lactic acid.
< 3 > a method for producing a patch, which is a method for producing the patch < 1 > or < 2 > above, comprising:
and a step of laminating the support and the adhesive layer.
ADVANTAGEOUS EFFECTS OF INVENTION
The present invention solves the above problems and achieves the above objects, and provides a blonanserin-containing patch preparation having high skin permeability and a method for producing the same.
Detailed Description
(Patch)
The patch has: the support and the adhesive layer on the support may have other elements.
< support body >
The support is not particularly limited and may be appropriately selected according to the purpose, and for example, a support commonly used in a pressure-sensitive adhesive sheet for skin application or a transdermal absorption preparation may be used.
The material of the support is not particularly limited, and may be appropriately selected according to the purpose, and examples thereof include: polyesters such as polyethylene terephthalate, polyolefins such as polyethylene and polypropylene, polyurethanes, ethylene-vinyl acetate copolymers, polyvinyl chloride, and the like.
The support may have a single-layer structure or a multi-layer structure. Further, the material may be woven cloth, nonwoven cloth, film, foam, porous, mesh structure, sheet, or flat plate.
In order to prevent static electricity from accumulating in the support, an antistatic agent may be contained in the woven fabric, nonwoven fabric, film, or the like constituting the support. In order to obtain good anchoring properties with the adhesive layer, a nonwoven fabric, a woven fabric, or a laminate of these and a film may be used as the support.
The thickness of the support is not particularly limited and may be appropriately selected depending on the purpose, and is preferably 10 μm or more and 100 μm or less, more preferably 15 μm or more and 50 μm or less for a film, and is preferably 50 μm or more and 2000 μm or less, more preferably 100 μm or more and 1000 μm or less for a porous sheet such as a woven fabric, a nonwoven fabric, or a foamable support.
< adhesive layer >
The pressure-sensitive adhesive layer contains (a) blonanserin or a salt thereof, (b) a thermoplastic elastomer, and (c) a nonvolatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is 1.5 molar equivalents or less relative to blonanserin contained in the pressure-sensitive adhesive layer, and may contain other components.
(a) Blonanserin or salt thereof
The "blonanserin" is a compound represented by the chemical name 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydroxycycloocta [ b ] pyridine, classified as SDA (5-hydroxytryptamine-dopamine antagonist), and is commercially available as an antipsychotic agent (atypical antipsychotic agent).
The blonanserin contained in the adhesive layer may be in a free form or may be a pharmaceutically acceptable salt, and is not particularly limited.
The pharmaceutically acceptable salt is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include pharmaceutically acceptable acid addition salts, inorganic salts, and organic salts.
The pharmaceutically acceptable salt may be used alone or in combination of two or more. In addition, the free form may be used in admixture with a salt.
The inorganic salt is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: hydrochloride, hydrobromide, nitrate, sulfate, phosphate, and the like.
Examples of the organic acid salt include: formates, acetates, trifluoroacetates, propionates, lactates, tartrates, oxalates, fumarates, maleates, citrates, malonates, methanesulfonates and the like. From the viewpoint of easy availability, the free form or hydrochloride is preferred, and from the viewpoint of skin permeability, the free form is more preferably used.
The content of blonanserin or a salt thereof in the pressure-sensitive adhesive layer, that is, the proportion of blonanserin or a salt thereof to 100% by mass of the total of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the purpose, and from the viewpoint of ensuring dispersibility in the pressure-sensitive adhesive layer and good skin permeability, the lower limit value is preferably 0.5% by mass or more, more preferably 0.75% by mass or more, further preferably 1% by mass or more, and particularly preferably 1.5% by mass or more, and the upper limit value is preferably 30% by mass or less, more preferably 25% by mass or less, further preferably 20% by mass or less, and particularly preferably 15% by mass or more.
(b) Thermoplastic elastomer
The "thermoplastic elastomer" in the present invention means a thermoplastic elastomer which softens when heated to exhibit fluidity and returns to a rubber-like elastomer when cooled.
The thermoplastic elastomer is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include: various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based, and olefin-based elastomers. In particular, from the viewpoint of satisfying both sufficient skin adhesiveness and low skin irritation, styrene-based thermoplastic elastomers are preferable, and styrene-based block copolymers are particularly preferable.
The styrene-based block copolymer is not particularly limited, and may be appropriately selected according to the purpose, and examples thereof include: styrene-butadiene block copolymers, styrene-butadiene-styrene block copolymers, styrene-isoprene-styrene block copolymers, styrene-ethylene/butylene-styrene block copolymers, styrene-ethylene/propylene-styrene block copolymers, styrene-isobutylene-styrene block copolymers, and the like. The "ethylene/butene" represents a copolymer block of ethylene and butene, and the "ethylene/propylene" represents a copolymer block of ethylene and propylene. These styrenic block copolymers may be used alone or in combination of two or more.
Among the styrene-based block copolymers, one or more selected from styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are preferable from the viewpoint of acquisition properties and handling properties in addition to the balance between sufficient skin adhesiveness of the adhesive layer and the suppression of adhesive residue due to the improvement in cohesive force, and a mixture of a styrene-isoprene block copolymer and a styrene-isoprene-styrene block copolymer is particularly preferable.
The lower limit of the proportion of the styrene-isoprene block copolymer in the mixture is not particularly limited and may be appropriately selected depending on the purpose, and is preferably 10% by mass or more, more preferably 15% by mass or more, further preferably 20% by mass or more, particularly preferably 40% by mass or more, and most preferably 50% by mass or more.
The upper limit of the proportion of the styrene-isoprene block copolymer in the mixture is not particularly limited and may be appropriately selected depending on the purpose, and is preferably 95% by mass or less, more preferably 90% by mass or less, further preferably 85% by mass or less, and particularly preferably 80% by mass or less.
The styrene content in the styrene-isoprene-styrene block copolymer is not particularly limited and may be appropriately selected depending on the purpose, and the styrene content in the copolymer is preferably 5 mass% or more and 60 mass% or less, more preferably 10 mass% or more and 50 mass% or less.
The molecular weight of the styrene-isoprene-styrene block copolymer is not particularly limited and may be appropriately selected depending on the purpose, and the weight average molecular weight measured by Gel Permeation Chromatography (GPC) is preferably 20000 or more and 500000 or less, more preferably 30000 or more and 300000 or less.
The styrene content in the styrene-isoprene block copolymer is not particularly limited and may be appropriately selected depending on the purpose, and the styrene content in the copolymer is preferably 5 mass% or more and 50 mass% or less, more preferably 10 mass% or more and 40 mass% or less.
The molecular weight of the styrene-isoprene block copolymer is not particularly limited and may be appropriately selected depending on the purpose, and the weight average molecular weight measured by GPC is preferably 10000 or more and 500000 or less, more preferably 20000 or more and 300000 or less.
