JP2012219055A - Adhesive preparation and package of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an adhesive preparation capable of improving adhesiveness of an adhesive layer by controlling property of an adhesive surface of the adhesive layer, and resultantly obtaining a property having difficulty in exfoliation/fallout from the skin even when being stuck onto the skin for long hours.SOLUTION: A physical property of the adhesive layer is controlled so that a contact angle between the adhesive surface of the adhesive layer of this adhesive preparation and a water drop becomes ≥106°. The physical property of the adhesive layer can be controlled by using a hydrophobic adhesive, or by adjusting the water content of the adhesive preparation to be ≤1.0 wt.%.

Description

  The present invention relates to a patch preparation with improved adhesion and a package thereof.

  Patch preparations have many advantages such as the ability to avoid drug absorption from the gastrointestinal tract and the first-pass effect in the liver, ease of administration in patients who have difficulty taking oral drugs, and the effect of preventing forgetting to administer the drug. Excellent dosage form. In recent years, such advantages have been attracting attention, and various types of patch preparations have been developed.

  A patch preparation generally has an adhesive layer on at least one surface of a support. However, when the adhesive surface is affixed to the skin, there has been a problem of peeling and dropping when applied for a long time. is there. Although various attempts have been made to suppress such peeling and dropping by examining the composition of the pressure-sensitive adhesive layer, it has not yet reached a satisfactory level.

  Under such circumstances, not the composition of the pressure-sensitive adhesive layer but the physical properties of the pressure-sensitive adhesive surface have been studied. The following are mentioned as technical literature related to the examination of the physical properties of the adhesive surface.

  Japanese Unexamined Patent Application Publication No. 2007-131618 (Patent Document 1) discloses a transdermally absorbable preparation in which the contact angle between an adhesive surface of an adhesive layer and a nicotine droplet is 20 ° to 60 °. However, this document discloses an improvement in the impregnation of the nicotine into the pressure-sensitive adhesive layer, the adhesiveness of the pressure-sensitive adhesive layer is not considered at all, and regarding the contact angle between the pressure-sensitive adhesive layer and water, There is no disclosure or suggestion.

  On the other hand, Japanese Patent Application Laid-Open No. 2002-145663 (Patent Document 2) discloses a patch obtained by laminating a hydrous gel on a support having a contact angle between its surface and water droplets of 90 ° or less. . However, there is no disclosure about the relationship between the adhesive surface of the adhesive layer and the contact angle between water droplets.

JP 2007-131618 A JP 2002-145663 A

  In view of the above, the present invention improves the adhesiveness of the pressure-sensitive adhesive layer by controlling the physical properties of the pressure-sensitive adhesive layer of the pressure-sensitive adhesive layer. It is an object to provide a patch preparation that is difficult to perform.

  As a result of intensive studies to solve the above problems, the present inventors have determined that the physical properties of the pressure-sensitive adhesive layer are such that the contact angle between the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer of the patch preparation and water droplets is 106 ° or more. It has been found that the adhesiveness of the pressure-sensitive adhesive layer can be improved by controlling the pressure, and the present invention has been completed.

Thus, the present invention relates to the following [1] to [7].
[1] A patch preparation having a pressure-sensitive adhesive layer containing a drug and a pressure-sensitive adhesive on at least one surface of a support, the pressure-sensitive adhesive layer having a temperature of 23 ± 2 ° C. and a relative humidity of 60 ± 10%. A patch preparation in which the contact angle between the adhesive surface and the water droplet is 106 ° or more.
[2] The adhesive preparation according to [1] above, wherein the adhesive comprises a rubber-based adhesive.
[3] The rubber-based pressure-sensitive adhesive includes a rubber-based elastomer having a viscosity average molecular weight of 1,600,000 to 6,500,000 and a rubber-based elastomer having a viscosity average molecular weight of 40,000 to 85,000. The patch preparation according to [2] above.
[4] The patch preparation according to [1] above, wherein the moisture content of the patch preparation is 1.0% by weight or less.
[5] The adhesive preparation according to the above [1], wherein the pressure-sensitive adhesive layer contains crosslinked polyvinylpyrrolidone.
[6] The patch preparation according to [1] above, wherein the drug is a polar drug.
[7] A patch preparation package, wherein the patch preparation according to any one of [1] to [6] is packaged with a water-impermeable packaging material.

According to the present invention, the adhesive property of the pressure-sensitive adhesive layer can be improved by controlling the physical properties of the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer, that is, the contact angle between the pressure-sensitive adhesive surface and the water droplets to be a predetermined value or more. it can. As a result, it is possible to provide a patch preparation that does not easily peel off or fall off from the skin even when applied to the skin for a long time.
When the contact angle between the adhesive surface and the water droplet is reduced, the adhesive layer component tends to bleed out to the adhesive surface, and the adhesive layer component that bleeds out to the adhesive surface exists between the skin and the adhesive surface. Therefore, it is estimated that the adhesive strength is reduced.

It is a figure which shows the correlation with the contact angle of an adhesive surface and a water droplet, and adhesive force about the adhesive preparation of Examples 1-3 and Comparative Examples 1-4.

  In the following, preferred embodiments of the invention are shown, but the detailed description and specific examples are intended for illustrative purposes only and do not limit the scope of the invention. The following description of the preferred embodiments is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

  The patch preparation of the present invention has a pressure-sensitive adhesive layer containing a drug and a pressure-sensitive adhesive on at least one surface of a support, and the pressure-sensitive adhesive layer under the conditions of a temperature of 23 ± 2 ° C. and a relative humidity of 60 ± 10%. The contact angle between the adhesive surface and the water droplet is 106 ° or more.

