JP6969352B2 - A method for manufacturing a skin adhesive, a skin adhesive, and a skin adhesive with a peeling sheet-like member. - Google Patents

Description

The present invention relates to a skin-adhesive adhesive containing a percutaneous absorbable agent, a skin-adhesive using the adhesive, and a method for producing a skin-adhesive with a peeling sheet-like member.

Conventionally, various skin-adhesive adhesives have been used for fixing wound coverings on the skin and medical devices to the skin. In addition, as a transdermal preparation for administering a transdermal drug through the skin into the living body, a transdermal external application such as a plaster, a poultice using an adhesive, or a transdermal adhesive sheet is applied. The agent is being developed. Among them, a transdermal adhesive sheet containing a transdermal adhesive in the adhesive has attracted attention because the administration operation is relatively easy and the dose can be controlled.

Since such a transdermal adhesive sheet is used by attaching an adhesive layer containing a transdermal drug to the skin surface, adhesiveness (adhesiveness) to the skin surface is required. In addition, in order to improve the therapeutic effect more reliably, it is expected to develop a transdermal patch that can continuously administer the drug to the affected area for a long time. Therefore, it is required to improve the drug solubility of the pressure-sensitive adhesive and the drug release property from the pressure-sensitive adhesive.

In order to meet such demands, rubber-based adhesives, acrylic-based adhesives, and silicone-based adhesives are often used as adhesives for skin application.

For example, the rubber-based pressure-sensitive adhesive contains styrene-isoprene-styrene block copolymer, polybutene, polyisobutylene, polyisoprene, ethylene-vinyl acetate copolymer, natural rubber, and the like as main components, and a pressure-sensitive adhesive or softening agent. , Stabilizer added is used.
Patent Document 1 discloses a pressure-sensitive adhesive containing a styrene-isoprene-styrene block copolymer, a paraffinic hydrocarbon having 10 to 30 carbon atoms and / or a naphthenic hydrocarbon and an alicyclic hydrocarbon resin.
Patent Document 2 discloses a patch or tape made of a thermoplastic elastomer made of an ABA-type block copolymer, a liquid component compatible with the thermoplastic elastomer, and a tackifier.
Patent Document 3 discloses a patch characterized by containing two types of synthetic rubber having different fluidities in the pressure-sensitive adhesive layer.

Further, as the silicone-based pressure-sensitive adhesive, those using silicone rubber, dimethylsiloxane base, diphenylsiloxane, or the like are known.
Patent Document 4 discloses a pressure-sensitive silicone adhesive comprising an adhesive strength enhancer such as a silicone liquid, a silicone resin, and a nonionic surfactant.
Patent Document 5 discloses a pressure-sensitive adhesive composition containing an organosiloxane-based polymer and an acrylic polymer containing a (meth) acrylic acid ester as a main component.
Patent Document 6 discloses a silicone-based adhesive for skin that contains a silicone resin and a modified silicone oil that is compatible with the silicone resin and is emulsified in water in oil.

Further, as an acrylic pressure-sensitive adhesive, Patent Document 7 describes a monomer containing a carboxyl group or a hydroxyl group, a copolymer obtained by copolymerizing a (meth) acrylic acid ester as an essential component, and a salt structure in a side chain. Disclosed is a transdermal absorption preparation using a monomer having a nitrogen atom which does not exist and a copolymer obtained by copolymerizing a (meth) acrylic acid ester as an essential component.
Patent Document 8 describes a pressure-sensitive adhesive composition comprising a water-insoluble copolymer containing N-vinyl-2-pyrrolidone as a constituent and a polymer containing a monoalkyl ester of maleic anhydride as a constituent. Disclose.

Further, Patent Documents 9 to 12 are polymers obtained by polymerizing 2-methacryloyloxyethyl phosphoricolin (hereinafter, abbreviated as MPC monomer) (hereinafter, abbreviated as MPC polymer, also referred to as a polymer having a phosphobetaine structure). Disclose a skin external preparation using.
Further, Patent Document 13 describes a composition for external use for warming, and suggests the use of N-methacryloylethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine polymer.

Japanese Unexamined Patent Publication No. 5-17346 Japanese Unexamined Patent Publication No. 2004-115774 Japanese Unexamined Patent Publication No. 2006-75588 Japanese Unexamined Patent Publication No. 5-194201 Japanese Unexamined Patent Publication No. 2005-314618 Japanese Unexamined Patent Publication No. 2009-273674 Japanese Unexamined Patent Publication No. 2000-44904 Japanese Unexamined Patent Publication No. 9-176604 Japanese Unexamined Patent Publication No. 2003-26608 Japanese Unexamined Patent Publication No. 2003-73251 Japanese Unexamined Patent Publication No. 2005-1708887 Japanese Unexamined Patent Publication No. 2014-28783 Japanese Unexamined Patent Publication No. 2003-250829

Rubber-based adhesives such as Patent Documents 1 to 3 and silicone-based adhesives such as Patent Documents 4 to 6 have high hydrophobicity, so that the solubility of the drug is insufficient and the selection range of the drug composition is wide. It had the drawback of being narrow.
In acrylic pressure-sensitive adhesives such as Patent Documents 7 and 8, in order to secure the cohesive force of the pressure-sensitive adhesive, a monomer having a carboxyl group or a hydroxyl group is copolymerized, but depending on the drug used, the influence of these functional groups may occur. In response, there was a problem that the amount of drug released was reduced. Moreover, the drug solubility is not sufficient.
The copolymers disclosed in Patent Documents 9 to 12 have problems in productivity, such as the need for a plurality of reactions and associated purification during the synthesis of the MPC monomer as a raw material. Further, the external preparations disclosed in Patent Documents 9 to 12 aim at a feeling of use that is not sticky after being applied to the skin. As the MPC monomer, the copolymerizable monomer is limited, and it is difficult to use the obtained MPC polymer for a pressure-sensitive adhesive.
Patent Document 13 suggests the use of a polymer having a carbobetaine structure as a patch. However, it did not satisfy the requirements for adhesiveness to the skin surface, peelability from the skin, solubility of the drug, and release of the drug from the adhesive.