The viscosity of the styrene-based block copolymer is not particularly limited and may be appropriately selected depending on the purpose, and from the viewpoint of improving the balance of adhesive properties, the lower limit of the solution viscosity at 25 ℃ of a 25 mass% toluene solution is preferably 500mPa · s or more, more preferably 900mPa · s or more, and the upper limit thereof is preferably 2000mPa · s or less, more preferably 1800mPa · s or less. The "solution viscosity at 25 ℃ of a 25 mass% toluene solution" is a value measured by a viscosity measurement method based on a styrene-isoprene-styrene block copolymer described in "pharmaceutical additives specification 2013" (published by pharmaceutical diaries) on page 395.
The styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer may be copolymers produced by a known method. Further, commercially available products satisfying the above characteristics can be used for the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, respectively. Further, a mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is also commercially available, and a commercially available mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer satisfying the above characteristics in the above mixing ratio can be suitably used.
Examples of commercially available products of the above-mentioned styrenic block copolymer include: "KRATON (registered trademark) D1111", "KRATON (registered trademark) D1163", "KRATON (registered trademark) D1113", "KRATON (registered trademark) D1119" manufactured by KRATON polymers; "JSR (registered trademark) SIS5229", "JSR (registered trademark) SIS5002", "JSR (registered trademark) SIS5403", "JSR (registered trademark) SIS5505", manufactured by JSR corporation; "Quintac (registered trademark) 3421", "Quintac (registered trademark) 3433N", "Quintac (registered trademark) 3520", "Quintac (registered trademark) 3450", and "Quintac (registered trademark) 3270", manufactured by japan ruing corporation.
Among them, "KRATON (registered trademark) D1163", "KRATON (registered trademark) D1113", "JSR (registered trademark) SIS5403", "JSR (registered trademark) SIS5505", "Quintac (registered trademark) 3433N", and/or "Quintac (registered trademark) 3520" are preferable from the viewpoints of the mixing ratio of the above styrene-isoprene-styrene block copolymer and the above styrene-isoprene block copolymer and the solution viscosity, and "JSR (registered trademark) SIS5505" and/or "Quintac (registered trademark) 3520" are particularly preferable.
The content of the thermoplastic elastomer in the pressure-sensitive adhesive layer, that is, the proportion of the thermoplastic elastomer to 100 mass% of the total of the constituent components of the pressure-sensitive adhesive layer, is not particularly limited and may be appropriately selected depending on the purpose, and the lower limit value is preferably 10 mass% or more, more preferably 15 mass% or more, and still more preferably 20 mass% or more, and the upper limit value is preferably 70 mass% or less, more preferably 65 mass% or less, and still more preferably 60 mass% or less. If the ratio is 10% by mass or more, the shape of the pressure-sensitive adhesive layer can be more reliably maintained, and if it is 70% by mass or less, the adhesiveness of the pressure-sensitive adhesive layer to the skin can be more reliably exhibited.
(c) Non-volatile hydrocarbon oils
The non-volatile hydrocarbon oil is not particularly limited and may be appropriately selected according to the purpose, and preferably includes a saturated hydrocarbon having about 10 to 200 carbon atoms or an unsaturated hydrocarbon having about 10 to 200 carbon atoms and is liquid at normal temperature, and examples thereof include: liquid paraffin, squalene, squalane, pristane and the like. Among these, liquid paraffin is more preferable from the viewpoint of easy availability.
Here, the normal temperature means a range of 15 to 25 ℃ in the general rule of the formulation of the Japanese pharmacopoeia. The same applies to the following description.
The liquid paraffin is a mixture of colorless and odorless liquid saturated hydrocarbons, but in the present invention, liquid paraffin or the like that meets the standards specified in the japanese pharmacopoeia, the united states pharmacopoeia, and the like can be preferably used. The nonvolatile hydrocarbon oil is preferably a nonvolatile hydrocarbon oil having a high viscosity, and from the viewpoint of adhesiveness, it is particularly preferable to use liquid paraffin having a high viscosity.
Specifically, the nonvolatile hydrocarbon oil preferably has a kinetic viscosity of 60mm at 40 ℃2More preferably 70 mm/s or more2(ii) at least s, more preferably 80mm2More than s. The upper limit of the dynamic viscosity is not particularly limited, but is preferably 500mm from the viewpoint of easy handling and easy acquisition, for example2Less than s, more preferably 250mm2The ratio of the water to the water is less than s. The "dynamic viscosity" as used herein refers to a value obtained by converting the viscosity (mPa · s) measured by the "2 nd method rotational viscometer method (2.12 single cylinder rotational viscometer (Brookfield type viscometer)) in the" 2.53 viscometry method "of the general test method of the" seventeenth modified japan pharmaceutical formulation "into the dynamic viscosity.
The content of the nonvolatile hydrocarbon oil in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the purpose, and is preferably more than 50 parts by weight and 800 parts by weight or less with respect to 100 parts by weight of the thermoplastic elastomer. When the content of the nonvolatile hydrocarbon oil is more than 800 parts by weight relative to 100 parts by weight of the thermoplastic elastomer, it becomes difficult to maintain the shape of the adhesive layer. On the other hand, when the content of the nonvolatile hydrocarbon oil is less than 50 parts by weight, the adhesive agent tends to be too hard, and thus sufficient skin adhesiveness tends not to be obtained. From such a viewpoint, the lower limit of the content of the nonvolatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 50 parts by weight or more, more preferably 60 parts by weight or more, and particularly preferably 70 parts by weight or more, and the upper limit is preferably 800 parts by weight or less, more preferably 600 parts by weight or less, and particularly preferably 500 parts by weight or less, with respect to 100 parts by weight of the thermoplastic elastomer. Even within this range, if the content of the nonvolatile hydrocarbon oil is large, the peeling stress in the adhesive performance tends to be low, and the bleeding of the adhesive during the sticking during storage tends to be observed, which tends to cause a trouble of being attached to a packaging material or clothes. On the other hand, when the content of the nonvolatile hydrocarbon oil is small, the skin adhesiveness is lowered particularly at the time of sweating or bathing, and the adhesive patch may fall off. From such a viewpoint, the content of the nonvolatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 80 parts by weight or more and 400 parts by weight or less, more preferably 90 parts by weight or more and 350 parts by weight or less, and particularly preferably 100 parts by weight or more and 300 parts by weight or less, relative to 100 parts by weight of the thermoplastic elastomer.
Amount of lactic acid-
The amount of lactic acid in the pressure-sensitive adhesive layer is not particularly limited as long as the skin permeability of the drug is not lowered, and may be appropriately selected according to the purpose as long as it is 1.5 molar equivalents or less with respect to blonanserin contained in the pressure-sensitive adhesive layer, and is preferably 1.4 molar equivalents or less, more preferably 1.25 molar equivalents or less, further preferably 1 molar equivalent or less, further preferably 0.75 molar equivalents or less, still further preferably 0.5 molar equivalents or less, and most preferably 0 molar equivalents.
