WO2018070370A1 - オキシブチニン含有経皮吸収製剤 - Google Patents
オキシブチニン含有経皮吸収製剤 Download PDFInfo
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- WO2018070370A1 WO2018070370A1 PCT/JP2017/036619 JP2017036619W WO2018070370A1 WO 2018070370 A1 WO2018070370 A1 WO 2018070370A1 JP 2017036619 W JP2017036619 W JP 2017036619W WO 2018070370 A1 WO2018070370 A1 WO 2018070370A1
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- oxybutynin
- adhesive composition
- patch
- support layer
- sensitive adhesive
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- 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
-
- 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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
Definitions
- the present invention relates to a transdermally absorbable preparation (patch) containing oxybutynin.
- the present application claims priority based on Japanese Patent Application No. 2016-200402 filed in Japan on October 11, 2016, the contents of which are incorporated herein by reference.
- Patches that administer drugs from the skin can avoid rapid increases in the blood concentration of drugs compared to injections and oral preparations, can easily maintain drug absorption, can avoid the first passage of the liver, and There are merits such as being able to stop medication when side effects occur.
- skin irritation such as pruritus, rash, pain, eczema and dermatitis may occur in the applied skin.
- Patent Document 1 describes a transdermally absorbable preparation (patch) containing cholesterols, which has a sufficient skin irritation reducing effect for a wide range of drugs.
- a patch using a cloth or the like as a support is excellent in flexibility and stretchability and easily follows changes in the shape of the skin, and therefore has excellent adhesion. It is desired to add cholesterols having an effect of reducing skin irritation to a patch using a support such as a cloth having such characteristics.
- Patent Document 2 describes an experimental result in which the adhesiveness of a transdermal preparation (patch) using a PET fabric as a support and blended with cholesterol is lowered due to the inclusion of cholesterol.
- An experimental result that can improve adhesion by including PIB (polyisobutylene) as an adhesive base is also described. Since it may be difficult to use PIB as an adhesive base depending on the drug used, other methods for improving adhesion are desired.
- the inventors added the cholesterol to the patch using a base fabric as the support, and the fluidity of the adhesive composition increased. I found out that it might change.
- the release property greatly affects the therapeutic effect of the drug, it is important for the patch to maintain a predetermined drug release property even after storage.
- the present invention uses a cloth or the like as a support, and in a patch containing cholesterols that are recognized to be effective in reducing skin irritation, maintains adhesiveness despite the increase in fluidity of the adhesive composition, and after storage It aims at reducing the time-dependent change of the drug release property.
- An oxybutynin-containing percutaneous absorption preparation (patch) according to the first aspect of the present invention comprises a base layer, at least a part of which has water repellency, and an adhesive laminated on one side of the support layer
- the pressure-sensitive adhesive layer contains a pressure-sensitive adhesive composition containing oxybutynin or a pharmaceutically acceptable salt thereof, cholesterols, and a rubber-based pressure-sensitive adhesive base.
- the oxybutynin-containing transdermal preparation (patch) according to the second aspect of the present invention may be the oxybutynin hydrochloride percutaneous absorption preparation according to the first aspect, wherein the oxybutynin may be oxybutynin hydrochloride.
- the oxybutynin-containing percutaneous absorption preparation (patch) according to the third aspect of the present invention is the oxybutynin-containing percutaneous absorption preparation according to the first aspect or the second aspect, wherein the portion having water repellency is a fluorine-containing compound. May be formed.
- the oxybutynin-containing transdermal absorption preparation (patch) according to the fourth aspect of the present invention is the oxybutynin-containing transdermal absorption preparation according to the first aspect to the third aspect, wherein the base fabric is a knitted fabric. There may be.
- the oxybutynin-containing transdermal absorption preparation (patch) according to the fifth aspect of the present invention is the oxybutynin-containing transdermal absorption preparation according to the first aspect to the fourth aspect, wherein the rubber-based adhesive base is A styrene-isoprene-styrene block copolymer may be contained.
- the oxybutynin-containing transdermal preparation (patch) according to the sixth aspect of the present invention is the oxybutynin-containing transdermal preparation according to any one of the second to fifth aspects, wherein the oxybutynin content is It may be 4% to 50% with respect to the pressure-sensitive adhesive composition, and the cholesterol may be cholesterol and the content thereof may be 0.05 to 10% with respect to the pressure-sensitive adhesive composition.
- the present invention reduces changes over time in adhesion and drug release. be able to.
- a patch (oxybutynin-containing transdermal absorption preparation) 1 of the present embodiment is configured to include a support layer 11 made of a base fabric. It is excellent in flexibility and stretchability and can easily follow changes in the shape of the skin, so it can be used in various fields and applications such as medical use and home use.
- FIG. 1 is a cross-sectional view in the thickness direction of the patch 1 of the present embodiment.
- the patch 1 includes a support layer 11 and a pressure-sensitive adhesive layer 12 laminated on one side of the support layer 11.
- the support body used for the support body layer 11 should just be a thing suitable for supporting the adhesive layer 12, and the base fabric excellent in the elasticity is preferable.
- Polyolefins such as polyethylene, polypropylene, and polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyethylene terephthalol, polyethylene naphthalate, polybutylene terephthalate, and other polyesters, nylon, silk, animal hair (for example, wool)
- Polyamides such as, polyurethane, celluloses such as cotton, etc., or laminates or mixtures thereof, porous bodies, foams, woven and non-woven fabrics, knitted fabrics, and laminates thereof It can be used as a property.
- the weaving method of the woven fabric and the knitting method of the knitted fabric are not particularly limited. Knitting, knitting, milling) and the like.
- the nonwoven fabric is not particularly limited, and may be a spunlace nonwoven fabric, a thermal bond nonwoven fabric, a spunbond nonwoven fabric, or the like.
- the basis weight of the base fabric may be 20 to 200 g / m 2 or 70 to 140 g / m 2 .
- the thickness of the base fabric may be 0.1 to 3 mm.
- the surface of the adhesive layer 12 of the patch 1 opposite to the surface in contact with the support layer 11 may be provided with a release coating 20 that is peeled off and removed before application to the affected area.
- the release coating 20 may be a film or sheet made of polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, celluloses such as paper, and the like, and those obtained by release treatment with silicone. it can.
- the support layer 11 has a water repellent surface 110 formed by water repellent treatment in at least one of the thickness directions.
- the water repellent surface 110 may be subjected to a water repellent treatment with a silicone-containing compound having a high water repellency, or may be subjected to a water repellency treatment with a fluorine-containing compound having a high water / oil repellency. Water repellent treatment with a fluorine-containing compound having oil repellency is more suitable.
- the water repellent surface 110 may be provided on the surface where the support layer 11 is in contact with the pressure-sensitive adhesive layer 12, or the support layer 11 may be provided on the surface opposite to the surface where the support layer 11 is in contact with the pressure-sensitive adhesive layer 12. It may be provided on the entire support.
- the water repellent surface 110 may be formed over the entire area in the surface direction of the support layer 11, or may be formed only in a region in contact with the pressure-sensitive adhesive layer 12. Further, a water repellent surface may be formed on the intermediate layer of the support layer 11. For example, when the support layer 11 is formed by superimposing two base fabrics, a water repellent surface can be formed therebetween.
