JP5285279B2 - Transdermal preparation - Google Patents
Transdermal preparation Download PDFInfo
- Publication number
- JP5285279B2 JP5285279B2 JP2007552906A JP2007552906A JP5285279B2 JP 5285279 B2 JP5285279 B2 JP 5285279B2 JP 2007552906 A JP2007552906 A JP 2007552906A JP 2007552906 A JP2007552906 A JP 2007552906A JP 5285279 B2 JP5285279 B2 JP 5285279B2
- Authority
- JP
- Japan
- Prior art keywords
- patch
- drug
- adhesive layer
- sensitive adhesive
- pressure
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
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Classifications
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- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
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- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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Description
本発明は、長期間の皮膚への貼付が可能な薬物含有貼付剤に関する。更に詳しくは、少なくとも１日間以上、好ましくは数日間以上貼付しても皮膚への付着性が十分でありながら、皮膚への安全性に優れ、薬物等の配合成分の結晶化がなく粘着物性に優れると共に、薬物の経皮吸収性が高くかつ薬物の含量安定性も良好な薬物含有貼付剤に関する。 The present invention relates to a drug-containing patch that can be applied to the skin for a long period of time. More specifically, it has excellent adhesion to the skin even if it is applied for at least one day or more, preferably several days or more. The present invention relates to a drug-containing patch which is excellent, has a high transdermal absorbability of a drug and has a good drug content stability.
貼付剤は、経皮吸収型製剤であることから、消化管や肝臓等による薬物代謝の影響を受け難く、血中濃度を一定に保つのが比較的容易なため、種々の薬物の投与形態として使用されてきた。現在では、例えば更年期障害や卵巣欠落症状、閉経後骨粗鬆症などの治療として行われるエストラジオールを使用したホルモン補充療法といった、長期間の継続的投与が必要とされる薬物を投与する際にも、貼付剤を使用する投与形態が注目されている。 Since the patch is a percutaneous absorption type preparation, it is not easily affected by drug metabolism due to the digestive tract, liver, etc., and it is relatively easy to keep the blood concentration constant. Have been used. Currently, even when administering a drug that requires long-term continuous administration, such as hormone replacement therapy using estradiol, which is performed as a treatment for menopause, ovarian loss, postmenopausal osteoporosis, etc. Attention has been focused on dosage forms using.
このようなホルモン等の投与に用いられる貼付剤は、経皮吸収型製剤としての前記特長に加え、消化管からでは吸収が困難であった天然型ホルモンを有効成分として配合できることから、より利用しやすい製剤としても提案されてきた(特許文献１)。 In addition to the above-mentioned features as a transdermal absorption preparation, such patches used for administration of hormones and the like can be used more effectively because natural hormones that were difficult to absorb from the digestive tract can be blended as active ingredients. It has also been proposed as an easy preparation (Patent Document 1).
しかしながら、ホルモン補充療法等の継続的な薬物治療が必要な疾患においては、治療期間が数ヶ月から数年と長期に及び、さらに貼付剤を用いた経皮投与を行う場合には一回あたりの皮膚への貼付時間を通常よりも長くする必要があることから、製剤の皮膚への付着性の低下やカブレなどの皮膚刺激性が生じるという問題点があり、かかる問題点を解決するために、アクリル系粘着剤とポリビニルピロリドンを配合した薬物含有貼付剤が提案されてきた (特許文献２および３)。
However, in diseases that require continuous drug treatment such as hormone replacement therapy, the treatment period may be as long as several months to several years. Since it is necessary to make the application time to the skin longer than usual, there is a problem that skin irritation such as reduction in adhesion of the preparation to the skin and fogging occurs, and in order to solve such problems, Drug-containing patches containing an acrylic adhesive and polyvinylpyrrolidone have been proposed (
また、薬物を長時間にわたり供給するには、経皮吸収型製剤中に多くの量の薬物を含有させなければならないことから、製剤中における薬物の結晶化を抑制するため、ポリビニルピロリドンを配合するなどの製剤的工夫を行うことも提案されてきた(特許文献５)。 In addition, in order to supply a drug over a long period of time, since a large amount of the drug must be contained in the transdermal preparation, polyvinyl pyrrolidone is added to suppress crystallization of the drug in the preparation. It has also been proposed to devise pharmaceutical preparations such as (Patent Document 5).
しかしながら、実際には、アクリル系粘着剤などの粘着性ポリマー物質とポリビニルピロリドンとを含有する貼付剤は、一般に粘着性ポリマー物質は疎水性高分子であるのに対して、ポリビニルピロリドンが水溶性高分子であることから、粘着剤層中でポリビニルピロリドンが溶解しにくく、粘着剤層の分離といった問題も生じやすい上、さらに、ポリビニルピロリドンは吸湿性が高いことから皮膚への付着性が経時的に低下してしまうといった問題も生じ、長期間の皮膚への貼付に適した製剤として、市場に供給することができる程度に十分に安定な製剤物性を有するものではなかった。 However, in practice, adhesive patches containing an adhesive polymer material such as an acrylic adhesive and polyvinylpyrrolidone are generally hydrophobic polymer, whereas polyvinylpyrrolidone is a highly water-soluble adhesive. Because it is a molecule, polyvinylpyrrolidone is difficult to dissolve in the adhesive layer, and problems such as separation of the adhesive layer are likely to occur. Furthermore, since polyvinylpyrrolidone is highly hygroscopic, its adhesion to the skin will deteriorate over time. As a formulation suitable for sticking to the skin for a long period of time, the formulation physical properties were not stable enough to be supplied to the market.
一方、経皮吸収型製剤において必要量の薬物を皮膚から吸収させることを目的としてポリエチレングリコール、プロピレングリコールモノラウレート、オレイン酸、パルミチン酸イソプロピル、ソルビタンモノラウレート、グリセリンモノラウレート、ラウリン酸メチル等の吸収促進剤を配合することは既に提案されているが(特許文献１および４〜９)、これらを有効成分と共に粘着基剤に単に配合しただけでは、有効成分である薬物と吸収促進剤が反応してその薬物の粘着剤層における含有量低下を引き起こしたり、薬物が結晶化するなどといった問題が生じ、製剤の安定性および安全性に優れた貼付剤を得ることはできなかった。
On the other hand, polyethylene glycol, propylene glycol monolaurate, oleic acid, isopropyl palmitate, sorbitan monolaurate, glycerin monolaurate, methyl laurate for the purpose of absorbing the required amount of drug from the skin in transdermal preparations Have already been proposed (
本発明は上記の問題点に鑑み、少なくとも１日間以上貼付しても皮膚への付着性が十分でありながら、皮膚への安全性が極めて高く、また、薬効成分の皮膚への透過性が非常に良好であり、かつ薬効成分および他の粘着剤層配合成分の析出がない、薬物含有貼付剤を提供することを課題とする。 In view of the above-mentioned problems, the present invention has extremely high safety to the skin even if it is applied for at least one day or more, yet has extremely high safety to the skin, and the permeability of medicinal ingredients to the skin is very high. It is an object of the present invention to provide a drug-containing patch that is excellent in treatment and has no precipitation of medicinal components and other adhesive layer compounding components.