The amount of lactic acid in the pressure-sensitive adhesive layer was measured according to the method described in JIS K8726.
Other components-
As other components, if necessary, the pressure-sensitive adhesive layer may contain (d) polyisobutylene, (e) an aliphatic dicarboxylic acid ester, (f) a glycerol monoether, (g) a liquid organic acid other than lactic acid, (h 1) a fatty acid monoester of a polyhydric alcohol, (h 2) a higher alcohol, (h 3) an alcohol-based solvent, (h 4) an amide-based solvent, (h 5) an ester-based solvent, (h 6) a carboxylate, (h 7) a lactone, (h 8) a surfactant, (h 9) a filler, (h 10) a crystallization inhibitor, and (i) a tackiness imparting agent.
(d) Polyisobutenes
Polyisobutylene may be added to adjust the adhesive properties.
The "polyisobutylene" used in the adhesive layer of the present invention means a polymer of isobutylene, which is an elastic rubbery semisolid or viscous substance, and is added in the present invention in order to impart sufficient skin adhesiveness.
The polyisobutylene may be used alone or in combination of a low-molecular-weight polyisobutylene having a viscosity average molecular weight of 30000 to 100000, a medium-molecular-weight polyisobutylene having a viscosity average molecular weight of 100000 to 500000, and a high-molecular-weight polyisobutylene having a viscosity average molecular weight of 500000 to 5000000. In view of achieving a balance between low skin irritation and high skin adhesiveness, it is particularly preferable to use the low-molecular-weight polyisobutylene in combination with the high-molecular-weight polyisobutylene or to use the medium-molecular-weight polyisobutylene alone.
As the polyisobutylene, a polymer of isobutylene produced by a method known per se can be used. In particular, polyisobutylene or the like which meets the standards specified in pharmaceutical additive specifications, united states pharmacopeia or the like can be preferably used as the adhesive layer of the present invention for skin application. Further, as the polyisobutylene, commercially available products each satisfying the above viscosity average molecular weight can be used.
Examples of the commercially available product of the low-molecular-weight polyisobutylene include: examples of the medium molecular weight polyisobutylene include "Oppanol (registered trademark) B10SFN", "Oppanol (registered trademark) B10N", "Oppanol (registered trademark) B12SFN", "Oppanol (registered trademark) B15SFN", and "Oppanol (registered trademark) B15N" manufactured by BASF corporation: examples of the high molecular weight polyisobutylene include "Oppanol (registered trademark) N50SF" and "Oppanol (registered trademark) N50" manufactured by BASF: "Oppanol (registered trademark) N80", "Oppanol (registered trademark) N100", "Oppanol (registered trademark) N150", and the like manufactured by BASF corporation.
Of these, from the viewpoint of the solubility at the time of preparing a coating liquid and the balance of adhesive properties of the obtained adhesive patch, the low-molecular-weight polyisobutylene is particularly preferably "Oppanol (registered trademark) B15SFN" or "Oppanol (registered trademark) B15N" having a viscosity average molecular weight of 50000 to 100000, the medium-molecular-weight polyisobutylene is particularly preferably "Oppanol (registered trademark) N50SF" or "Oppanol (registered trademark) N50", and the high-molecular-weight polyisobutylene is particularly preferably "Oppanol (registered trademark) N80".
The content of polyisobutylene in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the purpose, and when the content of polyisobutylene in the pressure-sensitive adhesive layer is too small, the enhancement of skin adhesiveness becomes insufficient, and when too large, there are cases where the skin irritation is deteriorated due to the excessive enhancement of skin adhesiveness, and there are problems such as residual gum at the time of peeling, poor solubility of a drug, and the like. Therefore, the lower limit of the content of the polyisobutylene in the pressure-sensitive adhesive layer is 0.1 part by weight or more, preferably 0.3 part by weight or more, more preferably 0.5 part by weight or more, and further preferably 1 part by weight or more, relative to 100 parts by weight of the thermoplastic elastomer, and the upper limit of the content of the polyisobutylene in the pressure-sensitive adhesive layer is 300 parts by weight or less, preferably 200 parts by weight or less, more preferably 150 parts by weight or less, and further preferably 100 parts by weight or less, relative to 100 parts by weight of the thermoplastic elastomer.
In a more specific preferred embodiment, the content of polyisobutylene in the pressure-sensitive adhesive layer is 0.1 to 50% by mass, more preferably 0.2 to 40% by mass, still more preferably 0.3 to 30% by mass, and particularly preferably 0.5 to 25% by mass.
(e) Aliphatic dicarboxylic acid esters
The aliphatic dicarboxylic acid ester is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: diesters which are liquid at ordinary temperature and are formed from a dicarboxylic acid having 2 to 12 carbon atoms such as diethyl adipate, diisopropyl adipate, diisobutyl adipate and the like, or a sebacic acid diester which is liquid at ordinary temperature such as diethyl sebacate, diisopropyl sebacate, dioctyldodecyl sebacate and the like, and a monohydric aliphatic alcohol having 1 to 20 carbon atoms. Among them, diisopropyl adipate and diisobutyl adipate are preferable from the viewpoint of improving the solubility and absorption promoting effect of the drug.
The lower limit of the content of the aliphatic dicarboxylic acid ester in 100 mass% of the total of the components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected according to the purpose, and is preferably 0.2 mass% or more, more preferably 0.5 mass% or more, still more preferably 0.7 mass% or more, and particularly preferably 1 mass% or more.
The upper limit of the content of the aliphatic dicarboxylic acid ester in 100 mass% of the total of the components constituting the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the purpose, and is preferably 20 mass% or less, more preferably 10 mass% or less, further preferably 5 mass% or less, and particularly preferably 3 mass% or less.
(f) Glycerol monoethers
The glycerin monoether is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: alpha-monoisostearyl glyceryl ether and the like
The lower limit of the content of the glycerin monoether in 100% by mass of the total of the components constituting the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected according to the purpose, and is preferably 0.01% by mass or more, more preferably 0.03% by mass or more, still more preferably 0.05% by mass or more, and particularly preferably 0.07% by mass or more.
The upper limit of the content of the glycerin monoether in 100% by mass of the total of the components constituting the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the purpose, and is preferably 10% by mass or less, more preferably 5% by mass or less, still more preferably 1.5% by mass or less, and particularly preferably 1.0% by mass or less.
(g) Liquid organic acids other than lactic acid
The liquid organic acid other than lactic acid is not particularly limited as long as it is liquid at ordinary temperature, and may be appropriately selected according to the purpose, and examples thereof include: aliphatic monocarboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, isostearic acid, enanthic acid (heptanoic acid), caprylic acid, and pelargonic acid (nonanoic acid); aliphatic unsaturated monocarboxylic acids such as oleic acid, linoleic acid, eicosenoic acid and docosahexaenoic acid; liquid carboxylic acids substituted with an alkoxy group such as methoxyacetic acid; carboxylic acids having a carbonyl group such as levulinic acid; sulfonic acids such as methanesulfonic acid, and the like.