In view of the above circumstances, the present invention is an adhesive for skin application, which is suitable for a skin adhesive having excellent adhesiveness to the skin surface, peelability from the skin, solubility of the drug, and release of the drug from the adhesive. The purpose is to provide.

Generally, in order to impart cohesive force to a polymer or improve the solubility of a drug, a method of introducing a highly polar group such as a carboxyl group or a hydroxyl group is known, but it is strongly mutual with the drug. It works and is not suitable in terms of drug release.
Therefore, the present inventors have applied a polymer containing a specific amount of a hydrophilic carbobetaine structure and / or a sulfobetaine structure and having a glass transition temperature and a mass average molecular weight in a specific range to the skin surface. We have found that it is possible to provide a patch having excellent adhesiveness, peelability when peeled from the skin, drug solubility, and drug release property, and have arrived at the present invention.
That is, the present invention contains at least one of the structures represented by the following general formulas 1 or 2 in total of 0.25 to 1.5 mmol / g, has a glass transition temperature of −60 ° C. to −5 ° C., and has a glass transition temperature of −60 ° C. to −5 ° C. The present invention relates to a pressure-sensitive adhesive for skin application, which comprises a urethane-based polymer (a) having a mass average molecular weight of 1000 to 3000000 and a transdermal agent (b).

(During the ceremony,
R ¹ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
R ² and R ⁴ each independently have an alkylene group having 1 to 6 carbon atoms.
R ³ , R ⁵ , and R ⁶ each independently have an alkyl group, an aryl group, an aralkyl group, or a pyridyl group.
Y is -COO ^- or -SO ₃ ^- represents,
* Represents the bonding position with the main chain of the urethane polymer. )

Further, the urethane-based polymer (a) contained in 100% by mass of the adhesive for skin application is preferably 20 to 99% by mass.

The present invention also relates to a skin patch having a sheet-like substrate and the above-mentioned layer of the skin patch adhesive.

Furthermore, in the present invention, the pressure-sensitive adhesive coating liquid containing the skin-sticking pressure-sensitive adhesive and the liquid medium is applied to a sheet-like substrate or a peeling sheet-like member to remove the liquid medium. A skin-adhesive pressure-sensitive adhesive layer containing a transdermal absorbable agent is formed on the sheet-like base material or the peel-off sheet-like member, and the peel-off sheet-like member or the sheet-like base material is laminated on the pressure-sensitive adhesive layer. The present invention relates to a method for producing a skin patch with a peeling sheet-like member.

Adhesion to the skin surface by using a urethane-based polymer (a) containing a specific amount of at least one of the structures represented by the general formulas 1 to 3 and having a glass transition temperature and a mass average molecular weight in a specific range. It was possible to provide a pressure-sensitive adhesive for skin application, which is excellent in peelability when peeled from the skin, solubility of a drug, and release of a drug from the pressure-sensitive adhesive.

The pressure-sensitive adhesive for skin application of the present invention is characterized by containing a urethane-based polymer (a). The urethane-based polymer (a) may also be referred to as a betaine resin (a).
<Urethane polymer (a), betaine resin (a)>
The betaine structure refers to a structure in which positive charges and negative charges are not adjacent to each other in the same molecule, and hydrogen atoms that can be dissociated are not bonded to the atoms having positive charges. Further, the urethane-based polymer (a) indicates a urethane-based polymer having this betaine structure in the molecular structure. By having a betaine structure in the molecule, it was possible to impart cohesive force to the resin, and to impart excellent drug solubility and drug release property.

Specifically, the urethane-based polymer in the present invention includes a structure represented by the following general formulas (1), (2) and (3).

(During the ceremony,
R ¹ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
The R ^{2, R} _4, ^{R 7} are each independently an alkylene group having 1 to 6 carbon atoms,
R ^3, R ⁵ , R ⁶ , R ⁸ and R ⁹ independently have an alkyl group, an aryl group, or an aralkyl group and a pyridyl group, respectively.
Y is -COO ^- or -SO ₃ ^-,
X represents O or NH
* Represents the bonding position with the main chain of the urethane polymer. )

Further, the urethane-based polymer in the present invention contains a polyol component, a polyisocyanate component, and a monomer that is a source for introducing a betaine structure as essential components, and a polyamine component, a monofunctional hydroxyl group component, or a monofunctional amine used as necessary. It is a reaction product with the components.

In the present invention, the urethane-based polymer containing the structure is polymerized after the tertiary amino group-containing monomer as a precursor for forming the structure is betainated using a betainizing agent (B) described later. Alternatively, it can be obtained by any method such as polymerizing a tertiary amino group-containing monomer as a precursor for forming the structure to obtain a polymer having a tertiary amino group, and then betainizing the polymer. It may be the one that was given.

