JP2008214311A - Preparation for percutaneous absorption - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preparation for percutaneous absorption, containing a sufficient amount of physiologically active substances and causing fewer skin irritation compared to conventional ones. <P>SOLUTION: The preparation for percutaneous absorption with low skin irritability can be obtained by adding a sufficient amount of physiologically active substances to a polyether polymer having a siloxane bond and regulating the amount of catalysts for ensuring stable curability. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a percutaneous absorption preparation for treating a diseased part of the body or administering a drug to the circulatory system or skin.

  In recent years, percutaneous absorption preparations aimed not only at the skin disease site but also for systemic action have made significant progress based on the concept of drug delivery systems, and in particular, their usefulness as sustained-release preparations has been recognized. Conventionally, as this type of transdermally absorbable preparation, a drug-impermeable support provided with an adhesive polymer layer containing a drug and a release auxiliary substance that usually promotes the release of the drug is known. The drug is administered to the diseased part of the body or the circulatory system by being attached to the body surface.

As an adhesive base for this transdermally absorbable preparation, an acrylic adhesive is used, and a transdermal absorption accelerator is added or the skeleton is modified (Patent Document 1), but the adhesiveness is lowered. There are problems with safety, such as increased skin irritation. Silicone elastomers, on the other hand, are particularly safe and are used as drug-holding carriers for implantable and transdermally absorbable preparations and other various preparations. In addition, in addition reaction curing type silicone resins, when nitrogen, sulfur, phosphorus, tin, and lead are included in the additive, there is a known problem that curing is inhibited (for example, Patent Documents 2 and 3). .
JP 2004-97730 A Japanese Patent No. 3085150 Japanese Patent No. 3461404

  The present invention solves the above-described conventional problems, and the object of the present invention is to have a sufficient amount of a drug that is less irritating to the skin than conventional transdermal absorption preparations. The object is to provide a transdermally absorbable preparation.

  As a result of intensive studies in view of such problems, the amount of catalyst should be specified in order to ensure that a sufficient amount of physiologically active substance is contained in the polyether polymer having a siloxane bond and that stable curability is ensured. Thus, a percutaneous absorption preparation with little skin irritation can be obtained, and the present invention has been completed.

  According to the transdermally absorbable preparation of the present invention, the skin irritation is small as compared with conventional transdermally absorbable preparations, and a sufficient amount of drug can be contained.

The present invention is described in detail below.
In the present invention, at least one pressure-sensitive adhesive composition layer is provided on a support.

  The support used in the transdermally absorbable preparation of the present invention is not particularly limited as long as it can hold the pressure-sensitive adhesive composition before curing, but the physiologically active substance contained in the pressure-sensitive adhesive composition is the support. Those which are lost from the back through the inside and do not cause a decrease in content are preferred. Specifically, urethane polymers such as polyether urethane, amide polymers such as polyether amide, acrylic polymers such as polyacrylate, olefin polymers such as polyethylene, polypropylene, and ethylene-vinyl acetate copolymer, polyethers Examples include ester polymers such as polyester. Among these, those that do not release a compound containing at least one element selected from nitrogen, sulfur, phosphorus, tin, and lead as constituent elements are preferable from the viewpoint of suppressing the formation inhibition of the pressure-sensitive adhesive composition layer on the support. Used. The support may be a single layer or a laminate composed of a plurality of layers, and in the case of a laminate, each layer may be made of the same material or different types of materials. The thickness of the substrate is not particularly limited and can be appropriately selected depending on the purpose and application, and is exemplified by 10 to 5000 μm.

  The pressure-sensitive adhesive composition laminated on the substrate comprises (A) a polyether polymer having at least one alkenyl group at the terminal and (B) a compound having 1 to 10 hydrosilyl groups in the molecule and ( C) A hydrosilylation catalyst and, if necessary, (D) a mixture comprising an organic liquid component is cured.

  The polymer (A) is a polyether polymer having at least one alkenyl group at the terminal. The alkenyl group is not particularly limited as long as it is a group containing a carbon-carbon double bond that is active for hydrosilylation reaction. The alkenyl group is preferably an aliphatic unsaturated hydrocarbon group having 2 to 20 carbon atoms, more preferably 2 to 6 carbon atoms (eg, vinyl group, allyl group, methylvinyl group, propenyl group, butenyl group, pentenyl group). Group, hexenyl group, etc.), preferably a cyclic unsaturated hydrocarbon group having 3 to 20 carbon atoms, more preferably 3 to 6 carbon atoms (eg, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, etc.) ), A methacryl group and the like.

From the viewpoint of easy synthesis reaction, preferred alkenyl groups include the following (1), (2)
Is mentioned. In the following formula, R ¹ is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, preferably a hydrogen atom or a methyl group.
(1) H ₂ C═C (R ¹ ) −
^{(2) HC (R 2)} = CH-
The polymer (A) has an average of at least 1, preferably 1 to 5, more preferably 1 to 3, and still more preferably 1 to 2 alkenyl groups per molecule. Polymer (A) If the average number of alkenyl groups in one molecule is less than 1, the curability will be insufficient, and if the number of alkenyl groups contained in one molecule is too large, the network structure will be dense. For this reason, the adhesive properties tend to decrease.

A typical example of the polyether polymer as the basic skeleton of the polymer (A) is a polyoxyalkylene polymer composed of a repeating unit represented by the general formula (—R ³ —O—). Here, -R ³ - is a divalent alkylene group. From the viewpoint of adhesive properties, skin irritation, and wettability to the skin, the main chain of the preferred polymer (A) is polyoxypropylene (that is, the above -R ³ -is -CH ₂ CH (CH ₃ )-). . Moreover, it is preferable also from the point of workability | operativity on acquisition. The polyether polymer may be composed of one type of repeating unit or may be composed of a plurality of repeating units. The polyether polymer may be a linear polymer or a branched polymer.

  All the parts other than the alkenyl group of the polymer (A) preferably comprise a polyether skeleton, but may contain other structural units. In that case, the total of the polyether skeleton in the polymer (A) is preferably 80% by weight or more, and more preferably 90% by weight or more.

  The molecular weight of the polymer (A) is preferably from 3,000 to 50,000, more preferably from 6,000 to 50,000, particularly preferably from 10,000 to 30,000 from the viewpoint of good workability at room temperature and obtaining good adhesive properties. When the number average molecular weight is less than 3,000, the obtained cured product tends to be brittle. Conversely, when the number average molecular weight exceeds 50,000, the viscosity tends to be high and workability tends to be lowered. The molecular weight is a polystyrene equivalent number average molecular weight measured by size exclusion chromatography. The bonding mode of the alkenyl group to the polyether polymer is not particularly limited, and examples thereof include a direct bond of an alkenyl group, an ether bond, an ester bond, a carbonate bond, a urethane bond, and a urea bond. Among these, a direct bond of an alkenyl group, an ether bond, an ester bond, and a carbonate bond that do not contain nitrogen, sulfur, phosphorus, tin, and lead as constituent elements are preferably used from the viewpoint of inhibiting curing inhibition.