These liquid organic acids have a function of assisting dissolution of the basic drug, can contain the basic drug in the adhesive layer at a high concentration, and also have an effect of improving dispersibility and percutaneous absorbability. From such a viewpoint, among these liquid organic acids, oleic acid, isostearic acid, and levulinic acid are preferable.
In the present invention, one or more kinds of liquid organic acids other than lactic acid may be selected and contained as necessary. Preferred combinations of the organic acids include levulinic acid and isostearic acid, levulinic acid and oleic acid, and isostearic acid and oleic acid.
The content of the liquid organic acid other than lactic acid is not particularly limited and may be appropriately selected according to the purpose, and is preferably 0.1% by mass or more and 20% by weight or less, more preferably 0.3% by mass or more and 15% by weight or less, further preferably 0.5% by mass or more and 10% by weight or less, and particularly preferably 1% by mass or more and 5% by weight or less, relative to the total amount of the pressure-sensitive adhesive layer.
Further, the content of blonanserin in the pressure-sensitive adhesive layer is preferably more than 0 molar equivalent and not more than 10 molar equivalents, more preferably 0.3 molar equivalent or more and not more than 5 molar equivalents, and still more preferably 0.5 molar equivalent or more and not more than 3 molar equivalents.
(h1) Fatty acid monoesters of polyols
In the present invention, the "fatty acid monoester of a polyhydric alcohol" refers to a compound in which one hydroxyl group of a polyhydric alcohol such as ethylene glycol, propylene glycol, or glycerin forms an ester bond with a fatty acid. The fatty acid monoester of the polyhydric alcohol contributes to the improvement of the solubility of the drug, and has an absorption-promoting effect without extremely lowering the cohesive force of the adhesive base.
The polyol constituting the fatty acid monoester of the polyol is not particularly limited, and may be appropriately selected depending on the purpose, and examples thereof include: ethylene glycol, propylene glycol, butylene glycol, glycerin, and the like.
The fatty acid constituting the fatty acid monoester of the polyhydric alcohol is not particularly limited and may be appropriately selected depending on the purpose, and is preferably a fatty acid having 8 to 18 carbon atoms, and examples thereof include capric acid, caprylic acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and the like.
Preferred examples of the polyol fatty acid monoester include propylene glycol monocaprylate and propylene glycol monolaurate. In order to improve the solubility and absorption-promoting effect of the drug, the content of the fatty acid monoester of the polyhydric alcohol is preferably 1% by mass or more, more preferably 2% by mass or more, and particularly preferably 5% by mass or more, relative to the total amount of the binder component. On the other hand, if a large amount of the fatty acid monoester of the polyol is added, the cohesive force of the adhesive force and the adhesive force are reduced, and therefore, the content of the fatty acid monoester of the polyol is preferably 30% by mass or less, more preferably 20% by weight or less, and particularly preferably 10% by weight or less with respect to the total amount of the adhesive component.
(h2) Higher alcohols
The higher alcohol is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: higher saturated aliphatic alcohols having 12 to 20 carbon atoms such as lauryl alcohol and isostearyl alcohol, which are liquid at room temperature; higher unsaturated aliphatic alcohols having 12 to 20 carbon atoms such as oleyl alcohol and being liquid at ordinary temperature.
Of these, lauryl alcohol and oleyl alcohol are preferable from the viewpoint of improving the solubility of the drug and the absorption promoting effect.
(h3) Alcohol solvent
The alcohol solvent is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include: polyhydric alcohols that are liquid at room temperature, such as ethylene glycol, propylene glycol, glycerin, 1, 3-butylene glycol, and polyethylene glycol having a molecular weight of about 100 to 600, monoalkyl ethers of polyhydric alcohols such as diethylene glycol monoethyl ether, and mono-fatty acid esters of polyhydric alcohols such as glycerol monooleate and glycerol monooleate.
Of these, ethylene glycol, propylene glycol, glycerin, 1, 3-butanediol, and diethylene glycol monoethyl ether are preferable from the viewpoint of improving the solubility of the drug.
(h4) Amide solvent
The amide solvent is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: pyrrolidones such as N-methyl-2-pyrrolidone and 2-pyrrolidone; imidazolidinones such as 1, 3-dimethyl-2-imidazolidinone; n-substituted toluidines such as crotamiton; and alkylamides such as formamide, N-methylformamide, N-dimethylformamide, N-methylacetamide, N-dimethylacetamide, and N-methylpropionamide.
Among the amide solvents, N-methyl-2-pyrrolidone, crotamiton, N-dimethylformamide, and N, N-dimethylacetamide are preferable, and N-methyl-2-pyrrolidone and crotamiton are more preferable, from the viewpoint of improving the solubility, dispersibility, and transdermal absorbability of the drug.
(h5) Ester-based solvent
The ester-based solvent is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include: diesters of dihydric alcohols with carboxylic acids, medium-chain fatty acid triglycerides, esters of polybasic carboxylic acids with monohydric aliphatic alcohols, and carbonates.
The diester of the diol and the carboxylic acid is not particularly limited, and may be appropriately selected according to the purpose, and examples thereof include: diesters of propylene glycol with caprylic acid, capric acid, lauric acid, oleic acid, and the like.
The medium-chain fatty acid triglyceride is a triglyceride comprising glycerol and a fatty acid having 6 to 12 carbon atoms such as caproic acid, caprylic acid, capric acid, and lauric acid, and in the present invention, caprylic acid triglyceride, a triglyceride mixture of caprylic acid and capric acid, a triglyceride mixture of caprylic acid, capric acid, and lauric acid, and the like, which are liquid at room temperature, can be used. Further, a fat or oil which is liquid at room temperature and contains a large amount of the medium-chain fatty acid triglyceride may be used. Examples of the oil and fat include olive oil, almond oil, safflower oil, soybean oil, corn oil, sesame oil, coconut oil, orange oil, ginger oil, spruce oil, rapeseed oil, castor oil, sunflower seed oil, cottonseed oil, peanut oil, and the like.
In the present invention, a commercially available product as a pharmaceutical product may be used as the medium-chain fatty acid triglyceride that is liquid at room temperature or the fat or oil containing the medium-chain fatty acid triglyceride that is liquid at room temperature.
The carbonate is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include cyclic carbonates of carbonic acid and diols having 2 to 10 carbon atoms, for example, ethylene carbonate, propylene carbonate, vinylene carbonate, and the like, with propylene carbonate being preferred.
Among the ester solvents, a mixture of medium-chain fatty acid triglycerides and a carbonate are preferable, and a mixture of caprylic acid and capric acid triglycerides and propylene carbonate are more preferable.