Here, examples of the tertiary amino group-containing monomer as a precursor before betaineization include a tertiary amino group-containing diol having 1 to 20 carbon atoms. For example, N-alkyldialkanolamines and N, N-dialkylmonoalkanolamines can be mentioned.
Examples of the N-alkyldialkanolamine include N-methyldiethanolamine, N-ethyldiethanolamine, N-propyldiethanolamine, N-butyldiethanolamine and N-methyldipropanolamine.
Examples of the N, N-dialkyl monoalkanolamine include N, N-dimethylethanolamine.
In addition, N, N-bis (2-hydroxyethyl) benzylamine, N, N-bis (2-hydroxyethyl) cyclohexylamine, diethanol-p-toluidine, diisopropanol-p-toluidine, N, N-bis (2) -Hydroxyethyl) aniline, N, N-bis (2-hydroxypropyl) aniline, N, N-bis (2-hydroxyethyl) -3-chloroaniline, N, N-bis (2-hydroxyethyl) -4- Plysincarbamide, N, N-bis (2-hydroxyethyl) -α-aminopyridine, 1,4-bis (2-hydroxyethyl) piperazine, 3-diethylaminopropane-1,2-diol, 3-dimethylaminopropane Examples of the tertiary amino group-containing monomer include -1,2-diol and the like.

[Betaining agent (B)]
The betainizing agent (B) is composed of a cyclic sulfonic acid ester (B1), an ω-halogenated alkyl sulfonic acid metal salt (B2), a cyclic carboxylic acid ester (B3) and an ω-halogenated alkyl carboxylic acid metal salt (B4). It is selected from the group of This is a group of compounds used for converting the amino group of the above-mentioned tertiary amino group-containing monomer into a sulfobetaine or a carbobetaine.

Examples of such a cyclic sulfonic acid ester (B1) include 1,2-ethansulton, 1,3-propanesulton, and 1,4-butansulton.

Examples of such an ω-halogenated alkyl sulfonic acid metal salt (B2) include sodium 2-chloroethanesulfonate, sodium 2-bromoethanesulfonate, sodium 3-chloropropanesulfonate, and sodium 3-bromopropanesulfonate. Examples thereof include sodium 4-chlorobutane sulfonate and sodium 4-bromobutane sulfonate.

Examples of such a cyclic carboxylic acid ester (B3) include β-propiolactone, γ-butyrolactone, and δ-valerolactone.

Examples of such ω-halogenated alkylcarboxylic acid metal salt (B4) include sodium 2-chloroacetate, sodium 2-bromoacetate, sodium 3-chloropropionate, sodium 3-bromopropionate, and 4-chlorobutyric acid. Examples thereof include sodium, sodium 4-bromobutyrate, sodium 5-chloropentate, sodium 5-bromopentanoate and the like.

[Polyol component]
The polyol component is not particularly limited, but glycols such as ethylene glycol, 1,4-butanediol, neopentyl glycol, butylethylpentanediol, glycerin, trimethylolpropane, and pentaerythritol, polyester polyols, and polyethers. Examples thereof include polyols, polyester polyols, polybutadiene polyols, hydrogenated polybutadiene polyols, polyisoprene polyols, hydrogenated polyisoprene polyols or polyurethane polyols which are reactants of polyether polyols and polyisocyanates, and polyether adducts of polyhydric alcohols.

[Polyisocyanate component]
Examples of the polyisocyanate component include aromatic polyisocyanates, aliphatic polyisocyanates, aromatic aliphatic polyisocyanates, and alicyclic polyisocyanates.

Examples of the aromatic polyisocyanate include 1,3-phenylenediocyanate, 4,4'-diphenyldiisocyanate, 1,4-phenylenediocyanate, 4,4'-diphenylmethane diisocyanate, 2,4-tolylene diisocyanate, and 2,6-triisocyanate. Range isocyanate, 4,4'-toluidine diisocyanate, 2,4,6-triisocyanate toluene, 1,3,5-triisocyanate benzene, dianisidine diisocyanate, 4,4'-diphenyl ether diisocyanate, 4,4', 4 " -Triphenylmethane triisocyanate and the like can be mentioned.

Examples of the aliphatic polyisocyanate include trimethylene diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate, pentamethylene diisocyanate, 1,2-propylene diisocyanate, 2,3-butylenediocyanate, 1,3-butylenediocyanate, dodecamethylene diisocyanate, and 2, 4,4-trimethylhexamethylene diisocyanate and the like can be mentioned.

Examples of the aromatic aliphatic polyisocyanate include ω, ω'-diisocyanate-1,3-dimethylbenzene, ω, ω'-diisocyanate-1,4-dimethylbenzeneω, ω'-diisocyanate-1,4-diethylbenzene, 1, Examples thereof include 4-tetramethylxylylene diisocyanate and 1,3-tetramethylxylylene diisocyanate.

Examples of the alicyclic polyisocyanate include 3-isocyanate methyl-3,5,5-trimethylcyclohexylisocyanate, 1,3-cyclopentanediisocyanate, 1,3-cyclohexanediisocyanate, 1,4-cyclohexanediisocyanate, and methyl-2,4. -Cyclohexanediisocyanate, methyl-2,6-cyclohexanediisocyanate, 4,4'-methylenebis (cyclohexylisocyanate), 1,4-bis (isocyanatemethyl) cyclohexane, 1,4-bis (isocyanatemethyl) cyclohexane and the like can be mentioned. can.

Further, a so-called adduct body formed by adding a trifunctional alcohol such as trimethylolpropane to the polyisocyanate, a biuret body obtained by reacting the polyisocyanate with water, and the polyisocyanate forming an isocyanurate ring. A weight or the like can also be used together. The above-mentioned reaction product of the polyhydric alcohol polyether adduct and diisocyanate can also be used as a polyisocyanate component.

As the polyisocyanate used for obtaining the urethane polymer, 4,4'-diphenylmethane diisocyanate, hexamethylene diisocyanate, 3-isocyanatemethyl-3,5,5-trimethylcyclohexylisocyanate (isophorone diisocyanate) and the like are preferable.