  The method for producing the polymer (A) is not particularly limited, and examples thereof include a method of introducing an alkenyl group after obtaining a polyether polymer. In this case, various known production methods can be applied to the polyether polymer, and a commercially available polyether polymer may be used. In addition, a method for introducing an alkenyl group into a polyether polymer is also known. For example, a monomer having an alkenyl group (eg, allyl glycidyl ether) and a monomer for synthesizing a polyether polymer are copolymerized. And a functional group that is reactive to the functional group into a polyether polymer in which a functional group (eg, hydroxyl group, alkoxide group) has been previously introduced into a desired portion (end of main chain, etc.) And a method of reacting a compound having both a group and an alkenyl group (eg, acrylic acid, methacrylic acid, vinyl acetate, acrylic acid chloride, etc.). However, a method in which a compound containing at least one element selected from nitrogen, sulfur, phosphorus, tin, and lead as a constituent element is not mixed is preferable.

  The compound (B) is a compound having 1 to 10 hydrosilyl groups in the molecule. The hydrosilyl group means a group having a Si—H bond. In the present invention, when two hydrogen atoms (H) are bonded to the same silicon atom (Si), it is calculated as two hydrosilyl groups. The chemical structure of the compound (B) other than the hydrosilyl group is not particularly limited. The number average molecular weight of the compound (B) calculated from the SiH value obtained by titration is preferably 400 to 3000, more preferably 500 to 1000. This is because if the number average molecular weight is too low, it tends to volatilize at the time of heat-curing, and it tends to be difficult to obtain a sufficient cured product, and if it is too high, the curing rate tends to be slow.

  The number of hydrosilyl groups contained in one molecule of the compound (B) is 1 to 10, preferably 2 to 8. If the number of hydrosilyl groups is two or more, a plurality of polymer (A) molecules can be cross-linked during curing, exhibiting a cohesive force preferable as a transdermal absorption preparation, and paste when peeled after being applied to the skin. The rest is less likely to occur. However, if the number of hydrosilyl groups is too large, cross-linking becomes too dense, and adhesive properties such as skin adhesive strength and tackiness are likely to deteriorate as a transdermal absorption preparation, and the stability of the compound (B) is poor. In addition, a large amount of hydrosilyl groups remain in the cured product even after curing, which is likely to cause skin irritation and voids. In addition, the density of the crosslinking affects the density between the polyether parts as the main chain of the polymer (A), and further affects the moisture permeability of the entire transdermally absorbable preparation. Therefore, the number of hydrosilyl groups in the compound (B) should be selected in consideration of the balance with the adhesive properties. Moreover, a compound (B) may be used independently and may be used together 2 or more types. The compound (B) is preferably compatible with the polymer (A). From the viewpoint of easy availability of raw materials and compatibility with the polymer (A), examples of suitable compounds (B) include organohydrogensiloxanes modified with organic groups. A typical example of the organohydrogensiloxane is a compound represented by the following formula (3).

上記式（３）のａの値が分子中のヒドロシリル基の数の数と一致する。ａ＋ｂの値は特に限定はないが好ましくは２〜５０である。Ｒは主鎖の炭素数が２〜２０の炭化水素基である。上記（３）の化合物は、未変性のメチルハイドロジェンシリコーンを変性してＲを導入することにより得ることができる。未変性のメチルハイドロジェンシリコーンとは、上記（３）においてＲが全てＨである化合物に相当し、株式会社シーエムシー発行（１９９０．１．３１）の「シリコーンの市場展望−メーカー戦略と応用展開−」にも記載されているように、各種変性シリコーンの原料として用いられている。Ｒの導入のための有機化合物としては、α−オレフィン、スチレン、α−メチルスチレン、アリルアルキルエーテル、アリルアルキルエステル、アリルフェニルエーテル、アリルフェニルエステル等が挙げられる。変性のために加える上述の有機化合物の量によって、変性後の分子中のヒドロシリル基の数を調節することができる。

The value of a in the above formula (3) matches the number of hydrosilyl groups in the molecule. The value of a + b is not particularly limited but is preferably 2-50. R is a hydrocarbon group having 2 to 20 carbon atoms in the main chain. The compound (3) can be obtained by modifying an unmodified methyl hydrogen silicone and introducing R. Unmodified methylhydrogen silicone corresponds to the compound in which R is all H in the above (3), and “Silicon market outlook—Manufacturer strategy and application development” issued by CMC Co., Ltd. (1990.1.31). As described in "-", it is used as a raw material for various modified silicones. Examples of the organic compound for introducing R include α-olefin, styrene, α-methylstyrene, allyl alkyl ether, allyl alkyl ester, allyl phenyl ether, allyl phenyl ester, and the like. The number of hydrosilyl groups in the molecule after modification can be adjusted by the amount of the organic compound added for modification.

  The ratio of the amount of the polymer (A) and the compound (B) in the pressure-sensitive adhesive composition for forming the pressure-sensitive adhesive layer is derived from the compound (B) with respect to the total amount of alkenyl groups derived from the polymer (A). Expressed by the total amount of hydrosilyl groups. Depending on the size of the total amount of hydrosilyl groups per mole of the total amount of alkenyl groups in the pressure-sensitive adhesive composition, the level of crosslinking density after curing is determined. Considering the balance between imparting appropriate tackiness and reducing the adhesive residue, etc., the total amount of hydrosilyl groups per 1 mol of the total amount of alkenyl groups is preferably 0.1 to 5.0 mol, more preferably 0. 4 to 4.0 moles.

It does not specifically limit as a hydrosilylation catalyst which is a catalyst (C) component, Arbitrary things can be used if a hydrosilylation reaction is accelerated | stimulated. Specifically, chloroplatinic acid, a platinum-vinylsiloxane complex (for example, platinum-1,3-divinyl-1,1,3,3, -tetramethyldisiloxane complex or platinum-1,3,5,7- Tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane complex), platinum-olefin complexes (e.g.
Pt _x (ViMe ₂ SiOSiMe ₂ Vi) _y , Pt [(MeViSiO) ₄ ] _z (where x, y, and z represent positive integers)) and the like. Among these, from the viewpoint of the activity of the catalyst, a platinum complex catalyst not containing a strong acid conjugate base as a ligand is preferable, a platinum-vinylsiloxane complex is more preferable, and platinum-1,3-divinyl-1,1 is preferable. 3,3, -tetramethyldisiloxane complex or platinum-1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane complex is particularly preferred.

  Next, the amount of the hydrosilylation catalyst (C) will be described. In the present invention, a sufficient amount of a physiologically active substance is contained in a polyether polymer having a siloxane bond, which is less irritating to the skin, and a catalyst amount is specified in order to ensure stable curability. It is characterized by doing.

From the above viewpoint, in the present invention, the total amount of the catalyst (C) needs to be 5 × 10 ⁻⁸ mol or more with respect to 1 mol of the total amount of alkenyl groups of the polymer (A). When the amount of the catalyst is less than this, it becomes difficult to obtain a pressure-sensitive adhesive composition layer while containing a sufficient amount of a physiologically active substance.