上記課題を解決するため、本発明者らは鋭意研究を重ねた結果、薬物を含有する貼付剤において、ポリビニルピロリドンとアクリル系粘着剤の双方に対して親和性のある液状成分を添加することにより上記課題を解決することができるのではないかと考え、この液状成分としてプロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレート、またはイソプロピルパルミテートを選択することにより、長期間にわたる適用においても製剤物性や皮膚への付着性に優れ、かつ経皮吸収性が極めて良好である薬物含有貼付剤が得られるとともに、さらに驚くべきことに、製剤中の薬物や他の配合成分の結晶化が抑制され、また、配合された薬物の経時的安定性にも優れる他、皮膚への安全性にも優れるという効果をも見出した。そしてさらに研究を進めた結果、本発明者らは、本発明の貼付剤にエストラジオールを配合することによって、前記効果を奏するエストラジオール含有貼付剤が実現できることをも見出し、本発明を完成させた。 In order to solve the above-mentioned problems, the present inventors have conducted extensive research, and as a result, in a patch containing a drug, by adding a liquid component having an affinity for both polyvinylpyrrolidone and an acrylic adhesive. Considering that the above problems can be solved, by selecting propylene glycol monolaurate, glyceryl monooleate, methyl laurate, or isopropyl palmitate as this liquid component, it can be formulated for long-term application. A drug-containing patch with excellent physical properties and adhesion to the skin and extremely good transdermal absorbability can be obtained, and surprisingly, crystallization of the drug and other ingredients in the preparation is suppressed. In addition to being superior in the stability of the formulated drug over time, it has also been found to be effective in skin safety. . As a result of further research, the present inventors have also found that an estradiol-containing patch exhibiting the above-mentioned effects can be realized by blending estradiol into the patch of the present invention, thereby completing the present invention.
すなわち、本発明は、薬物、プロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレートおよびイソプロピルパルミテートからなる群から選択される１種または２種以上の液状成分、ポリビニルピロリドン、ならびに、アクリル系粘着剤を含有する粘着剤層を含む貼付剤に関する。
また本発明は、粘着剤層全体の質量を基準として、アクリル系粘着剤を６０〜８０質量％、プロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレートおよびイソプロピルパルミテートからなる群から選択される１種または２種以上の液状成分を合計で１〜２５質量％、ならびに、ポリビニルピロリドンを５〜１５質量％含有することを特徴とする、前記貼付剤に関する。
さらに本発明は、アクリル系粘着剤が、アクリル酸、アクリル酸２−エチルヘキシルおよび酢酸ビニルからなることを特徴とする、前記の貼付剤に関する。
本発明はまた、ポリビニルピロリドンの重量平均分子量が８，０００〜１，３００，０００であることを特徴とする、前記の貼付剤に関する。
そしてまた、本発明は、薬物が、エストラジオールであることを特徴とする、前記の貼付剤に関する。That is, the present invention relates to one or more liquid components selected from the group consisting of drugs, propylene glycol monolaurate, glyceryl monooleate, methyl laurate and isopropyl palmitate, polyvinylpyrrolidone, and acrylic The present invention relates to a patch comprising an adhesive layer containing an adhesive.
Further, the present invention is selected from the group consisting of 60 to 80% by mass of acrylic adhesive, propylene glycol monolaurate, glyceryl monooleate, methyl laurate and isopropyl palmitate based on the mass of the entire adhesive layer. It is related with the said adhesive agent characterized by containing 1-25 mass% in total of 1 type, or 2 or more types of liquid components and 5-15 mass% of polyvinylpyrrolidone.
Furthermore, the present invention relates to the above-mentioned patch, wherein the acrylic pressure-sensitive adhesive comprises acrylic acid, 2-ethylhexyl acrylate and vinyl acetate.
The present invention also relates to the above-mentioned patch, wherein the weight average molecular weight of polyvinylpyrrolidone is 8,000 to 1,300,000.
The present invention also relates to the above-mentioned patch, wherein the drug is estradiol.
前記の構成とすることにより、本発明の貼付剤は、剥がれることなく（脱落することなく）１日間以上、さらには３日間以上の貼付が可能であり、しかも貼付剤によりカブレ等の皮膚刺激を生じることがほとんどなく、経皮吸収性に優れ、さらに結晶析出や粘着剤層の分離、ブリード、糊残り等の製剤的な問題も生ずることがない貼付剤として提供することが可能となる。 By adopting the above-described configuration, the patch of the present invention can be applied for 1 day or more, and further 3 days or more without peeling (without dropping), and the patch can cause skin irritation such as fogging. It can be provided as a patch that is hardly generated, has excellent percutaneous absorbability, and does not cause formulation problems such as crystal precipitation, separation of an adhesive layer, bleed, and adhesive residue.
本発明によれば、少なくとも１日間以上、さらには３日間以上貼付しても、皮膚への付着性が十分でありながら、カブレなどの皮膚刺激性が極めて低い皮膚への安全性に優れた薬物含有貼付剤を提供することができる。また、本発明の貼付剤は、薬物およびその他の配合成分の結晶析出がなく、その上、薬物の変性や分解などによる含有量低下についても従来の製剤に比べ大きく改善されていることから、配合された薬物およびその他の成分の安定性に極めて優れたものであり、安定に長期保存することが可能であるとともに、製剤の安全性も良好なものである。
そしてまた、本発明によれば、プロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレートおよびイソプロピルパルミテートからなる群から選択される１種または２種以上の液状成分の配合によっても粘着剤層がブリード及び糊残りを引き起こすことのない、製剤物性が非常に良好な貼付剤を提供することができる。さらに、本発明の貼付剤は、薬物の皮膚透過性が極めて高く、十分に薬物の効果を発揮させることができるものであるうえ、１日間以上、さらには３日間以上という長期間にわたって、持続的に体内に薬物を供給することが可能である。さらにまた、本発明の貼付剤に薬物として非ステロイド性抗炎症剤、性ホルモン、副腎皮質ホルモン等を配合することによって、前記効果を奏する貼付剤を提供することができる。
なお、かかる効果を全て同時に実現する薬物含有貼付剤は、本発明により初めて実現されたものである。According to the present invention, a drug excellent in safety to the skin having a very low skin irritation such as fogging while having sufficient adhesion to the skin even when applied for at least 1 day or even 3 days or more. A containing patch can be provided. In addition, the patch of the present invention has no crystal precipitation of the drug and other compounding ingredients, and furthermore, the content reduction due to drug denaturation or decomposition is greatly improved compared to conventional preparations. The drug and other ingredients are extremely excellent in stability, can be stored stably for a long time, and the safety of the preparation is also good.