- the portion having water repellency formed on the support layer 11 is not a planar shape like the water repellent surface 110 but may be a three-dimensional shape formed on a part of the support layer 11. Good. It may be a spot-like water-repellent part or a streak-like water-repellent part formed over both the thickness direction and the surface direction in the support layer 11.
- a water repellent portion may be formed on a part of the knitting pattern.
- the base fabric may be formed from a material that has been subjected to a water repellent treatment in advance.
- the support layer 11 can be provided with water repellency by forming the support layer 11 using a base fabric formed using filaments or yarns that are entirely or partially water repellent treated. That is, it is sufficient that at least a part of the support layer 11 has water repellency.
- a base fabric may be formed from a material that has been subjected to a water repellent treatment in advance, or the water repellent treatment may be performed after the base fabric is formed.
- water repellency can be imparted by reacting or adhering a water repellent such as a silicone-containing compound or a fluorine-containing compound to the fiber or base fabric. More specifically, water repellency is obtained by spraying a solution or emulsion containing a water repellent on the fiber or base fabric, or immersing the fiber or base fabric in a solution containing the water repellent. Can be granted. By dipping, the entire fiber or base fabric can be made water repellent, which is more preferable.
- the water repellent agent is not particularly limited, and is a fluorine-based one.
- Asahi Guard E trade name, Asahi Glass
- NK Guard S trade name, Nikka Chemical
- Unicapolon trade name, Union Chemical
- TS guard trade name, Tokai Oil
- Dick guard trade name, Dainippon Ink
- the patch is held horizontally with the base fabric side facing upward, What is necessary is just to determine by whether a water droplet is dripped on a base fabric, when water droplets of purified water are dripped gently. It can also be determined using an instrument such as a micropipette such that when 20 drops of purified water at 20 ° C. defined by Japanese Pharmacopoeia general rules are dropped, the mass becomes 0.90 to 1.10 g.
- the support layer 11 When at least a part of the support layer 11 has water repellency, it has a good effect on the change over time of the adhesive property and the drug release property of the adhesive composition laminated as the adhesive layer 12. Details will be described later.
- the water-repellent surface 110 By forming the water-repellent surface 110 over the entire area where the support layer 11 is in contact with the pressure-sensitive adhesive layer 12, it is possible to bring about a better effect due to the change over time of the adhesive composition adhesion and drug release characteristics.
- the pressure-sensitive adhesive layer 12 includes a pressure-sensitive adhesive composition containing a drug that exhibits medicinal effects, cholesterols, and a lipophilic pressure-sensitive adhesive base. Cholesterols that have a sufficient skin irritation reducing effect for a wide range of drugs are blended in the adhesive composition as skin irritation inhibitors.
- the drug compounded in the adhesive composition is selected from the group consisting of oxybutynin, tolterodine, asenapine, bisoprolol, risperidone, nicotine, and citalopram, or a pharmaceutically acceptable salt thereof, from the viewpoint of the need to reduce skin irritation. And one or more basic drugs as well as pharmaceutically acceptable salts thereof. Among these, when oxybutynin hydrochloride is selected as a drug, the effect of this embodiment is particularly exerted.
- the adhesive composition includes antihypertensives such as atenolol, amlodipine and captopril, vasodilators such as isosorbide nitrate and nitroglycerin, capsaicin, red pepper extract, red pepper powder, red pepper tincture, nonyl acid vanillylamide and other warming agents.
- antihypertensives such as atenolol, amlodipine and captopril
- vasodilators such as isosorbide nitrate and nitroglycerin, capsaicin, red pepper extract, red pepper powder, red pepper tincture, nonyl acid vanillylamide and other warming agents.
- Sensitizers non-steroidal anti-inflammatory analgesics such as indomethacin, camphor, ketoprofen, methyl salicylate, glycol salicylate, diclofenac sodium, flurbiprofen, felbinac, meloxicam, loxoprofen, hormones such as estradiol, norethisterone, estriol, ketotifen, etc.
- Antihistamines memantine, anti-Alzheimer drugs such as donepezil, sertraline, fluoxetine, paroxetine, citalopram, fluvoxamine Antidepressant drugs, gastric ulcer drugs such as teprenone, overactive bladder drugs such as solifenacin, bronchodilators such as tulobuterol, cold sensates such as menthol and mint oil, Parkinson's disease drugs such as pergolide and rotigotine, retinoids, etc. Vitamins and so on.
- skin irritation inhibitor skin irritation caused by these drugs or medicinal ingredients is also reduced. Any of these drugs can be selected as the drug contained in the adhesive layer 12 of the patch 1 of the present embodiment. In addition, drugs other than those listed here may be selected.
- oxybutynin hydrochloride is a drug used for the treatment of “overactive bladder” having symptoms such as urgency and frequent urination.
- oxybutynin hydrochloride is mainly administered orally, and side effects such as dry mouth, constipation and sleepiness caused by metabolites due to the first-pass effect of the liver are known.
- Patches containing oxybutynin hydrochloride are used to reduce side effects caused by oral administration.
- Oxybutynin hydrochloride may cause skin irritation such as pruritus, erythema, rash, pain, eczema and dermatitis in rare cases when administered from the skin. Therefore, it is one of the drugs that are desired to be blended with cholesterol skin irritation inhibitors.
- Oxybutynin has the chemical name ⁇ -phenylcyclohexaneglycolic acid 4- (diethylamino) -2-butynyl.
- the oxybutynin used in the present embodiment is not limited to the hydrochloride, and may be free oxybutynin or other pharmaceutically acceptable oxybutynin salts, and combinations thereof. Also good.
- the pharmaceutically acceptable salt of oxybutynin may be an inorganic acid salt or an organic acid salt, so far, for example, in addition to hydrochloride, inorganic acid salts such as hydrobromide and silicate, and Organic acid salts such as acetate, citrate, fumarate and maleate are known.
- the content of the drug in the patch varies depending on the type of drug, the disease to be treated, the method of administration, the composition of the adhesive composition, etc., but is usually preferably 4 to 50% by mass based on the total amount of the adhesive composition, It may be 5 to 30% by mass or 8 to 17% by mass.
- the drug is less than 4% by mass, it tends to be difficult to obtain a sufficient therapeutic effect.
- the content of the drug is in each of the above ranges, the skin irritation of the patch tends to be relaxed or less, the intended therapeutic effect is easily obtained, and the adhesiveness of the patch is also likely to be appropriate.
- the content of the drug exceeds 50% by mass, the skin irritation of the patch tends to be strong.
- the drug is oxybutynin, the content may be 5 to 30% by mass or 8 to 17% by mass, based on the total amount of the adhesive composition, when converted as its hydrochloride salt if necessary. It is desirable that
- Epidermal cells are the center of skin immunity by releasing many inflammation-inducing substances such as cytokines, chemokines, inflammatory mediators and cell growth factors, and by expressing cytokine receptors, adhesion factors and MHC class II on the cells. (Skin Immunity Handbook (Chugai Medical Company)).
- inflammation-inducing substances released by epidermal cells include interleukin (IL) -1 ⁇ , IL-10, IL-12, IL-18, TNF- ⁇ , GM-CSF, IL-6, IL-7, IL -15, TGF- ⁇ , amphiregulin, HB-EGF, bFGF, VEGF, PDGF, SCF, IFN- ⁇ , IFN- ⁇ , TGF- ⁇ , MIP-3 ⁇ , IP-9, IP-10, Mig, IL-8 , GRO ⁇ , RANTES, MCP-1, TARC, prostaglandins, leukotrienes, substance P, reactive oxygen species and nitrogen oxides, which are very diverse, each of which interacts in complex ways to regulate immune responses .