Moreover, it is desirable to adjust the addition amount of a hydrosilylation catalyst (C) with the element which comprises the physiologically active substance contained in an adhesive composition layer. When a physiologically active substance that does not contain nitrogen, sulfur, phosphorus, tin, or lead as a constituent element is included, the amount of the catalyst (C) is 5 × 10 5 with respect to 1 mol of the total amount of alkenyl groups of the polymer (A). It is ^-8 to 5 × ^{10 -3} mol, preferably in order to ensure proper curing rate, pot life. However, many physiologically active substances contain nitrogen, sulfur, phosphorus, tin, and lead as constituent elements. When the bioactive substance containing any one of nitrogen, sulfur, phosphorus, tin and lead as a constituent element is included, the amount of the catalyst (C) is set to 1 mol of the total amount of alkenyl groups in the polymer (A). 5 × 10 ⁻³ mol or more is preferable for obtaining a stable pressure-sensitive adhesive composition layer while containing a sufficient amount of a physiologically active substance.

  The physiologically active substance in the present invention is not particularly limited and can be used. As described above, in order to obtain a stable adhesive composition layer, the elements constituting the physiologically active substance to be contained in the adhesive composition layer It is desirable to adjust the addition amount of the hydrosilylation catalyst (C).

Specific examples of physiologically active substances include
1. β-adrenergic agonists such as albuterol, bambuterol, vitorterol, carbuterol, clenbuterol, chlorprenalin, denopamine, dioxetedrine, dopexamine, ephedrine, epinephrine, etafedrine, ethyl norepinephrine, isonoterine, promoterol, Naral, mabuterol, metaproterenol, methoxyphenamine, oxyfedrine, pyrbuterol, prenalterol, procaterol, protokilol, reproterol, limiterol, ritodrine, soterenol, terbuterol and xamoterol
2. β-adrenergic blocking agents such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befnolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucmolol, befetolol, bufuralol, bunitrolol, bupranolol, butidolol hydrochloride, butofrolol hydrochloride Carteolol, carvedilol, seriprolol, cetamolol, chloranolol, zilevorol, epanolol, esmolol, indenolol, labetalol, levobanolol, mepindolol, metipranolol, metoprolol, moprolol, nadoxolol, nifenalol, nipprelolol, oxyprenolol, oxyprenolol Practolol, prone Roll, propranolol, sotalol, Sul Fina roll, talinolol, tertatolol, timolol, toliprolol and xibenolol
3. Analgesics such as chlorobutanol; narcotic analgesics such as alfentanil, allylprozin, alphaprozin, anilellidine, benzylmorphine, benzitolamide, buprenorphine, butorphanol, clonitazene, codeine, methylcodeine bromide, codeine phosphate phosphate, codeine sulfate , Desomorphin, Dextromoramide, Dezocine, Diampromide, Dihydrocodeine, Enol acetate dihydrocodeine, Dihydromorphine, Dimenoxadol, Dimefeptanol, Dimethylthianbutene, Dioxafetil butyrate, Dipipanone, Epeptosine, Ethoheptadine, Ethylmethylthianbutene, Ethylmorphene Ethone Fentanyl, hydrocodone, hydromorphone, hydroxypentidine, isomethadone, ketobe Don, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone hydrochloride, methopone, morphine, morphine derivative, mylofine, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam , Pentazocine, phenadoxone, phenazosin, pheoperidine, pimidine, pyritramide, proheptazine, promedol, properidine, propyram, propoxyphene, sufentanil and thyridine and non-narcotic analgesics such as acetaminophen, acetylsalicylsalicylic acid and alclofenac
4). Anti-anginal drugs such as acebutolol, alprenolol, aminodarone, amlodipine, arotinolol, atenolol, bepridil, bevantolol, bukumolol, bufetrol, bufuralol, bunitrolol, bupranolol, carazolol, carteolol, carvedilol, ceriprolol, maleic acid Cinepasset, diltiazem, epanolol, felodipine, galopamil, imolamine, indenolol, isosorbide dinitrate, isradipine, limaprost, mepindolol, metoprolol, molsidomine, nadolol, nicardipine, nifedipine, nifenarol, nilvadipine, nipradilol Oxyfedrine, ozagrel, penbutolol, Nitric acid pentaerythritol, pindolol, professional story roll, propranolol, sotalol, terodiline, timolol, toliprolol and verapamil
5. Antiarrhythmic drugs such as acebutol, acecaine, adenosine, azimarin, alprenolol, amiodarone, amoproxan, aprindine, arotinolol, atenolol, bevanthrol, bretylium tosylate, bubumolol, bufetrol, bunaphthol, bunitrolol, buprinolol, butidoline hydrochloride Capobenic acid, carazolol, carteolol, cifenline, chloranolol, disopyramide, encainide, esmolol, flecainide, galopamil, hydroquinidine, indecainide, indenolol, ipratropium bromide, lidocaine, loradimine, lorcainide, meventurinol, methiprenololidine, , Nifenalol, oxyprenolol, pen Troll, pindolol, Pirumenoru, practolol, Purajimarin, procainamide hydrochloride, pro neta roll, propafenone, propranolol, Pirinorin, quinidine sulfate, quinidine, sotalol, talinolol, timolol, tocainide, verapamil, Bikuijiru and xibenolol
6). Antidepressants: Bicyclic systems such as vinedaline, caroxazone, citalopram, dimetazan, indalpine, fencamine, indeloxazine hydrochloride, nefopam, nomifensine, oxytryptane, oxypertin, paroxetine, sertraline, thiazesim, trazodone and zometapine; hydrazide / hydrazine , For example, benmoxine, iproclozide, iproniazide, isocarboxazide, niaramide, octamoxine and phenelzine; pyrrolidones such as cotinine, rolicipurine and rolipram; tetracyclic systems such as maprotiline, metralindole, mianserin and oxaprotilin. Tricyclic systems such as azinazolam, amitriptyline, amitriptyline, amoxapine, buttriptyline, clomipramine, demexeptiline, desipramine, dibenzepine, dimetracrine, dothiepine, doxepin, fluacidine, imipramine, imipramine N-oxide, iprindol, lofepramine, Metapramine, nortriptyline, noxiptylline, opipramol, pizotirin, propizepine, protriptyline, quinupramine, tianeptine and trimipramine; and others such as adrafinil, benactidine, bupropion, butacetin, deanol, aceanolate deanol, acetamidobenzoyl dool, Etoperidone, febalmamate, femoxeti , Fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypersinin, levofacetoperan, medifoxamine, minaprine, moclobemide, oxafurozan, piberalin, prolintan, piriscideanol, rubidium chloride, sulpiride, sultopride, teniloxazine, tozalinone, tofenacin , Troxatone, tranylcypromine, L-tryptophan, risperidone, viloxazine and zimeldine
7). Antiestrogens, such as dermadinone acetate, ethamoxytrifetol, tamoxifen and toremifene
8). Anti-gonadotropins such as danazol, gestrinone and paroxypropion
9. Antihypertensive agents: arylethanolamine derivatives such as amosulalol, bufuralol, direvalol, labetalol, pronetalol, sotalol and sulfinalol; aryloxypropanolamine derivatives such as acebutolol, alprenolol, arotinolol, atenolol, betaxolol, bevantolol , Bisoprolol, bopindolol, bunitrolol, bupranolol, butofilolol, carazolol, cartezolol, carvedilol, ceriprolol, cetamolol, epanolol, indenolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nipprelolol, oxiprenolol, penbutrol Pindolol, propranolol, talinolol, te Laolol, timolol and triprolol; benzothiadiazine derivatives such as althiazide, bendroflumethiazide benzthiazide, benzylhydrochlorothiazide, butiazide, chlorothiazide, chlorthalidone, cyclopenthiazide, cyclothiazide, diazoxide, epithiazide, ethiazide, fenquizone, hydrochlorothiazide , Hydroflumethiazide, methylclothiazide, methicrane, metrazone, paraflutizide, polythiazide, tetrachloromethiazide and trichloromethiazide; N-carboxyalkyl (peptide / lactam) derivatives such as alacepril, captopril, cilazapril, delapril, enalapril, enara Prirat, Hoshinopril, Lisinopril, Mobiletipril, Perindopril Quinapril and ramipril; dihydropyridine derivatives such as amlodipine, felodipine, isradipine, nicardipine, nifedipine, nilvadipine, nisoldipine and nitrendipine; guanidine derivatives such as betanidin, debrisoquine, guanabenz, guanacrine, guanazodine, guanazudin, guanazudin, Guanoxane; hydrazine