In addition, according to the present invention, the pressure-sensitive adhesive layer can be obtained by blending one or more liquid components selected from the group consisting of propylene glycol monolaurate, glyceryl monooleate, methyl laurate and isopropyl palmitate. Can provide a patch with very good physical properties without causing bleeding and adhesive residue. Furthermore, the patch of the present invention has a very high skin permeability of the drug, and can sufficiently exert the effect of the drug, and is sustained over a long period of 1 day or more, further 3 days or more. It is possible to supply drugs into the body. Furthermore, by incorporating a nonsteroidal anti-inflammatory agent, sex hormone, adrenocortical hormone, or the like as a drug into the patch of the present invention, a patch exhibiting the above effects can be provided.
The drug-containing patch that realizes all of these effects simultaneously is realized for the first time by the present invention.
以下、本発明の好適な実施形態について詳細に説明する。
本発明の貼付剤は、支持体層、粘着剤層および剥離ライナー層が順に積層されている貼付剤であって、前記粘着剤層は、少なくとも、有効成分である薬物の他、アクリル系粘着剤、ポリビニルピロリドン、ならびに、プロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレートおよびイソプロピルパルミテートからなる群から選択される１種または２種以上の液状成分を含有する。Hereinafter, preferred embodiments of the present invention will be described in detail.
The patch of the present invention is a patch in which a support layer, a pressure-sensitive adhesive layer, and a release liner layer are sequentially laminated. The pressure-sensitive adhesive layer includes at least an active ingredient, an acrylic pressure-sensitive adhesive, and the like. , Polyvinyl pyrrolidone, and one or more liquid components selected from the group consisting of propylene glycol monolaurate, glyceryl monooleate, methyl laurate and isopropyl palmitate.
本発明の貼付剤に用いられる薬物は、特に限定されないが、アクリル酸のようなカルボキシル基を構成単位に含むアクリル系粘着剤および液状成分との相互作用が少ない薬物が、製剤からの放出性が良好でありかつ分解を引き起こさないという点で好ましい。例としては、エストラジオール、エストロンおよびエストリオール等の卵胞ホルモン、プロゲステロン、酢酸ノルエチステロン等の黄体ホルモン、デキサメタゾン、ヒドロコルチゾン、プレドニゾロン、フルオシノニド、プロピオン酸クロベタゾール、吉草酸ベタメタゾン、酢酸プレドニゾロン、酢酸ヒドロコルチゾン等の副腎皮質ホルモン、ケトプロフェン、ロキソプロフェン、イブプロフェン、フルルビプロフェン、インドメタシン、ジクロフェナク、フェルビナク、ピロキシカム、メロキシカム、サリチル酸メチル、サリチル酸グリコール、バルデコキシブ、セレコキシブ、ロフェコキシブ、グリチルレチン酸、グリチルリチン酸、アセトアミノフェン、アスピリン等の非ステロイド性抗炎症剤などを挙げることができる。中でも、粘着剤層への溶解性に乏しく結晶析出を引き起こす傾向のある、エストラジオール、酢酸ノルエチステロン、インドメタシン、ジクロフェナク、セレコキシブ、ロフェコキシブが好適に用いられる。また、その中でもエストラジオールは、特に良好な皮膚透過速度が持続する効果が得られるため、より好ましい。本発明の貼付剤に用いられるエストラジオールは、エストラ−１，３，５（１０）−トリエン−３，１７β−ジオールを意味し、その形態としては無水物であっても水和物であってもよい。
本発明の貼付剤における上記薬物の配合量は、特に制限されないが、少なくとも１日間以上、好ましくは３日間以上という長期間にわたって薬物を持続的に体内へ供給をするにあたり、十分な経皮吸収性および粘着物性を確保するという観点から、粘着剤層全体の質量を基準として、粘着剤層中に１〜８質量％配合されることが好ましい。
また、有効成分として、上記の薬物２種以上を配合することもできる。The drug used in the patch of the present invention is not particularly limited, but an acrylic adhesive such as acrylic acid containing a carboxyl group as a constituent unit and a drug having little interaction with a liquid component have a release property from the preparation. It is preferable in that it is good and does not cause decomposition. Examples include follicular hormones such as estradiol, estrone, and estriol, progesterone, progesterone, progesterone, progesterone, and corticosteroids such as dexamethasone, hydrocortisone, prednisolone, fluocinonide, clobetasol propionate, betamethasone valerate, prednisolone acetate, and hydrocortisone acetate. , Ketoprofen, loxoprofen, ibuprofen, flurbiprofen, indomethacin, diclofenac, felbinac, piroxicam, meloxicam, methyl salicylate, glycol salicylate, valdecoxib, celecoxib, rofecoxib, glycyrrhetinic acid, glycyrrhizic acid, non-steroidal asteroid, etc. Examples include anti-inflammatory agents. Among them, estradiol, norethisterone acetate, indomethacin, diclofenac, celecoxib, and rofecoxib, which have poor solubility in the pressure-sensitive adhesive layer and tend to cause crystal precipitation, are preferably used. Among them, estradiol is more preferable because an effect of maintaining a particularly good skin permeation rate can be obtained. The estradiol used in the patch of the present invention means estra-1,3,5 (10) -triene-3,17β-diol, and the form thereof may be anhydrous or hydrated. Good.
The compounding amount of the above-mentioned drug in the patch of the present invention is not particularly limited. However, sufficient transdermal absorbability is required for continuously supplying the drug into the body for a long period of at least 1 day, preferably 3 days or longer. From the viewpoint of securing the adhesive properties, it is preferable that 1 to 8% by mass of the adhesive layer is blended based on the mass of the entire adhesive layer.
Moreover, two or more kinds of the above-mentioned drugs can be blended as active ingredients.
本発明による貼付剤の粘着剤層には、粘着基剤としてアクリル系粘着剤を用いる。これは、アクリル系粘着剤は、透湿性が高いため、炭化水素系の粘着基剤と比べて長期間貼付時の皮膚への負担を軽減することができ、また、他の粘着基剤よりも薬物の溶解性が高いため、１製剤中により多くの量の薬物を含有することが可能となるためである。本発明に用いられるアクリル系粘着剤は、アクリル酸の炭素数が４〜１２の長鎖エステルモノマーを主成分とするポリマーであれば特に限定されないが、カルボキシル基を有するアクリル系粘着剤もしくは構成成分のアクリル酸エステルとしてアクリル酸オクチルを含有するアクリル系粘着剤は、適度な粘接着力や凝集力を持つために好ましく用いられ、また、アクリル酸、アクリル酸２−エチルヘキシルおよび酢酸ビニルから構成されるアクリル系粘着剤は、後述のポリビニルピロリドン添加時の粘着剤層の粘着物性および相溶性に優れるために特に好ましく使用される。 In the adhesive layer of the patch according to the present invention, an acrylic adhesive is used as an adhesive base. This is because acrylic adhesives have high moisture permeability, so the burden on the skin when applied for a long period of time can be reduced compared to hydrocarbon adhesive bases, and more than other adhesive bases. This is because the drug has high solubility, so that a larger amount of drug can be contained in one preparation. The acrylic pressure-sensitive adhesive used in the present invention is not particularly limited as long as it is a polymer mainly composed of a long-chain ester monomer having 4 to 12 carbon atoms of acrylic acid, but an acrylic pressure-sensitive adhesive having a carboxyl group or a constituent component An acrylic pressure-sensitive adhesive containing octyl acrylate as an acrylic acid ester is preferably used because it has appropriate adhesive strength and cohesive strength, and is composed of acrylic acid, 2-ethylhexyl acrylate and vinyl acetate. The acrylic pressure-sensitive adhesive is particularly preferably used because it is excellent in the pressure-sensitive adhesive properties and compatibility of the pressure-sensitive adhesive layer when polyvinylpyrrolidone described later is added.