- IL interleukin
- skin irritation reduction refers to so-called skin such as prostaglandin E2 (PGE2), IL-1 ⁇ , IL-6, and IL-8 caused by drugs in an in vitro test using epidermal cells. It means that production of stimulation mediators is reduced and / or in vivo, skin irritation such as erythema / scab and edema formation of the skin by drugs is reduced.
- the skin irritation can be evaluated by, for example, the skin primary irritation index (PII).
- ком ⁇ онент Cholesterols selected from cholesterol, cholesterol derivatives and cholesterol analogs are used as skin irritation inhibitors to be blended in the adhesive composition, and the blending amount is 0.05% by mass or more based on the total amount of the adhesive composition. It is preferable.
- Cholesterols are alcohols having a steroid skeleton selected from cholesterol, cholesterol derivatives and cholesterol analogs. Cholesterol in the narrow sense is (3 ⁇ ) -cholesta-5-en-3-olcholesta-5-en-3 ⁇ -ol, which is known as an essential component of higher animal cell membranes.
- the cholesterol derivative means, for example, a natural or synthetic cholesterol derivative derived from animals, plants, microorganisms, and fungi, and examples thereof include acyl cholesterol which is an ester body in which a fatty acid is bonded to a hydroxy group.
- the cholesterol analog means a natural or synthetic cholesterol analog
- phytosterols such as plant cell-derived sitosterol, stigmasterol, fucostol, spinasterol, campesterol and brassicasterol, and fungus-derived ergosterol. Etc. are exemplified. One of these can be used alone, or two or more can be mixed and used.
- cholesterol is preferable, and wool-derived cholesterol is more preferable.
- Cholesterol, cholesterol derivatives, and cholesterol analogs are all classified as steroids, and belong to a subgroup called sterol (steroid alcohol).
- the adhesive composition may contain any one of these cholesterols or a combination of two or more. Since these cholesterols have the effect of reducing skin irritation caused by drugs such as oxybutynin, the combination of these compounds can reduce skin irritation caused by drugs such as oxybutynin.
- the amount of cholesterol blended is preferably 0.05% by mass or more based on the total amount of the pressure-sensitive adhesive composition, for example, 0.05 to 30% by mass, 0.1 to 25% by mass, 0.5 to 20% by mass, It may be up to 15% by mass. However, although depending on the type of the adhesive composition, if the blending amount of cholesterol exceeds 15% by mass, adhesiveness of the patch may not be sufficiently obtained. The amount is good, and 10% by mass or less is more preferable.
- Cholesterols blended as skin irritation inhibitors are substances whose melting point exceeds 100 ° C., and of course they are solid at room temperature (1-30 ° C.), so even if they are blended into a pressure-sensitive adhesive composition, the pressure-sensitive adhesive composition It was predicted that there would be no change that would enhance the fluidity (plasticity) of things. However, surprisingly, when cholesterols were added to the adhesive composition, it was found that the fluidity (plasticity) of the adhesive composition was increased.
- the fluidity of the pressure-sensitive adhesive composition is remarkably increased, and it can be stored when stored under severe conditions, or even at room temperature and pressure.
- the adhesive composition gradually penetrates deeply into the support layer, the adhesiveness of the patch may be greatly reduced, and a phenomenon may occur in which the drug release property changes. This phenomenon becomes more prominent by increasing the amount of cholesterol.
- a patch in which a pressure-sensitive adhesive composition containing cholesterols is laminated on a base fabric formed of polyester knitted fabric is stored at 60 ° C. for 2 weeks after preparation, and the adhesiveness does not contain cholesterols. It may be about 50%.
- the drug releasability when the release time is 5 hours may increase about twice as compared with the case where no cholesterol is added.
- a water-repellent part is provided at least in part.
- the water repellent surface 110 is provided in at least one of the thickness directions in the support layer 11 made of a base fabric.
- the water repellent surface 110 may be subjected to a water repellency treatment with a silicone compound having a high water repellency, or may be subjected to a water repellency treatment with a fluorine compound having a high water repellency / oil repellency. Water repellent treatment with a fluorine compound having oil repellent action is more suitable.
- the support layer 11 having a water-repellent portion such as the water-repellent surface 110 in part, the fluidity of cholesterols blended in the pressure-sensitive adhesive layer 12 can be suppressed, and when stored under severe conditions The adhesiveness of the patch 1 and the drug release property can be maintained.
- the adhesive composition may further contain a percutaneous absorption enhancer that is a component for adjusting the transdermal absorbability of the drug.
- the percutaneous absorption enhancer that can be used may be any compound that has been conventionally recognized to promote transdermal absorption in the skin.
- organic acids for example, organic acids, fatty acids having 6 to 20 carbon chains, fatty alcohols, fatty acid esters, amides, ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters and ethers (above saturated and unsaturated) Or any of cyclic and straight-chain branched), lactic acid esters, acetate esters, monoterpene compounds, sesquiterpene compounds, Azone, Azone derivatives, Pyrothiodecane, glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters (Span system), polysorbate (Tween system), polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil system (HCO system), polyoxyethylene Alkyl ethers, sucrose Such as fatty acid esters and vegetable oils.
- lactic acid esters for example, organic acids having 6 to 20 carbon chains, fatty alcohols, fatty acid esters, amides, ethers, aromatic organic acids, aromatic alcohol
- Such organic acids include aliphatic (mono, di or tri) carboxylic acids (acetic acid, propionic acid, citric acid (including anhydrous citric acid), isobutyric acid, caproic acid, caprylic acid, lactic acid, maleic acid, pyruvic acid, Oxalic acid, succinic acid, tartaric acid, etc.), aromatic carboxylic acid (phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid, etc.), alkylsulfonic acid (methanesulfonic acid, ethanesulfonic acid, propylsulfonic acid, butanesulfonic acid, polyoxy) Ethylene alkyl ether sulfonic acid, etc.), alkyl sulfonic acid derivatives (N-2-hydroxyethylpiperidine-N′-2-ethanesulfonic acid), cholic acid derivatives (dehydrocholic acid, etc.), or salts thereof (for example,
- transdermal absorption promoters include, for example, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, Cetyl alcohol, methyl laurate, hexyl laurate, diethanolamide laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol Cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate, geraniol, thymol, eugenol, terpineol, l-menthol, borneolo
- oleyl alcohol, lauryl alcohol, isostearyl alcohol, lauric acid diethanolamide, glycerol monocaprylate, glycerol monocaprate, glycerol monooleate, sorbitan monolaurate, propylene glycol monolaurate, polyoxyethylene lauryl ether and pyrothiodecane Is preferred.
- fatty acids having 6 to 20 carbon atoms are preferable, and oleic acid is particularly preferable. Two or more kinds of such transdermal absorption enhancers may be mixed and used.
- the adhesive composition contains a transdermal absorption promoter, the fluidity of the adhesive composition tends to be high.
- the mass ratio of the drug to cholesterol may be 400: 1 to 1:10, 300: 1 to 1: 5, 150: 1 to 1: 1, and even 15: 1 to 1: 1. Good. With this mass ratio, skin irritation can be reduced without affecting the skin permeability of drugs such as oxybutynin.