and phthalazine series, such as budralazine, cadralazine, dihydralazine, endralazine, hydralcarbazine, hydralazine, pheniprazine, pyrrazine, and todralazine; imidazole derivatives, such as clonidine, lofexidine, phentolamine, thiamenidine and tronidine; quaternary ammonium compounds , Odor Azamethonium chloride, chloroisondamine chloride, hexamethonium, bis (methyl sulfate) pentacinium, pentamethonium bromide, pentolinium tartrate, phenactopinium chloride and trimethidiunam methosulfate; quinazoline derivatives such as alfuzosin, bunazosin, doxazosin, prazosin Terazosin and trimazosin; reserpine derivatives, vietaserpine, deserpidine, resinnamine, reserpine and syrosingopine; sulfonamide derivatives such as ambuside, clopamide, furosemide, indapamide, kinetazone, trypamide and xipamide; and others such as adimarin, γ-aminobutyric acid, Bufeniode, chlorthalidone, cicletaine, cyclosidomine, cryptenamine tannate, fenoldopam, furosek Nan, Indamine, Ketanserin, Metobutamate, Mecamylamine, Methyldopa, Methyl 4-pyridyl ketone thiosemicarbalzone, Metrazone, Minoxidil, Musolimine, Pardiline, Penpidine, Pinacidil, Piperoxane, Primaperone, Protoveratrines, Laubacin, Recimetol, Rilmenidene, Saralasin, sodium nitroprusside, ticrinafen, trimetaphane, camsylate, tyrosinase and urapidil
10. Anti-inflammatory (non-steroidal) agents: aminoaryl carboxylic acid derivatives such as enfenamic acid, etofenamate, flufenamic acid, isonyxine, meclofenamic acid, mefanamic acid, niflumic acid, talniflumate, telofenamate and tolfenamic acid; aryl Acetic acid derivatives such as acemetacin, alclofenac, ampenac, bufexamac, synmetacin, clopilac, diclofenac sodium, etodolac, felbinac, fenclofenac, fenclolac, fenclozic acid, fenthiazac, glucametacin, ibufenac, indomethacin, isofezolac , Isoxepak, Ronazolac, Methazic acid, Oxamethasine, Progouritacin, Sulindac, Thiaramid, Tolmeti Arylbutyric acid derivatives such as bumadizone, butybufen, fenbufen and xembusine; arylcarboxylic acid derivatives such as cridanac, ketorolac and tinolidine; arylpropionic acid derivatives such as aluminoprofen, beoxaprofen, bucuroxy acid, carprofen , Fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuprofaxam, indoprofen, ketoprofen, loxoprofen, miloprofen, naproxen, oxaprozin, picketprofen, pirprofen, pranoprofen, protidic acid, suprofen and thiaprofenic acid; Pyrazoles such as diphenamisole and epilysole; pyrazolones such as apazone, Nspiperilone, feprazone, mofebutazone, morazon, oxyphenbutazone, phenibutazone, pipebuzone, propifenazone, lamifenazone, sukibzone and thiazolinobutazone; salicylic acid derivatives such as acetaminosalol, aspirin, benolylate, bromosaligenate, calcium acetylsalicylate, diflunisalicylate, Etherealate, fendosaur, gentisic acid, glycol salicylate, imidazolic salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine, palsalimide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamine o-acetic acid, salicylsulfuric acid, salsalic Rate and sulfasalazine; thiazinecarbox Midoids such as droxicam, isoxicam, piroxicam and tenoxicam; and others such as ε-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, diphene Pyramide, ditazole, emorzone, guayazulene, nabumetone, nimesulide, orgothein, oxaceptol, paraniline, perisoxal, pifoxime, proquazone, valdecoxib, ketorolac, proxazole and tenidap
11. Antitumor agents: 2-aminolevulinic acid and alkylating agents: alkyl sulfonates such as busulfan, improsulfan and piperosulfan; aziridines such as benzodepa, carboxone, metuledepa and uredepa; ethyleneimine and methylmelamines such as Artretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; nitrogen mustard systems such as chlorambucil, chlornafazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine , Mechlorethamine hydrochloride, melphalan, nobenbiquine, phenesterine, prednisotin, trophosphamide and uracil mustard; nitrosourea, eg , Carmustine, chlorozotocin, hotemustine, lomustine, nimustine and ranimustine; and others, such as dacarbazine, mannomustine, mitoblonitol, mitractol, and pipobroman; antibiotics such as aclacinomycin, actinomycin F1, anthromycin, azaserine, bruomycin, Mycin, carubicin, cardinophilin, chromomycin, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, mitomycin, mycophenolic acid, nogaramycin, olivomycin, pepromycin, pricamycin, porphy Romycin, puromycin, streptonigrin, streptozocin, tubercidine, ubenimex, zino Antimetabolites: folic acid analogs such as denopterin, methotrexate, pteropterin and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiapurine and thioguanine; and pyrimidine analogs such as ancitabine, Azacitidine, 6-azauridine, carmofur, cytarabine, doxyfluridine, enositabine, furoxyuridine, fluroouracil and tegafur; enzymes such as L-asparaginase; and others such as acegraton, ansacrine, bestlabsyl, bisplatin, carboplatin, cisplatin, defophamide , Demecorsin, diadicone, erfornitine, ellipticine acetate, etoglucide, etoposide, gallium nitrate, hydro Siurea, interferon-α, interferon-β, interferon-γ, interleukin-2, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenmet, pirarubicin, podophyllic acid, 2-ethidrazide, procarbateni Poside, tenuazonic acid, triadiquone, 2,2 ′, 2 ″ -trichlorotriethylamine, urethane, vinblastine, vincristine and vindesine; Anti-adrenal systems such as aminoglutethimide, mitotane and trilostane; antiandrogens such as flutamide and niluta De; and antiestrogen-based, for example, tamoxifen and toremifene
12 Antiparkinson agents such as amantadine, benserazide, bietanautin, biperidene, bromocriptine, budipine, carbidopa, deprenyl, dexetimide, dietadine, droxidopa, etopropazine, ethylbenzhydramine, levodopa, naxagolide, pergolide, pyrrolidiprodine, primoditin And trihexyphenidyl hydrochloride
13. Antiprostatic hypertrophy agents, eg, guestnolone caproate, mepaltricin
14 Antipsychotics: butyrophenones such as benperidol, bromperidol, droperidol, fluanizone, haloperidol, melperone, moperone, pipamperon, sniperone, timiperone and trifluperidol; phenothiazines such as acetophenazine, butaperazine, carfenazine, chlorproe Tagine, Chlorpromazine, Crospyrazine, Cyamemazine, Dixylazine, Fluphenazine, Imicropazine, Mepazine, Mesoridazine, Methoxypromazine, Metophenazate, Oxaflumazine, Perazine, Pericazine, Perimethazine, Perphenazine, Piperacetazine, Pipothiazine, Prochlorperazine, Promazine Sulforidazine, thiopropazate, thioridazine, trifluoperazine and triflupro Gins; thioxanthenes such as chlorprothixene, clopenthixol, flupentixol and thiothixene; other tricyclics such as benzquinamide, carpipramine, clocapramine, clomaclan, clothiapine, clozapine, opipramol, protipendil, tetrabenazine And other such as alizaprid, amisulpride, bramate, fluspirylene, morindon, penfluridol, pimozide, spirylene and sulpiride
15. Antispasmodic agents such as aribendol, ambusetamide, aminopromazine, apotropine, methylbebonium sulfate, bietamivelin, butavelin, butropium bromide, N-butylscopolammonium bromide, caroverine, simetropium bromide, cinnamedrine, clevopride, conidium oxyacid, hydrochloric acid Coniine, cyclonium iodide, diphemerin, diisopromine, dioxafetil butyrate, diponium bromide, drophenine, emepronium bromide, etavelin, fecremin, phenalamide, phenovelin, fenpiplan, fenpiberinium bromide, fentonium bromide, flavoxate, furopropion, Gluconic acid, guaiactinamine, hydramidazine, hymechromone, leiopyrrole, mebevelin, moxaverine, nafiberine, oct Miramine, octaverine, pentapiperide, phenamaside hydrochloride, phloroglucinol, pinaberium bromide, piperylate, pipoxolan hydrochloride, pramiberin, prifinium bromide, propridine, propiban, propilomazine, prozapine, racephemin, rosiverine, spasmolitol, strontium iodide, sultroponium iodide Thiemonium iodide, tiquidium bromide, tilopramide, trepibutone, trichromyl, triphorium, trimebutine, N, N-1-trimethyl-3,3-diphenylpropylamine, tropendyl, trospium chloride and xennitropium bromide