本発明の貼付剤における上記アクリル系粘着剤の配合量は、特に制限されないが、粘着剤層全体の質量を基準として６０質量％以上とする場合には、アクリル粘着剤によってもたらされる粘着力、凝集力等の粘着物性が特に良好となる傾向にあるため好ましく、さらに、アクリル系粘着剤以外の他の成分を充分な配合量で配合することを考慮すると、粘着剤層全体の質量を基準として８０質量％以下とすることがより好ましく、したがって、粘着剤層全体の質量を基準として６０〜８０質量％で配合されることが特に好ましい。 The blending amount of the acrylic pressure-sensitive adhesive in the patch of the present invention is not particularly limited, but when it is 60% by mass or more based on the mass of the whole pressure-sensitive adhesive layer, the adhesive force and aggregation brought about by the acrylic pressure-sensitive adhesive It is preferable because the adhesive physical properties such as strength tend to be particularly good. Furthermore, considering that other components other than the acrylic pressure-sensitive adhesive are added in a sufficient amount, 80% based on the mass of the entire pressure-sensitive adhesive layer. More preferably, the blending amount is 60% by weight or less based on the weight of the entire pressure-sensitive adhesive layer.
さらに、長期間にわたって薬物を体内へ供給するために多くの量の薬物を安定に配合する必要があることから、本発明の貼付剤の粘着剤層にはポリビニルピロリドンが配合される。ポリビニルピロリドンを粘着剤層中に含有させた場合には、薬物は粘着基剤中でポリビニルピロリドンに取り込まれて非晶質化し、製剤中に分散されるため、粘着剤層中の薬物濃度を見かけ上増大させつつ薬物の結晶化が抑制されるとともに、薬物間の相互作用が打ち消されて皮膚への放出特性が向上するという効果を得ることができる。 Furthermore, since it is necessary to stably mix a large amount of drug in order to supply the drug to the body over a long period of time, polyvinylpyrrolidone is blended in the adhesive layer of the patch of the present invention. When polyvinyl pyrrolidone is included in the adhesive layer, the drug is incorporated into the polyvinyl pyrrolidone in the adhesive base, becomes amorphous, and is dispersed in the preparation. Therefore, the drug concentration in the adhesive layer is apparent. While increasing the amount, the crystallization of the drug is suppressed, and the interaction between the drugs is canceled to improve the release characteristics to the skin.
粘着剤層中におけるポリビニルピロリドンの配合量は、特に制限されないが、粘着剤層全体の質量を基準として、１５質量％以下で配合されることが好ましく、５〜１５質量％で配合されることが特に好ましい。これは、ポリビニルピロリドンの配合量が１５質量％以下である場合には、アクリル系粘着剤の含量を減少させる必要がないため、ポリビニルピロリドンの析出や粘着剤層の層分離等といった貼付剤としての付着性に影響を与える現象が起こり難く、また、５質量％以上であると上記のポリビニルピロリドンによる効果が顕著に現れる傾向にあるためである。 The blending amount of polyvinyl pyrrolidone in the pressure-sensitive adhesive layer is not particularly limited, but is preferably blended at 15% by mass or less, based on the mass of the entire pressure-sensitive adhesive layer, and may be blended at 5 to 15% by mass. Particularly preferred. This is because when the blending amount of polyvinyl pyrrolidone is 15% by mass or less, it is not necessary to reduce the content of the acrylic pressure-sensitive adhesive. Therefore, as a patch such as precipitation of polyvinyl pyrrolidone or layer separation of the pressure-sensitive adhesive layer. This is because a phenomenon that affects adhesiveness is unlikely to occur, and when the content is 5% by mass or more, the effect of the above-described polyvinyl pyrrolidone tends to be prominent.
また、本発明の貼付剤に用いられるポリビニルピロリドンの重量平均分子量としては、８，０００〜１，３００，０００が好ましく、１０，０００〜２００，０００が特に好ましい。これは、重量平均分子量が１，３００，０００以下のものは良好な水溶性を有し、溶媒やアクリル系粘着剤への溶解度も良好であることから、結果として、貼付剤としての付着性および粘着剤層の均一性に優れた製品を、ばらつきが生じることなく製造することが容易となる傾向にあり、また、８，０００以上の重量平均分子量を有するものは、薬物を分散させる効果が極めて良好で、膏体の凝集力を維持することが容易となる傾向にあるためである。また、重量平均分子量が１０，０００〜２００，０００である場合には、粘着力および凝集力に特に優れる傾向にある。
なお、本発明の貼付剤に配合されるポリビニルピロリドンは、架橋されていないものを用いる。架橋されているものを用いる場合には、溶媒やアクリル系粘着剤への溶解度が低く、結果として貼付剤としての付着性の低下や粘着剤層の均一性の低下による製品のばらつきが生じやすくなるからである。Moreover, as a weight average molecular weight of polyvinylpyrrolidone used for the patch of this invention, 8,000-1,300,000 are preferable and 10,000-200,000 are especially preferable. This is because those having a weight average molecular weight of 1,300,000 or less have good water solubility and good solubility in solvents and acrylic pressure-sensitive adhesives. Products having excellent uniformity of the pressure-sensitive adhesive layer tend to be easily manufactured without variation, and those having a weight average molecular weight of 8,000 or more are extremely effective in dispersing the drug. This is because it tends to be good and easy to maintain the cohesive strength of the paste. Further, when the weight average molecular weight is 10,000 to 200,000, the adhesive force and the cohesive force tend to be particularly excellent.
In addition, the polyvinylpyrrolidone mix | blended with the patch of this invention uses what is not bridge | crosslinked. When using a cross-linked product, the solubility in a solvent or acrylic adhesive is low, and as a result, product variations are likely to occur due to reduced adhesiveness and adhesive layer uniformity as a patch. Because.