  “Contact angle” is a physical property value that is an index of ease of wettability / hardness of a solid surface, and refers to an angle formed between a tangent of a droplet on a solid surface and the solid surface when the liquid is dropped on the solid surface. . The contact angle is generally measured using the θ / 2 method, and can be measured using a contact angle meter sold by Kyowa Interface Science Co., Ltd. or the like.

  When the contact angle is less than 106 °, the adhesive force of the adhesive surface is drastically reduced, and when the patch preparation is applied to the skin, it is difficult to ensure sufficient adhesion to the skin. The upper limit of the contact angle is not particularly limited, but is preferably 120 ° or less from the viewpoint of adhesion to human skin.

  In order to set the contact angle to 106 ° or more, it is necessary to make the adhesive surface of the adhesive layer difficult to wet. Examples of the influence on the wetness of the adhesive surface of the adhesive layer include the hydrophobicity of the adhesive layer and the moisture content of the patch preparation.

  In order to make the pressure-sensitive adhesive layer hydrophobic, it is preferable to use a hydrophobic pressure-sensitive adhesive as the pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer. As the hydrophobic adhesive, a rubber-based adhesive is preferable as will be described later. Moreover, it is preferable to make an adhesive layer contain an organic liquid component.

  Further, the moisture content of the patch preparation is preferably 1.0% by weight or less, and more preferably 0.9% by weight or less. Here, the moisture content (% by weight) of the patch preparation refers to the weight of the patch preparation (release liner) including the support, the pressure-sensitive adhesive layer, and the moisture weight in the patch preparation including the release liner, if present. Is included, and the weight is multiplied by 100. When the water content of the patch preparation exceeds 1.0% by weight, the contact angle between the water droplet and the adhesive surface tends to decrease. The lower limit is not particularly limited, but is preferably 0.1% by weight or more from the viewpoint of the stability of the patch preparation. Such control of the moisture content can be achieved by a method known per se. For example, this can be achieved by producing a patch preparation under low relative humidity conditions and packaging it with a water-impermeable packaging material. In order to control the water content more effectively, the patch preparation is packaged by a water-impermeable packaging material together with a desiccant to form a package, or a water-impermeable packaging containing a desiccant. It is preferable to package with a material and store in the package.

  The water content of the patch preparation is preferably controlled within the above range before being applied to the skin. In particular, when the patch preparation is packaged with a water-impermeable packaging material and contained in the package, the package is opened, and the patch preparation is taken out of the package, and then the skin is sufficiently short. It is desirable to affix to. The skin adhesiveness of the patch preparation is greatly affected by the initial adhesive force immediately after being applied to the skin. If the adhesive is first firmly adhered to the skin, then the moisture content of the patch preparation increases and the adhesive strength decreases. This is because sufficient adhesion to the skin tends to be maintained. This is considered to be because the adhesive surface of the patch preparation is adapted to the unevenness of the skin at the initial stage of the application, and an intermolecular force is generated, thereby exerting a physical anchor effect. If the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer is hydrophilic at the initial stage of skin patching, the adhesive surface does not become familiar with the unevenness of the skin, and the adhesive force of the patch preparation to the skin is very low.

  According to the present invention, by controlling the moisture content of the patch preparation to the above moisture content, a normal time until the patch preparation is taken out from the package and applied to the skin, for example, within 8 hours after opening the package, preferably If it is within 4 hours, the hydrophobicity of the adhesive surface of the patch preparation can be maintained, and it becomes possible to maintain good adhesion at the time of skin application.

  The support used in the present invention is not particularly limited, but the additive or drug contained in the pressure-sensitive adhesive layer penetrates the support and is lost from the back and does not cause a decrease in content. That is, a material in which these components are substantially impermeable is preferable. Specifically, polyester resins such as polyethylene terephthalate; polyamide resins such as nylon; vinyl resins such as polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer and ionomer resin; polytetrafluoroethylene, etc. Examples thereof include a film made of a fluorocarbon resin, a metal foil, or a laminate film thereof. In order to improve the adhesion (sticking property) with the pressure-sensitive adhesive layer, a laminate film of a non-porous film and a porous film made of the above materials is used as the support, and the pressure-sensitive adhesive layer is formed on the porous film side. It is preferable to do.

The porous film is not particularly limited as long as the anchoring property of the pressure-sensitive adhesive layer is good, and examples thereof include paper, woven cloth, unemployed cloth, mechanically perforated sheet, and the like, particularly paper, woven cloth, Nonwoven fabric is preferred. The thickness of the porous film is preferably about 10 μm to 500 μm in consideration of improvement of anchoring property and flexibility of the patch preparation. In the case of a thin patch preparation such as a plaster type or an adhesive tape type, the thickness is preferably about 10 μm to 200 μm. The woven or nonwoven fabric, be these basis weight and ^{5g / m 2 ~30g / m 2} , preferred in terms of anchor property improvement.

  The patch preparation of the present invention has an adhesive layer on at least one surface of the support. The pressure-sensitive adhesive layer contains a pressure-sensitive adhesive. The pressure-sensitive adhesive is not particularly limited as long as the contact angle of the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer can be adjusted to the above value, and is an acrylic pressure-sensitive adhesive, rubber-based pressure-sensitive adhesive, vinyl ether-based pressure-sensitive adhesive, vinyl ester-based pressure-sensitive adhesive. An adhesive, a polyester-type adhesive, etc. are mentioned, These are used individually or in combination of 2 or more types.

  From the viewpoint of skin adhesiveness, a hydrophobic pressure-sensitive adhesive is preferable as the pressure-sensitive adhesive in order to set the contact angle of the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer to 106 ° or more. Acrylic pressure-sensitive adhesives are hydrophobic and have a slight hydrophilicity, and when an adhesive layer is formed, many adhesives to the skin are good. However, since many have functional groups, when a drug is contained in the pressure-sensitive adhesive layer, it is necessary to design a patch preparation in consideration of its reactivity. Therefore, in the present invention, a rubber adhesive is preferably used from the viewpoint of drug stability.