- the adhesive layer 12 of the patch contains substantially no water. “Contains substantially no water” means that the pressure-sensitive adhesive layer 12 is composed of a non-aqueous material. However, the pressure-sensitive adhesive layer 12 is allowed to contain a trace amount of moisture of 5% by mass or less derived from the raw material or the manufacturing environment.
- Adhesive base As the adhesive base, a rubber-based adhesive base is used because of its adhesion to the skin and low irritation to the skin.
- Rubber adhesive bases include styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer (SIS), polyisoprene, polyisobutylene (PIB), butyl rubber, styrene-butadiene copolymer, styrene-butadiene- Examples include styrene block copolymer (SBS), styrene-butadiene rubber (SBR), natural rubber, polybutadiene, and polysiloxanes. Among them, SIS, PIB, and polysiloxane are preferable. SIS and PIB are preferred from the viewpoint of cohesive strength.
- SIS has the characteristic of pseudo-crosslinking with styrene domains and can be used as an adhesive base that can be hot-melt coated.
- the adhesive base using SIS is excellent in adhesive force and holding power, and is also suitable for combination with a support layer composed of a base fabric excellent in stretchability.
- the SIS may be 5 to 60% or 10 to 35% as a mass ratio of styrene in the copolymer.
- the molecular weight of SIS may be 20,000 to 500,000 and may be 50,000 to 350,000.
- the mass ratio of the diblock body in SIS may be 50% or less, and may be 35% or less.
- the amount of the adhesive base is usually determined in consideration of the formation of the adhesive layer 12 and sufficient skin permeability of a drug such as oxybutynin. It is 5 to 90% by mass based on the total amount of the pressure-sensitive adhesive composition, and may be 10 to 70% by mass, 10 to 50% by mass, and further 10 to 30% by mass.
- the pressure-sensitive adhesive layer 12 may further contain a plasticizer.
- Plasticizers include oils such as paraffinic process oil, naphthenic process oil and aromatic process oil; squalane; squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil and peanut oil; silicon oil Dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate and diisopropyl sebacate; diethylene glycol; polyethylene glycol; Examples include glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton.
- liquid paraffin liquid polybutene, isopropyl myristate, diethyl sebacate and hexyl laurate are preferable, and liquid polybutene, isopropyl myristate and liquid paraffin are particularly preferable.
- two or more of these plasticizers may be used in combination.
- the amount of the plasticizer is usually 10 to 70% by mass based on the total amount of the adhesive composition. Yes, it may be 10 to 60% by mass, and further 10 to 50% by mass. The more the plastic composition contains a plasticizer, the more easily the fluidity of the adhesive composition.
- the pressure-sensitive adhesive layer 12 may further contain a tackifier resin that is a component that adjusts the adhesiveness of the pressure-sensitive adhesive composition to the skin.
- tackifier resins include rosin, rosin glycerin ester, hydrogenated rosin, rosin derivatives such as hydrogenated rosin glycerin ester and rosin pentaerythrester, and alicyclics such as Alcon P100 (trade name, Arakawa Chemical Industries).
- saturated hydrocarbon resins aliphatic hydrocarbon resins such as Quinton B170 (trade name, Nippon Zeon), terpene resins such as Clearon P-125 (trade name, Yasuhara Chemical), and maleic resin.
- hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin and terpene resin are particularly preferable.
- the blending amount of the tackifying resin is usually 5 to 70% by mass based on the total amount of the adhesive composition in consideration of sufficient adhesive strength as the patch 1 and irritation to the skin at the time of peeling. It may be ⁇ 60% by mass, and further 10 ⁇ 50% by mass.
- the manufacturing method of the patch 1 is demonstrated.
- the manufacturing method of the patch 1 which consists of a base fabric and has the support body layer 11 which has the water-repellent surface 110 in at least one of the thickness direction is demonstrated.
- the water repellent treatment is applied to at least one of the thickness directions of the base fabric to form the water repellent surface 110, and the support layer 11 is formed.
- the water repellent surface 110 may be subjected to a water repellent treatment with a silicone compound having a high water repellency, or may be subjected to a water repellent treatment with a fluorine compound having a high water repellency / oil repellency.
- the entire base fabric may be subjected to a water repellent treatment by taking out and drying (support layer preparation step).
- the patch 1 using a rubber-based adhesive base, using a mixer such as a kneader or a mixer, an adhesive base, a drug, cholesterols, and a plasticizer, a tackifying resin, and other additives as necessary.
- a mixer such as a kneader or a mixer
- an adhesive base a drug, cholesterols, and a plasticizer, a tackifying resin, and other additives
- it is heated and melted and directly spread on the support layer 11, and then pressed and laminated on the support layer 11, or the melt is once spread on a paper or film that has been subjected to a peeling treatment. Thereafter, the support layer 11 is pressed and laminated. Subsequently, the patch 1 is obtained by cutting into an appropriate size.
- the patch 1 having the above-described configuration can be produced by other methods that are generally known.
- a pressure-sensitive adhesive composition containing a drug such as oxybutynin is thermally melted, applied to the release paper or support layer 11, and then bonded to the support layer 11 or release paper to obtain this agent.
- an adhesive composition component containing a drug such as oxybutynin is dissolved in a solvent such as toluene, hexane or ethyl acetate, spread on a release paper or support layer 11 and dried to remove the solvent, and then the support layer or release layer. It is possible to obtain this agent by laminating it with a pattern paper.
- various pharmacologically acceptable additives such as stabilizers, antioxidants, fragrances, fillers and percutaneous absorption enhancers may be added within a range not impairing the object of the present invention. Can do.
- Sample A is a patch obtained by laminating an adhesive composition containing no cholesterols on a support layer made of a base fabric.
- Sample B is a patch obtained by laminating a pressure-sensitive adhesive composition containing 3% by mass of cholesterol with respect to a total amount of 100% by mass of the pressure-sensitive adhesive composition on a support layer made of a base fabric.
- Sample C was prepared by applying a pressure-sensitive adhesive composition containing 3% by mass of cholesterol to the support layer 11 made of a base fabric having a water-repellent surface 110 containing a fluorine compound with respect to 100% by mass of the total amount of the pressure-sensitive adhesive composition.
- 110 is a patch 1 laminated on 110.
- Sample D like Sample C, is a pressure-sensitive adhesive containing 3% by weight of cholesterol with respect to 100% by weight of the total amount of the pressure-sensitive adhesive composition on a support layer 11 comprising a base fabric having a water repellent surface 110 containing a fluorine compound.
- the patch 1 is obtained by laminating the composition on the water repellent surface 110, and the content of oxybutynin hydrochloride as a drug is 10% by mass.
- the water repellent surfaces 110 of Sample C and Sample D are provided on the entire surface where the base fabric is in contact with the adhesive composition of the adhesive layer 12.
- Any adhesive composition laminated as an adhesive layer contains oxybutynin hydrochloride as a drug and contains a lipophilic adhesive base.
- a component table of the adhesive composition laminated on each sample is shown in Table 1. “Other additives” in the table are additives including a component that adjusts the absorbability of a drug, a component that adjusts adhesiveness, and the like. Each component is mixed to form a solution, and if necessary, a solvent is added. The solution is cast on a release-treated PET (polyethylene terephthalate) film, and then the solvent is dried to form an adhesive layer (140 g / m 2). ) Was formed.