[Polyamine component]
When obtaining a urethane-based polymer, a polyamine component can be used if necessary. Examples of the polyamine component include ethylenediamine, isophoronediamine, phenylenediamine, 2,2,4-trimethylhexamethylenediamine, tolylenediamine, hydrazine, piperazine, hexamethylenediamine, propylenediamine, dicyclohexylmethane-4,4-diamine, and the like. Examples thereof include diamines such as 2-hydroxyethylethylenediamine, di-2-hydroxyethylethylenediamine, di-2-hydroxyethylpropylenediamine, 2-hydroxypropylethylenediamine, and di-2-hydroxypropylethylenediamine. Isophorone diamine and 2,2,4-trimethylhexamethylenediamine are preferable because the reaction can be easily controlled and the hygiene is excellent.
By using the polyamine component, a urea bond having a higher cohesive force than the urethane bond is formed, so that a pressure-sensitive adhesive having a large cohesive force can be obtained.

[Hydroxy group component of monofunctional]
The monofunctional hydroxyl group component used as one of the terminal terminators when obtaining a urethane-based polymer is not particularly limited, and methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1 -Hexanol, 1-octanol and the like can be mentioned, and one or more selected from these groups can be used. Ethanol is preferable because it is less irritating to the skin even if it remains in the patch.

[Monofunctional amine component]
The monofunctional amine component used as one of the terminal terminators as well as the monofunctional hydroxyl component is not particularly limited, and hexylamine, octylamine, diethylamine, dodecylamine, hexadecylamine, octadecylamine, stearylamine, etc. Examples thereof include oleylamine, cyclohexylamine, monoethanolamine, monopropanolamine, diethanolamine, dipropanolamine and the like.
By using these monofunctional hydroxyl group components and / or monofunctional amine components as end-capping agents, the stability of the urethane polymer over time can be improved.

In the present invention, the urethane-based polymer is prepared by using a polyol component which is an essential component, a polyisocyanate component, and a monomer which is a source for introducing a betaine structure as necessary, a polyamine component, a monofunctional hydroxyl group component, or a monofunctional polymer. All the components of the amine component of the above may be reacted at the same time (one-shot method), or may be reacted sequentially. In order to surely produce a desired urethane-based polymer as a main product, a sequential reaction in which at least one of these components is sequentially reacted is preferable. When preparing a urethane-based polymer by a sequential reaction, for example, the following method can be applied.

A step of reacting a polyol component, a polyisocyanate component, and a monomer that is a source of introduction of a betaine structure under conditions of excess polyisocyanate component to obtain a urethane prepolymer having an isocyanate group at the terminal, and then the above-mentioned urethane prepolymer and polyamine component. A method comprising a step of reacting with and to obtain a polyurethane polyurea having an isocyanate group at the terminal, and finally, a step of reacting the remaining isocyanate group with a monofunctional hydroxyl component and / or a monofunctional amine component.

The method of proceeding with the sequential reaction is not limited to the method exemplified above.

The urethane-based polymer of the present invention may be produced by reacting raw materials in a solvent-free environment or by reacting them in an organic solvent.
Examples of the organic solvent include ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, ester compounds such as methyl acetate, ethyl acetate, butyl acetate, ethyl lactate and methoxyethyl acetate, and ethers such as diethyl ether and ethylene glycol dimethyl ether. Various solvents such as system compounds, aromatic compounds such as toluene and xylene, aliphatic compounds such as pentane and hexane, and halogenated hydrocarbon compounds such as methylene chloride, chlorobenzene and chloroform can be used.

In addition, when synthesizing a urethane-based polymer, a catalyst can be added as needed, for example, metal-based catalysts such as dibutyltin diacetate, dibutyltin dilaurate, dioctyltin dilaurate, and dibutyltin dimarate; 1,8-diaza-. Bicyclo (5,4,0) undecene-7, 1,5-diazabicyclo (4,3,0) nonen-5, 6-dibutylamino-1,8-diazabicyclo (5,4,0) undecene-7, etc. Tertiary amines; reactive tertiary amines such as triethanolamine, etc. may be mentioned, and these may be used alone or in combination of two or more.
The isocyanate group-containing urethane prepolymer is preferably obtained by reacting the above-mentioned polyol component, the polyisocyanate component, and the monomer that is the source of introducing the betaine structure in an organic solvent in the presence of a catalyst at 120 ° C. or lower, preferably 70 to 70. It is more preferable to react at 110 ° C. for 1 to 20 hours. When the temperature is higher than 110 ° C., it becomes difficult to control the reaction rate, and it becomes difficult to obtain a urethane prepolymer having a predetermined molecular weight and structure.
The reaction between the isocyanate group and the polyamine component is preferably carried out in an organic solvent at 60 ° C. or lower. If the temperature is higher than that, it becomes difficult to control the reaction rate, and it becomes difficult to obtain a urethane-based polymer having a predetermined molecular weight and structure.