In the present invention, the alcohol-based solvent, the amide-based solvent, and the ester-based solvent may be used by selecting one or more of them as necessary.
The content of these solvents is not particularly limited and may be appropriately selected according to the purpose, and is preferably 0.1 mass% or more and 20 mass% or less, more preferably 0.5 mass% or more and 15 mass% or less, with respect to the total amount of the pressure-sensitive adhesive layer.
(h6) Carboxylic acid salts
The carboxylate is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: salts of aliphatic monocarboxylic acids, alicyclic monocarboxylic acids, aliphatic dicarboxylic acids, and the like.
The aliphatic monocarboxylic acid is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: short chain fatty acids having 2 to 7 carbon atoms such as acetic acid, butyric acid and caproic acid, medium chain fatty acids having 8 to 11 carbon atoms such as caprylic acid and capric acid, long chain fatty acids having 12 or more carbon atoms such as lauric acid, myristic acid, stearic acid, isostearic acid and oleic acid, hydroxymonocarboxylic acids such as glycolic acid, lactic acid, 3-hydroxybutyric acid and mandelic acid, monocarboxylic acids substituted with an alkoxy group such as methoxyacetic acid, and monoketoacids such as levulinic acid.
The alicyclic monocarboxylic acid is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include: alicyclic monocarboxylic acids having 6 to 8 carbon atoms such as cyclohexanecarboxylic acid, and the like.
The aliphatic dicarboxylic acid is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include: sebacic acid, adipic acid, malic acid, maleic acid, fumaric acid, and the like.
Preferred examples of the carboxylic acid include a long-chain fatty acid having 12 or more carbon atoms and a hydroxymonocarboxylic acid, and examples thereof include myristic acid, stearic acid, isostearic acid, lauric acid, oleic acid, and the like. More preferably lauric acid, or oleic acid.
The salt of the carboxylic acid is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and amine salt, and sodium salt is preferred from the viewpoint of easy availability and the effect of improving percutaneous absorption.
(h7) Lactones
The lactone is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include: 5-membered cyclic lactones such as ascorbic acid and erythorbic acid.
In the patch of the present invention, sodium oleate, sodium lactate, ascorbic acid, or erythorbic acid is preferable as the carboxylate or lactone in view of the stability-improving effect or percutaneous absorbability-improving effect of the drug.
When the carboxylate or the lactone is contained in the adhesive agent of the present invention, the content thereof in the adhesive layer is not particularly limited and may be appropriately selected according to the purpose, and is preferably 0.1 mol or more and 5 mol or less, and more preferably 0.2 mol or more and 3 mol or less, based on 1 mol of the drug. When the amount of the compound added is less than 0.1 mol based on 1 mol of the drug, a sufficient effect of improving percutaneous absorption may not be obtained, and when the amount added is more than 5 mol based on 1 mol of the drug, the physical properties of the preparation such as adhesive properties may be deteriorated.
(h8) Surface active agent
The surfactant is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include: examples of the nonionic surfactant include polyoxyethylene alkyl phenyl ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene alkyl amino ethers such as polyoxyethylene lauryl amine and polyoxyethylene oleyl amine, polyoxyethylene polyoxypropylene copolymers such as Pluronic (registered trademark) L-31, pluronic (registered trademark) L-44, anionic surfactants such as sodium lauryl sulfate, cationic surfactants such as alkyltrimethylammonium salts, alkyldimethylammonium salts, and carboxyl alkyl amines, and two or more kinds of these surfactants may be selected from alkyl betaine surfactants such as alkyl sodium sulfate.
Among the above surfactants, nonionic surfactants which are liquid at ordinary temperature are preferable from the viewpoint of improving percutaneous absorption, polyoxyethylene higher aliphatic alcohol ethers which are liquid at ordinary temperature and sorbitan fatty acid esters are more preferable, and polyoxyethylene lauryl ether and sorbitan monolaurate are particularly preferable.
In the adhesive patch of the present invention, the content of the surfactant in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected according to the purpose, and is preferably 0.01% by mass or more and 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less.
(h9) Filler
In order to control the flexibility of the pressure-sensitive adhesive layer, a filler may be contained.
The filler is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include: silicon compounds such as anhydrous silicic acid, light anhydrous silicic acid, and hydrous silicic acid, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, water-soluble polymers such as polyvinyl alcohol, dried aluminum hydroxide gel, aluminum compounds such as hydrous aluminum silicate, kaolin, and titanium oxide. The fillers may be used alone or in combination of two or more.
The content of the filler is not particularly limited, and may be appropriately selected according to the purpose, and may be contained in a range capable of maintaining high skin permeability and sufficient cohesive force and adhesive force as a patch. Among these, the content is preferably 10% by mass or less, more preferably 5% by mass or less, and most preferably 2% by mass or less, based on the total amount of the binder component.
(h10) Crystallization inhibitor
In order to suppress crystallization of the drug, a crystallization inhibitor may be contained in the pressure-sensitive adhesive layer.
The crystallization inhibitor is not particularly limited, and may be appropriately selected according to the purpose, and examples thereof include: polyvinyl pyrrolidone, vinyl acetate-vinyl pyrrolidone copolymers, polyvinyl caprolactam-polyvinyl acetic acid-polyethylene glycol graft copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, and the like. The crystallization inhibitors may be used alone or in combination of two or more.
The content of the crystallization inhibitor is not particularly limited, and may be appropriately selected according to the purpose, and may be contained within a range capable of maintaining the adhesive force as a patch. Among these, the content is preferably 0.01 to 10 mass%, more preferably 0.1 to 5 mass%, based on the total amount of the binder component.
(i) Adhesion-imparting agent
The adhesive patch may contain an adhesion-imparting agent from the viewpoint of improving the adhesive force of the adhesive layer.
In the present invention, the "adhesion imparting agent" is an adhesion imparting agent generally used in the field of patch preparations, and is not particularly limited, and may be appropriately selected depending on the purpose, and examples thereof include: rosin-based resins, polyterpene-based resins, coumarone-indene resins, petroleum-based resins, terpene-phenolic resins, alicyclic saturated hydrocarbon resins, and the like.
The adhesion-imparting agent may be added to achieve an adhesive force necessary for obtaining a sufficient drug effect, but if the adhesion-imparting agent is added in a large amount, the drug release property is lowered or the skin irritation property is increased, and therefore, the content of the adhesion-imparting agent is preferably 50% by mass or less, more preferably 30% by mass or less, further preferably 20% by mass or less, further preferably 10% by mass or less, particularly preferably 5% by mass or less, with respect to the total amount of the adhesive component, and most preferably no adhesion-imparting agent is contained.
< other elements >
The patch may be provided with a release liner generally used in the art. That is, the adhesive patch of the present invention may be an adhesive patch in which a support, an adhesive layer, and a release liner are laminated in this order.