  Examples of rubber-based pressure-sensitive adhesives suitable for the purpose of the present invention include elastomers of styrene-diene-styrene block copolymers (for example, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, etc.); Examples thereof include pressure-sensitive adhesives including rubber-based elastomers such as polyisoprene, polyisobutylene, polybutadiene, and silicone rubber, and these are used alone or in combination of two or more.

  Among these, a pressure-sensitive adhesive containing polyisobutylene as the rubber-based elastomer is preferable in consideration of the balance of pressure-sensitive adhesive properties, stability, and safety. A rubber-type elastomer can be used individually or in combination of 2 or more types according to the viscosity average molecular weight. In the following description, when a rubber-based pressure-sensitive adhesive is used, the rubber-based elastomer used indispensable is referred to as a first rubber-based elastomer, and the rubber-based elastomer further blended depending on the purpose is a second rubber-based elastomer and a third rubber-based elastomer. It is called an elastomer.

  The viscosity average molecular weight of the first rubber-based elastomer is not particularly limited, but is preferably 1,600,000 to 6,500,000, more preferably 2,000,000 to 6,000,000, still more preferably 2. , 500,000 to 5,500,000, most preferably 3,000,000 to 5,000,000. When the viscosity average molecular weight of the first rubber-based elastomer is 1,600,000 or more, the molecular chain is sufficiently long and complicatedly entangled, and the pressure-sensitive adhesive layer can easily hold a large amount of the organic liquid component. When the viscosity average molecular weight of the first rubber-based elastomer is 6,500,000 or less, it becomes easy to balance the adhesive physical properties such as tack when combined with other components.

Here, the “viscosity average molecular weight” is a flow time measured at 20 ° C. using a capillary 1 with an Ubbelohde viscometer, and a Staudinger index (J ₀ ) is calculated using the following Schulz-Blaschke equation (equation 1). determined, then the following mark Houwink - are those calculated by substituting the J ₀ value to the Sakurada equation (2 expression).

  If desired, the pressure-sensitive adhesive may further contain a second rubber-based elastomer having a viscosity average molecular weight of 40,000 to 85,000. By using a second rubber-based elastomer that is more fluid than the first rubber-based elastomer in combination, the first rubber-based elastomer and other pressure-sensitive adhesive layer components are prevented from separating, and the pressure-sensitive adhesive layer Appropriate flexibility can be imparted.

  In addition, when the viscosity average molecular weight of the second rubber-based elastomer is less than 40,000, the affinity between the second rubber-based elastomer and the other adhesive layer component is high, and the other adhesive layer component and the first The affinity with the rubber-based elastomer may be reduced, and these may be separated. On the other hand, when the viscosity average molecular weight of the second rubber-based elastomer exceeds 85,000, the first rubber-based elastomer and the second rubber-based elastomer have high affinity, and the other pressure-sensitive adhesive layer component and the second rubber The affinity with the base elastomer may be reduced, and these may be separated.

  The type of the second rubber-based elastomer is independently selected from those similar to the first rubber-based elastomer. The first rubber-based elastomer and the second rubber-based elastomer may be the same or different, but it is preferable to use the same type from the viewpoint of the compatibility of both.

  The ratio of the second rubber-based elastomer in the pressure-sensitive adhesive layer is not particularly limited, but is preferably 50 to 200 parts by weight, more preferably 50 to 150 parts by weight with respect to 100 parts by weight of the first rubber-based elastomer. Parts by weight, most preferably in the range of 90 to 110 parts by weight. If the amount of the second rubber-based elastomer is less than 50 parts by weight, only the characteristics of the first rubber-based elastomer may appear. On the other hand, if the amount of the second rubber-based elastomer is more than 200 parts by weight, the cohesive force of the pressure-sensitive adhesive layer may be reduced.

  Moreover, when mix | blending a 2nd rubber-type elastomer in order to further strengthen the cohesive force of an adhesive layer, it is preferable to use the rubber-type elastomer whose viscosity average molecular weight is higher than a 1st rubber-type elastomer. If desired, a third rubber-based elastomer may be added to the adhesive.

  The total content of the pressure-sensitive adhesive including the first and second elastomers is not particularly limited, but is preferably 30% to 92.5% by weight, more preferably 50%, based on the total weight of the pressure-sensitive adhesive layer. % By weight to 90% by weight, most preferably 70% by weight to 80% by weight.

  The pressure-sensitive adhesive can contain a tackifier as necessary. Examples of such tackifiers include polybutenes, rosin resins, terpene resins, petroleum resins, coumarone resins, and the like. These may be used alone or in combination of two or more. it can. The content of the tackifier relative to the total weight of the pressure-sensitive adhesive is preferably in the range of 30% to 90% by weight, more preferably 50% to 70% by weight. By setting the content of the tackifier to 30% by weight or more, good tack performance can be obtained. On the other hand, when it exceeds 90% by weight, the pressure-sensitive adhesive layer tends to break down, which is not preferable.

  As described above, the hydrophobic rubber-based pressure-sensitive adhesive is preferable in the present invention. However, as described later, when an organic liquid component having a certain degree of polarity is included, the compatibility with them is insufficient. There is a possibility. In such a case, in order to ensure compatibility with the organic liquid component, it is preferable that the pressure-sensitive adhesive layer contains crosslinked polyvinylpyrrolidone. Cross-linked polyvinyl pyrrolidone can be obtained by cross-linking polymerization of N-vinyl-2-pyrrolidone in the presence of a suitable catalyst.