<Betaine structure content>
Although the betaine structure itself is highly hydrophilic, the polymer (a) can be made water-insoluble by controlling the amount contained in the urethane-based polymer (a). In the present invention, the term "water-insoluble" means that 1 g of a polymer is placed in 99 g of ion-exchanged water at 25 ° C., stirred, left at 25 ° C. for 24 hours, water is removed, and the polymer is dried under reduced pressure to reduce mass. Is 5% or less. Since the polymer (a) is water-insoluble, water resistance can be imparted to the adhesive layer, and peeling of the adhesive layer from the skin due to contact with water can be suppressed.
The betaine structure content of the polymer (a) in the present invention is 0.25 to 1.5 mmol / g, preferably 0.3 to 1.3 mmol / g, and preferably 0.3 to 1.2 mmol / g. Is particularly preferable. When it is 0.25 mmol / g or more, excellent drug solubility and cohesive force can be imparted. Further, when the content is 1.5 mmol / g or less, the wettability to the skin is improved, so that excellent skin adhesiveness can be imparted and the water resistance of the adhesive can be improved.
In addition, the betaine structure content can be calculated by an analytical method such as NMR or GC-MS.

<Glass transition temperature>
The glass transition temperature (hereinafter, also referred to as Tg) of the urethane polymer (a) is −60 ° C. to −5 ° C., preferably −55 to −15 ° C. When the Tg is −60 ° C. or higher, cohesive force can be imparted, and the generation of adhesive residue when the adhesive is peeled off from the skin can be suppressed. Further, when the Tg is −5 ° C. or lower, the wettability to the skin is improved, so that excellent skin adhesiveness can be imparted.
The glass transition temperature is a value obtained by DSC (Differential Scanning Calorimetry).

<Mass average molecular weight (Mw)>
The mass average molecular weight of the polymer (a) is 10,000 to 3,000,000, preferably 15,000 to 2,000,000. When the molecular weight is 10,000 or more, cohesive force can be imparted, and the generation of adhesive residue when the adhesive is peeled off from the skin can be suppressed. Further, when the content is 3,000,000 or less, the solvent solubility of the resin is improved, and the viscosity is appropriate, so that the coating suitability is improved.

For the mass average molecular weight of the polymer (a), a value measured by gel permeation chromatography (GPC) in terms of standard polystyrene is adopted. As the measuring device and the measuring conditions, the following condition 1 is basically applied, and the condition 2 is allowed depending on the solubility of the sample and the like. However, depending on the polymer species, an appropriate carrier (eluent) and a column suitable for the carrier may be selected and used as appropriate. For other matters, reference is made to JISK7252-1 to 4: 2008. The poorly soluble polymer compound shall be measured at a soluble concentration under the following conditions.
When it is difficult to measure the molecular weight of the polymer (a), the mass average molecular weight of the betaineized precursor polymer can be used as the mass average molecular weight of the polymer (a). The mass average molecular weight of the betaineized precursor polymer is a value measured by gel permeation chromatography (GPC) in terms of standard polystyrene, and the measuring device and the measuring conditions are basically according to the following condition 3.
(Condition 1)
Column: TOSOHTSKgelSuperHZM-H,
TOSOHTSKgelSuperHZ4000,
TOSOHTSKgelSuperHZ2000
Carrier using a column connected to: Tetrahydrofuran Measurement temperature: 40 ° C
Carrier flow rate: 1.0 ml / min
Sample concentration: 0.1% by mass
Detector: RI (refractive index) detector Injection amount: 0.1 ml
(Condition 2)
Column: Carrier connecting two TOSOHTSKgelSuperAWM-H: 10 mM LiBr / N-methylpyrrolidone Measurement temperature: 40 ° C.
Carrier flow rate: 1.0 ml / min
Sample concentration: 0.1% by mass
Detector: RI (refractive index) detector Injection amount: 0.1 ml
(Condition 3)
Column: TOSOHTSKgelSuperAW4000,
TOSOHTSKgelSuperAW3000,
TOSOHTSKgelSuperAW2500
Use a column that connects
Carrier: Mixture of N, N-dimethylformamide (1L), triethylamine (3.04g), LiBr (0.87g) Measurement temperature: 40 ° C.
Carrier flow rate: 0.6 ml / min

The pressure-sensitive adhesive for skin application of the present invention preferably contains 20 to 99% by mass of the polymer (a) in 100% by mass of the pressure-sensitive adhesive for skin application, and more preferably 25 to 99% by mass. By setting the proportion of the polymer (a) to 20% by mass or more, desired performance such as drug solubility and drug release can be exhibited.

<Transdermal drug (b)>
The agent that can be added in the present invention is not particularly limited, and is, for example, a general anesthesia agent, a sleeping agent, an analgesic agent, an anti-inflammatory analgesic agent, a steroid hormone agent, an excitatory / stimulant agent, a neuropsychiatric agent, a local anesthetic agent, and the like. For skeletal muscle relaxants, self-sustaining nerve agents, anti-allergic agents, anti-histamine agents, cardiotonic agents, arrhythmia agents, diuretics, antihypertensive agents, vasoconstrictors, vasodilators, calcium channel blockers, antibacterial agents, for parasitic skin diseases Agents, skin softeners, antibiotics, anesthetics, cough suppressants, antipruritic agents, hypnotics, psychoenergetic agents, asthma agents, hormone secretion promoters, anti-ulcer agents, anticancer agents, vitamin agents, skin-beautifying ingredients, etc. And so on.

When the skin patch of the present invention is used as a topical patch, examples of the drug contained in this patch include indomethacin, ketoprofen, flurbiprofen, loxoprofen, loxoprofen sodium, piroxicam, and meroxycam. Examples thereof include anti-inflammatory analgesics such as ketolorac, felbinac, diclofenac, and diclofenac sodium. The content of the drug is not particularly limited, but is usually about 0.1 to 20% by mass with respect to the entire adhesive layer. Any drug for wound healing, topical administration, systemic administration, etc. may be added. Specifically, anti-inflammatory analgesics, steroidal anti-inflammatory agents, vasodilators, antihypertensive diuretics, anesthetics, antihistamines, antitumor agents, antihypertensive / arrhythmia agents, antidepressants / antidepressants, local anesthetics, Examples include hormonal agents, asthma / nasal allergy treatment agents, anticoagulants, antispasmodics, and fat-soluble vitamins.
The blending amount of the drug varies depending on the type of the drug and the purpose of use of the patch, but is preferably in the range of 0.1% by mass to 40% by mass in 100% by mass of the adhesive for skin application.