本発明の貼付剤に配合されるポリビニルピロリドンは水溶性高分子であり、疎水性高分子であるアクリル系粘着剤とは極性が大きく異なるため、ポリビニルピロリドンとアクリル系粘着剤を含有する貼付剤は、不溶のポリビニルピロリドンが粘着剤層中に分散して粘着物性が低下してしまうという問題が生じる。これを防ぐために、本発明においては、ポリビニルピロリドンとアクリル系粘着剤の双方に対して親和性のある液状成分を添加する必要があると考え、この液状成分としてプロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレートおよびイソプロピルパルミテートから選択される１種または２種以上を採用した。これらのうち、特に好ましいのは、プロピレングリコールモノラウレート、あるいは、グリセリルモノオレエートとメチルラウレートとの併用、もしくは、グリセリルモノオレエートとイソプロピルパルミテートとの併用である。さらにまた、かかる液状成分の添加によって、良好な粘着物性が得られるという効果の他、経皮吸収性や薬物の安定性にも優れた製剤が得られた。 The polyvinylpyrrolidone blended in the patch of the present invention is a water-soluble polymer, and since the polarity is significantly different from the acrylic adhesive that is a hydrophobic polymer, the patch containing polyvinylpyrrolidone and the acrylic adhesive is Insoluble polyvinylpyrrolidone is dispersed in the pressure-sensitive adhesive layer, resulting in a problem that the physical properties of the pressure-sensitive adhesive are lowered. In order to prevent this, in the present invention, it is considered necessary to add a liquid component having an affinity for both polyvinylpyrrolidone and the acrylic pressure-sensitive adhesive. As this liquid component, propylene glycol monolaurate, glyceryl monooleate are used. One or more selected from ate, methyl laurate and isopropyl palmitate were employed. Of these, propylene glycol monolaurate, a combination of glyceryl monooleate and methyl laurate, or a combination of glyceryl monooleate and isopropyl palmitate is particularly preferable. Furthermore, the addition of such a liquid component yielded a preparation excellent in transdermal absorbability and drug stability in addition to the effect of obtaining good adhesive properties.
そしてまた、このようなポリビニルピロリドンとアクリル系粘着剤の双方に対して親和性のある液状成分の添加は、以下に述べるような利点をも有する。すなわち、（かかる液状成分を含有しない）ポリビニルピロリドンとアクリル系粘着剤とを含有する粘着剤層、または、上記４種の液状成分（プロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレートおよびイソプロピルパルミテート）よりも極性の高い液状成分、例えば、ポリエチレングリコールやジプロピレングリコール等の存在下でポリビニルピロリドンとアクリル系粘着剤とを含有する粘着剤層は、ポリビニルピロリドンが水溶性の高分子であるために吸湿しやすく、そのために初期の付着性は高くても徐々に吸湿することによって粘着層全体の極性がくずれ、アクリル系粘着剤の粘着力が低下して皮膚への付着性が低下する。 In addition, the addition of a liquid component having affinity for both polyvinylpyrrolidone and the acrylic pressure-sensitive adhesive also has the following advantages. That is, an adhesive layer containing polyvinylpyrrolidone (which does not contain such a liquid component) and an acrylic adhesive, or the above four liquid components (propylene glycol monolaurate, glyceryl monooleate, methyl laurate and isopropyl) In the pressure-sensitive adhesive layer containing polyvinylpyrrolidone and an acrylic pressure-sensitive adhesive in the presence of a liquid component having a polarity higher than that of palmitate, for example, polyethylene glycol or dipropylene glycol, polyvinylpyrrolidone is a water-soluble polymer. Therefore, it is easy to absorb moisture. Therefore, even if the initial adhesion is high, by gradually absorbing moisture, the polarity of the entire pressure-sensitive adhesive layer is lost, and the adhesive strength of the acrylic pressure-sensitive adhesive is reduced, thereby reducing the adhesion to the skin.
一方、上記の４種の液状成分よりも極性が低い疎水性の液状成分、例えばイソプロピルミリステートやミネラルオイル等を、ポリビニルピロリドンおよびアクリル系粘着剤と共に配合して得られた粘着剤層は、吸湿性は低いものの、粘着剤層全体の疎水性が高くなりすぎるために薬物が製造時、あるいは製造後経時的に結晶化するのみならず、その結果として薬物の経皮吸収性も低下する。
これに対し、上記の液状成分、特に、プロピレングリコールモノラウレートの使用、あるいは、グリセリルモノオレエートとメチルラウレートとの併用、もしくは、グリセリルモノオレエートとイソプロピルパルミテートとの併用においては、いずれも長鎖脂肪鎖と水酸基との組み合わせにより、適度な疎水性と極性を発揮することができるため、製剤の吸湿を防ぎながらも薬物の結晶化を抑制することができる。On the other hand, a pressure-sensitive adhesive layer obtained by blending a hydrophobic liquid component having a lower polarity than the above four liquid components, such as isopropyl myristate and mineral oil, together with polyvinylpyrrolidone and an acrylic pressure-sensitive adhesive, Although the properties are low, the hydrophobicity of the entire pressure-sensitive adhesive layer becomes too high, so that the drug is not only crystallized at the time of production or after the production, but as a result, the transdermal absorbability of the drug is also lowered.
On the other hand, in the use of the above liquid components, in particular, propylene glycol monolaurate, or the combined use of glyceryl monooleate and methyl laurate, or the combined use of glyceryl monooleate and isopropyl palmitate, In addition, since the combination of the long-chain fatty chain and the hydroxyl group can exhibit appropriate hydrophobicity and polarity, crystallization of the drug can be suppressed while preventing moisture absorption of the preparation.
粘着剤層中におけるこれら液状成分の配合量は、特に制限されないが、粘着剤層全体の質量を基準として、合計で２５質量％以下で配合されることが好ましく、１〜２５質量％で配合されることがさらに好ましく、１０〜２５質量％で配合されることが特に好ましい。配合量が２５質量％以下である場合には、アクリル系粘着剤の含量を減少させる必要がないため、粘着力、凝集力および付着性の低下といった問題が生じ難く、１％以上である場合には、上記効果が顕著に得られる傾向にあるためである。 The amount of these liquid components in the pressure-sensitive adhesive layer is not particularly limited, but it is preferably 25% by mass or less based on the total mass of the pressure-sensitive adhesive layer, preferably 1 to 25% by mass. More preferably, it is particularly preferably blended at 10 to 25% by mass. When the blending amount is 25% by mass or less, there is no need to reduce the content of the acrylic pressure-sensitive adhesive, and thus problems such as a decrease in adhesive strength, cohesive strength, and adhesion are unlikely to occur. This is because the above effects tend to be remarkably obtained.