- PET polyethylene terephthalate
- a base fabric having no water repellent surface was used as a support layer, and an adhesive layer was laminated.
- a base fabric having a water repellent surface 110 was used as the support layer 11 and an adhesive layer 12 was laminated.
- the base fabric used was a knitted fabric made of polyester such as PET and knitted by knit fabric with a basis weight of 100 g / m 2 . The material was appropriately cut and hermetically packaged in an aluminum laminate packaging material.
- the adhesive strength was measured by the probe tack method (JIS Z 0237). After preparation of the sample patch (hereinafter referred to as “initial state”) and after sealing and packaging in an aluminum laminate packaging material at 60 ° C. for 2 weeks (hereinafter referred to as “after storage”) Measurements were made. Separate samples are used for the two measurements under different conditions. A case where the adhesive strength after storage decreased by 10% or more with respect to the adhesive strength in the initial state was judged as “deteriorated with time”.
- Sample A and Sample B are adhesive compositions comprising the same components as the above-mentioned sample.
- Samples A and B in this experiment are adhesive compositions that are not laminated on the support layer.
- Sample B ′ is a pressure-sensitive adhesive composition containing 5% by mass of cholesterol with respect to 100% by mass of the total amount of the pressure-sensitive adhesive composition.
- Each adhesive composition contains oxybutynin hydrochloride as a drug and contains a lipophilic adhesive base.
- a component table of each adhesive composition is shown in Table 3. “Other additives” in the table are additives including a component that adjusts the absorbability of a drug, a component that adjusts adhesiveness, and the like.
- Table 4 shows the results. As a result of the viscosity measurement at 65 ° C., it was confirmed that the viscosity of the pressure-sensitive adhesive composition was remarkably lowered by adding cholesterols.
- Example 3 Release evaluation (3-1 Sample preparation) The prepared three types of samples (samples A, B, and C) were prepared using the same components and methods as the samples (samples A, B, and C) used in Experiment 1.
- FIG. 2 shows the measurement result of Sample A. It was observed that the drug release rate increased as the release time passed in the initial state. After storage, it was observed that the drug release rate was slightly higher than the initial state.
- FIG. 3 shows the measurement result of Sample B. In the sample B containing cholesterols, in the initial stage, the drug release rate almost the same as that of the sample A containing no cholesterols was maintained. On the other hand, after storage, it was observed that the drug release rate increased by about 20% compared to the measurement result of Sample A. It is considered that the decrease in the viscosity of the pressure-sensitive adhesive composition due to the combination of cholesterols observed in Experiment 2 affects the time-dependent change in drug release.
- FIG. 4 shows the measurement result of Sample C. It was observed that the drug release rate changed little between the initial state and after storage. It is considered that by using the support layer 11 having the water repellent surface 110, an increase in the drug release rate due to the inclusion of cholesterols can be suppressed.
- Example 4 Skin permeability evaluation (4-1 sample preparation) The two types of samples prepared (sample A and sample C) were prepared using the same components and methods as the samples used in experiment 1 (sample A and sample C).
- the tank solution is collected every predetermined time, and the drug concentration in each solution is quantified by high performance liquid chromatography. From this quantitative result, the maximum permeation rate Jmax of the drug was calculated.
- the water repellent surface 110 in at least one of the thickness directions on the support layer 11 made of a base fabric, it was stored under severe conditions. In some cases, it has been shown that changes in adhesion and drug release can be reduced. It was also shown that there was little effect on drug skin permeability.
- Sample E is a patch in which an adhesive composition containing 3% by mass of cholesterol is laminated on a support layer made of a base fabric having no water repellent surface 110 with respect to 100% by mass of the total amount of the adhesive composition. is there.
- Samples F, G, H, I, J, K, and L are 3% by mass of cholesterol on the support layer 11 made of a base fabric having a water repellent surface 110 with respect to 100% by mass of the total amount of the adhesive composition. It is a patch 1 in which a pressure-sensitive adhesive composition containing a kind is laminated on a water repellent surface 110.
- AG84 is used as a water repellent on the water repellent surfaces 110 of the samples F, G, H, I, and J.
- AG84 contains a fluorine-containing compound.
- the NK guard S is used as a water repellent on the water repellent surfaces 110 of the samples K and L.
- the NK guard S contains a fluorine-containing compound.
- Each adhesive composition contains oxybutynin hydrochloride as a drug and contains a lipophilic adhesive base.
- a component table of each adhesive composition is shown in Table 7. “Other additives” in the table are additives including a component that adjusts the absorbability of a drug, a component that adjusts adhesiveness, and the like.
- Table 8 shows the results. After storage, the maximum permeation rate of Sample E having no water repellent surface is significantly reduced. In the samples F, G, H, I, J, K, and L provided with the water repellent surface 110, the maximum permeation speed after storage is generally improved as compared with the sample E.
- the ratio of the maximum transmission speed after storage with respect to the initial state (hereinafter referred to as “maximum transmission speed maintenance ratio”) exceeds 50%. However, among the samples F, G, H, I, J, K, and L provided with the water repellent surface 110, the maximum transmission rate maintenance rate of the sample F having a water repellent concentration of 0.5% on the water repellent surface 110 is one. The lowest. It is considered that the maximum transmission rate maintenance rate can be improved by increasing the water repellent concentration of the water repellent surface 110.
- Sample preparation is a patch obtained by laminating a pressure-sensitive adhesive composition containing 3% by mass of cholesterol with respect to a total amount of 100% by mass of the pressure-sensitive adhesive composition on a support layer made of a base fabric having no water-repellent surface 110. is there.
- the support layer 11 made of a base fabric having a water-repellent surface 110 is coated with a pressure-sensitive adhesive composition containing 3 mass% cholesterol on the water-repellent surface 110 with respect to 100 mass% of the total amount of the pressure-sensitive adhesive composition. It is the laminated patch 1.
- Asahi Guard E060 is used as a water repellent on the water repellent surface 110 of Sample N. Asahi Guard E060 contains a fluorine-containing compound.
- Each adhesive composition contains oxybutynin hydrochloride as a drug and contains a lipophilic adhesive base.
- Table 10 shows a component table of each adhesive composition. “Other additives” in the table are additives including a component that adjusts the absorbability of a drug, a component that adjusts adhesiveness, and the like.
- Table 11 shows the results. After storage, the maximum permeation rate of sample M having no water repellent surface is significantly reduced. In the sample N provided with the water repellent surface 110, the maximum permeation speed after storage is improved as compared with the sample E. Even when stored for a long period of one month, it is considered that the maximum permeation rate of the drug can be maintained to a certain extent by providing the water-repellent surface 110.
- the thickness of the pressure-sensitive adhesive layer was measured after the preparation of the sample patch (initial state) and after sealing and packaging in an aluminum laminate packaging material and storing at 60 ° C. for 1 week (after storage).
- Table 12 shows the results. After storage, the thickness of the pressure-sensitive adhesive layer of Sample E that does not have a water-repellent surface is significantly reduced. In the samples F, G, H, I, J, K, and L provided with the water repellent surface 110, the thickness of the adhesive layer after storage is thicker than that of the sample E.