  An organic liquid component having a relatively high solubility of a drug having a polarity tends to have a high polarity and consequently tends to ooze out from the pressure-sensitive adhesive layer. The cross-linked polyvinyl pyrrolidone acts to help retain the first organic liquid component in the pressure-sensitive adhesive layer. In addition, since crosslinked polyvinylpyrrolidone has a hydrophilic group, it is presumed to retain moisture when the water content in the patch preparation increases. In such a case, it is presumed that the retention capacity for the lipophilic organic liquid component already retained in the cross-linked polyvinyl pyrrolidone tends to decrease.

  The above-mentioned crosslinked polyvinylpyrrolidone is commercially available under trade names such as “Collidon CL”, “Collidon CL-M” (BASF Japan Ltd), “Polyplastone” (ISP Japan Ltd), and “Crospovidone” (Gokyo Sangyo). Are available. In consideration of the effect on the added amount, the one having the smallest particle diameter is effective because it has the largest surface area, and “Koridon CL-M” is preferable from this viewpoint. The amount of the crosslinked polyvinylpyrrolidone is preferably in the range of 5 to 40 parts by weight, more preferably 10 to 20 parts by weight with respect to 100 parts by weight of the pressure-sensitive adhesive.

  The pressure-sensitive adhesive layer contains a drug. Such a drug is not particularly limited, and a drug that can be administered to a mammal such as a human through its skin, that is, has a polarity capable of transdermal absorption is preferable. Specific examples of such drugs include general anesthetics, sleep / sedation, antipsychotics, antidepressants, mood stabilizers, psychostimulants, anxiolytics, antidepressants, migraine Therapeutic drugs, antiemetics, antipruritic drugs, cerebral circulation / metabolism improving drugs, nootropics, local anesthetics, skeletal muscle relaxants, autonomic nerve drugs, antispasmodics, Parkinson's disease drugs, antihistamines, antiallergic drugs , Cardiotonic, antiarrhythmic, diuretic, antihypertensive, vasoconstrictor, coronary vasodilator, peripheral vasodilator, angina treatment, hyperlipidemia, respiratory stimulant, antitussive expectorant, bronchi Dilators, bronchial asthma drugs, hormone drugs, peptic ulcer drugs, analgesics / antipyretic drugs, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, hemostatic drugs, drugs for the treatment of gout / hyperuricemia, diabetes treatment Drugs, antirheumatic drugs, antineoplastic drugs, antibacterial drugs, antifungal drugs, antiviral drugs, Antiparasitics, drugs for purulent diseases, drugs for parasitic skin diseases, drugs, and the like non smoking adjuvant.

  The concentration of the drug in the pressure-sensitive adhesive layer is not particularly limited as long as it can exert the effect of the drug and does not impair the pressure-sensitive adhesive properties of the pressure-sensitive adhesive, but is preferably 0 with respect to the total weight of the pressure-sensitive adhesive layer. 0.01% by weight to 5% by weight, more preferably 0.2% by weight to 3% by weight. If the amount is less than 0.01% by weight, the therapeutic effect may not be sufficient. If the amount is more than 5% by weight, skin irritation may occur or the drug may precipitate in the adhesive layer.

  The present invention is more advantageous when a drug having polarity is used. Here, since a drug having a polarity has a polar group in its chemical structure, it is difficult to dissolve in a hydrophobic adhesive layer an amount sufficient to administer an effective amount to a subject. Means a drug. More specifically, the partition coefficient (n-octanol / water), that is, logPow is 0.5 to 5.5 and the melting point is 100 ° C. or higher. In order for the effects of the present invention to be fully exerted, the logPow of the drug having polarity is preferably 1.0 to 5.0, more preferably 3.0 to 5.0. The upper limit of the melting point of the drug is not particularly limited, but is practically preferably 300 ° C. or lower.

  When the log Pow of the drug is less than 0.5, the drug has high polarity, and even with the present invention, it may not be possible to prevent the crystal of such a highly polar drug from precipitating in the adhesive layer. . On the other hand, when the log Pow of the drug exceeds 5.5, since the drug is highly hydrophobic, the possibility that such drug crystals precipitate in the adhesive layer is small, and the usefulness of the present invention is not so great. .

  Here, “logPow” of a drug is an index representing the hydrophilicity or hydrophobicity of the drug, and “OECD GUIDELINE FOR THE TESTING OF CHEMICALS 107, Adopted by the Council on 27th July 1995, Partition Coefficient (n-octanol / water), Shake FIask Method "means the value measured for each drug. The logarithmic base of logPow is 10. In this embodiment, logPow is calculated using logP calculation software “Cache (registered trademark, manufactured by Fujitsu)”. In the measurement (calculation) of logPow, the chemical structural formula of the drug is input to the calculation software, and the measurement (calculation) is performed.

The melting point of the above drug means a value measured by the following method.
Apparatus: Melting point measurement device manufactured by MIYAMOTO RIKEN IND JAPAN This is the melting point.

  Among the polar drugs, the female hormone estradiol and its related substances are used as drugs for treating climacteric disorders. A related substance of estradiol is a substance having biological properties similar to those of estradiol, and has similar physical and chemical properties. Estradiol and its related substances include estradiol (4.008; melting point 179 ° C.), estrone (4.535; melting point 256 ° C.), estriol (3.239; melting point 282 ° C.), ethinyl estradiol (4.017; melting point) Estrogen such as 146 ° C. (hemi body)), and lutein hormone such as norlergestromine (progestin) (3.689; melting point 131 ° C.). The numerical values in parentheses indicate the logPow and melting point of each substance.