The release liner is not particularly limited, and may be appropriately selected according to the purpose, and for example, the following may be used: cellophane, polyolefin such as polyethylene and polypropylene, polyester such as polyethylene terephthalate, and resin film such as polystyrene; aluminum films; a foamed polyethylene film or a foamed polypropylene film; a laminate of two or more of the above. Further, as the release liner, a release liner subjected to silicone processing, fluororesin processing, embossing processing, hydrophilic processing, hydrophobic processing, or the like may be used.
The thickness of the release liner is not particularly limited and may be appropriately selected depending on the purpose, and is preferably 10 μm or more and 200 μm or less, and more preferably 15 μm or more and 150 μm or less.
(method for producing adhesive preparation)
The method for producing the adhesive patch is a method for producing the adhesive patch, and includes: the step of laminating the support and the adhesive layer may further include another step.
The adhesive layer and the support are as described above.
< Process for laminating support body and adhesive layer >
The step of laminating the support and the pressure-sensitive adhesive layer is not particularly limited, and may be appropriately selected depending on the purpose, and examples thereof include: and a method of laminating the support by pressure-bonding the pressure-sensitive adhesive layer.
< other working procedures >
The other step is not particularly limited and may be appropriately selected according to the purpose, and examples thereof include a step of laminating a release liner.
The release liner is as described above.
Lamination process of release liner
The step of laminating the release liner is not particularly limited, and may be appropriately selected according to the purpose, and examples thereof include: a step (spreading/drying step) of spreading a coating liquid for forming the adhesive layer on a release liner and drying a solvent in the coating liquid to laminate the adhesive layer on the surface of the release liner, before the step of laminating the support and the adhesive layer; or a step of laminating the support and the pressure-sensitive adhesive layer, followed by pressure-bonding the release liner to the pressure-sensitive adhesive layer.
-spreading/drying procedure-
The spreading/drying step is not particularly limited, and may be appropriately selected according to the purpose, and examples thereof include: a method in which (a) blonanserin or a salt thereof, (b) a thermoplastic elastomer, and (c) a nonvolatile hydrocarbon oil are dissolved or dispersed in a solvent such as toluene, respectively, to prepare a coating liquid for forming an adhesive layer, the obtained coating liquid is applied to a release liner, and then the release liner is dried.
The coating is not particularly limited and may be appropriately selected according to the purpose, and may be performed using a conventional coater such as a roll coater, die coater, gravure roll coater, reverse roll coater, roll lick coater, dip roll coater, wire bar coater, blade coater, or spin coater.
The solvent used in the coating liquid is not particularly limited and may be appropriately selected according to the purpose, and is preferably a solvent capable of uniformly dissolving or dispersing the components (a), (b), and (c), and examples thereof include: aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, aliphatic hydrocarbons such as hexane and heptane, ethers such as tetrahydrofuran, diethyl ether and tert-butyl methyl ether, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, alcohols such as ethanol, propanol and butanol, and acetates such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate.
These solvents may be used alone, or two or more kinds may be used in combination. Since the solubility of each component constituting the pressure-sensitive adhesive layer is good, it is preferable to use an aromatic hydrocarbon such as toluene, an alicyclic hydrocarbon such as cyclohexane or methylcyclohexane, or an aliphatic hydrocarbon such as hexane or heptane, singly or in combination; or by combining aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as hexane and heptane, and acetic acid esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate.
The drying is not particularly limited, and may be appropriately selected according to the purpose, and is preferably performed under heating, for example, at a temperature of about 40 ℃ to 150 ℃, and the drying temperature, drying time, and drying method may be adjusted according to the solvent and the amount used.
The weight per unit area of the dried adhesive layer may be adjusted depending on the necessary skin adhesiveness and transdermal absorbability. The range in which the skin-adhesive property can be obtained and the production can be carried out is not particularly limited, and may be appropriately selected depending on the purpose, and the pressure-sensitive adhesive layer after drying is preferably 10g/m2Above and 1000g/m2Below, more preferably 20g/m2Above and 800g/m2The amount of the surfactant is preferably 30g/m or less2Above and 600g/m2The following.
Examples
The present invention will be described with reference to examples, but the present invention is not limited to these examples.
< example 1: production of adhesive Patch
The components constituting the adhesive layer were weighed in accordance with the formulation shown in table 1. The numerical values of the components in table 1 are% by mass. First, a styrene-based block copolymer was dissolved in toluene, and blonanserin and liquid paraffin were added thereto and mixed and stirred to prepare a coating liquid for forming an adhesive layer.
The coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film as a release liner. After drying in an oven at 50 ℃ for 60 minutes, a PET film (support) was laminated on the surface of the pressure-sensitive adhesive layer, and cut into a size of 15cm × 30cm to obtain a patch.
[ Table 1]
Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | Example 8 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | |
Blonanserin | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 10.0 | 3.0 | 3.0 | 3.0 | 3.0 | 10.0 |
Styrene-isoprene-styrene copolymer | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 | 20.0 | 20.0 | - | 35.0 | 35.0 | 20.0 |
Polyisobutenes | - | - | - | - | - | - | - | 15.0 | - | - | - | - |
Liquid paraffin | 62.0 | 54.0 | 53.90 | 53.50 | 53.25 | 53.0 | 25.0 | 54.0 | - | 52.75 | 52.5 | 20.0 |
Acrylic adhesive | - | - | - | - | - | - | - | - | 97.0 | - | - | - |
Propylene glycol monocaprylate | - | 5.0 | 5.0 | 5.0 | 5.0 | 5.0 | - | 5.0 | - | 5.0 | 5.0 | - |
Diisopropyl adipate | - | 2.0 | 2.0 | 2.0 | 2.0 | 2.0 | - | 2.0 | - | 2.0 | 2.0 | - |
Benzyl alcohol | - | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | - | 1.0 | - | 1.0 | 1.0 | - |
Lactic acid | - | - | 0.1 | 0.5 | 0.75 | 1.0 | - | - | - | 1.25 | 1.5 | 5.0 |
Polybutylene | - | - | - | - | - | - | 15.0 | - | - | - | - | 15.0 |
Alicyclic saturated hydrocarbon resin | - | - | - | - | - | - | 25.0 | - | - | - | - | 25.0 |
Sesame oil | - | - | - | - | - | - | 5.0 | - | - | - | - | 5.0 |
Cohesion force | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 2 | 3 |
Adhesive force | 2 | 2 | 2 | 2 | 2 | 1 | 1 | 3 | 2 | 1 | 1 | 1 |
Relative to the skin permeability of the existing preparation | 2.1 | 3.0 | 3.3 | 3.2 | 2.7 | 2.2 | 2.8 | 5.1 | 0.6 | 1.9 | 1.6 | 1.4 |
Molar equivalent of lactic acid to blonanserin | 0.0 | 0.0 | 0.1 | 0.7 | 1.0 | 1.4 | 0.0 | 0.0 | 0.0 | 1.7 | 2.0 | 2.0 |
< test example 1: evaluation of skin permeability >
The ventral skin of depilated male hairless rats (HWY/Slc, SPF, 5 weeks old) was peeled off and punched out into a circle of 2.5cm diameter. The patch prepared in example was punched out into a circular shape having a diameter of 1.3cm, attached to the skin of a rat, placed in a vertical diffusion cell, and the test was started by a percutaneous absorption test automatic sampling device (manufactured by CosMED Pharmaceutical). The test was carried out at a liquid temperature of 32 ℃ using a buffer as a receiving solution. A portion of the receiving solution was sampled 24 hours after the start of the test, and the amount of the drug in the receiving solution that permeated through the skin of rats was quantified by HPLC. As a control preparation containing blonanserin, lonasen (registered trademark) tape (existing preparation) was used. The measurement was performed on 3 to 6 patches, and the average value of the measurement values was calculated, and the drug skin permeability was evaluated by multiplying the value of the Lonasen (registered trademark) tape by several times. The results are shown in Table 1.