- the ratio of the thickness of the pressure-sensitive adhesive layer after storage with respect to the initial state (hereinafter referred to as “thickness maintenance ratio”) exceeds 50%. It is considered that the fluidity of the pressure-sensitive adhesive layer is increased by adding cholesterols to the pressure-sensitive adhesive layer, the pressure-sensitive adhesive layer bites into the support layer after storage, and the thickness of the pressure-sensitive adhesive layer is reduced. On the other hand, it is considered that the thickness of the pressure-sensitive adhesive layer 12 can be maintained to a certain degree by providing the water-repellent surface 110 on the support layer 11 as in samples F, G, H, I, J, K, and L.
- FIG. 6 shows the correlation between the “thickness maintenance ratio” of eight types of samples (samples E, F, G, H, I, J, K, and L) and the “maximum transmission speed maintenance ratio” measured in Experiment 5. .
- the higher the thickness maintenance rate the higher the maximum transmission rate maintenance rate. It is considered that by providing the water-repellent surface 110 and reducing the biting of the pressure-sensitive adhesive layer 12 into the support layer 11, it is possible to further maintain the maximum permeation rate of the drug and to maintain the skin permeability. That is, it is considered from this result that it is effective to provide the water-repellent surface 110 to reduce the biting of the pressure-sensitive adhesive layer 12 into the support layer 11 in order to reduce the change in drug release with time. .
- the present invention can be applied to a patch (transdermal absorption preparation) containing oxybutynin.
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Abstract
Description
本願は、2016年10月11日に、日本に出願された特願2016-200402号に基づき優先権を主張し、その内容をここに援用する。
支持体層11に用いる支持体は、粘着剤層12を支持するのに適したものであればよく、伸縮性に優れた基布が好ましい。ポリエチレン、ポリプロピレン、ポリブタジエン、などのポリオレフィン類、エチレン酢酸ビニル共重合体、ポリ塩化ビニル、ポリエチレンテレフタトール、ポリエチレンナフタレート、ポリブチレンテレフタレート、などのポリエステル類、ナイロン、絹、獣毛(例えば羊毛)、などのポリアミド類、ポリウレタン、木綿のようなセルロース類など、または、これらの積層体もしくは混合物であってもよく、多孔体、発泡体、織布及び不織布、編布、並びにこれらのラミネート品などの性状として使用できる。織布の織り方や編布の編み方は、特に制限されず、例えば、経編み(トリコット編み、デンビートリコット編み、サテン編み、アトラス編み、平編み、リブ編み、パール編み)、丸編み(両面メリヤス編み、メリヤス編み、フライス編み)等が挙げられる。不織布は特に制限されず、スパンレース不織布、サーマルボンド不織布、スパンボンド不織布等であってよい。
ここで、基布の目付は20~200g/m2であってよく、70~140g/m2であってもよい。また基布の厚みは0.1~3mmであってもよい。
また、支持体層11の中間層に撥水面を形成してもよい。例えば二つの基布を重ね合わせて支持体層11を形成する場合に、その間に撥水面を形成することもできる。
ここで、支持体層11に形成する撥水性を有する部位は、撥水面110のような面状の形状でなく、支持体層11中の一部に形成される立体的な形状であってもよい。支持体層11中の厚さ方向と面方向の両方にわたって形成される斑状の撥水部位や、スジ状の撥水部位であってもよい。基布の編成パターンに合わせて、その編成パターンの一部に撥水部位を形成してもよい。
また、予め撥水処理された材料から基布を形成してもよい。全体もしくは一部が撥水処理されたフィラメントや糸を用いて形成した基布を用いて支持体層11を形成することで、支持体層11に撥水性を持たせることができる。
すなわち、支持体層11の少なくとも一部が撥水性を有していればよい。
撥水面110を支持体層11が粘着剤層12と接する面の全域にわたって形成することで、粘着組成物の付着性や薬物の放出性の経時変化により良好な効果をもたらすことができる。
粘着剤層12は、薬効を発揮する薬物と、コレステロール類と、親油性の粘着基剤とを含有する粘着組成物を備えている。広範な薬物に対して十分な皮膚刺激の低減効果が認められるコレステロール類を皮膚刺激抑制剤として粘着組成物に配合している。
粘着組成物に配合される薬物としては、皮膚刺激低減の必要性の観点から、オキシブチニン、トルテロジン、アセナピン、ビソプロロール、リスペリドン、ニコチン、及びシタロプラム、またはこれらの薬学的に許容できる塩からなる群より選択される1以上の塩基性薬物並びにその薬学的に許容される塩が挙げられる。これらの中でも塩酸オキシブチニンを薬物として選択した場合に本実施形態の効果が特に発揮される。
皮膚刺激抑制剤の配合により、これらの薬物又は薬効成分による皮膚刺激も低減される。本実施形態の貼付剤1の粘着剤層12に含有する薬物には、これらの薬物の何れかを選択できる。また、ここに挙げられた薬物以外の薬物を選択してもよい。
粘着組成物に配合する皮膚刺激抑制剤として、コレステロール、コレステロール誘導体及びコレステロール類似体から選択されるコレステロール類が使用され、その配合量は粘着組成物の全量を基準として0.05質量%以上であることが好ましい。
粘着組成物は更に、薬物の経皮吸収性を調節する成分である経皮吸収促進剤を含有してもよい。使用され得る経皮吸収促進剤としては、従来皮膚での経皮吸収促進作用が認められている化合物のいずれであってもよい。例えば有機酸類、炭素鎖数6~20の脂肪酸、脂肪アルコール、脂肪酸エステル、アミド、エーテル類、芳香族系有機酸、芳香族系アルコール、芳香族系有機酸エステル及びエーテル(以上は飽和、不飽和のいずれでもよく、また、環状、直鎖状分枝状のいずれでもよい)、乳酸エステル類、酢酸エステル類、モノテルペン系化合物、セスキテルペン系化合物、エイゾン(Azone)、エイゾン(Azone)誘導体、ピロチオデカン、グリセリン脂肪酸エステル類、プロピレングリコール脂肪酸エステル類、ソルビタン脂肪酸エステル類(Span系)、ポリソルベート系(Tween系)、ポリエチレングリコール脂肪酸エステル類、ポリオキシエチレン硬化ヒマシ油系(HCO系)、ポリオキシエチレンアルキルエーテル類、ショ糖脂肪酸エステル類及び植物油などが挙げられる。