  The pressure-sensitive adhesive layer preferably contains an organic liquid component. Due to the presence of the organic liquid component, a sustained and stable release over a long time can be achieved while maintaining a high drug release rate. Such an organic liquid component is not particularly limited. However, the drug having polarity preferably used in the present invention has a log Pow of 0.5 to 5.5 and a certain degree of hydrophilicity / hydrophobicity balance. It is desirable to have a good hydrophilic / hydrophobic balance.

  Accordingly, the organic liquid component (first organic liquid component) preferably used in the present invention is preferably a polyhydric alcohol having two or more hydroxyl groups in the molecule. Specific examples of the polyhydric alcohol include glycols such as ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, and polypropylene glycol, which are used alone or in combination of two or more. Used. More preferred polyhydric alcohols include propylene glycol and dipropylene glycol.

  The content of the first organic liquid component in the pressure-sensitive adhesive layer is preferably in the range of 1 to 15 parts by weight, more preferably 2 to 10 parts by weight with respect to 100 parts by weight of the total weight of the pressure-sensitive adhesive. Is within.

  In the present invention, the pressure-sensitive adhesive layer may further contain another organic liquid component (second organic liquid component). Examples of the organic liquid component include fatty acid alkyl esters having at least a part of hydroxyl groups of a polyhydric alcohol, for example, one of n hydroxyl groups of an n-valent alcohol that is a polyhydric alcohol. -(N-1) hydroxyl group is an ester formed by ester bond with a carboxyl group of a fatty acid, more specifically, one of three hydroxyl groups of a trihydric alcohol such as glycerin or Of the two hydroxyl groups of dihydric alcohols such as ethylene glycol and propylene glycol, one hydroxyl group is an ester formed by ester bonding of two hydroxyl groups with the fatty acid carboxyl group, and the fatty acid carboxyl group and ester Examples include esters formed by bonding. Such an organic liquid component has a hydrophilic portion and a hydrophobic portion in its molecule, and is therefore suitable as the second organic liquid component for the purpose of the present invention. From the viewpoint of the balance between hydrophilicity and hydrophobicity, the second organic liquid component is preferably a monoester formed by ester-bonding one hydroxyl group with a fatty acid among the hydroxyl groups of the polyhydric alcohol.

  Examples of the mono fatty acid ester of the polyhydric alcohol include glycerin monocaprylate (for example, trade name “Sefsol 318”), propylene glycol monocaprylate (for example, trade name “Sefsol 218”), and propylene glycol monolaurate (for example, trade name “ Mono-fatty acid esters of propylene glycol such as Riquemar PL-100 "," Unisafe PGML "), propylene glycol monostearate (for example, trade name" Rikemar PS-100 "," EMALEX PG-MS "), ethylene glycol monostearate Examples include mono-fatty acid esters of ethylene glycol such as rates (for example, trade names “DN Wax MM”, “EMALEX EGS-A”), and these are used alone or in combination of two or more. It is. From the standpoint of maintaining the drug solubility of the first organic liquid component and further promoting the permeation of the drug having polarity from the elastomer to the skin and the skin irritation, propylene glycol mono Laurate.

  The content of the second organic liquid component in the pressure-sensitive adhesive layer is preferably 0.1 to 15 parts by weight, more preferably 1 to 10 parts by weight with respect to 100 parts by weight of the total pressure-sensitive adhesive. Part.

  Furthermore, in this invention, another organic liquid component (3rd organic liquid component) can be contained in an adhesive layer. As such an organic liquid component, for example, a monovalent aliphatic alcohol, particularly a monovalent aliphatic alcohol having about 10 to 22 carbon atoms is preferable from the viewpoint of sufficient hydrophobicity. Specific examples of the monovalent aliphatic alcohol include oleyl alcohol, geraniol, octyldodecanol, stearyl alcohol, isostearyl alcohol, cetanol and the like, and these are used alone or in combination of two or more. From the viewpoint of the solubility of the drug having polarity, a linear alcohol is effective instead of a branched alcohol, and oleyl alcohol is more preferable. The content of the third organic liquid component in the pressure-sensitive adhesive layer is preferably in the range of 0.1 to 35 parts by weight, more preferably 1 to 20 parts by weight with respect to 100 parts by weight of the total pressure-sensitive adhesive. Is within.

  If desired, the pressure-sensitive adhesive layer can contain an additional organic liquid component (fourth organic liquid component) for the purpose of plasticizing the pressure-sensitive adhesive layer and reducing skin irritation, for example. Specifically, phthalic acid esters such as bis (2-ethylhexyl) phthalate and diisononyl phthalate; fatty acid esters such as diisopropyl adipate, diethyl sebacate and isotridecyl myristate; particularly ethyl laurate, isopropyl myristate and palmitic acid A fatty acid alkyl ester comprising a higher fatty acid having 12 to 18 carbon atoms such as isopropyl, octyl palmitate and ethyl oleate and a lower monohydric alcohol having 1 to 8 carbon atoms; a fatty acid having 8 to 10 carbon atoms; olive oil, castor oil, Oils and fats such as lanolin; ethyl acetate, ethanol, dimethyl decyl sulfoxide, methyl octyl sulfoxide, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol Organic solvents; hydrocarbons such as squalene and liquid paraffin; liquid unsaturated fatty acids such as oleic acid, linoleic acid, and linolenic acid; other examples include ethoxylated stearyl alcohol and N-methylpyrrolidone. To liquid at room temperature. Moreover, these are used individually or in combination of 2 or more types. Among these, fatty acid alkyl esters are preferable from the viewpoint of improving the adhesiveness by improving the compatibility of the adhesive layer components. In particular, from the viewpoint of stability and the effect of promoting percutaneous absorption, fatty acid esters composed of higher fatty acids having 12 to 16 carbon atoms and lower monohydric alcohols having 1 to 4 carbon atoms are more preferable.