本発明の貼付剤の粘着剤層中には、上記必須成分である薬物、アクリル系粘着剤、ポリビニルピロリドン、ならびに、プロピレングリコールモノラウレート、グリセリルモノオレエート、メチルラウレートおよびイソプロピルパルミテートからなる群から選択される１種または２種以上の液状成分の他、上記の効果を損ねない範囲内に於いて、さらに吸収促進剤を含有させてもよく、使用され得る吸収促進剤としては、従来皮膚での吸収促進作用が認められている化合物のいずれでも良く、例えば炭素鎖数６〜２０の脂肪酸、脂肪アルコール、脂肪酸エステル、アミド、またはエーテル類、芳香族系有機酸、芳香族系アルコール、芳香族系有機酸エステルまたはエーテル（以上は飽和、不飽和のいずれでもよく、また、環状、直鎖状分枝状のいずれでもよい）、さらに、乳酸エステル類、酢酸エステル類、モノテルペン系化合物、セスキテルペン系化合物、エイゾン（Ａｚｏｎｅ）、エイゾン（Ａｚｏｎｅ）誘導体、ピロチオデカン、グリセリン脂肪酸エステル類、プロピレングリコール脂肪酸エステル類、ソルビタン脂肪酸エステル類（Ｓｐａｎ系）、ポリソルベート系（Ｔｗｅｅｎ系）、ポリエチレングリコール脂肪酸エステル類、ポリオキシエチレン硬化ヒマシ油系（ＨＣＯ系）、ポリオキシエチレンアルキルエーテル類、ショ糖脂肪酸エステル類、植物油等が挙げられる。 The adhesive layer of the patch of the present invention comprises the above-mentioned essential ingredients, an acrylic adhesive, polyvinylpyrrolidone, and propylene glycol monolaurate, glyceryl monooleate, methyl laurate and isopropyl palmitate. In addition to one or two or more liquid components selected from the group, an absorption accelerator may be further contained within a range not impairing the above effects. Any of the compounds that are recognized to promote absorption by the skin may be used, for example, fatty acids having 6 to 20 carbon chains, fatty alcohols, fatty acid esters, amides, or ethers, aromatic organic acids, aromatic alcohols, Aromatic organic acid esters or ethers (they may be saturated or unsaturated, and may be cyclic, linear branched Furthermore, lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, azone, azone derivatives, pyrothiodecane, glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan Fatty acid esters (Span type), polysorbate type (Tween type), polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil type (HCO type), polyoxyethylene alkyl ethers, sucrose fatty acid esters, vegetable oil, etc. It is done.
具体的には、カプリル酸、カプリン酸、カプロン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、イソステアリン酸、オレイン酸、リノール酸、リノレン酸、ラウリルアルコール、ミリスチルアルコール、オレイルアルコール、イソステアリルアルコール、セチルアルコール、ラウリン酸ヘキシル、ラウリン酸ジエタノールアミド、ミリスチン酸イソプロピル、ミリスチン酸ミリスチル、ミリスチン酸オクチルドデシル、パルミチン酸セチル、サリチル酸、サリチル酸メチル、サリチル酸エチレングリコール、ケイ皮酸、ケイ皮酸メチル、クレゾール、乳酸セチル、乳酸ラウリル、酢酸エチル、酢酸プロピル、グラニオール、チモール、オイゲノール、テルピネオール、ｌ−メントール、ボルネオロール、ｄ−リモネン、イソオイゲノール、イソボルネオール、ネロール、ｄｌ−カンフル、グリセリンモノカプリレート、グリセリンモノカプレート、グリセリンモノラウレート、ソルビタンモノラウレート、ショ糖モノラウレート、ポリソルベート２０、プロピレングリコール、ポリエチレングリコールモノラウレート、ポリエチレングリコールモノステアレート、ポリオキシエチレンラウリルエーテル、ＨＣＯ−６０、ピロチオデカン、オリーブ油が好ましく、特にラウリルアルコール、イソステアリルアルコール、ラウリン酸ジエタノールアミド、グリセリンモノカプリレート、グリセリンモノカプレート、ソルビタンモノラウレート、ポリオキシエチレンラウリルエーテル、ピロチオデカンが好ましい。
Specifically, caprylic acid, capric acid, caproic 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, hexyl laurate, diethanolamide laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol, Cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate, graniol, thymol, eugenol, terpineol, l-menthol, borneolol, d-limonene, iso Igenol, isoborneol, nerol, dl-camphor, glycerol monocaprylate, glycerol monocaprate, glycerol monolaurate, sorbitan monolaurate, sucrose monolaurate,
このような吸収促進剤は２種以上混合して使用しても良く、貼付剤としての充分な透過性及び発赤、浮腫等の皮膚への刺激性等を考慮して、粘着剤層全体の質量に基づき、好ましくは０．０１〜２０質量％、さらに好ましくは０．０５〜１０質量％、特に好ましくは０．１〜５質量％で配合することができる。 Two or more kinds of such absorption enhancers may be used in combination, and considering the sufficient permeability as a patch and irritation to the skin such as redness and edema, the mass of the entire pressure-sensitive adhesive layer Based on the above, it is preferably 0.01 to 20% by mass, more preferably 0.05 to 10% by mass, and particularly preferably 0.1 to 5% by mass.
また、本発明の貼付剤の粘着層には上記効果を損ねない範囲内に於いて、可塑剤を含有させてもよく、またその可塑剤 は湿式粉砕の溶媒としても使用できる。使用され得る可塑剤としては、石油系オイル（例えば、パラフィン系プロセスオイル、ナフテン系プロセスオイル、芳香族系プロセスオイル等）、スクワラン、スクワレン、植物系オイル（例えば、オリーブ油、ツバキ油、ひまし油、トール油、ラッカセイ油）、シリコンオイル、二塩基酸エステル（例えば、ジブチルフタレート、ジオクチルフタレート等）、液状ゴム（例えば、ポリブテン、液状イソプレンゴム）、液状脂肪酸エステル類（ミリスチン酸イソプロピル、ラウリン酸ヘキシル、セバシン酸ジエチル、セバシン酸ジイソプロピル）、ジエチレングリコール、ポリエチレングリコール、サリチル酸グリコール、プロピレングリコール、ジプロピレングリコール、トリアセチン、クエン酸トリエチル、クロタミトン等が挙げられる。特に流動パラフィン、液状ポリブテン、クロタミトン、セバシン酸ジエチル、ラウリン酸ヘキシルが好ましい。 Further, the adhesive layer of the patch of the present invention may contain a plasticizer within the range where the above effects are not impaired, and the plasticizer can also be used as a solvent for wet grinding. Plasticizers that can be used include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil), silicon oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, sebacine) Diethyl acetate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton, etc.Liquid paraffin, liquid polybutene, crotamiton, diethyl sebacate, and hexyl laurate are particularly preferable.
これらの可塑剤は２種以上を混合して使用しても良く、粘着剤層全体の質量に基づくこのような可塑剤の配合量は、充分な透過性及び貼付剤としての充分な凝集力の維持を考慮して合計で、好ましくは３〜３０質量％、さらに好ましくは３〜２０質量％、特に好ましくは３〜１０質量％であることができる。 These plasticizers may be used as a mixture of two or more, and the amount of such plasticizer based on the mass of the entire pressure-sensitive adhesive layer is sufficient for sufficient permeability and sufficient cohesive strength as a patch. In consideration of maintenance, the total content is preferably 3 to 30% by mass, more preferably 3 to 20% by mass, and particularly preferably 3 to 10% by mass.
