WO2008044336A1

WO2008044336A1 - Crystal-containing adhesive preparation

Info

Publication number: WO2008044336A1
Application number: PCT/JP2007/001104
Authority: WO
Inventors: Takaaki Terahara; Kazunosuke Aida; Yasunari Michinaka; Akio Takeuchi; Naoyuki Uchida
Original assignee: Hisamitsu Pharmaceutical Co., Inc.
Priority date: 2006-10-11
Filing date: 2007-10-11
Publication date: 2008-04-17
Also published as: JPWO2008044336A1; JP5243254B2

Abstract

It is intended to provide an adhesive preparation which makes it possible to transdermally supply a drug sustainedly over at least 24 hours. Namely, an adhesive preparation having a pressure-sensitive adhesive layer on one face of a support, wherein the pressure-sensitive adhesive layer contains more than 5% by mass, preferably more than 5% by mass but less than 15% by mass, of a drug in a molten state and in a crystalline state and the drug in a crystalline state contained in the pressure-sensitive adhesive layer is distributed in a smaller amount on the surface of the pressure-sensitive adhesive layer to be adhered to the skin than in the support side of the pressure-sensitive adhesive layer.

Description

Specification

Crystal-containing patch

Technical field

[0001] The present invention relates to a patch containing a drug in a dissolved state and a crystalline state in an adhesive layer. Furthermore, the present invention relates to a patch that has excellent adhesion to the skin and can be continuously absorbed from the skin at a high absorption rate even in the state where drug crystals are precipitated in the adhesive layer.

Background art

[0002] The technology of a transdermal absorption preparation that absorbs a drug contained in an adhesive layer through the skin is one of useful drug delivery systems for administering a drug for the treatment of a disease. The formulation has been devised. In a patch that is a typical percutaneous absorption preparation, the drug supplied into the body from the preparation depends on the concentration gradient between the drug concentration dissolved in the adhesive layer and the drug concentration on the skin surface. If only a small amount of drug can be dissolved in the adhesive layer because it moves through the skin tissue, the absorption rate will decrease and it will be difficult to obtain a sufficient therapeutic effect. When the drug is consumed and the concentration gradient cannot be maintained, the absorption rate is lowered and the therapeutic effect is not sustained. For this reason, in order to maintain good percutaneous absorption of the drug over a long period of time and maintain the therapeutic effect of the absorbed drug, more drug is present in the adhesive layer in the dissolved state. However, it is necessary to maintain a sufficient concentration.

However, drugs with low saturation solubility in the adhesive layer limit the amount of drug that can be dissolved, thus increasing the absorption rate and increasing the drug concentration necessary to maintain absorption over a long period of time. It was difficult to maintain in the adhesive layer.

[0003] Under such a background, as one of means for continuously supplying a drug from the skin, a technique for incorporating the drug so as to be equal to or higher than the saturation solubility of the adhesive layer has been developed. . For example, the fiber collection provided between the adhesive layer and the support film A drug-containing base material layer made of a coalescence is dispersed in a solid state and unevenly distributed, and the adhesive layer contains a transdermal absorption preparation containing the drug in a dissolved state (see Patent Document 1), chronic bronchitis, When the content ratio of the crystal-type mouthpiece is 0.1 to 10 in the plaster layer containing allobuterol, which is a therapeutic agent for bronchial asthma, etc. Skin resorbable preparation (see Patent Document 2), coronary vasodilator isosorbide dinitrate (melting point 70 ° C) containing at least 1.5 times the saturated solubility of the adhesive and recrystallized, melting point 50 ~ Dissolve drugs with a saturation solubility of 1.2 times or more in adhesives such as transdermal patches (see Patent Document 3) and acrylic copolymers containing recrystallized particles at 60 ° C. Percutaneous absorbability that is recrystallized and contains recrystallized particles of almost uniform size Formulation (refer to Patent Document 4), crystal mixed percutaneous absorption preparation that has been subjected to aging for a long time at low and high temperatures in order to deposit recrystallized particles in the adhesive uniformly and stably (Patent Document) (See 5).

However, in these technologies, the crystals are uniformly dispersed in the adhesive layer, and the crystals are deposited even on the surface of the adhesive layer, that is, the part that adheres to the skin and mucous membrane, so that the drug is completely dissolved in the adhesive layer. Compared to the case, the adhesive strength tends to decrease, and the applied state of the preparation to the skin surface tends to be insufficient, resulting in decreased adhesion to the skin and mucous membranes, and as a result, drug absorption does not continue for a long time. There was an inconvenience. In addition, as a method of unevenly distributing crystals in the pressure-sensitive adhesive layer, a method of providing a drug-containing base material layer between the pressure-sensitive adhesive layer and the support film (see Patent Document 1), and a low temperature for controlling the precipitation of crystals. Have been proposed (see Patent Documents 4 and 5). However, in these methods, a special layer for holding the drug is provided, or the aging is performed for a long time. There was a problem that the process became complicated, such as requiring an (aging) process.

-On the other hand, donepezil, which is an acetylcholinesterase inhibitor, is used as a therapeutic agent for dementia of Alhaima type 1, and tandospirone, which is a serotonin 5 HT 1 A receptor agonist, is used as an antidepressant. Used force When dementia or psychiatric disease progresses, it becomes difficult to take orally. In such cases, parenteral administration such as transdermal administration has been attracting attention as an administration form. For example, Patent Document 6 proposes a preparation for parenteral administration of donepezil hydrochloride as an ointment or suppository, and Patent Document 7 discloses a transdermal substance contained in an adhesive composition in a dispersed state. Absorption formulations have also been proposed. Although these drugs are expected to be effective as plasma preparations with plasma concentrations similar to those obtained by oral administration, they need to be replaced in order to continue treatment over a long period of time. There was a desire to provide a smaller area formulation.