<Adhesive enhancer>
The pressure-sensitive adhesive for skin application of the present invention can further contain a pressure-sensitive adhesive. Examples of the tackifier include rosin, hydrogenated rosin, rosin ester, terpene resin, modified terpene resin, hydrogenated terpene resin, terpene phenol resin, petroleum resin, kumaron-inden resin, phenol resin, xylene resin, and alicyclic group. Saturated hydrocarbon resin and the like can be mentioned.
When these tackifiers are blended, the tack, the adhesive and the holding power can be easily adjusted. In addition, these may be used alone or in combination of two or more. The blending amount of the tackifier varies depending on the type, polarity and the like, but is usually used in the range of 1% by mass to 50% by mass in the mass% of the pressure-sensitive adhesive for skin application.

<Transdermal absorption promoter>
In the present invention, a transdermal absorption promoter can be further added in order to improve the solubility and diffusivity of the drug in the pressure-sensitive adhesive layer.
Specific examples of the transdermal absorption promoter include silicones such as dimethylpolysiloxane, animal and vegetable oils such as olive oil, carboxylic acids such as lactic acid, liquid paraffins, hydrocarbons such as wax, lauric acid, myristic acid, and olein. Higher fatty acids such as acids, higher alcohols such as hexyldecanol, octyldodecanol, and isostearyl alcohol, monohydric alcohol fatty acid esters such as isopropyl myristate, hexyl laurate, octyldodecyl myristate, butyl stearate, and decyl oleate, 2. -Alcohols such as hexyldecanol, 2-octyldecanol, glycerin, nonionic surfactants such as polyoxyethylene nonylphenyl ether, fatty acid glycerin ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester, polybutene, poly Examples thereof include liquid resins such as isoprene, polyacrylic acid and polymethacrylic acid, and oily vitamins such as retinol, retinol palmitate, tocophenol and tocophenol acetate.
When these transdermal absorption promoters are blended, the viscosity of the pressure-sensitive adhesive layer for skin application can be adjusted. In particular, when a highly hydrophobic compound such as isopropyl myristate is used in combination with a polyhydric alcohol such as glycerin, it also has an effect of promoting transdermal absorption of the drug. The blending amount of the transdermal absorption promoter varies depending on the type and polarity, the type of the pressure-sensitive adhesive, the polarity and the molecular weight, etc., but is usually in the range of 0.5% by mass to 50% by mass in the mass% of the pressure-sensitive adhesive for skin application. Used in.

Further, in the pressure-sensitive adhesive for skin application of the present invention, additives such as a thickener, an antioxidant, a moisturizer, and a pH adjuster can be appropriately used as optional components as long as the purpose is not impaired. In particular, when it is used as a skin-adhesive adhesive that comes into direct contact with the skin, it is preferable to use a moisturizer together.

The skin patch of the present invention can be obtained by directly or indirectly laminating a pressure-sensitive adhesive layer containing a polymer (a) and a transdermal agent (b) on a sheet-like substrate.
For example, a pressure-sensitive adhesive layer containing a skin-adhesive pressure-sensitive adhesive containing a polymer (a) and a transdermal agent (b) and a pressure-sensitive adhesive coating liquid containing a liquid medium are applied and dried on a sheet-like substrate. And laminating a peeling sheet-like member (also referred to as a liner) on the pressure-sensitive adhesive layer, a skin patch with a peeling sheet member can be obtained. Alternatively, a pressure-sensitive adhesive coating liquid is applied and dried on the peeling sheet-shaped member to form a pressure-sensitive adhesive layer, and a sheet-shaped base material is laminated on the pressure-sensitive adhesive layer to form skin with the peeling sheet member. A patch can be obtained.

As the sheet-like base material used in the present invention, a flexible base material usually used for a skin patch can be used, and the present invention is not particularly limited. Specifically, for example, a polymer film such as polyester, polyolefin, or cellulose ester; a woven fabric, knitted fabric, or non-woven fabric made of polyester, polyolefin, cellulose ester, polyurethane, polyamide, or the like; or paper can be used. The thickness of these supports is usually set to 50 μm to 300 μm, preferably 70 μm to 200 μm in the case of a base material, although it depends on the type of patch.

Of the sheet-like substrates, coarse and porous materials such as non-woven fabrics may come off if they are dissolved in a liquid medium and applied to the support, and even if they do not come off, they may come off inside. Since it permeates to the above, it also consumes an extra solution, and the above-mentioned manufacturing method of laminating a pressure-sensitive adhesive layer formed by applying and drying a pressure-sensitive adhesive coating liquid on another substrate in advance is preferable.

The release sheet member is not particularly limited, and a known release film can be used. For example, films such as polyester, polyvinyl chloride, polyvinylidene chloride, and polyethylene terephthalate, which have been peeled off by applying silicone resin, fluororesin, etc. to the contact surface with the adhesive layer, high-quality paper, glassin paper, etc. Papers such as, high-quality paper, glassin paper, etc., and a laminated film of polyolefin are used. The thickness of the release film is usually 10 to 200 μm, preferably 25 to 100 μm.

Further, as the patch, in addition to the support layer and the pressure-sensitive adhesive layer, other commonly used functional layers such as a liner and a surface protective layer can be laminated.