さらに、本発明の貼付剤の粘着剤層には上記効果を損ねない範囲内に於いて、粘着付与樹脂を含有させてもよく、使用され得る粘着付与樹脂としては、ロジン誘導体（例えば、ロジン、ロジンのグリセリンエステル、水添ロジン、水添ロジンのグリセリンエステル、ロジンのペンタエリストールエステル等）、脂環族飽和炭化水素樹脂（例えばアルコンＰ１００、荒川化学工業）、脂肪族系炭化水素樹脂（例えばクイントンＢ１７０、日本ゼオン）、テルペン樹脂（例えばクリアロンＰ−１２５、ヤスハラケミカル）、マレイン酸レジン等が挙げられる。これらのうち、特に水添ロジンのグリセリンエステル、脂環族飽和炭化水素樹脂、脂肪族系炭化水素樹脂、テルペン樹脂が好ましい。 Further, the pressure-sensitive adhesive layer of the patch of the present invention may contain a tackifying resin within a range that does not impair the above effects. Examples of the tackifying resin that can be used include rosin derivatives (for example, rosin, Rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester, rosin pentaerythritol ester, etc.), alicyclic saturated hydrocarbon resins (eg Alcon P100, Arakawa Chemical Industries), aliphatic hydrocarbon resins (eg Quinton B170, Nippon Zeon), terpene resins (for example, Clearon P-125, Yasuhara Chemical), resin maleate and the like. Among these, hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin are particularly preferable.
このような粘着付与樹脂の粘着剤層全体の質量に基づく配合量は、貼付剤としての充分な粘着力及び剥離時の皮膚への刺激性を考慮して、好ましくは５〜７０質量％、さらに好ましくは５〜６０質量％、特に好ましくは１０〜５０質量％であることができる。 The blending amount based on the mass of the entire pressure-sensitive adhesive layer of the tackifying resin is preferably 5 to 70% by mass in consideration of sufficient adhesive strength as a patch and irritation to the skin at the time of peeling. Preferably it is 5-60 mass%, Most preferably, it can be 10-50 mass%.
またさらに、本発明の貼付剤には、必要に応じて、抗酸化剤、充填剤、架橋剤、防腐剤、紫外線吸収剤を配合することができ、抗酸化剤としては、トコフェロール及びこれらのエステル誘導体、アスコルビン酸、アスコルビン酸ステアリン酸エステル、ノルジヒトログアヤレチン酸、ジブチルヒドロキシトルエン（ＢＨＴ）、ブチルヒドロキシアニソール等が望ましい。充填剤としては、炭酸カルシウム、炭酸マグネシウム、ケイ酸塩（例えば、ケイ酸アルミニウム、ケイ酸マグネシウム等）、ケイ酸、硫酸バリウム、硫酸カルシウム、亜鉛酸カルシウム、酸化亜鉛、酸化チタン等が望ましい。架橋剤としては、アミノ樹脂、フェノール樹脂、エポキシ樹脂、アルキド樹脂、不飽和ポリエステル等の熱硬化性樹脂、イソシアネート化合物、ブロックイソシアネート化合物、有機系架橋剤、金属または金属化合物等の無機系架橋剤が望ましい。防腐剤としては、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等が望ましい。紫外線吸収剤としては、ｐ−アミノ安息香酸誘導体、アントラニル酸誘導体、サリチル酸誘導体、クマリン誘導体、アミノ酸系化合物、イミダゾリン誘導体、ピリミジン誘導体、ジオキサン誘導体等が望ましい。
このような抗酸化剤、充填剤、架橋剤、防腐剤、紫外線吸収剤は、合計で、貼付剤の粘着剤層全体の質量に基づいて、好ましくは１０質量％以下、さらに好ましくは５質量％以下、特に好ましくは２質量％以下の量で配合されることができる。Furthermore, the patch of the present invention may contain an antioxidant, a filler, a crosslinking agent, a preservative, and an ultraviolet absorber as necessary. As the antioxidant, tocopherols and esters thereof are used. Derivatives, ascorbic acid, ascorbic acid stearic acid ester, nordihuman log ayretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like are desirable. As the filler, calcium carbonate, magnesium carbonate, silicate (for example, aluminum silicate, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like are desirable. Examples of the crosslinking agent include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. desirable. As the preservative, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate and the like are desirable. As the ultraviolet absorber, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like are desirable.
Such antioxidants, fillers, crosslinking agents, preservatives, and ultraviolet absorbers are preferably 10% by mass or less, more preferably 5% by mass based on the total mass of the adhesive layer of the patch. In the following, it can be particularly preferably blended in an amount of 2 mass% or less.
上記構成をとる本発明の貼付剤は、適宜製造することができ、例えば、薬物を含む粘着剤層成分をトルエン、ヘキサン、酢酸エチル等の溶媒に溶解させ、剥離ライナーまたは支持体上に伸展して溶剤を乾燥除去後、支持体または剥離ライナーと張り合わることにより得ることができる。 The patch of the present invention having the above-described configuration can be produced as appropriate. For example, a pressure-sensitive adhesive layer component containing a drug is dissolved in a solvent such as toluene, hexane, or ethyl acetate, and is spread on a release liner or a support. Then, after removing the solvent by drying, it can be obtained by pasting with a support or a release liner.
本発明の貼付剤における支持体層は、粘着剤層を支持するのに適したものであれば特に限定されないが、伸縮性または非伸縮性のものを用いることができる。例えば布、不織布、ポリウレタン、ポリエステル、ポリ酢酸ビニル、ポリ塩化ビニリデン、ポリエチレン、ポリエチレンテレフタレート、アルミニウムシート等、又はそれらの複合素材から選択されるが、長期間（例えば少なくとも１日間以上、さらには３日間以上）の適用に伴い入浴等を考慮して、撥水素材であるかもしくは撥水素材で１面がコーティングされているものであることが望ましい。また、本発明の貼付剤の支持体の厚みは２０μｍ〜８０μｍが好ましい。これは、２０μｍ以上であると適切な強度を得るのが容易な傾向にあり、また８０μｍ以下であると柔軟性に優れる傾向にあるため、長期間の貼付に耐え易いためである。 The support layer in 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 one can be used. For example, selected from cloth, non-woven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, aluminum sheet, or a composite material thereof, but for a long period (for example, at least 1 day or more, and further 3 days In consideration of bathing or the like with application of the above, it is desirable that the material is a water repellent material or one surface is coated with a water repellent material. The thickness of the support of the patch of the present invention is preferably 20 μm to 80 μm. This is because if it is 20 μm or more, it tends to be easy to obtain an appropriate strength, and if it is 80 μm or less, it tends to be excellent in flexibility, so that it is easy to withstand long-term sticking.
本発明の貼付剤における剥離ライナー層としては、具体的にはポリエチレンテレフタラート等のポリエステル、ポリ塩化ビニル、ポリ塩化ビニリデン等のフィルム、上質紙とポリオレフィンとのラミネートフィルム等を用いることができる。これらの剥離ライナー層においては、皮膚に貼付する粘着剤層表面側から剥離ライナーを剥離する際の作業容易性を高めるために、剥離ライナー層の粘着剤層と接触する側の面にフッ素処理またはシリコーン処理を施すことが好ましい。 As the release liner layer in the patch of the present invention, specifically, a polyester film such as polyethylene terephthalate, a film such as polyvinyl chloride or polyvinylidene chloride, a laminate film of fine paper and polyolefin, or the like can be used. In these release liner layers, in order to enhance the workability when peeling the release liner from the surface of the pressure-sensitive adhesive layer applied to the skin, the surface of the release liner layer on the side in contact with the pressure-sensitive adhesive layer is treated with fluorine. It is preferable to apply a silicone treatment.