[0005] Patent Document 1: Japanese Patent No. 2 6 9 7 1 9 1

Patent Document 2: Japanese Patent No. 2 7 5 3 8 0 0

Patent Document 3: Japanese Patent Application Laid-Open No. 6 3-30 0 8 8 18

Patent Document 4: JP-A-6 0-1 8 5 7 1 3

Patent Document 5: Japanese Unexamined Patent Publication No. 2 0 0 5 _ 3 5 0 3 7 3

Patent Document 6: Japanese Patent Laid-Open No. 11-3 1 5 0 1 6

Patent Document 7: WO 2 0 0 3/0 3 2 9 60

Disclosure of the invention

Problems to be solved by the invention

[0006] The present invention provides a patch in which a dissolved drug and a crystalline drug coexist in the adhesive layer, and suppresses a decrease in skin adhesive force caused by crystallization of the drug to a minimum. 2 It is an object to provide a patch capable of continuously supplying a drug from the skin for 4 hours or more.

Means for solving the problem

[0007] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a patch containing a drug in a pressure-sensitive adhesive layer in a dissolved state and a crystalline state is applied to the skin. It has been found that it is possible to produce a patch that shows good adhesive strength and that further improves the skin absorption rate of the drug even if the drug compounded in excess of the drug saturation solubility in the adhesive composition is present as crystals. It was.

[0008] That is, the present invention comprises a pressure-sensitive adhesive layer on one side of a support, and the pressure-sensitive adhesive layer is a five-layered material. A drug containing more than 5% by weight, preferably more than 5% by weight and less than 15% by weight in a dissolved state and in a crystalline state, and the crystalline drug in the adhesive layer is from the support side of the adhesive layer. The present invention also relates to a patch that is less distributed on the surface of the pressure-sensitive adhesive layer that adheres to the skin.

The present invention also relates to a patch in which no crystalline drug exists on the surface of the pressure-sensitive adhesive layer that adheres to the skin.

Furthermore, the present invention relates to a patch characterized in that in the pressure-sensitive adhesive layer, there are more drugs present in a crystalline state than drugs present in a dissolved state.

Furthermore, in the present invention, the drug contained in the pressure-sensitive adhesive layer is selected from the group consisting of donevezil, tandspirone, amproxol, and risperidone, and pharmaceutically acceptable salts thereof. The present invention relates to one or more types of patches, wherein the pressure-sensitive adhesive layer contains at least one tackifying resin selected from styrene-isoprene-styrene block copolymer and alicyclic saturated hydrocarbon or terpene resin. It relates to a patch to be used.

The present invention also relates to a patch wherein the blending ratio of the styrene-isoprene-styrene block copolymer and the tackifying resin contained in the pressure-sensitive adhesive layer is from 1: 1 to 1:10.

The present invention will be described more specifically as follows.

(1) In a patch having a pressure-sensitive adhesive layer on one side of a support, the pressure-sensitive adhesive layer contains 5 to 15% by mass of a drug in a dissolved state and a crystalline state with respect to the total weight of the adhesive layer. A patch in which the drug in a crystalline state in the pressure-sensitive adhesive layer is distributed less on the surface of the pressure-sensitive adhesive layer on the side that adheres to the skin than the support side of the pressure-sensitive adhesive layer.

(2) The patch according to the above (1), wherein the amount of the drug contained in the pressure-sensitive adhesive layer is 2 to 25 times the saturated solubility in the pressure-sensitive adhesive layer.

(3) The patch according to (1) or (2), wherein the amount of the drug present in a crystalline state in the pressure-sensitive adhesive layer is 5 to 10% by mass with respect to the total mass of the pressure-sensitive adhesive layer. (4) The patch according to any one of (1) to (3), wherein no drug in the crystalline state is present on the surface of the pressure-sensitive adhesive layer that adheres to the skin.

(5) The patch according to any one of (1) to (4), wherein the drug present in a crystalline state in the pressure-sensitive adhesive layer is greater than the drug present in a dissolved state in the pressure-sensitive adhesive layer.

(6) The drug contained in the adhesive layer is at least one selected from the group consisting of donevezil, tandospirone, amproxol, and risperidone, and pharmaceutically acceptable salts thereof. The patch according to any one of (1) to (5) above.

(7) The patch according to (6), wherein the drug contained in the adhesive layer is donevezil, tandospirone, risperidone, or a pharmaceutically acceptable salt thereof.

(8) The patch according to any one of (1) to (7), wherein the pressure-sensitive adhesive layer contains a styrene-isoprene-styrene block copolymer.

(9) The adhesive agent according to any one of (1) to (8), wherein the adhesive layer contains a styrene-isoprene-styrene block copolymer and an adhesion-imparting resin.

(10) The patch according to (9), wherein the tackifying resin is at least one selected from an alicyclic saturated hydrocarbon resin or a terpene resin.

(1 1) The above (9), wherein the blending ratio of the styrene-isoprene-styrene block copolymer and the tackifier resin contained in the pressure-sensitive adhesive layer is 1: 1 to 1:10.

The patch according to (1 0).

(12) The patch according to any one of (8) to (11), wherein the pressure-sensitive adhesive layer further contains at least one selected from pressure-sensitive adhesives made of polyisobutylene or an acrylic polymer.

(1 3) Any one of the above (8) to (12), wherein the pressure-sensitive adhesive layer further contains at least one plasticizer selected from the group consisting of liquid rubber, petroleum oil, and liquid fatty acid esters. The patch according to crab. (14) The patch according to (13), wherein the liquid rubber is liquid polybutene.

(15) The patch according to (13), wherein the petroleum oil is liquid paraffin.

(16) The patch according to (13), wherein the liquid fatty acid ester is isopropyl myristate.

(17) The pressure-sensitive adhesive layer further comprises at least one selected from the group consisting of fatty acids having 6 to 20 carbon atoms, esters of the fatty acids, amides of the fatty acids, pyrothiodecane, and propylene glycol fatty acid esters. The patch according to any one of (8) to (16), which comprises an absorption promoter.

(18) The patch according to any one of the above (1) to (17), wherein the adhesive strength measured with a peel measuring machine of the patch is 300 g / cm or more.

(19) The adhesive strength measured with a peel measuring machine is 300 g / cm to 700 g / cm.

The patch according to (18).

(20) The patch according to any one of (1) to (19), wherein the adhesive strength measured with a probe tack tester of the patch is 200 gf (gram weight) or more. (2 1) The patch according to (20), wherein the adhesive strength measured with a probe tack tester is 200 gf to 500 gf.