  Furthermore, in consideration of the improvement in transdermal absorbability of a drug having polarity, a fatty acid having 8 to 10 carbon atoms may be used in combination with the fatty acid ester. Examples of the fatty acid having 8 to 10 carbon atoms include caprylic acid (octanoic acid; C8), pelargonic acid (nonanoic acid; C9), capric acid (decanoic acid; C10), and the like.

  The content of the fourth organic liquid component in the pressure-sensitive adhesive layer is preferably in the range of 1 to 30 parts by weight, more preferably in the range of 5 to 10 parts by weight with respect to 100 parts by weight of the total pressure-sensitive adhesive. It is. By setting the content of the fourth organic liquid component to 1 part by weight or more, plasticization of the pressure-sensitive adhesive layer occurs effectively, and skin irritation can be reduced. On the other hand, when the content of the organic liquid component exceeds 30 parts by weight, the organic liquid component may not be held in the pressure-sensitive adhesive layer due to the cohesive force of the pressure-sensitive adhesive layer. The liquid component may bloom on the surface of the pressure-sensitive adhesive layer, resulting in poor adhesion.

  As long as the characteristics of the present invention are not impaired, the pressure-sensitive adhesive layer may contain other additives such as absorption promoters such as pyrrolidone carboxylic acid ester, ascorbyl palmitate, tocopherol acetate, natural vitamin E, dibutylhydroxytoluene, Antioxidants such as butylhydroxyanisole, amine-ketone antioxidants such as 2,6-tert-butyl-4-methylphenol, and aromatics such as N, N′-di-2-naphthyl-p-phenylenediamine Secondary amine type anti-aging agent, monophenol type anti-aging agent such as 2,2,4-trimethyl-1,2-dihydroquinoline polymer, 2,2′-methylenebis (4-ethyl-6-tert-butylphenol) ) And other polyphenolic aging agents such as 2,5-tert-butylhydroquinone Stopper, filler such as kaolin, hydrous silicon dioxide, zinc oxide, starch acrylate 1000, softening agent such as polybutene, benzoic acid, sodium benzoate, chlorhexidine hydrochloride, sorbic acid, methyl parahydroxybenzoate, butyl paraoxybenzoate, etc. Preservative, yellow iron oxide, yellow ferric oxide, ferric oxide, black iron oxide, carbon black, carmine, β-carotene, copper chlorophyll, edible blue No. 1, edible yellow No. 4, edible red No. 2, licorice extract Coloring agents such as fennel oil, d-camphor, dl-camphor, peppermint oil, d-borneol, l-menthol, and other flavoring agents such as spearmint oil, clove oil, vanillin, bergamot oil, lavender oil, etc. It can be included. The content of the additive is preferably 1% by weight to 10% by weight based on the total weight of the pressure-sensitive adhesive layer.

  In the patch preparation of the present invention, the thickness of the pressure-sensitive adhesive layer is usually 20 μm to 400 μm, preferably 30 μm to 300 μm.

  In the present invention, the above-mentioned pressure-sensitive adhesive layer can be subjected to a crosslinking treatment by physical crosslinking by irradiation with radiation such as ultraviolet irradiation or electron beam irradiation, chemical crosslinking with a crosslinking agent, or the like. In order to perform a crosslinking treatment without adversely affecting components such as a drug contained in the pressure-sensitive adhesive layer, a chemical crosslinking treatment with a crosslinking agent is preferable. Such crosslinking agents include isocyanate compounds (isocyanate crosslinking agents), epoxy crosslinking agents, aziridine crosslinking agents, melamine crosslinking agents, peroxide crosslinking agents, oxazoline crosslinking agents, urea crosslinking agents, amino compounds. A crosslinking agent, a carbodiimide-based crosslinking agent, a coupling agent-based crosslinking agent (for example, a silane coupling agent), or the like can be used. These may be used alone or in combination of two or more.

  The patch preparation of the present invention can be provided as a percutaneous absorption type preparation for local action or systemic action, either as a matrix type or a reservoir type. As the dosage form, various dosage forms such as a patch type, an adhesive tape type, and a sheet type can be used.

  As described above, the moisture content of the patch preparation in addition to the hydrophobicity of the pressure-sensitive adhesive layer can be cited as an effect on the wettability of the adhesive surface of the pressure-sensitive adhesive layer. It can be well controlled by producing it under a low relative humidity condition and packaging it with a moisture-impermeable packaging material. Accordingly, the present invention also provides a patch preparation package comprising a patch preparation having a wettability property as described above on the pressure-sensitive adhesive layer surface, and a water impermeable packaging material.

  In the above-mentioned package of the patch preparation of the present invention, as the water-impermeable packaging material, a packaging material in which aluminum foil is laminated on a commonly used packaging material is used. Preferably, (A) physical strength is increased. A laminated film having a layer structure composed of an imparting layer, (B) a moisture blocking layer, and (C) a sealant layer is used.

Specific examples of the material constituting the layer for imparting (A) physical strength in the laminated film include, for example, polyester, high-density polyethylene, polypropylene, polyamide, and vinyl chloride. The thickness of the layer (A) imparting physical strength is preferably about 10 μm to 100 μm.
Next, as a specific example of the material constituting the (B) moisture-blocking layer, for example, a metal foil such as an aluminum foil can be cited. The thickness of the (B) moisture blocking layer is preferably about 5 μm to 90 μm.
Subsequently, specific examples of the material constituting the sealant layer (C) include, for example, polyacrylonitrile resins such as methyl acrylate / butadiene / acrylonitrile copolymer, low density polyethylene, ethylene vinyl acetate copolymer, ethylene vinyl Examples include alcohol copolymers. Since polyacrylonitrile-based resin has low adsorptivity to drugs, it is effective in stabilizing the drug amount in the patch preparation. (C) The thickness of the sealant layer is preferably about 10 μm to 100 μm. The above thickness is particularly preferable for stably storing the patch preparation.