16. Anti-anxiety drugs: arylpiperazines such as buspirone, gepirone and ipsapilone; benzodiazepine derivatives such as alprazolam, bromazepam, camazepam, chlordiazepoxide, clobazam, chlorazepate, cothiazepam, cloxazolam, diazepam, ethyllofazepam, fluzopameptam Frutoprazepam, halazepam, ketazolam, lorazepam, loxapine, medazepam, methaclazepam, mexazolam, nordazepam, oxazepam, oxazolam, pinazepam, prazepam and tofisopam; carbamates such as cyclalbamate, emylcamate, probamate Others, for example, Alpiden, Ben Kutamin, captodiamine, chlormezanone, Echihokishin, Furuorezon, glutamic acid, hydroxyzine, Mekuroraruurea, main phenoxy salon, Okisanamido, phenazine glycolate Doll, Surikuron
17. Calcium regulators such as calcifediol, calcitonin, calcitriol, clodronic acid, dihydrotaxosterol, elcatonin, etidronic acid, ipriflavone, pamidronic acid, parathyroid hormone and teriparatide acetate
18. Cardiotonic agents such as acephylline, acetyl digititoxin, 2-amino-4-picoline, anrinone, benfurosyl semisuccinate, bucladecin, cerberoside, camfotamide, combaratoxin, simarin, denopamine, deslanoside, digitaline, digitalis, digitoxin , Digoxin, dobutamine, dopamine, dopexamine, enoximone, erythrofrein, phenalkamine, guitarin, gitoxin, glycosamine, heptaminol, hydrastinine, ibopamine, lanotodises, metamibum, milrinone, neriifolin, oleandrin, ouabaline, Prosilaridin, resibehogenin, silalene, silarenin, strophanthin, sulmazole, theobromine and xamotero
19. Chelating agents such as deferodimine, sodium dithiocarb, sodium disodium edetate, disodium edetate, sodium edetate, trisodium edetate, penicillamine, trisodium calcium pentenoate, pentectinic acid, succimale and trientine
20. Dopamine receptor agonists such as bromocriptine, dopexamine, fenoldopam, ibopamine, lisuride, naxagolide and pergolide
21. Enzyme inducer (liver), eg flumesinol
22. Estrogens: Non-steroidal estrogens such as benzestrol, bropaloestrol, chlorotrianisene, dienestrol, diethylstilbestrol, diethylstilbestrol dipropionate, dimestrol, phosfestol, hexestrol, meta Lenstril and metestrol; and steroidal estrogens such as colpolmon, conjugated estrogen hormone, equilenin, equilin, estradiol, estradiol benzoate, 17β-cypionate estradiol, estriol, estrone, ethinyl estradiol, mestranol, mexestrol, mita Trienediol, clobetasone butyrate, quinestradiol and quinestrol
23. Glucocorticoids, such as 21-acetoxyprefunenolone, arclomethasone, algestone, amicinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, brobetazone, crocortron, clopredonol, corticosterone, cortisone, cortibazole, deflazacort, Desonide, Desoxymethazone, Dexamethasone, Diflorazone, Diflucortron, Difluprednate, Enoxolone, Fluazacort, Fluchloronide, Flumethasone, Flunisolide, Fluocinolone Atonide, Fluocinonide, Fluocortin Butyl, Flucortron, Fluperolone acetate, Fluperolone acetate Fluprednidone, fluprednisolone, fluland lenolide, formocortal, harshi Nido, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone phosphate, 21-hydrocortisone sodium succinate, hydrocortisone tebutate, madipredone, medorizone, meprednisone, methiol prednisolone, mometasone flanate, parameterzone, predonical Bait, prednisolone, 21-diethylaminoacetate prednisolone, sodium prednisolone phosphate, sodium prednisolone succinate, 21-m-sulfobenzoate prednisolone sodium, 21-stearoylglycolate prednisolone, tebutonic acid prednisolone, 21-trimethylacetate prednisolone, prednisone, Prednival, prednylidene, 21-diethylaminoacetic acid Down, thixotropic Col tar, Torianshinoron, birds Ann Shino Ron acetonide, birds Ann Shino Ron Veneto acetonide and birds Ann Shino Ron hexacetonide
24. Mineralcorticoids such as aldosterone, deoxycorticosterone, deoxycorticosterone acetate and fludrocortisone
25. Monoamine oxidase inhibitors, such as deprenyl, iproclozide, iproniazide, isocarboxazide, moclobemide, octomoxine, pargyline, phenelzine, phenoxypropazine, pivalylbenzhydrazine, prodipine, troxatone and tranylcypromine
26. Muscle relaxants (skeletal), for example, afroqualon, alcuronium, atracurium besylate, baclofen, benzocamine, benzoquinonium chloride, C-carevacine, carisoprodol, chlormezanone, chlorphenesin carbamate, chlorproetadine, cloxoxazone, Kuraray, cyclalbamate, cyclobenzaprine, dantrolene, decamethonium bromide, diazepam, eperisone, fazazinium bromide, flumetramide, galamine triethiodide, hexacarbacolin bromide, hexafluorenium bromide, idrosilamide, methyl laurexium sulfate, leptodactillin, Memantine, mefenesin, mefenoxalon, metaxalone, metcarbamol, metocrine iodide, nimetazepam, orphenadrine, panclonide bromide , Fenprobamate, pheniramidol, pipeclium bromide, promoxolane, quinine sulfate, styramate, succinylcholine bromide, succinylcholine iodide, succinylcholine iodide, succinonium bromide, tetrazepam, thiocorchicoside, tizanidine, tolperisone, tubocurarine chloride, Vecuronium bromide, Pridinol mesylate and Zoxolamine
27. Narcotic antagonists such as amifenazole, cyclazocine, levalorphan, nazide, nalmufene, nalorphine, narolphine dinicotinate, naloxone and naltrexone
28. Progestogens, for example, allylestrenol, anagandone, chlormadinone acetate, dermadinone acetate, demegestone, desogestrel, dimethisterone, didrogesterone, ethisterone, ethinodiol, flurogestone acetate, guestden, caprolate guestnolone, haloprogesterone, 17-hydroxy-16-methyleneprogesterone , 17α-hydroxyprogesterone, caproic acid 17α-hydroxygesterone, linestrenol, medrgestone, medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethinodolyl, norgesterone, norgestimate, norgestrel, norgestrienone, norbinisterone, penta Guestron, progesterone, promegestone, ki Ngestrone and Trengestone and their esters
29. Vasodilators (coronary arteries), e.g., amotrifen, bendazole, benfurosyl hemisuccinate, benzodiolone, croacidin, chromonal, clobenfurol, clonitrate, dilazep, dipyridamole, dropreniramine, efroxate, erythritol, erythritol tetranitrate, etaphenone, phengerelin, phlegreline, Phen, hexestrol bis (β-diethylaminoethyl ether), hexobenzine, itramine tosylate, kerin, lidofrazine, mannitol hexanitrate, medivazine, nicorandil, nitroglycerin, pentaerythritol tetranitrate, pentrinitrol, perhexiline, pimefilin, prenylamine, Propatyl nitrate, pyridophylline, trapidyl, trichromyl, trimetazidine, li Acid trolnitrate and bisnadine and peripheral vasodilators such as aluminum nicotinate, bamethane, bencyclane, betahistine, bradykinin, brobincamine, buhoniod, bufuromezil, butalamine, cetiezil, cyclonicate, cinepazide, cinnarizine, cyclandrate, diisopropylamine dichloramine , Eledoisin, phenoxydil, flunaricin, heronicate, ifenprodil, inositol niacate, isoxyspurine, kallidin, kallikrein, moxycilite, nafuronyl, nicametate, nicergoline, nicofuranose, nicotinyl alcohol, nilidrin, pentifylline, pentoxyphyllin, pentoxyphyllin Protaglandin E1, slotoctyl and xanthinal niacinate
30. Benzodiazepine antagonists such as flumazenil
31. Bronchodilators: Ephedrine derivatives such as albuterol, bambuterol, vitorterol, carbuterol, clenbuterol, chlorprenalin, dioxededrine, ephedrine, epinifrine, eprodinol, etafedrine, ethyl norepinephrine, fenoterol, isotoprenaline, proetherol Renol, N-methylephedrine, pyrbuterol, procaterol, protokyol, reproterol, limiterol, soterenol, terbutaline and tulobuterol; quaternary ammonium compounds such as methylbebonium sulfate, curtropium bromide, ipratropium bromide and oxitropium bromide; xanthine Derivatives, for example, acefylline, acefylline Perazine, ambuphylline, aminophylline, bamifilin, choline theophylline, doxophilin, daphylline, enprofilin, etamiphilin, etophylline, guaytylin, proxyphylline, theobromine, 1-theobromine acetic acid and theophylline; and others such as, for example, fencepyrido, medivadin, methoxyphe Namin and Tretkinol
32. Other incontinence treatments such as oxybutynin, osteoporosis treatments such as risedronate, antihistamines such as ketofetin acetate, diabetes treatments such as tolbutamide, and ventilation treatments such as colchicine
Etc. These can be used in combination of two or more as required.