(22) The patch according to any one of (1) to (2 1), wherein an area to which the patch is applied is 5 to 40 cm ² .

(23) Dissolving the drug and the adhesive base in a solvent, coating the obtained solution on the release liner, drying and removing the solvent, and then bonding the support to this Said (1) ~

(22) A method for producing the patch according to any one of the above.

The invention's effect

In a conventional patch containing an excessive amount of drug, the amount of drug added is much higher than the saturated solubility of the drug in the adhesive layer, so crystals concentrate on the surface of the release liner side of the adhesive layer. It was deposited and could not be provided as a product. this On the other hand, in a patch having an adhesive layer containing 5 to 15% by mass, preferably 5 to 10% by mass of a drug in a dissolved state and a crystalline state with respect to the total weight of the adhesive layer of the present invention. It was found that a phenomenon that crystals hardly precipitate at the interface between the pressure-sensitive adhesive layer and the release liner was observed. Although the detailed reason why such a phenomenon occurs is not necessarily clear, in the adhesive layer of the adhesive patch of the present invention, the crystalline drug in the adhesive layer adheres to the skin rather than the support side of the adhesive layer. This is because there is less distribution on the surface of the pressure-sensitive adhesive layer. That is, this is because the density of the drug in the crystalline state in the pressure-sensitive adhesive layer is directed from the surface of the pressure-sensitive adhesive layer adhering to the skin to the surface adhering to the support (the surface opposite to the surface of the pressure-sensitive adhesive layer). As a result, the density of the crystalline drug changes stepwise, continuously, discontinuously, or irregularly, and as a result, the crystalline drug in the adhesive layer adheres to the skin rather than the support side of the adhesive layer. In the surface of the pressure-sensitive adhesive layer on the side to be used, a state where it is distributed less is included. Further, when no crystal is present on the surface of the pressure-sensitive adhesive layer that adheres to the skin, the drug in a crystalline state may be present in any distribution state inside the pressure-sensitive adhesive layer. In addition, in the case of a conventional patch containing an excessive amount of drug, even if no crystal deposition is observed immediately after production, it is stored at room temperature (25 ° C) for a long time (from 3 days to about 2 weeks) Crystals are intensively deposited on the surface of the pressure-sensitive adhesive layer on the release liner side, but such a phenomenon does not occur in the patch of the present invention. In particular, when donepezil or tandospirone or a pharmaceutically acceptable salt thereof is used as a drug, these phenomena become remarkable. Furthermore, when donepezil or tandospirone or a pharmaceutically acceptable salt thereof is used as a drug, the solubility of these drugs in acrylic copolymers is high, so that these drugs are excessively added. In order to mix | blend, the drug exceeding 15 mass% must be mix | blended with respect to the total weight of an adhesive layer, and the phenomenon like the patch of this invention will not arise. Therefore, in the present invention, considering the solubility of the drug in the adhesive, an appropriate adhesive for the drug is selected, and the compounding ratio of the drug with respect to the total mass of the adhesive layer is 5 to 15% by mass, preferably 5 to 1. According to the present invention, the pressure-sensitive adhesive is 0% by mass. Despite the fact that drugs with saturation solubility or higher are included in the crystalline state in the drug layer, they have sufficient adhesive strength to adhere to the skin for 24 hours, and have excellent drug absorbability and drug efficacy. It can be used as a patch for imparting durability to the skin. Furthermore, it is possible to provide a patch that exhibits a stable therapeutic effect in the treatment of diseases and the like and can be used safely as a pharmaceutical product.

BEST MODE FOR CARRYING OUT THE INVENTION

[001 1] Hereinafter, preferred embodiments of the present invention will be described in detail.

The configuration of the patch of the present invention is not particularly limited, but for example, a form including a single adhesive layer shown in FIG. 1 is preferable. That is, the support surface is provided with a drug-containing pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer surface is covered with a release liner layer that is peeled and removed when the preparation is used.

[0012] Since the drug contained in the adhesive layer of the patch of the present invention is blended in the base at a concentration equal to or higher than the saturation solubility, the drug in a dissolved state and a crystalline state exist together. That is, in the adhesive layer of the patch of the present invention, a drug that cannot be dissolved because it exceeds the saturation solubility exists in a crystalline state. Furthermore, the patch of the present invention can improve the drug absorption rate depending on the amount of the drug even in the concentration range exceeding the saturation solubility of the drug in the adhesive layer. The drug in the crystalline state may be either a crystal that does not dissolve in the manufacturing process of the patch, or a crystal that is recrystallized after dissolving in the manufacturing process, and the effect of the present invention does not change in both cases. The drug saturation solubility in the pressure-sensitive adhesive layer in the present invention is preferably from 0.1 to 5% by mass, and more preferably from 0.5 to 4.5% by mass. If the amount is less than 0.1% by mass, there are few drugs in the dissolved state, so that the drug is not sufficiently absorbed from the skin, or the dissolved drug tends to be consumed and the sustainability of absorption tends to be impaired. On the other hand, when the saturation solubility is 5% by mass or more, it is necessary to mix a large amount of drug in the pressure-sensitive adhesive layer in order to cause the drug to exist in a crystalline state, which is not only efficient but also drug absorption. Sustainability tends to be insufficient.

[0013] That is, the drug contained in the patch of the present invention is not particularly limited as long as it is effective for treatment. Although not specified, it can be blended in an amount of 5 to 15% by mass with respect to the total mass of the pressure-sensitive adhesive, preferably an amount exceeding 5% by mass to an amount less than 15% by mass, more preferably 5.1 to 1 4. 9 mass ^{0 / o, 5. 5~ 1} 4. 5 mass ⁰ / o, or 6-1 4 mass ⁰ / o, more preferably from 6 1 0% by weight or 8-1 0% by weight. If the amount of the drug is less than 5% by mass, the absorbed amount of the drug is insufficient and a sufficient therapeutic effect cannot be obtained continuously. On the other hand, if it exceeds 15 mass%, the physical properties of the preparation will be adversely affected. Further, the drug concentration contained in the pressure-sensitive adhesive layer can be blended at 1 to 150 times the saturated solubility in the pressure-sensitive adhesive layer, but more preferably 2 to 25 times.