  The preferred embodiment of the packaging material used in the present invention is that the (A) layer for imparting physical strength, (B) the layer for blocking moisture and (C) the sealant layer are PET film, aluminum foil and polyacrylonitrile resin film, respectively. In particular, by adopting an aluminum foil having a thickness of 6 μm or more as a layer that blocks moisture (B), the condition in the package can be maintained substantially constant. Using such a packaging material, the patch preparation is packaged with the polyacrylonitrile resin film inside, so that the conditions in the package can be maintained substantially constant even when stored for a long period of time. The water content of the adhesive layer of the preparation and the contact angle between the adhesive surface and water are maintained substantially constant.

  The above-mentioned package of the patch preparation of the present invention preferably further includes a desiccant. As the desiccant packaged together with the patch preparation, those usually used in pharmaceutical preparations and food packaging can be used, and examples thereof include silica gel, aluminum oxide and zeolite.

  In another preferred embodiment of the package of the patch preparation of the present invention, the patch preparation having the hydrophobic adhesive layer described above is packaged with a water-impermeable packaging material containing a desiccant. Is mentioned. Examples of the packaging material containing a desiccant include water-impermeable packaging materials having a drying function, such as a water-impermeable resin film formed by mixing and kneading the desiccant as described above. It is done.

  This invention also provides the method of improving the adhesiveness of the adhesive layer of a patch preparation. In the above-mentioned method, in the adhesive preparation having an adhesive layer containing a drug and an adhesive on at least one surface of the support, the adhesive layer is adhered under the conditions of a temperature of 23 ± 2 ° C. and a relative humidity of 60 ± 10%. The contact angle between the surface and the water droplet is controlled to be 106 ° or more. Examples of the method for controlling the physical properties of the adhesive layer of the patch preparation so that the contact angle is 106 ° or more include making the adhesive layer hydrophobic or controlling the water content of the patch preparation.

  Examples of the method for making the pressure-sensitive adhesive layer hydrophobic include a method for preparing a pressure-sensitive adhesive layer using a hydrophobic pressure-sensitive adhesive such as a rubber-based pressure-sensitive adhesive as described above. Further, a method of controlling the water content with respect to the total weight of the patch preparation to 1.0% by weight or less, preferably 0.9% by weight or less can be mentioned. As described above, the method for controlling the moisture content of the patch preparation is as described above. The patch preparation is manufactured under conditions of low relative humidity, and is packaged with a moisture-impermeable packaging material. The method to make a body is mentioned. When packaging the patch preparation with a water-impermeable packaging material, it is more preferable to enclose the desiccant or to use a packaging material containing the desiccant as the water-impermeable packaging material.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In the following, “parts” means all parts by weight, and “%” means all parts by weight.

<Preparation of adhesive A>
14.7 parts of polyisobutylene having a viscosity average molecular weight of 4,000,000 as the first rubber elastomer, 14.7 parts of polyisobutylene having a viscosity average molecular weight of 55,000 as the second rubber elastomer, and a tackifier As a result, 44.2 parts of polybutene was mixed to obtain an adhesive A.

[Example 1]
73.2 parts Adhesive A, 2.4 parts dipropylene glycol, 2.4 parts propylene glycol monolaurate, 6 parts oleyl alcohol, 6 parts isopropyl myristate, and 10 parts crosslinked polyvinylpyrrolidone ( “Collidon CL-M” and BASF Japan Ltd. (hereinafter simply referred to as “BASF”) are mixed and further toluene is added and mixed, and then 0.4 parts of estradiol is added and mixed to form an adhesive layer A coating solution was obtained. A polyester film (thickness: 75 μm) was used as a release liner, and the coating solution was applied to the dried liner so that the thickness after drying was 240 μm and dried. Subsequently, this was transferred to the nonwoven fabric surface of the support to obtain an original fabric. The original fabric was punched into square pieces with an area of 5 cm ² to obtain a rough patch preparation A. In addition, as a support body, the laminated film of the polyester nonwoven fabric (weight per unit area 12g / m < ² >) and the polyester film (2 micrometers in thickness) was used. This is wrapped with a desiccant in a packaging material composed of a laminated film composed of a PET film, an aluminum foil and a polyacrylonitrile-based resin film, and left to stand for 4 weeks at 25 ° C. and a relative humidity of 60%. A patch preparation of Example 1 was obtained (packaging with a desiccant).

[Example 2]
The patch preparation of Example 1 was taken out of the packaging material and allowed to stand for 4 hours under the conditions of room temperature 23 ± 2 ° C. and relative humidity 60 ± 10% to obtain the patch preparation of Example 2.

[Example 3]
The patch preparation of Example 1 was taken out of the packaging material and allowed to stand for 8 hours under the conditions of room temperature 23 ± 2 ° C. and relative humidity 60 ± 10% to obtain the patch preparation of Example 3.

[Comparative Example 1]
A patch preparation of Comparative Example 1 was obtained in the same manner as in Example 1 except that the rough patch preparation A was packaged in a packaging material formed by laminating an aluminum foil and a polyacrylonitrile film without adding a desiccant ( Normal packaging).

[Comparative Example 2]
A patch preparation of Comparative Example 2 was obtained in the same manner as in Example 1 except that the crude patch preparation A was stored without packaging with a packaging material and without using a desiccant (non-packaging).