  In this invention, an organic liquid component can be contained as a component (D) in an adhesive composition. Addition of liquid component (D) reduces pain and skin irritation when peeling adhesive tape for skin application or transdermal absorption preparation from the skin surface, and improves drug diffusibility by plasticizing the adhesive In some cases, it may contribute to improving the release of a drug on the skin surface.

  Although it does not specifically limit as liquid component (D) used for this invention, It has compatibility with each component and what can melt | dissolve and disperse | distribute uniformly in an adhesive layer is preferable.

As such a liquid component (D),
a) Polyhydric alcohols such as ethylene glycol, diethylene glycol, dipropylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, butanediol, triethylene glycol and glycerin b) Oils and fats such as olive oil, camellia oil, soybean oil, castor oil and lanolin c) Fatty acids such as oleic acid d) Polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan Tetraoleate, polyoxyethylene lauryl ether, polyoxyethylene laurate, sorbitan monooleate, sorbitan trioleate, Liquid surfactants such as rubitan sesquioleate, e) methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate, methyl stearate, methyl oleate, ethyl laurate, ethyl myristate, Ethyl oleate, isopropyl myristate, isopropyl palmitate, butyl palmitate, isostearyl palmitate, isostearyl palmitate, octyl palmitate, octyl stearate, octyldodecyl myristate, isotridecyl myristate, diisopropyl adipate, octyl palmitate , Octyl stearate, diethyl sebacate, caprylic glyceride, pelargonic glyceride, capric glyceride, triethyl citrate, tributyl acetyl citrate F) Hydrocarbons such as liquid paraffin, squalane and squalene g) Ethanol, ethyl acetate, dimethyl sulfoxide, isosorbitol, dimethyl decyl sulfoxide, methyl octyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl Examples thereof include organic solvents such as pyrrolidone and dodecylpyrrolidone. These organic liquid components can be used by mixing one or more kinds as necessary.

  Among the organic liquid components, those that do not contain a compound containing at least one element selected from nitrogen, sulfur, phosphorus, tin, and lead as constituent elements are preferably used from the viewpoint of suppressing the inhibition of formation of the pressure-sensitive adhesive composition. It is done. A preferred liquid component is a fatty acid ester because of its excellent drug diffusibility.

  Content of these liquid components (D) is 0.001-2.0 with respect to the weight 1 of a polymer (A), Preferably it is 0.001-1.5. When the content of the liquid component (D) is out of this weight ratio, practical skin adhesion and low skin irritation cannot be obtained, and the release of the drug is not sufficient.

  The pressure-sensitive adhesive composition for forming the pressure-sensitive adhesive layer may contain components other than the above (A) to (D). These components include pressure-sensitive adhesives, tackifiers, adhesion-imparting agents, storage stabilizers for compound (B), and other components.