[0014] In the present invention, the drug crystals present in the pressure-sensitive adhesive layer are adhesively applied to the skin even though they are uniformly dispersed in the pressure-sensitive adhesive base composed mainly of a hydrophobic polymer. Almost no precipitation occurs on the surface of the agent layer. Further, the drug crystals existing in the pressure-sensitive adhesive layer of the present invention are concentrated on the surface of the pressure-sensitive adhesive layer even when they are dissolved or melted once and become supersaturated and then recrystallized and dispersed in the pressure-sensitive adhesive layer. Precipitation is suppressed. For this reason, the patch of the present invention has sufficient adhesive strength to the skin as in the case of a soluble preparation in which no crystals exist in the adhesive layer, and the preparation peels off from the skin during the application. It is possible to continuously administer the drug from the skin for a period of at least 24 hours.

Next, in the patch of the present invention, there are fewer drug crystals distributed on the surface of the pressure-sensitive adhesive layer that adheres to the skin than the drug crystals distributed inside the pressure-sensitive adhesive layer (the support side of the pressure-sensitive adhesive layer). It is characterized by that. The surface of the pressure-sensitive adhesive layer as used herein refers to the pressure-sensitive adhesive layer side of the solid / solid interface existing at the boundary where the pressure-sensitive adhesive is in contact with the skin when the patch is applied to the skin. The adhesive strength of the pressure-sensitive adhesive decreases when it is precipitated. The patch of the present invention should have few crystals to such an extent that the pressure-sensitive adhesive strength does not decrease, and more preferably, the adhesive layer surface on the side that adheres to the skin. There are no crystals. If there are no crystals on the surface of the pressure-sensitive adhesive layer that adheres to the skin, the surface of the pressure-sensitive adhesive layer that adheres to the skin is a smooth flat surface with no irregularities at the optical microscope level. As observed.

The distribution state of the drug crystals on the surface of the pressure-sensitive adhesive layer can be evaluated based on an index representing the crystal precipitation state by observing the state of the drug crystals deposited on a predetermined region of the surface of the pressure-sensitive adhesive base with the naked eye or an optical microscope. it can. In addition, when a crystal is deposited on the surface of the adhesive layer, the adhesive strength of the patch decreases, and therefore, it can be evaluated by measuring the adhesive strength with a probe tack tester or a peel measuring instrument. The adhesive strength measured with the probe tack tester of the patch of the present invention is 200 gf (gram weight) or more, preferably 200 gf to 500 gf. The adhesive strength measured with a pill measuring machine is 300 gf. / cm or more, preferably 300 gf / cm to 1000 gf / cm, more preferably 300 gf / cm to 700 gf / cm. These adhesive forces can be relatively evaluated. For example, when the adhesive strength of the pressure-sensitive adhesive layer containing a drug at a concentration at which crystals do not precipitate in the pressure-sensitive adhesive layer, preferably the adhesive strength of the pressure-sensitive adhesive layer when containing no drug is 100%, 40% or more, preferably 45% or more, more preferably 50% or more, more than 60%, 70% or more, 80% or more Those having an adhesive strength of 85% or higher, an adhesive strength of 90% or higher, and an adhesive strength of 95% or higher are preferable.

Inside the pressure-sensitive adhesive layer, the drug crystals are distributed more than the surface on the side that adheres to the skin, and expressed as the concentration of the drug contained in the pressure-sensitive adhesive layer minus the saturation concentration, 2. 5 to 14.9% is contained as crystals, and more preferably 4.8 to 10%. 1 4. If it exceeds 9%, the cohesive strength of the adhesive base itself decreases, and there is a concern that it may cause cohesive failure after application to the skin. On the other hand, if it is less than 2.5%, when the patch is applied to the skin, the drug crystals are dissolved and absorbed, resulting in a shortage of drug in the preparation, and the absorption of the drug does not continue. There are no particular limitations on the type of drug that can be incorporated into the patch, as long as it is a drug that crystallizes in the adhesive beyond the saturation concentration. Specific examples include hypnotic sedatives (flurazebam, rilmazaphone, etc.) Antipyretic anti-inflammatory analgesics (Butol Phanolol, perisoxal, etc.) Excitement ■ Stimulant (methamphetamine, methylphenidate, etc.), Psychiatry and nerve agent (Cita mouth plum, flupoxamine, risperidone, etc.), local anesthetic (lidocaine, pro forcein, etc.) Urinary agents (such as oxiputinin), skeletal muscle relaxants (such as tizanidine, eperisone, pridinol), autonomic nerve agents (such as carpronium, neostigmine), anti-parkinsonian agents (pergolide, promocri) Puchin, trihexyphenidyl, amantadine, pramipexole, rovinirole, rotigotine, etc.), antihistamine

(Cremastine, diphenhydramine, etc.), bronchodilators (pro-powered terols, etc.), cardiotonic agents (isoprenalin, dopamine, etc.), coronary vasodilators (diltiazem, verapamil, etc.), peripheral vasodilators (dicamethate, trazoline, etc.), circulation Ring organ agents (flunarizine, dicardipine, benidipine, efonidipine, etc.), arrhythmic agents (propranolol, alprenolol, etc.), antiallergic agents

(Ketotifen, azelastine, etc.), antipruritic agents (betahistine, diphenide, etc.), serotonin receptor antagonist antiemetics (ondansetron, palonosetron, etc.), narcotic analgesics (morphine, fentanyl, etc.), non-sterolide Anti-inflammatory analgesics (ketoprofen, diclofenac sodium, etc.), antibiotics (erythromycin, chloramphenicol, etc.), sex hormones (progesterone, estradiol, etc.), coronary vasodilators (isosorbide nitrate, etc.), nootropics

(Donevezil, rivastigmine, etc.), expectorants (amproxol, etc.), and anti-anxiety drugs (tandospirone, buspirone, etc.). Among these, donevezil, tandospirone, amproxol, and risperidone are preferable, and particularly, risperidone and donepezil have a remarkable effect. As these drugs, pharmaceutically acceptable salts may be used, and molecular and salt drugs having different saturation concentrations in the adhesive may be mixed. In addition, these molecular and salt drugs can be used even if they have different crystal forms.