< test example 2: evaluation of cohesion force >
The cohesive force of the adhesive layer of the adhesive patch was evaluated in 4 stages by finger stick test (finger touch test) based on the following criteria. The results are shown in Table 1.
3: no residual gum was confirmed at all.
2: the residual gum was hardly observed, and the range was free from problems.
1: the cohesive force was slightly insufficient, but was within a range without problems.
0: residual gum, non-formation, etc. were observed, and the cohesive force was significantly insufficient.
< test example 3: evaluation of adhesion >
The adhesiveness to the adhesive layer of the adhesive patch was evaluated in 4 stages by finger tack (finger touch test) based on the following criteria. The results are shown in Table 1.
3: exhibits the same degree of adhesion as the Lonasen (registered trademark) adhesive tape.
2: slightly lower than the adhesion of the Lonasen (registered trademark) tape.
1: the adhesiveness was weak, and the fingers were easily peeled off.
0: completely unattached and clearly peeled.
< example 2: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 1.
< example 3: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 1.
< example 4: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 1.
< example 5: production of adhesive preparation
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the pressure-sensitive adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 1.
< example 6: production of adhesive preparation
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 1.
< example 7: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in comparative example 2, except that the components constituting the adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 1.
< example 8: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the adhesive layer were replaced with the formulations shown in table 1, the styrene-based block copolymer and polyisobutylene were dissolved in toluene, and then blonanserin, liquid paraffin, and various additives were added.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 1.
< comparative example 1: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the adhesive layer were replaced with the formulations shown in table 1, and that blonanserin was added after mixing the acrylic adhesive and ethyl acetate.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 1.
Comparative example 2: production of adhesive preparation
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the pressure-sensitive adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 1.
< comparative example 3: production of adhesive preparation
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 1.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 1.
< comparative example 4: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the adhesive layer were replaced with the formulations shown in table 1 and applied so that the thickness of the dried adhesive layer became about 60 μm.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 1.
From the results shown in table 1, it was confirmed that example 1 using a styrene-isoprene-styrene block copolymer as an adhesive base polymer exhibited higher permeability than comparative example 1 using an acrylic adhesive base of the formulation technology of patent document 1. In addition, example 7, which did not use lactic acid, showed higher permeability than comparative example 4, which used the formulation technology of patent document 2, and it was found that skin permeability tended to decrease due to the addition of a large amount of lactic acid.
The patches of examples 2 and 8, in which the additive was added in example 1, exhibited skin permeability more than 3 times higher than that of the conventional preparation. On the other hand, in comparative examples 2 to 4, since lactic acid was added in an amount of more than 1.5 molar equivalents, the skin permeability was lower than that of the patch of example 2, and further, a tendency was observed that the skin permeability was decreased depending on the amount of lactic acid added, and a phenomenon was observed that crystals were precipitated in the adhesive layer of the preparation stored after production.
< example 9: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 2.
[ Table 2]
Example 1 | Example 9 | Example 10 | Example 11 | Example 12 | Example 13 | Example 14 | Example 15 | Example 16 | |
Blonanserin | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 |
Styrene-isoprene-styrene copolymer | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 | 35.0 |
Liquid paraffin | 62.0 | 59.0 | 56.0 | 55.0 | 60.0 | 59.5 | 53.5 | 53.0 | 52.5 |
Propylene glycol monocaprylate | - | - | 5.0 | 5.0 | - | - | 5.0 | 5.0 | 5.0 |
Adipic acid diisopropyl ester | - | 2.0 | - | 2.0 | 2.0 | 2.0 | 2.0 | 2.0 | 2.0 |
Benzyl alcohol | - | 1.0 | 1.0 | - | - | - | 1.0 | 1.0 | 1.0 |
Alpha-monoisostearyl glyceryl ether | - | - | - | - | - | 0.5 | 0.5 | 1.0 | 1.5 |
Cohesion force | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 |
Adhesive force | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
Relative to the skin permeability of the existing preparation | 2.1 | 2.5 | 2.1 | 2.9 | 2.9 | 6.5 | 7.3 | 6.5 | 7.1 |
< example 10: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 2.
< example 11: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 2.
< example 12: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the pressure-sensitive adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 2.
< example 13: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 2.
< example 14: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 2.
< example 15: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 2.
< example 16: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 2.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 2.
As shown in the results in table 2, it is understood from example 1 and examples 9 to 12 that diisopropyl adipate exhibits a higher absorption promoting effect. In addition, the adhesive patches of examples 13 to 16 exhibited skin permeability 6 times or more higher than that of the conventional preparation, and α -monoisostearyl glyceryl ether exhibited a higher absorption promoting effect.
< example 17: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the adhesive layer were replaced with the formulations shown in table 3.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 3.
[ Table 3]
Example 17 | Example 18 | Example 19 | |
Blonanserin | 3.0 | 3.0 | 3.0 |
Styrene-isoprene-styrene copolymer | 35.0 | 35.0 | 35.0 |
Liquid paraffin | 59.5 | 59.5 | 59.5 |
Adipic acid diisobutyl ester | 2.0 | - | - |
Sebacic acid diisopropyl ester | - | 2.0 | - |
Sebacic acid Ethyl ester | - | - | 2.0 |
Alpha-monoisostearyl glyceryl ether | 0.5 | 0.5 | 0.5 |
Cohesion force | 3 | 3 | 3 |
Adhesive force | 2 | 2 | 2 |
Drug skin permeability relative to existing preparations: (Bei) | 6.8 | 5.8 | 5.0 |
< example 18: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the adhesive layer were replaced with the formulations shown in table 3.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 3.
< example 19: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the pressure-sensitive adhesive layer were replaced with the formulations shown in table 3.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 3.
From the results shown in table 3, the patches of examples 17 to 19, which contained various aliphatic dicarboxylic acid esters, all exhibited skin permeability 4 times or more higher than that of the conventional preparation.