As an adhesive,
a) Natural rubber, styrene-butadiene rubber (SBR), polyisoprene rubber, polyisobutylene rubber, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-isobutylene -Natural rubber or synthetic rubber such as styrene block copolymer (SIBS) b) Silicon rubber c) Acrylic copolymers such as acrylic acid ester, (meth) acrylic acid- (meth) acrylic acid ester copolymer d) Starch acrylate, polyacrylic acid, sodium polyacrylate, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMCNa), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), methyl vinyl ether maleic anhydride Polymers, sodium alginate, propylene glycol alginate, pectin, xanthan gum, xanthan gum, locust bean gum, guar gum, gum arabic Roh junk emissions include hydrophilic polymers such as sodium hyaluronate. These pressure-sensitive adhesive components can be mixed in an appropriate combination of one or more if necessary.

  Tackifiers and tackifiers include phenol resins, modified phenol resins, terpene phenol resins, xylene phenol resins, cyclopentadiene-phenol resins, xylene resins, petroleum resins, phenol-modified petroleum resins, rosin ester resins, low molecular weight polystyrene Resin, terpene resin and the like. When these are used to improve the adhesive properties, they may be used alone or in combination of two or more. The amount of the tackifier and the adhesion promoter used is preferably 10 to 100 parts by weight, more preferably 15 to 50 parts per 100 parts by weight of the total amount of the polymer (A) and the compound (B). Parts by weight. If the amount used is too large, the moisture permeability of the pressure-sensitive adhesive layer decreases, which is not preferable.

Examples of storage stabilizers for compound (B) include compounds containing aliphatic unsaturated bonds, organic phosphorus compounds, organic sulfur compounds, nitrogen-containing compounds, tin-based compounds, and organic peroxides. Storage stabilizer suppresses conversion of hydrosilyl group (Si-H group) to Si-OH group in compound (B) (due to standing for a long time or mixing of moisture), improving pot life of coating From the viewpoint of suppressing the formation inhibition of the pressure-sensitive adhesive composition, among the above storage stabilizers, a compound containing at least one element selected from nitrogen, sulfur, phosphorus, tin, and lead as a constituent element Those which do not contain are preferably used. The blending amount of the storage stabilizer is preferably 10 ⁻⁶ to 10 ⁻¹ mol with respect to 1 mol of the total amount of hydrosilyl groups contained in the pressure-sensitive adhesive composition due to the compound (B).

  The pressure-sensitive adhesive composition for forming the pressure-sensitive adhesive layer may contain a water-soluble organic polymer or a water-absorbing polymer for improving the water resistance, sweat resistance, water absorption, etc. of the pressure-sensitive adhesive layer. Furthermore, other plasticizers, softeners, fillers, pigments, surfactants, ultraviolet absorbers, antioxidants, antibacterial agents, and the like may be blended. At this time, it is preferable not to use an organic solvent, but the use thereof is not denied.

  The pressure-sensitive adhesive layer in the transdermal absorption preparation of the present invention is formed by curing the above-described pressure-sensitive adhesive composition. Here, the curing means that a hydrosilylation reaction is performed between the polymer (A) and the compound (B) by heating. Examples of the curing conditions include leaving at 40 to 180 ° C. for 1 to 60 minutes. If it is desired to complete the curing, it may be further left at 40 to 80 ° C. for several days.

  The viscosity at the time of curing is preferably 10 to 1000 Pa · s. This viscosity can be controlled by the ratio of the amounts of the components (A) to (C) and the kind and amount of the storage stabilizer for the compound (B) described above.

  In addition, a plurality of pressure-sensitive adhesive layers may be laminated if at least one pressure-sensitive adhesive composition layer containing a physiologically active substance is present. The method for laminating the pressure-sensitive adhesive layer on the support is not particularly limited. For example, a method in which the pressure-sensitive adhesive composition is applied to one surface of the support and then cured under the above conditions, or a release agent is applied in advance. A method of bonding the support after the adhesive composition is coated on the prepared sheet (release sheet) and cured. As the release agent, various release agents such as silicone, olefin and fluorine are known and can be used as appropriate. Of these, olefin-based and solvent-free addition-curable silicone-based release agents are preferable from the viewpoint of ensuring cost and releasability.

  The thickness of the pressure-sensitive adhesive layer is not particularly limited, and may be, for example, 10 to 5000 μm.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the examples, and various applications are possible without departing from the technical idea of the present invention. is there.

(Synthesis of polymer A)
An oxypropylene polymer glycol having a number average molecular weight of 3000 was obtained by a polymerization method using caustic alkali. According to the method of Synthesis Example 1 of JP-A-5-117521, propylene oxide was polymerized using a double metal cyanide complex catalyst (zinc hexacyanocobaltate) using the oxypropylene polymer glycol as an initiator, and the number average molecular weight 28,000 polymers were obtained. The polymer is converted to an allyl group using a 28% methanol solution of sodium methylate and allyl chloride, and then desalted and purified to have approximately two allyl group ends in one molecule. A polyoxyalkylene polymer (Polymer A) was obtained. The allyl terminal group amount of the obtained polymer was 0.12 mmol / g.

(Synthesis of Compound B)
In the presence of a platinum catalyst, 0.6 equivalent of α-methylstyrene of the total hydrosilyl group amount is added to methyl hydrogen silicone represented by the following formula (4) (wherein x is an average of 5), and 1 molecule A compound (compound B) having an average of 2.5 hydrosilyl groups therein was obtained. The hydrosilyl group content of this compound was 3.2 mmol / g.

（実施例１）「粘着剤組成物に含有される生理活性物質に窒素、イオウ、リン、スズ、鉛を構成元素に含まない経皮吸収製剤」
重合体（Ａ）１００重量部に対して、化合物（Ｂ）を２．３重量部、生理活性物質としてケトプロフェンを５重量部加えて、ヒドロシリル化触媒である白金−１，３−ジビニル−１，１，３，３−テトラメチルジシロキサン錯体（３重量％白金イソプロパノール溶液）０．１重量部、マレイン酸ジメチル０．０３重量部を十分に混合して粘着剤組成物を得た。このときの（Ｃ）の触媒量は重合体（Ａ）のアルケニル基の総量１モルに対し、１．２５×１０^−３モルに相当する。この粘着剤組成物を室温にしてシリコーン剥離処理を施した剥離紙の処理面上に、硬化後の厚みが５０μｍになるように塗工して、１３０℃で５分間硬化させて粘着剤層を形成した。次に硬化した粘着剤層の上に、支持体として透湿性ポリウレタンシート（（株）シーダム製ＤＳＵ−２１４−ＣＤＢ、３０μｍ）（坪量３５ｇ／ｍ２）を１２０℃で５ｋｇ／ｃｍ２、速度２ｍ／ｍｉｎの条件にてラミネートした。このようにして、経皮吸収製剤を得ることができた。

(Example 1) “Percutaneous absorption preparation containing no physiologically active substances nitrogen, sulfur, phosphorus, tin, or lead as constituent elements in the adhesive composition”
To 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and 5 parts by weight of ketoprofen as a physiologically active substance are added, and platinum-1,3-divinyl-1, which is a hydrosilylation catalyst, A pressure-sensitive adhesive composition was obtained by sufficiently mixing 0.1 part by weight of 1,3,3-tetramethyldisiloxane complex (3% by weight platinum isopropanol solution) and 0.03 part by weight of dimethyl maleate. At this time, the catalyst amount of (C) corresponds to 1.25 × 10 ⁻³ mol with respect to 1 mol of the total amount of alkenyl groups of the polymer (A). The pressure-sensitive adhesive composition was coated on the treated surface of the release paper that had been subjected to silicone release treatment at room temperature so that the thickness after curing was 50 μm, and cured at 130 ° C. for 5 minutes to form a pressure-sensitive adhesive layer. Formed. Next, on the cured pressure-sensitive adhesive layer, a moisture-permeable polyurethane sheet (DSU-214-CDB, manufactured by Seadam Co., Ltd., 30 μm) (basis weight 35 g / m 2) as a support is 5 kg / cm 2 at 120 ° C., and a speed of 2 m / m 2. Lamination was performed under the condition of min. In this way, a percutaneous absorption preparation could be obtained.