The pharmaceutically acceptable salt of the drug in the patch of the present invention is not particularly limited. In the case of a basic drug, it may be an inorganic salt or an organic salt, and may be an inorganic salt. Hydrochloric acid, odorous acid, kaiic acid, etc. It is used well. Examples of organic salts include acetic acid, citrate, fumaric acid, maleic acid, etc. Among these, acetate is preferably used. In the case of an acidic drug, an alkali metal salt is exemplified, and among them, a sodium salt is preferably used.

In the present invention, when the drug form is a pharmaceutically acceptable acid addition salt, it is desirable to contain a basic compound in the adhesive layer, and the basic compound used is basic. Low molecular compounds containing nitrogen (eg, triethanolamine, diisopropanolamine, diethanolamine, etc.), low molecular compounds containing basic nitrogen (eg, aminoalkyl methacrylate copolymer _ E, polyvinylacetyl jetylamino) Acetate, polyvinyl pyridine, etc.), basic alkali metal salts (sodium acetate, potassium acetate, sodium borate, sodium carbonate, trisodium citrate, sodium silicate, etc.), sodium hydroxide, potassium hydroxide, etc. Among them, triethanolamine, diisopropyl Panolamine, diethanolamine, aminoalkyl methacrylate copolymer_E, polyvinylacetate dimethylaminoacetate, sodium acetate, sodium silicate, sodium hydroxide, etc. are preferred, especially triethanolamine, amino Alkyl methacrylate copolymer_E, sodium acetate, and sodium hydroxide are preferred. These compounds act on a chemically acceptable acid addition salt of a drug by a plasticizer in a solution or a pressure-sensitive adhesive layer in the manufacturing process of the drug product, thereby generating a drug molecular type and / or an ion-pair compound. It is also possible to improve skin permeability.

Examples of the solvent used in this case include solvents used in the preparation of preparations such as lower alcohol, toluene, ethyl acetate, hexane, and cyclohexane, and plasticizers contained in the adhesive layer of the preparation. Examples of solvents and plasticizers include methanol, ethanol, isopropanol, toluene, ethyl acetate, cyclohexane, liquid paraffin, liquid polybutene, and isopropyl myristate. Among these, methanol, ethanol, and myristate Propyl and liquid paraffin are preferred.

For the pressure-sensitive adhesive layer of the present invention, as described above, if the drug crystals on the surface of the pressure-sensitive adhesive layer that adheres to the skin are in a distribution state that is less than the drug crystals inside the pressure-sensitive adhesive layer, what kind of prescription is used? For example, a rubber polymer or an acrylate ester polymer can be used as the adhesive base.

Rubber polymers include styrene-isoprene-styrene block copolymer (hereinafter abbreviated as S I S), isoprene rubber, polyisobutylene (hereinafter abbreviated as P I B), styrene-butadiene-styrene block copolymer.

(Hereinafter abbreviated as SBS), styrene-butadiene rubber (hereinafter abbreviated as SBR), polysiloxane and the like. Of these hydrophobic polymers, S I S and P I B are preferable, and S I S is particularly preferable.

Examples of acrylate-based polymers include 2_ethyl hexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2_ethyl hexyl methacrylate, and the like. The copolymer is not particularly limited as long as it contains at least one monomer of a (meth) acrylic acid derivative and is copolymerized, but preferably contains 50% or more of 2-ethylhexyl acrylate. Specific examples of adhesives include acrylic acid listed as adhesives in the Pharmaceutical Additives Dictionary 2000 (edited by the Japan Pharmaceutical Additives Association).

■ Acrylic acid octyl ester copolymer, acrylic acid 2_ethylhexyl ■ Vinylpyrrolidone copolymer solution, acrylic acid ester ■ Vinyl acetate copolymer, acrylic acid 2_ethylhexyl ■ Methacrylic acid 2_ethylhexyl ■ Copolymers of dodecyl methacrylate, methyl acrylate ■ acrylic acid 2_ethyl hexyl copolymer resin emulsion, acrylic polymer alkanolamine liquid and other adhesives, DURO- TAK acryl adhesive series _ (Such as 87-4098, 87-2194, 87-9301, 87-2979, 87-2074, etc.), Eudragit series (Higuchi Shokai), etc. can be used. Two or more of these hydrophobic polymers may be used in combination, and the blending amount based on the mass of the entire composition of these high molecules is determined in consideration of the formation of the pressure-sensitive adhesive layer and sufficient permeability. It is preferably 5 to 90% by mass, more preferably 10 to 70% by mass, and particularly preferably 10 to 50% by mass.

[0020] The pressure-sensitive adhesive layer of the patch of the present invention may contain a tackifying resin in order to supplement the adhesive strength to the skin. Examples of tackifying resins that can be used include rosin derivatives (eg, rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythryl! Rosin ester of rosin), alicyclic saturated hydrocarbon resins ( For example, Alcon P 100, Arakawa Chemical Industries), aliphatic hydrocarbon resin (for example, Quinton B 1700, Nippon Zeon), terpene resin (for example, Clearon P-1 125 Yashara Chemical), resin maleate, etc. Can be mentioned. Among them, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin are preferable, and the use of alicyclic saturated hydrocarbon resin and terpene resin constitutes an adhesive base. It is easy to obtain a patch having such a structure because it dissolves in the amorphous part of the amorphous polymer or semi-crystalline polymer and raises the glass transition temperature to induce drug crystallization inside the adhesive layer. . The blending amount of the tackifying resin based on the entire composition of the pressure-sensitive adhesive layer is 5 to 70% by mass, preferably 5% in consideration of sufficient adhesive strength as a patch and irritation to the skin at the time of peeling. ˜60 mass%, more preferably 10 to 50 mass%.

[0021] Further, a styrene-isoprene-styrene block copolymer is preferably used as the adhesive base, and an alicyclic saturated hydrocarbon (eg, Alcon P100) or a combination of terpene resins is preferably used as the tackifier resin. In the case where the ratio of SIS in the pressure-sensitive adhesive layer to the tackifier resin is 1: 1 to 1:10, preferably 1: 3 to 1: 9 A preparation having a crystal distribution as described above can be suitably constructed, and has a sufficient adhesive force to the skin and is a patch preparation with excellent skin permeability of the drug. Can do.