粘着基剤としては、皮膚への付着性と皮膚への刺激の少なさからゴム系粘着基剤が用いられる。
粘着剤層12はさらに可塑剤を含有してもよい。可塑剤としては、パラフィン系プロセスオイル、ナフテン系プロセスオイル及び芳香族系プロセスオイルなどの石油系オイル;スクワラン;スクワレン;オリーブ油、ツバキ油、ひまし油、トール油及びラッカセイ油などの植物系オイル;シリコンオイル;ジブチルフタレート及びジオクチルフタレートなどの二塩基酸エステル;ポリブテン及び液状イソプレンゴムなどの液状ゴム;ミリスチン酸イソプロピル、ラウリン酸ヘキシル、セバシン酸ジエチル及びセバシン酸ジイソプロピルなどの液状脂肪酸エステル類;ジエチレングリコール;ポリエチレングリコール;サリチル酸グリコール;プロピレングリコール;ジプロピレングリコール;トリアセチン;クエン酸トリエチル;クロタミトンなどが例示できる。これらの中でも、流動パラフィン、液状ポリブテン、ミリスチン酸イソプロピル、セバシン酸ジエチル及びラウリン酸ヘキシルが好ましく、特に、液状ポリブテン、ミリスチン酸イソプロピル及び流動パラフィンが好ましい。これらの可塑剤は2種以上混合して使用してもよい。
粘着剤層12はさらに、粘着組成物の皮膚への粘着性を調節する成分である粘着付与樹脂を含有してもよい。粘着付与樹脂としては、ロジン、ロジンのグリセリンエステル、水添ロジン、水添ロジンのグリセリンエステル及びロジンのペンタエリストールエステルなどのロジン誘導体、アルコンP100(商品名、荒川化学工業)などの脂環族飽和炭化水素樹脂、クイントンB170(商品名、日本ゼオン)などの脂肪族系炭化水素樹脂、クリアロンP-125(商品名、ヤスハラケミカル)などのテルペン樹脂、マレイン酸レジンなどが挙げられる。これらの中でも、特に水添ロジンのグリセリンエステル、脂環族飽和炭化水素樹脂、脂肪族系炭化水素樹脂及びテルペン樹脂が好ましい。
次に、貼付剤1の製造方法を説明する。ここでは、基布からなり、撥水面110を厚さ方向の少なくとも一方に有する支持体層11を備える貼付剤1の製造方法を説明する。まず基布の厚さ方向の少なくとも一方に撥水処理を施して撥水面110を形成し、支持体層11を形成する。撥水面110は撥水作用が高いシリコーン化合物により撥水処理を施してもよいし、撥水・撥油作用が高いフッ素化合物により撥水処理を施してもよい。撥水処理剤を含有する溶液中に浸漬した後、取り出して乾燥させることで基布全体を撥水処理してもよい(支持体層準備工程)。
(実験1)付着性の評価
(1-1 サンプルの作成)
以下の4種類のサンプルを作成した(サンプルA、B、C、D)。サンプルAは、基布からなる支持体層にコレステロール類を含有しない粘着組成物を積層した貼付剤である。サンプルBは、基布からなる支持体層に、粘着組成物の合計量100質量%に対して3質量%のコレステロール類を含有する粘着組成物を積層した貼付剤である。サンプルCはフッ素化合物を含有する撥水面110を有する基布からなる支持体層11に、粘着組成物の合計量100質量%に対して3質量%のコレステロール類を含有する粘着組成物を撥水面110に積層した貼付剤1である。サンプルDは、サンプルC同様、フッ素化合物を含有する撥水面110を有する基布からなる支持体層11に、粘着組成物の合計量100質量%に対して3質量%のコレステロール類を含有する粘着組成物を撥水面110に積層した貼付剤1であり、薬物である塩酸オキシブチニンの含有率を10質量%としたものである。なお、サンプルCとサンプルDの撥水面110は、基布が粘着剤層12の粘着組成物と接する面全体に設けられている。
各成分を混和して溶液とし、必要であれば溶剤を加え、その溶液を離型処理したPET(ポリエチレンテレフタレート)フィルムの上にキャストした後、溶剤を乾燥して粘着剤層(140g/m2)を形成した。さらに、サンプルAとサンプルBでは、撥水面を有さない基布を支持体層とし、粘着剤層を積層した。サンプルCとサンプルDでは、撥水面110を有する基布を支持体層11とし、粘着剤層12を積層した。基布はPETなどのポリエステルを材質とし、目付が100g/m2でメリヤス編により編成した編布を用いた。適宜裁断し、アルミラミネート包材中に密封包装した。
プローブタック法による粘着力の測定を行った(JIS Z 0237)。サンプルの貼付剤の調製後(以降、これを「初期状態」という)と、アルミラミネート包材中に密封包装して60℃で2週間保存した後(以降、これを「保存後」という)において測定を行った。これら条件の異なる二つの測定には、別々のサンプルを使用している。初期状態の粘着力に対して、保存後の粘着力が10%以上低下しているものを「経時低下あり」と判断した。
表2に結果を示す。初期状態において、サンプルB及びサンプルCは、サンプルAに比べ粘着力が低下している。コレステロール類を含有させることで、初期状態において粘着力が低下することが観測された。保存後においては、サンプルBの粘着力が著しく低下している。撥水面110を設けたサンプルCにおいては、保存後の粘着力がサンプルBより大きく改善している。撥水面110を有する支持体層11を用いることで、粘着剤層12に配合されたコレステロール類による粘着組成物の流動を抑制することができ、保存後の貼付剤1の付着性を維持することができたと考察される。
また、薬物の含有率を10%としたサンプルDにおいても、保存後も初期状態と変わらず粘着力を維持できている。薬物の含有率を治療効果に合わせて調整した場合においても、撥水面110を設けることによるコレステロール類による粘着組成物の流動を抑制する効果は十分発揮されると考察される。
(実験2)粘着組成物の流動性の評価
(2-1 サンプルの作成)
以下の3種類のサンプルを作成した(サンプルA、B、B´)。サンプルA及びサンプルBは、上述のサンプルと同一の成分からなる粘着組成物である。本実験におけるサンプルA,Bは、支持体層には積層されていない粘着組成物である。サンプルB´は、粘着組成物の合計量100質量%に対して5質量%のコレステロール類を含有する粘着組成物である。
定試験力押出形細管式レオメータ(フローテスタ(島津製作所))を用い、65℃における各サンプルの流出速度を測定して粘度を算出した。
表4に結果を示す。65℃における粘度測定の結果、コレステロール類を配合することで粘着組成物の粘度が著しく低下することが確認された。
(実験3)放出性の評価
(3-1 サンプルの作成)
作成した3種類のサンプル(サンプルA、B、C)は実験1で用いたサンプル(サンプルA、B、C)と同じ成分、方法により作成した。
米国薬局方放出試験法に記載の回転シリンダー法により薬物の放出率の測定を行った。実験1と同様、サンプルの貼付剤の調製後(初期状態)と、アルミラミネート包材中に密封包装して60℃で2週間保存した後(保存後)において測定を行った。これら条件の異なる二つの測定には、別々のサンプルを使用している。
図2にサンプルAの測定結果を示す。初期状態において放出時間が経過するにつれて、薬物の放出率が増加しているのが観測された。保存後においては、初期状態より薬物の放出率は若干高くなっていることが観測された。
図3にサンプルBの測定結果を示す。コレステロール類を含有するサンプルBにおいて、初期段階では、コレステロール類を含まないサンプルAの薬物の放出率とほぼ同等の薬物の放出率を維持していた。一方、保存後においては、サンプルAの測定結果と比べ、薬物の放出率が20%程度増加していることが観測された。実験2で観測されたコレステロール類配合による粘着組成物の粘度低下が薬物の放出性の経時変化に影響を与えていると考察される。
図4にサンプルCの測定結果を示す。薬物の放出率が初期状態と保存後とでほとんど変化していないことが観測された。撥水面110を有する支持体層11を用いることで、コレステロール類を含有することによる薬物の放出率の増加を抑えることができていると考察される。
(実験4)皮膚透過性の評価
(4-1サンプルの作成)
作成した2種類のサンプル(サンプルA及びサンプルC)は実験1で用いたサンプル(サンプルA及びサンプルC)と同じ成分、方法により作成した。