(Example 2) "Percutaneously absorbable preparation containing any one of nitrogen, sulfur, phosphorus, tin and lead as a constituent element in a physiologically active substance contained in an adhesive composition"
To 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and 5 parts by weight of lidocaine as a physiologically active substance are added, and platinum-1,3-divinyl-1, which is a hydrosilylation catalyst, 1.0 part by weight of 1,3,3-tetramethyldisiloxane complex (3% by weight platinum isopropanol solution) and 0.03 part by weight of dimethyl maleate were sufficiently mixed to obtain a pressure-sensitive adhesive composition. At this time, the catalyst amount of (C) corresponds to 1.25 × 10 ⁻² mol with respect to 1 mol of the total amount of alkenyl groups of the polymer (A).
The pressure-sensitive adhesive composition was brought to room temperature, coated on the treated surface of the release paper subjected to the silicone release treatment so that the thickness after drying was 50 μm, and dried at 130 ° C. for 5 minutes. After that, it was transferred to a moisture-permeable polyurethane sheet (same as in the above example) as a support to obtain a transdermal absorption preparation.

(Comparative Example 1) “Percutaneously absorbable preparation containing any of nitrogen, sulfur, phosphorus, tin and lead as a constituent element in a physiologically active substance contained in an adhesive composition”
To 100 parts by weight of the polymer (A), 2.3 parts by weight of the compound (B) and 5 parts by weight of lidocaine as a physiologically active substance are added. (C) Platinum-1,3-divinyl as a hydrosilylation catalyst A pressure-sensitive adhesive composition was obtained by sufficiently mixing 0.1 part by weight of -1,1,3,3-tetramethyldisiloxane complex (3% by weight platinum isopropanol solution) and 0.03 part by weight of dimethyl maleate. At this time, the catalyst amount of (C) corresponds to 1.25 × 10 ⁻³ mol with respect to 1 mol of the total amount of alkenyl groups of the polymer (A). The pressure-sensitive adhesive composition was coated on the treated surface of release paper that had been subjected to silicone release treatment at room temperature so that the thickness after curing was 50 μm and heated at 130 ° C. for 5 minutes. Could not be formed and a transdermal absorption preparation could not be obtained.

(Comparative Example 2)
100 parts by weight of an acrylic copolymer obtained by copolymerizing 65 parts by weight of 2-ethylhexyl acrylate, 30 parts by weight of 2-methoxyethyl acrylate, and 5 parts by weight of acrylic acid is dissolved in 200 parts by weight of toluene and homogeneous. An adhesive solution was prepared. This solution was mixed so as to be 5 parts by weight of ketoprofen with respect to 100 parts by weight of the acrylic copolymer, applied to the release sheet subjected to the release treatment so that the thickness after drying was 50 μm, After drying for 5 minutes, the composition was transferred to a moisture-permeable polyurethane sheet (same as in the above example) as a support to obtain a transdermally absorbable preparation.

(Skin irritation)
The transdermal absorption preparation cut to a width of 20 mm was applied to the back of the volunteer, and a roller having a weight of 1 kg was reciprocated once for pressure bonding. After 6 hours, the percutaneously absorbable preparation was peeled off, and the amount of exfoliated corneum was measured using the peeled percutaneously absorbable preparation. That is, the sample peeled from the back of the volunteer is immersed in keratin staining solution (GentianViolet 1%, BrilliantGreen 0.5%, distilled water 98.5%) manufactured by Wako Pure Chemical Industries, Ltd. for about 30 minutes to stain the skin keratin. went. Thereafter, the sample was thoroughly washed with distilled water and then dried for 24 hours. The pressure-sensitive adhesive layer surface of the dried sample was observed using a microscope, image analysis was performed, and the keratin exfoliated area ratio was obtained.

上記結果より、これまでの粘着剤に比較して皮膚刺激性が小さく、十分な量の生理活性物質を含有させることが出来る経皮吸収製剤を提供することが明らかである。

From the above results, it is clear that a percutaneous absorption preparation can be provided that has a skin irritation smaller than that of conventional adhesives and can contain a sufficient amount of a physiologically active substance.

Claims (10)

In a skin patch in which a pressure-sensitive adhesive composition layer comprising a polyether polymer having a siloxane bond is formed on a support, at least one of the pressure-sensitive adhesive composition layers contains a physiologically active substance, and A mixture comprising the polymer (A), the compound (B) and the catalyst (C) is cured, and the total amount of the catalyst (C) is 5 with respect to 1 mol of the total amount of alkenyl groups in the polymer (A). A transdermally absorbable preparation characterized by being at least 10 ⁻⁸ mol.
(A) Polyether polymer having at least one alkenyl group at the terminal (B) Compound having 1 to 10 hydrosilyl groups in the molecule (C) Hydrosilylation catalyst   The percutaneous absorption preparation according to claim 1, wherein the physiologically active substance contains any one of nitrogen, sulfur, phosphorus, tin and lead as a constituent element. The percutaneous absorption preparation according to claim 1 or 2, wherein the total amount of the catalyst (C) is 5 x 10 ^-3 mol or more per 1 mol of the total amount of alkenyl groups of the polymer (A). The pressure-sensitive adhesive composition layer further comprises
(D) The transdermally absorbable preparation according to any one of claims 1 to 3, which is obtained by curing a mixture containing an organic liquid component.   The percutaneously absorbable preparation according to claim 1, wherein the polyether polymer of the polymer (A) is polyoxypropylene.   The total amount of hydroxyl groups of the compound (B) is 0.4 to 4 moles per mole of the total amount of alkenyl groups of the polymer (A).   The percutaneous absorption preparation according to claim 1, wherein the hydrosilylation catalyst (C) is a platinum-vinylsiloxane complex.   The percutaneous absorption preparation according to claim 1, wherein the liquid component (D) is a fatty acid ester.   The percutaneous absorption preparation according to claim 1, wherein the content ratio of the polymer (A) and the liquid component (D) is 1.0: 0.001 to 1.0: 1.5. (A) Polyether polymer having at least one alkenyl group at the terminal on the support (B) Compound having 1 to 10 hydrosilyl groups in the molecule (C) Hydrosilylation catalyst and optionally ( D) A composition comprising an organic liquid component contains a physiologically active substance and then cured to form an adhesive composition layer, wherein the composition for transdermal absorption according to claims 1 to 9 is produced. Method.