[0022] The pressure-sensitive adhesive layer of the present invention may contain a plasticizer as necessary. Plasticizers that can be used include petroleum oils (eg, paraffinic process oil, liquid paraffin, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oils (eg, olive oil) Oil, camellia oil, castor oil, tall oil, laccase oil), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, liquid polybutene, liquid isoprene rubber), Liquid fatty acid esters (eg, isopropyl myristate, hexyl laurate, jetyl sebacate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, salicylate glycol, propylene glycol, dipropylene glycol Toriasechin, Kuen acid triethyl, Kurotami tons, etc. can be mentioned up. Among these, liquid paraffin, liquid polybutene, isopropyl myristate, decyl sebacate, and hexyl laurate are preferable, and liquid polybutene, isopropyl myristate, or liquid baraffine is particularly preferable.

Two or more of these components may be used in combination, and the blending amount based on the entire composition of the adhesive layer of such a plasticizer will maintain sufficient permeability and sufficient cohesive strength as a patch preparation. In consideration of the total, it can be blended in an amount of 10 to 70% by mass, preferably 10 to 60% by mass, and more preferably 10 to 50% by mass.

[0023] In addition to the above, the pressure-sensitive adhesive layer of the present invention may further contain an absorption enhancer. As the absorption enhancer that can be used, any of the compounds that have been conventionally recognized to absorb absorption in the skin. For example, a saturated or unsaturated fatty acid having 6 to 20 carbon atoms, a saturated or unsaturated fatty alcohol having 2 to 10 carbon atoms, or an ester of a saturated or unsaturated fatty acid having 6 to 20 carbon atoms. Amides of saturated or unsaturated fatty acids having 6 to 20 carbon atoms, ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers (above saturated or unsaturated Either Well, it can be either cyclic or straight-chain branched), lactic acid esters, acetate esters, monoterpene compounds, sesquiterpene compounds, Azone, Azone Derivatives, Pyrothiodecane, Glycerin fatty acid esters, Propylene glycol fatty acid esters, Sorbitan fatty acid esters (Span series) Polysorbate series (Tween series), Polyethylene glycol fatty acid esters, Polyoxyethylene hardened castor oil series (HCO) Type), polyoxyethylene alkyl ethers, sucrose fatty acid esters, vegetable oils and the like. Specifically, strong prillic acid, cabric acid, cabronic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol , Isostearyl alcohol, cetyl alcohol, methyl laurate, hexyl laurate, diethanolamide laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, key Cinnamic acid, Key Methyl cinnamate, Cresol, Cetyl lactate, Lauryl lactate, Ethyl acetate, Pill acetate, Geraniol, Thymol, Eugenol, Terbineoyl, I -men! , Porneolol, d-limonene, isoeugenol, isoporneol, nerol, dI-camphor, glycerin monocaprylate, glycerin mono-force plate, glycerin monolaurate, glycerin monooleate, sorbitan monolaurate, sucrose Monolaurate, Polysorbate 20, Propylene glycol, Propylene glycol monolaurate, Polyethylene glycol monolaurate, Polyethylene glycol monostearate, Polyoxyethylene lauryl ether, HCO_60, Pyrothiodecane, Olive oil, etc. In particular, oleic acid, oleyl alcohol, lauryl alcohol, isostearyl alcohol, lauric acid diethanol amide, glycerin mono force prelate, glycerin mono force Rate, glycerin Monooree Ichito, sorbitan monolaurate, propylene glycol one Rumonora Ureates, polyoxyethylene lauryl ether, and pyrothiodecane are preferred.

Two or more types of such absorption enhancers may be used in combination. Considering sufficient permeability as a patch preparation and irritation to the skin such as redness and edema, the entire composition of the adhesive layer Is preferably 0.1 to 20% by mass, more preferably 0.05 to 10% by mass, and particularly preferably 0.1 to 5% by mass. be able to.

[0024] The support layer of the patch of the present invention is not particularly limited as long as it is suitable for supporting the pressure-sensitive adhesive layer, but a stretchable or non-stretchable layer can be used. For example, cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, aluminum sheet, or a composite material thereof can be used. When the adhesive layer is laminated on the support, it may or may not have water vapor permeability. In the present invention, even a closed patch (having almost no water vapor permeability) does not decrease the skin permeability of the drug.

Further, the thickness of the support of the patch of the present invention is preferably 20 m to 80 m.

If it is less than 2 O m, it may be difficult to apply the patch to the skin, and if it exceeds 80 m, the flexibility is impaired, and it tends to cause a decrease in adhesion and primary skin irritation. is there.

Furthermore, the preparation area of the patch of the present invention is preferably 5 to 40 cm ² . If it is less than 5 cm ² , the absorbed amount of the drug will be insufficient and a sufficient therapeutic effect will not be obtained, and if it exceeds 40 cm ² , the end of the patch will easily peel off when applied for a long time, or the support This is because there is a tendency that wrinkles are likely to occur.

[0025] The patch of the present invention can be produced, for example, by the following method.

For example, an adhesive base containing a drug is melted by heat, applied to a release liner or support, and then bonded to a support or release paper to obtain this agent. In addition, the adhesive base component containing the drug is dissolved in an organic solvent such as toluene, hexane, ethyl acetate, lower alcohol, cyclohexane, etc., and is spread on a release liner or support to remove the solvent. After drying and removing at a predetermined temperature, it is possible to obtain this agent by laminating it with a support or a release liner. More specifically, the adhesive component having a drug saturation solubility of 0.1 to 5% by mass is mixed with a lower alcohol or toluene so that the concentration of the drug with respect to the total mass of the adhesive is 5 to 15% by mass. Dissolve in organic preparations such as ethyl acetate, hexane, and hexane and disperse uniformly in an adhesive base composed mainly of a hydrophobic polymer, and then extend it onto a release liner or support. After the organic solvent is dried at a predetermined temperature and almost completely removed, the adhesive patch of the present invention can be produced by pasting it with a support or a release liner. The thickness of the pressure-sensitive adhesive layer containing the drug thus obtained is preferably 20 _m to 150 Um, more preferably about 50 m to 120 m, but is not particularly limited as long as it is not extremely < There is no.