< example 20: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 4.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 4.
[ Table 4]
Example 5 | Example 20 | Example 21 | Example 22 | |
Blonanserin | 3.0 | 3.0 | 3.0 | 3.0 |
Styrene-isoprene-styrene copolymer | 35.0 | 35.0 | 35.0 | 35.0 |
Liquid paraffin | 53.25 | 51.7 | 51.7 | 53.1 |
Propylene glycol monocaprylate | 5.0 | 5.0 | 5.0 | 5.0 |
Adipic acid diisopropyl ester | 2.0 | 2.0 | 2.0 | 2.0 |
Benzyl alcohol | 1.0 | 1.0 | 1.0 | 1.0 |
Lactic acid | 0.75 | - | - | - |
Oleic acid | - | 2.3 | - | - |
Isostearic acid | - | - | 2.3 | - |
Levulinic acid | - | - | - | 0.9 |
Cohesion force | 3 | 3 | 3 | 3 |
Adhesive force | 2 | 2 | 2 | 2 |
Relative to the skin permeability of the existing preparation | 2.7 | 2.2 | 3.1 | 2.4 |
Molar equivalent of acid to blonanserin | 1.0 | 1.0 | 1.0 | 1.0 |
< example 21: production of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 4.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 4.
< example 22: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the components constituting the pressure-sensitive adhesive layer were replaced with the formulations shown in table 4.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 4.
From the results shown in table 4, examples 20 to 22 to which liquid organic acids other than lactic acid were added showed the same permeability as example 5 to which lactic acid was added, and a phenomenon of suppressing crystallization of blonanserin was observed.
< example 23: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 5.
[ Table 5]
Example 23 | Example 24 | Example 25 | Example 26 | Example 27 | Example 28 | Example 29 | Example 30 | |
Blonanserin | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 3.0 | 3.9 | 3.9 |
Styrene-isoprene-styrene copolymer | 35.0 | 35.0 | 35.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 |
Polyisobutenes | - | - | - | 15.0 | 15.0 | 15.0 | 15.0 | 15.0 |
Liquid paraffin | 58.0 | 51.5 | 52.6 | 58.5 | 53.9 | 54.2 | 52.2 | 52.8 |
Propylene glycol monocaprylate | - | 5.0 | 5.0 | - | - | - | - | - |
Diisopropyl adipate | 2.0 | 2.0 | 2.0 | 2.0 | 1.0 | 1.0 | 1.0 | 1.0 |
Benzyl alcohol | - | 1.0 | 1.0 | - | - | - | - | - |
Alpha-monoisostearyl glyceryl ether | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.1 | 0.1 | 0.1 |
Polyoxyethylene lauryl ether | 1.5 | - | - | - | - | - | - | - |
Isostearic acid | - | 2.0 | - | - | 0.5 | 1.0 | 1.9 | 1.3 |
Levulinic acid | - | - | 0.9 | 1.0 | 1.2 | 0.8 | 1.0 | 1.0 |
Alicyclic saturated hydrocarbon resin | - | - | - | - | 5.0 | 5.0 | 5.0 | 5.0 |
Cohesion force | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 |
Adhesive force | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
Relative to the skin permeability of the existing preparation | 7.2 | 6.1 | 7.5 | 5.7 | 5.1 | 4.7 | 4.7 | 4.8 |
< example 24: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 5.
< example 25: production of adhesive Patch
Adhesive patches were produced in the same manner as in example 1, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 5.
< example 26: production of adhesive Patch >
Adhesive patches were produced in the same manner as in example 8, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 5.
< example 27: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 8, except that the components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 5.
< example 28: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 8, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 5.
< example 29: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 8, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesiveness were evaluated in the same manner as in example 1. The results are shown in Table 5.
< example 30: preparation of adhesive Patch
Adhesive patches were produced in the same manner as in example 8, except that the respective components constituting the adhesive layer were replaced with the formulations shown in table 5.
Skin permeability, cohesion, and adhesion were evaluated in the same manner as in example 1. The results are shown in Table 5.
From the results shown in table 5, the patches of examples 24 to 30, which contained aliphatic dicarboxylic acid ester, glycerin monoether, and polyoxyethylene lauryl ether or liquid organic acid other than lactic acid, all exhibited skin permeability 4 times or more higher than that of the conventional preparation.
Examples of the embodiment of the present invention include the following embodiments.
< 1 > a patch having: and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a nonvolatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is more than 0 molar equivalent and 1.5 molar equivalent or less relative to blonanserin contained in the pressure-sensitive adhesive layer.
< 2 > a patch having: and an adhesive layer on the support, wherein the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a nonvolatile hydrocarbon oil, and does not contain lactic acid.
< 3 > the patch according to < 1 > or < 2 > above, wherein the thermoplastic elastomer comprises a styrenic block copolymer.
< 4 > the patch according to the above < 3 >, wherein the styrene-based block copolymer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.
< 5 > the adhesive patch according to any one of the above < 1 > to < 4 >, wherein the adhesive layer comprises polyisobutylene.
< 6 > the patch according to any one of the above < 1 > -5 >, wherein the adhesive layer contains an aliphatic dicarboxylic acid ester.
< 7 > the patch according to any one of the above < 1 > -6 >, wherein the adhesive layer contains glycerol monoether.
The adhesive patch according to any one of < 8 > to < 1 > to < 7 >, wherein the adhesive layer contains a liquid organic acid other than lactic acid.
< 9 > a method for producing an adhesive patch according to any one of the above < 1 > to < 8 >, which comprises: and a step of laminating the support and the adhesive layer.
Claims (9)
1. A patch, having:
a support body, and
a layer of an adhesive on the support body,
the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a nonvolatile hydrocarbon oil, and the amount of lactic acid in the adhesive layer is more than 0 molar equivalent and 1.5 molar equivalent or less relative to blonanserin contained in the adhesive layer.
2. A patch, having:
a support body, and
a layer of an adhesive on the support body,
the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a nonvolatile hydrocarbon oil, and does not contain lactic acid.
3. The patch according to claim 1 or 2,
the thermoplastic elastomer comprises a styrenic block copolymer.
4. The patch of claim 3 wherein,
the styrene block copolymer is a mixture of styrene-isoprene-styrene block copolymer and styrene-isoprene block copolymer.
5. The patch according to any one of claims 1 to 4,
the adhesive layer comprises polyisobutylene.
6. The patch according to any one of claims 1 to 5,
the adhesive layer includes an aliphatic dicarboxylic acid ester.
7. The patch according to any one of claims 1 to 6,
the adhesive layer comprises a glycerol monoether.
8. The patch according to any one of claims 1 to 7,
the adhesive layer contains a liquid organic acid other than lactic acid.
9. A method for producing a patch according to any one of claims 1 to 8, which comprises:
and a step of laminating the support and the adhesive layer.
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