The present invention will be described in more detail with reference to the following examples, but the following examples do not limit the scope of rights of the present invention in any way. In the examples, "parts" and "%" represent "parts by mass" and "% by mass", respectively, and Tg means the glass transition temperature.

<Measurement method of glass transition temperature>
The glass transition temperature can be measured by DSC (Differential Scanning Calorimetry) as follows. The solution of the polymer (a) was dried to dryness, about 2 mg of the obtained polymer was weighed on an aluminum pan, the test container was set in the DSC measurement holder, and the chart obtained under the heating condition of 10 ° C./min. Read the endothermic peak. The peak temperature at this time is defined as the glass transition temperature of the present invention.

<Measurement method of hydroxyl value>
It was measured by the method described in JISK-1557.

[Manufacturing Example 1]
In a 4-necked flask equipped with a stirrer, a reflux cooling tube, a nitrogen introduction tube, an introduction tube, and a thermometer, 10 parts of N-methyldiethanolamine as a monomer having a tertiary amino group and Sanniks PP4000 as a polyol component (hydroxyl value:: 26.8 KOHmg / g (manufactured by Sanyo Kasei Co., Ltd.) was charged in 77.14 parts, and hexamethylene diisocyanate as a polyisocyanate component was charged in 18.71 parts. rice field. Subsequently, 0.002 part of dibutyltin dilaurate was added thereto as a catalyst, and the mixture was reacted at 110 ° C. for 3 hours.
Then, the temperature was lowered to 40 ° C., and 1.39 parts of isophorone diamine was added dropwise as a polyamine component over 2 hours to carry out a chain extension reaction. Further, 0.144 parts of hexylamine was added as a terminal terminator and reacted at 40 ° C. for 30 minutes to obtain a solution of a betaine precursor polymer, that is, a polymer having a tertiary amino group.
Next, 11.43 parts (equal molar amount of N-methyldiethanolamine used) of 1,4-butaneslton as a betaine agent was added to the obtained solution of the polymer having a tertiary amino group, and the temperature was 70 ° C. for 10 hours. The reaction was carried out to betaine the amino group. After confirming that the amine oxide conversion rate exceeded 99%, the mixture was cooled and taken out, and then the solvent was completely volatilized in an oven to obtain the polymer (a).
The resulting betaine structure content of the ^polymer, C 13 -NMR measurement results from 0.71 mmol / g.
The Tg of the obtained polymer (a) was measured by DSC at −27 ° C., and the mass average molecular weight was measured by GPC to be 300,000.

[Production Examples 2 to 16], [Comparative Production Examples 1 to 5]
The polymer (a) was synthesized by the same method as in Production Example 1 with the compounding composition shown in Table 1.

The symbols in the table are as follows.
<Polyol having a tertiary amino group>
MDEA: N-methyldiethanolamine EDTA: N-ethyldiethanolamine DMAP: 3-dimethylaminopropane-1,2-diol <polyol>
PP4000: Sanniks PP4000 (polyoxypropylene glycol, hydroxyl value: 26.8 KOHmg / g, manufactured by Sanyo Chemical Industries, Ltd.)
P4010: Kuraray polyol P4010 (aliphatic polyester polyol, hydroxyl value 28KOHmg / g, manufactured by Kuraray Co., Ltd.)
GI-3000: Hydroxyl-terminated polybutadiene with both ends (hydroxyl value: 27.7KOHmg / g, manufactured by Nippon Soda Corporation)
<Polyisocyanate component>
HDI: Hexamethylene diisocyanate IPDI: Isophorone diisocyanate <Polyamine component>
IPDA: Isophorone Diamine BDA: 1,4-Butane Diamine HA: Hexylamine <Betaining Agent>
Betaining Agent 1: 1,4-Butansultone Betaining Agent 2: 2-Sodium Chloroacetate Betaining Agent 3: β-Propiolactone Betaining Agent 4: 1,3-Propane Sultone Betaining Agent 5: 4-bromo Sodium butane sulfonate

[Example], [Comparative example]
The polymer (a) synthesized in the production example and the comparative production example was dissolved in a mixed solvent of ethyl acetate and ethanol (mass ratio 70:30) so that the solid content concentration was 30%, and the solid content of the polymer (a) was dissolved therein. After adding 3 parts of loxoprofen sodium as a transdermal absorbable agent to 100 parts and dissolving the mixture, the mixture was coated on a polyethylene terephthalate film with an applicator so as to have a dry coating film of 30 μm, and dried at 100 ° C. for 2 minutes.
Next, another stripped polyethylene terephthalate film was laminated on the pressure-sensitive adhesive layer side to prepare a skin patch with a peeling sheet-like member (hereinafter referred to as a patch sheet).

(1) Adhesive strength After cutting this patch sheet to a width of 25 mm and a length of 75 mm, the peeled polyethylene terephthalate film was removed, and the patch was attached to a bakelite plate at 23 ° C. and 65% RH. After crimping with a roll according to JIS and allowing it to stand for 20 minutes, it was peeled off in the 180 degree direction at a speed of 300 mm / min under an environment of 23 ° C. and 65% RH, and a peeling force having a width of 25 mm was measured.
〇: 12N <Adhesive strength Δ: 8N <Adhesive strength ≤12N
×: Adhesive strength ≤ 8N

(2) Adhesive residue Using the same sample as the one whose adhesive strength was measured in (1) above, the tactile sensation of the adhesive was evaluated by a thumb test. After releasing the finger, it was visually evaluated whether the adhesive remained on the finger.
〇: No glue transfer on the finger ×: No glue transfer on the finger