Brief Description of Drawings

[0026] [Fig. 1] Fig. 1 illustrates a cross section of the patch of the present invention.

FIG. 2 is a graph showing the results of measuring the skin permeation rate at 24 hours after applying the patches of Examples 2 and 3 of the present invention and the patch of Comparative Example 7.

Further, the features of the present invention will be described in detail with reference to examples. These can be variously modified without departing from the technical idea of the present invention. In the examples, “%” means mass%.

Example 1

[0028] A patch having the following composition containing 9.0% of donepezil as a drug was produced.

■ S I S: Tackifying resin = 1: 1

Donepezil 9.0%

SIS 2 1. 0% Polyisobutylene 1 4. 9% Alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 2 1. 0% Liquid paraffin 27.1% Oleic acid 7.0%

After 100% donevezil, oleic acid and fluid / raffine were well pulverized and mixed, S I s, polyisobutylene, tackifying resin and toluene were added and stirred to obtain a solution. The solution thus obtained was applied onto a release liner, and then the solvent was removed by drying to form a 1 O Om thick adhesive layer. A polyester film (S cot c h p ak 9732) as a support was bonded to this and cut into a predetermined size to obtain a patch. The patch was enclosed in a moisture-proof packaging bag and stored at room temperature for 2 weeks before being subjected to the test described below.

Example 2

A patch with the following composition containing 9.0% of donepezil hydrochloride as a drug was produced.

S I S: Tackifying resin = 1 3

Donepezil hydrochloride 9.0%

S I S 1 1. 8% Polyisobutylene 1 2. 6% Alicyclic saturated hydrocarbon resin (Alcon P—100) 35.4% Liquid paraffin 1 8. 9% Sodium acetate 5.3% Oleic acid 7.0%

100% A patch was obtained by the same production method as in Example 1.

Example 3

A patch having the following composition containing 9.0% of donepezil as a drug was manufactured.

S I S: Tackifying resin = 1: 5

Donepezil 9.0% SIS 8.7% Polyisobutylene 1 0. 3% Alicyclic saturated hydrocarbon resin (Alcon P—100) 43. 3% Liquid paraffin 21.7% Oleic acid 7.0%

100% A patch was obtained by the same production method as in Example 1.

Example 4

[0031] A patch having the following composition containing 10% of tandospirone as a drug was produced.

■ S I S: Tackifying resin = 1: 3.4

Tandospirone 1 0. 0% S I S 1 4.4%

DURO-TAK 87-4098 1 0. 0% Alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 48. 6% Liquid paraffin 1 2.0% Propylene glycol monolaurate 5.0%

100% A patch was obtained by the same production method as in Example 1.

Example 5

[0032] A patch containing the following composition containing donepezil 10.0% as a drug was produced.

■ S I S: Tackifying resin = 1: 6.3

Donepezil 1 0. 0%

S I S 7.7%

DURO-TAK 87-4098 1 2. 0% Terpene resin (Clearon P— 1 25) 48.6% Liquid paraffin 1 6.7% Glycerol monolaurate 5.0% 100% A patch was obtained by the same production method as in Example 1.

Example 6

An adhesive patch having the following composition containing 10.0% of tandospirone citrate as a drug was produced.

■ S I S: Tackifying resin = 1: 9

Candonic tandospirone 1 0.0% S I S 5.4%

DURO-TAK 87-4098 1 0. 0% Terpene resin (Clearon P— 1 25) 48.6% Liquid paraffin 1 2.0% Acetic acid 4.7% Sodium acetate 4.3% Pyrothiodecane 5.0%

100% A patch was obtained by the same production method as in Example 1.

[Comparative Example 1]

A patch having the following composition was produced in the same manner as in Example 1.

Donepezil 1 5. 0%

D u ro-T A K 87-251 6 69. 0% Polyisobutylene 1 0.0. 0% Palmitic acid 3.0% Cetyl palmitate 3.0%

1 00%

[Comparative Example 2]

Donepezil 25. 0%

D uro-T ak 87-251 6 70.5% Palmitic acid 3.0% Diethanolamide laurate 1.5%

1 00%

[0036] [Comparative Example 3]

Donepezil 1 5. 0%

D u ro-T ak 87-251 6 79.5% Cetyl palmitate 3.0% Benzyl alcohol 2.0% Diethanolamide laurate 0.5%

1 00%

[0037] [Comparative Example 4]

Tandospirone 20. 0%

D u ro-T ak 87— 21 94 65. 0% Isopropyl myristate 1 5. 0%

1 00%

[0038] [Comparative Example 5]

S IS: Tackifying resin = 1: 2.4

(No donepezil 0.0%) SIS 1 8.5% Polyisoptylene 3% Alicyclic saturated hydrocarbon resin (Arcon P_1 00) 44.2% Liquid paraffin 27.0% Oleic acid 3.0%

00%

[0039] [Comparative Example 6] A patch having the following composition was produced in the same manner as in Example 1.

S IS: Tackifying resin = 1: 2.4

Donepezil 0.3% S 1 S 1 18.4% Polyisobutylene 3% Alicyclic saturated hydrocarbon resin (Arcon P_ 1 00) 44.0% Liquid paraffin 27.0% Oleic acid 3.0%

1 00%

[Comparative Example 7]

S IS: Tackifying resin = 1: 2.4

Donepezil hydrochloride 5.0% SIS 1 6.0% Polyisoptylene 6.8% Alicyclic saturated hydrocarbon resin (Alcon P_ 1 00) 38.8% Liquid paraffin 27.4% Sodium acetate 3.0% Sorbitan monolaurate 3.0%

1 00%

[Test Example 1]

Hairless mouse skin permeation test

The back skin of the hairless mouse was peeled off, and the dermis side was placed on the receptor layer side, and attached to a flow-through cell (5 cm ² ) in which 37 ° C hot water was circulated around the outer periphery. The patches obtained in Examples 1 to 6 and Comparative Examples 1 to 7 were affixed to the stratum corneum side, and physiological saline was used for the receptor layer every 5 hours at a rate of 5 ml / hr (hr). Sampling was performed for up to 24 hours. The receptor solution obtained every hour is measured accurately and the drug concentration is measured by high performance liquid chromatography. The permeation rate per hour was calculated, and the skin permeation rate per unit area in a steady state was determined. The results are shown in Table 1 below.