[Comparative Example 3]
The patch preparation of Example 1 was taken out of the packaging material and allowed to stand for 48 hours under the conditions of room temperature 23 ± 2 ° C. and relative humidity 60 ± 10% to obtain the patch preparation of Comparative Example 3.

[Comparative Example 4]
The patch preparation of Example 1 was taken out from the packaging material and allowed to stand for 72 hours under the conditions of room temperature 23 ± 2 ° C. and relative humidity 60 ± 10% to obtain the patch preparation of Comparative Example 4.

[Experimental example]
The following tests were conducted on the patch preparations of the above Examples and Comparative Examples.

[Experimental Example 1] Adhesion test for stainless steel plate <Test method>
According to JIS standard “Z0237 (adhesive tape / adhesive sheet test method)”, measurement was performed using a stainless steel plate. In this experimental example, the value measured with a test piece having a width of 12 mm was written as it was.

[Experiment 2] Contact angle measurement test <Test method>
Using the contact angle measuring device “Model DropMaster 300” manufactured by Kyowa Interface Science Co., Ltd., the contact angle between the adhesive surface of the adhesive layer of each patch preparation of Examples and Comparative Examples and water was measured as shown below. went.
Measuring method Contact angle (droplet method)
Measuring range Contact angle: 0 to 180 °
Measurement accuracy Contact angle: ± 1 °
Display resolution Contact angle: 0.1 °
Determination of measurement position Operation on PC screen Preparation of quantitative droplets Automatic liquid control / recognition recognition Automatic Contact angle analysis Automatic Each adhesive preparation prepared in the examples and comparative examples is placed on the glass slide glass with the adhesive layer surface Fixed vertically upward and attached to the device. The release liner was peeled off, water was brought into contact with the adhesive surface, and the contact angle after 5 seconds was measured under conditions of room temperature 23 ± 2 ° C. and relative humidity 60 ± 10%. The amount of water droplets was adjusted to 1.0 μL.

[Experiment 3] Moisture content measurement test <Test method>
The patch preparation having a release liner for protecting the adhesive surface of the pressure-sensitive adhesive layer was cut into 16 mmΦ test pieces as they were, and the water content (weight) in the patch preparation was measured with a Karl Fischer moisture meter. Using the measured value and the weight of the patch preparation (including the release liner) measured in advance, the moisture content (%) in the patch preparation was determined.

  The results in Experimental Examples 1 to 3 are shown in Table 1.

  From the results of the adhesion test to stainless steel plate shown in Table 1 and the measurement results of the contact angle, the contact angle between the adhesive surface of the adhesive layer and water droplets for the adhesive preparations of Examples 1 to 3 and Comparative Examples 1 to 4 FIG. 1 shows the relationship between the adhesive strength and the adhesive strength of the patch preparation. From FIG. 1, two linear relationships are recognized between the adhesive force and the contact angle of the patch preparation. The two straight lines (y = 0.4303x−43.114 and y = −0.0113x + 3.6174) intersect at a contact angle (x) = approximately 106 ° (105.8 °), but contact from this intersection When the corner becomes smaller, the adhesive strength of the patch preparation decreases rapidly. On the other hand, even if the contact angle is larger than this intersection, the adhesive force of the patch preparation is almost constant and hardly changed. From the above results, it was confirmed that the contact angle between the pressure-sensitive adhesive surface of the pressure-sensitive adhesive layer and the water droplets needs to be 106 ° or more in order for the adhesive preparation to have sufficient adhesiveness.

  In addition, the contact angle between the adhesive surface of the adhesive layer and the water droplets of the adhesive preparations prepared in Examples 1 to 3 of the present invention was 106 ° or more, and the water content was 0.9% or less. . On the other hand, the contact angle of the patch preparations prepared in Comparative Examples 1 to 4 was less than 106 °, and the moisture content exceeded 1.0%.

  That is, from the results of the above experimental examples, in the patch preparation of the present invention, it is necessary to show good skin adhesion as a result of being packaged with a desiccant by a water-impermeable packaging material and controlled to a low water content. It was shown that the hydrophobic adhesive surface is retained. Further, when the patch preparation of the present invention is applied to the skin, the hydrophobic adhesive surface is maintained and good skin adhesion is maintained as long as the patch preparation is taken out from the package and then applied within a normal time. It was shown to get.

  As described above, according to the present invention, not the composition of the pressure-sensitive adhesive layer but the physical properties of the pressure-sensitive adhesive surface is improved, thereby improving the adhesiveness of the pressure-sensitive adhesive layer, and as a result, when applied to the skin for a long time. In addition, it is possible to provide a patch preparation that is hardly peeled off or detached from the skin.

Claims (7)

  An adhesive preparation having an adhesive layer containing a drug and an adhesive on at least one surface of a support, the adhesive surface of the adhesive layer under conditions of a temperature of 23 ± 2 ° C. and a relative humidity of 60 ± 10% A patch preparation having a contact angle with a water droplet of 106 ° or more.   The adhesive preparation according to claim 1, wherein the adhesive comprises a rubber-based adhesive.   The rubber-based pressure-sensitive adhesive contains a rubber-based elastomer having a viscosity average molecular weight of 1,600,000 to 6,500,000 and a rubber-based elastomer having a viscosity average molecular weight of 40,000 to 85,000. 2. The patch preparation according to 2.   The patch preparation according to claim 1, wherein the moisture content of the patch preparation is 1.0% by weight or less.   The adhesive preparation according to claim 1, wherein the pressure-sensitive adhesive layer contains crosslinked polyvinylpyrrolidone.   The patch preparation according to claim 1, wherein the drug is a drug having polarity.   A package of patch preparation, wherein the patch preparation according to any one of claims 1 to 6 is packaged by a water-impermeable packaging material.

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