(3) Drug Solubility The polymer (a) synthesized in Production Examples and Comparative Production Examples was dissolved in a mixed solvent of ethyl acetate and ethanol (weight ratio 70:30) so that the solid content concentration was 30%, and the above-mentioned Polymer (a) To 100 parts of solid content, loxoprofen sodium as a transdermal absorbable agent was added in a fixed amount (3 parts, 5 parts, 7 parts, 9 parts, 13 parts, 17 parts, 21 parts) and dissolved. Then, it was applied on a polyethylene terephthalate film with an applicator so as to have a dry coating film of 30 μm, and dried at 100 ° C. for 2 minutes.
Next, another stripped polyethylene terephthalate film was laminated on the pressure-sensitive adhesive layer side to prepare a patch.
After storing this patch in a constant temperature and humidity chamber at 25 ° C.-60% for 1 month, the presence or absence of crystal precipitation of the drug in the pressure-sensitive adhesive layer was visually observed and evaluated. The maximum amount of drug added in which crystals were not formed was defined as the maximum amount of drug dissolved in the pressure-sensitive adhesive, and the judgment was made according to the following criteria.
⊚: 17 parts ≤ maximum drug dissolution amount 〇: 9 parts ≤ maximum drug dissolution amount <17 parts Δ: 5 parts ≤ maximum drug dissolution amount <9 parts ×: maximum drug dissolution amount <5 parts

(4) Drug-releasing property The polymer (a) synthesized in the production examples and the comparative production examples was dissolved in an ethyl acetate solvent so that the solid content concentration was 30%, and the film was transdermally charged to 100 parts of the resin solid content. Loxoprofen sodium as an absorbable agent is added in the maximum amount of the polymer (a) obtained in (3), and two parts of lactic acid are added and dissolved as a transdermal absorption promoter, and then the same as in (3) above. Then, a patch having a laminated structure composed of polyethylene terephthalate / adhesive layer / peeled polyethylene terephthalate film was prepared, and cut into ^{a circular shape (= 3.14 cm 2) having a diameter of 2 cm.}
The peeled skin on the back of the nude mouse was set in a Franz-type diffusion cell, and the polyethylene terephthalate film peeled from the above-mentioned patch was peeled off from the skin, and an exposed adhesive layer was attached to examine the skin permeability.
As the receptor solution, a phosphate buffer solution (pH 7.2) was used, and the amount of loxoprofen sodium transferred from the patch to the receptor solution through the skin was measured by HPLC after 24 hours. The skin permeability of loxoprofen sodium was determined by dividing the amount of loxoprofen sodium in the receptor solution after 24 hours by the amount of loxoprofen sodium in the patch and then multiplying by 100.
〇: 6 [%] ≤ skin permeability Δ: 3 [%] ≤ skin permeability <6 [%]
×: Skin permeability <3 [%]

As can be seen from Table 2, the polymers (a) of Comparative Examples 1 and 2 do not have a betaine structure or have an insufficient content, so that the drug solubility is poor, the cohesive force is low, and adhesive residue is generated. To do. Since the polymer (a) used in Comparative Example 3 had a very large amount of betaine structure introduced, the interaction between the polymer (a) and the drug became strong, and the drug release property decreased.
In Comparative Example 4, since the molecular weight of the polymer (a) was low, the cohesive force decreased and adhesive residue was generated. In Comparative Example 5, since the Tg of the polymer (a) was high, the wettability to the skin was lowered and the adhesive strength was lowered.
On the other hand, the polymer (a) used in the examples obtained well-balanced and good results in all physical properties.

Claims (5)

It contains at least one of the structures represented by the following general formulas 1 or 2 in total of 0.25 to 1.5 mmol / g, has a glass transition temperature of -60 ° C to -5 ° C, and has a mass average molecular weight of 10. A pressure-sensitive adhesive for skin application, which comprises a urethane-based polymer (a) of 000 to 3,000,000 and a transdermal agent (b).

(During the ceremony,
R ¹ is an alkylene group having 1 to 6 carbon atoms or a hydroxyalkylene group having 1 to 6 carbon atoms,
R ² and R ⁴ each independently have an alkylene group having 1 to 6 carbon atoms.
R ³ , R ⁵ , and R ⁶ each independently have an alkyl group, an aryl group, an aralkyl group, or a pyridyl group.
Y is -COO ^- or -SO ₃ ^- represents,
* Represents the bonding position with the main chain of the urethane polymer. ) The pressure-sensitive adhesive for skin application according to claim 1, wherein the urethane-based polymer (a) contained in 100% by mass of the pressure-sensitive adhesive for skin application is 20 to 99% by mass. A skin patch having a sheet-like substrate and a layer of the skin patch adhesive according to claim 1 or 2. The pressure-sensitive adhesive coating solution containing the skin-sticking pressure-sensitive adhesive and the liquid medium according to claim 1 or 2 is applied to a sheet-like substrate, the liquid medium is removed, and the skin is transdermally applied onto the sheet-like substrate. A method for producing a skin patch with a peeling sheet-shaped member, wherein a pressure-sensitive adhesive layer containing an absorbent agent is formed, and a peeling sheet-shaped member is laminated on the pressure-sensitive adhesive layer. The pressure-sensitive adhesive coating liquid containing the skin-sticking pressure-sensitive adhesive and the liquid medium according to claim 1 or 2 is applied to the peeling sheet-shaped member, the liquid medium is removed, and the peeling sheet-shaped member is covered. A method for producing a skin patch with a peeling sheet-like member, which forms a pressure-sensitive adhesive layer containing a transdermal absorbable agent and laminates a sheet-like base material on the pressure-sensitive adhesive layer.