[Test Example 2]

Adhesion test

The adhesive strengths of the patches obtained in Examples 1 to 6 and Comparative Examples 1 to 4 were measured with a probe tack tester and a peel measuring machine, respectively. The results are shown in Table 1 below.

[Test Example 3]

Saturation solubility measurement test

In each of the Examples and Comparative Examples, preparations with different drug amounts were prepared and then stored at room temperature for 2 weeks. The drug crystals in each preparation were visually confirmed. From the results, the drug concentration of the drug product in which drug crystals were confirmed was defined as the saturated drug solubility in each of the bases of Examples and Comparative Examples. The results are shown in Table 1 below.

[Test Example 4]

Observation of crystals inside the adhesive layer

The state of drug crystals precipitated in the adhesive base was observed with the naked eye or an optical microscope to confirm the presence or absence of crystals. The results are shown in Table 1 below.

[Test Example 5]

Observation of crystals on the adhesive surface

The state of drug crystals precipitated in a predetermined area on the surface of the adhesive was observed with the naked eye or an optical microscope, and evaluated based on an index representing the next crystal precipitation state. The results are shown in Table 1 below.

○: Sparse crystal deposition is observed on the adhesive surface

X · ■ 'There is crystal precipitation on the adhesive surface 1

¾ «

秦 ^ t X…

In the patches of Comparative Examples 1 to 4, only the acrylic adhesive is used as the adhesive. Therefore, the solubility of the drug is large, and in order to compound the drug excessively, an amount of 15% by mass or more must be blended, and crystals are deposited on the surface of the pressure-sensitive adhesive layer on the release liner side, The effect of the present invention was not obtained. On the other hand, in Examples 4 to 6, an acrylic adhesive is used, but it is also used in conjunction with a SIS adhesive, which reduces the solubility of the drug, and the amount of the drug is 1 About 0% by mass is sufficient, and the effect of the present invention can be obtained.

Comparative Example 5 shows the adhesive strength when no drug is blended. The adhesive strength of the adhesives of the present invention shown in Examples 1 to 6 is somewhat reduced by the blending of the drugs. It was shown that it still retains sufficient adhesive strength. Comparative Example 6 is an example in which the amount of the drug is too small, and it can be seen that sufficient results cannot be obtained at the maximum skin permeation rate. Similarly, in Comparative Example 7, the adhesive strength slightly decreased with the addition of the drug, and crystal precipitation was observed inside the adhesive layer. However, when the amount of the drug was 5% by mass, the maximum skin permeation rate was sufficient. A good value was obtained. In addition, when stored at room temperature (25 ° C) for 2 weeks, crystals that were not observed immediately after production were observed on the surface of the release liner side of the adhesive layer.

[Test Example 5]

Hairless mouse skin permeation test

In the same manner as in Test Example 1, using the patch described in Examples 2 and 3 and the patch of Comparative Example 7, 1 hour, 3 hours, 5 hours, 7 hours, 9 hours After 11 hours, 11 hours, 13 hours, 15 hours, 17 hours, 19 hours, 21 hours, and 23 hours, skin permeation rates were measured.

The result is shown in figure 2. 2, the horizontal axis represents time (hour) and the vertical axis indicates skin permeation speed of ^{(g / cm 2 / hr)} . In Fig. 2, the black circle mark (book) indicates the case of the patch of Example 2, the black square mark (country) indicates the case of the patch of Example 3, and the white circle mark (◯) indicates the patch of Comparative Example 7. Each case of the agent is shown.

As a result, the patches of Examples 2 and 3 of the present invention can keep the skin permeation rate substantially constant from about 12 hours to 23 hours after the start of the test. However, the patch of Comparative Example 7 reached the maximum in about 9 — 11 hours after the start of the test, and then the skin permeation rate decreased, indicating that it was not persistent.

Also, the cumulative amount of transmission up to 24 hours later is

Patch 2 of Example 2; U g / _C m2,

Patch 289 of Example 3; U g / _C m2,

Patch 203 of Comparative Example 7; U g / cm ² ,

Met.

Industrial applicability

The present invention provides a patch that has sufficient adhesive strength to adhere to the skin for 24 hours, is excellent in skin absorbability of a drug, and has sustained drug efficacy. It exhibits a stable therapeutic effect by, is safe and useful as a pharmaceutical, and has industrial applicability.

Claims

The scope of the claims

[1] In a patch having an adhesive layer on one side of a support, the adhesive layer contains more than 5% by mass of a drug in a dissolved state and in a crystalline state, and the crystalline drug in the adhesive layer is adhesive An adhesive patch characterized by being distributed less on the surface of the pressure-sensitive adhesive layer on the side that adheres to the skin than on the support side of the adhesive layer.

[2] The patch according to claim 1, wherein no drug in a crystalline state is present on the surface of the pressure-sensitive adhesive layer that adheres to the skin.

[3] The patch according to claim 1 or 2, wherein in the pressure-sensitive adhesive layer, the drug present in a crystalline state is more than the drug present in a dissolved state.

[4] The drug contained in the adhesive layer is at least one selected from the group consisting of donepezil, tandospirone, ambroxol, and risperidone, and pharmaceutically acceptable salts thereof. The patch according to any one of claims 1 to 3.

[5] The pressure-sensitive adhesive layer contains at least one tackifying resin selected from the group consisting of a styrene-isoprene-styrene block copolymer, and an alicyclic saturated hydrocarbon and a terpene resin. The patch according to any one of Items 1 to 4 of the range.

[6] The ratio of the styrene-isoprene-styrene block copolymer and the tackifier resin contained in the pressure-sensitive adhesive layer is 1: 1 to 1:10. The patch according to crab.