ヘアレスマウスの背部皮膚を採取し、皮膚の角質層側に貼付剤を適用し、真皮側がレセプター槽側になるようにフロースルー型フランツセル(透過面積3cm2)に装着し、セルの温度を32℃に保つ。
図5に結果を示す。図5のグラフの縦軸は、3回の実験結果から算出した薬物の透過速度の平均値を示している。算出した薬物の透過速度のうち最大の透過速度Jmaxを表5に示す。サンプルAとサンプルCにおいて、図5及び表5に示すように最大値及び経時的変化ともに、ほぼ違いはなかった。すなわち、支持体層11が撥水面110を有し、その撥水面110に粘着剤層12を積層したとしても、薬物の皮膚透過性にはほとんど影響がないことが示された。
(実験5)撥水面の違いによる皮膚透過性の評価
(5-1 サンプルの作成)
表6および表7に示すように、8種類のサンプルを作成した(サンプルE、F、G、H、I、J、K、L)。サンプルEは、撥水面110を有さない基布からなる支持体層に、粘着組成物の合計量100質量%に対して3質量%のコレステロール類を含有する粘着組成物を積層した貼付剤である。一方、サンプルF、G、H、I、J、K、Lは、撥水面110を有する基布からなる支持体層11に、粘着組成物の合計量100質量%に対して3質量%のコレステロール類を含有する粘着組成物を撥水面110に積層した貼付剤1である。
サンプルK、Lの撥水面110には、NKガードSが撥水剤として使用されている。NKガードSは、含フッ素化合物を含んでいる。
上記の8種類のサンプルに対して、実験4と同様の方法で、薬物の最大透過速度Jmaxを算出した。サンプルの貼付剤の調製後(初期状態)と、アルミラミネート包材中に密封包装して60℃で1週間保存した後(保存後)において測定を行った。これら条件の異なる二つの測定には、別々のサンプルを使用している。
表8に結果を示す。保存後においては、撥水面を有さないサンプルEの最大透過速度が著しく低下している。撥水面110を設けたサンプルF、G、H、I、J、K、Lにおいては、保存後の最大透過速度がサンプルEよりおおむね改善している。初期状態に対する保存後の最大透過速度の割合(以降、「最大透過速度維持率」という)は、いずれも50%を超えている。
しかしながら、撥水面110を設けたサンプルF、G、H、I、J、K、Lの中で、撥水面110の撥水剤濃度が0.5%のサンプルFの最大透過速度維持率が一番低い。撥水面110の撥水剤濃度を高めることで、最大透過速度維持率を改善できると考察される。
(実験6)保存期間の違いによる皮膚透過性の評価
(6-1 サンプルの作成)
表9および表10に示すように、2種類のサンプルを作成した(サンプルM,N)。サンプルNは、撥水面110を有さない基布からなる支持体層に、粘着組成物の合計量100質量%に対して3質量%のコレステロール類を含有する粘着組成物を積層した貼付剤である。一方、サンプルNは、撥水面110を有する基布からなる支持体層11に、粘着組成物の合計量100質量%に対して3質量%のコレステロール類を含有する粘着組成物を撥水面110に積層した貼付剤1である。
上記の2種類のサンプルに対して、実験4と同様の方法で、薬物の最大透過速度Jmaxを算出した。サンプルの貼付剤の調製後(初期状態)と、アルミラミネート包材中に密封包装して60℃で1か月保存した後(保存後)において測定を行った。これら条件の異なる二つの測定には、別々のサンプルを使用している。
表11に結果を示す。保存後においては、撥水面を有さないサンプルMの最大透過速度が著しく低下している。撥水面110を設けたサンプルNにおいては、保存後の最大透過速度がサンプルEより改善している。一か月もの長期間保存する場合においても、撥水面110を設けることで薬物の最大透過速度を一定程度維持できると考察される。
(実験7)保存後における粘着剤層の評価
(7-1 サンプルの作成)
サンプルは、実験5の8種類のサンプル(サンプルE、F、G、H、I、J、K、L)と同じ成分、方法により作成した。
サンプルの貼付剤の調製後(初期状態)と、アルミラミネート包材中に密封包装して60℃で1週間保存した後(保存後)において粘着剤層の厚みの測定を行った。
表12に結果を示す。保存後においては、撥水面を有さないサンプルEの粘着剤層の厚みが著しく減少している。撥水面110を設けたサンプルF、G、H、I、J、K、Lにおいては、保存後の粘着剤層の厚みはサンプルEより厚い。初期状態に対する保存後の粘着剤層の厚みの割合(以降、「厚み維持率」という)は、いずれも50%を超えている。
粘着剤層にコレステロール類が配合されることで、粘着剤層の流動性が増大し、保存後において、粘着剤層が支持体層に食い込み、粘着剤層の厚みが減少したと考察される。一方、サンプルF、G、H、I、J、K、Lのように、撥水面110を支持体層11に設けることで、粘着剤層12の厚みを一定程度維持できると考察される。
11 支持体層
12 粘着剤層
20 剥離被覆物
110 撥水面
Claims (6)
- 基布からなり、少なくとも一部が撥水性を有する支持体層と、
前記支持体層の片面に積層された粘着剤層と、を備える貼付剤であって、
前記粘着剤層は、オキシブチニンまたはその薬学的に許容される塩と、コレステロール類と、ゴム系粘着基剤とを含む粘着組成物を含有する、オキシブチニン含有経皮吸収製剤。 - 前記オキシブチニンが塩酸オキシブチニンである、請求項1に記載のオキシブチニン含有経皮吸収製剤。
- 前記撥水性を有する部位が含フッ素化合物によって形成された、請求項1または請求項2に記載のオキシブチニン含有経皮吸収製剤。
- 前記基布が編布である、請求項1から請求項3のいずれか一項に記載のオキシブチニン含有経皮吸収製剤。
- 前記ゴム系粘着基剤がスチレン-イソプレン-スチレンブロック共重合体を含有する、請求項1から請求項4のいずれか一項に記載のオキシブチニン含有経皮吸収製剤。
- 前記オキシブチニンの含有率が前記粘着組成物に対して4%から50%であり、
前記コレステロール類が、コレステロールであって、その含有率が前記粘着組成物に対して0.05~10%である、
請求項2から請求項5のいずれか一項に記載のオキシブチニン含有経皮吸収製剤。
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JP2020040945A (ja) * | 2018-09-07 | 2020-03-19 | 株式会社メディカルフロント | ホスホン酸ジエステル誘導体類を含有する貼付剤、及びその製造方法 |
WO2020175395A1 (ja) * | 2019-02-27 | 2020-09-03 | 久光製薬株式会社 | 貼付剤 |
US11872320B2 (en) | 2021-02-25 | 2024-01-16 | Hisamitsu Pharmaceutical Co., Inc. | Method for treating osteoarthritis |
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JP7078855B2 (ja) | 2018-09-07 | 2022-06-01 | 株式会社メディカルフロント | ホスホン酸ジエステル誘導体類を含有する貼付剤、及びその製造方法 |
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US11872320B2 (en) | 2021-02-25 | 2024-01-16 | Hisamitsu Pharmaceutical Co., Inc. | Method for treating osteoarthritis |
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JP6663503B2 (ja) | 2020-03-11 |
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CN109803649A (zh) | 2019-05-24 |
ES2971854T3 (es) | 2024-06-10 |
KR102317575B1 (ko) | 2021-10-25 |
TWI706794B (zh) | 2020-10-11 |
EP3498272A4 (en) | 2020-04-22 |
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