さらに本発明について、実施例により詳細に説明する。本発明はこれらの実施例に限定されるものではなく、各成分の配合順序も限定されない。また、本発明の技術思想を逸脱しない範囲での種々の変更が可能である。なお、以下において、「％」は全て質量％を意味するものとする。 Further, the present invention will be described in detail by examples. The present invention is not limited to these examples, and the blending order of each component is not limited. Various modifications can be made without departing from the technical idea of the present invention. In the following, “%” means all mass%.
実施例1Example 1
上記組成のうち、アクリル系粘着剤溶液を除く全成分を混合し、均一になるまで攪拌した。これにアクリル系粘着剤溶液（固形分４５％）を添加してさらに均一になるまで攪拌して粘着剤溶液を調製した。この粘着剤溶液をシリコーン処理したポリエチレンテレフタレート(ＰＥＴ)製フィルム上に塗工した後、８０℃で約１０分間乾燥して溶媒を除去し、厚さ８０μｍの粘着剤層を形成させた。次に、支持体であるＰＥＴフィルムを貼り合わせて裁断し、本発明の貼付剤を得た。 Of the above composition, all components except the acrylic adhesive solution were mixed and stirred until uniform. An acrylic pressure-sensitive adhesive solution (solid content: 45%) was added thereto and stirred until it became more uniform to prepare a pressure-sensitive adhesive solution. This pressure-sensitive adhesive solution was coated on a silicone-treated polyethylene terephthalate (PET) film, and then dried at 80 ° C. for about 10 minutes to remove the solvent, thereby forming a pressure-sensitive adhesive layer having a thickness of 80 μm. Next, a PET film as a support was bonded and cut to obtain a patch of the present invention.
以下、実施例１の方法に従い、下記各組成を用いて、実施例２〜５の貼付剤を製造した。
実施例２
Example 2
実施例３Example 3
実施例４Example 4
実施例５Example 5
さらに、実施例１の方法に従い、下記各組成を用いて、比較例１〜５の貼付剤を製造した。
比較例１
Comparative Example 1
比較例２Comparative Example 2
比較例３Comparative Example 3
比較例４Comparative Example 4
比較例５Comparative Example 5
試験例１．皮膚透過性試験
上記で得られた貼付剤（実施例１〜５および比較例２〜５）を用いて、以下の手順に従って皮膚透過性試験を行った。なお、比較例１の貼付剤は薬物が結晶化したため、皮膚透過性試験を行うことができなかった。
ヘアレスマウス背部皮膚を剥離し、真皮側をレセプター側層として、３２℃の温水を外周部に循環させたフロースルーセルに装着した。次に、皮膚の角質層側に各貼付剤（製剤適用面積５ｃｍ２）を貼付し、レセプター層としてＰＢＳ溶液を用いて５ｍｌ／ｈで２時間毎に２４時間までレセプター溶液をサンプリングし、その流量を測定すると共に高速液体クロマトグラフィーを用いて薬物濃度を測定した。得られた測定値から1時間当たりの薬物透過速度を算出するとともに、皮膚の単位面積あたりの薬物の最大透過速度（μｇ／ｃｍ２／ｈ）を求めた。結果を表１、表２および図１に示す。 Test Example 1 Skin permeability test Using the patches obtained above (Examples 1 to 5 and Comparative Examples 2 to 5), a skin permeability test was performed according to the following procedure. Note that the skin permeation test could not be performed with the patch of Comparative Example 1 because the drug crystallized.
The dorsal skin of the hairless mouse was peeled off, and attached to a flow-through cell in which warm water at 32 ° C. was circulated around the outer periphery with the dermis side as the receptor side layer. Next, each patch (formulation application area 5 cm 2 ) was applied to the stratum corneum side of the skin, and the receptor solution was sampled at a rate of 5 ml / h every 2 hours for up to 24 hours using a PBS solution as the receptor layer. And the drug concentration was measured using high performance liquid chromatography. The drug permeation rate per hour was calculated from the obtained measured values, and the maximum drug permeation rate (μg / cm 2 / h) per unit area of the skin was determined. The results are shown in Table 1, Table 2 and FIG.
表１、表２および図１の結果から、本発明の貼付剤である実施例１〜５はいずれも、比較例２および３と比較して少なくとも２倍以上の優れた皮膚透過速度を有していることが明らかになった。また、比較例１は結晶化してしまったのに対し、実施例１の貼付剤は結晶化することなく製剤安定性に優れたものであることが理解される。 From the results shown in Tables 1 and 2 and FIG. 1, each of Examples 1 to 5 as the patch of the present invention has an excellent skin permeation rate at least twice as high as that of Comparative Examples 2 and 3. It became clear that. Moreover, it is understood that Comparative Example 1 has been crystallized, whereas the patch of Example 1 is excellent in formulation stability without being crystallized.
試験例２．薬物含量試験
作成した貼付剤（実施例１および比較例５）を１０ｃｍ２に打ち抜き、６０℃で１ヶ月間保存した後、テトラヒドロフラン２０ｍｌ及びアセトニトリル１０ｍｌを加えて１時間振とうした。その抽出液に内標準溶液（１２．９ｍｍｏｌ／ｌ ｐ−ヒドロキシ安息香酸ｎ−ブチルアセトニトリル溶液）４ｍｌを加え、さらにアセトニトリルを加えて１００ｍｌにメスアップし、高速液体クロマトグラフィーにより各貼付剤に含まれているエストラジオールの量を定量した。その結果を表１に示す。 Test Example 2 The patch (Example 1 and Comparative Example 5) prepared for the drug content test was punched into 10 cm 2 and stored at 60 ° C. for 1 month, and then 20 ml of tetrahydrofuran and 10 ml of acetonitrile were added and shaken for 1 hour. 4 ml of internal standard solution (12.9 mmol / l p-hydroxybenzoic acid n-butylacetonitrile solution) is added to the extract, and further acetonitrile is added to make up to 100 ml, which is contained in each patch by high performance liquid chromatography. The amount of estradiol that has been quantified. The results are shown in Table 1.
表１の結果より、６０℃で１ヶ月保存した後には、比較例５の製剤では、エストラジオールの含有量が当初製剤中に含有されていた量の約８０％にまで低下していたのに対し、本発明の貼付剤である実施例１では、初期に製剤中に含有されていたエストラジオールの約９５％が残存していたことから、本発明の貼付剤が含有された薬物の安定性に優れた安全性の高い製剤であることが理解される。 From the results in Table 1, after storing at 60 ° C. for 1 month, in the preparation of Comparative Example 5, the content of estradiol was reduced to about 80% of the amount contained in the original preparation. In Example 1, which is the patch of the present invention, about 95% of the estradiol initially contained in the preparation remained, so that the stability of the drug containing the patch of the present invention was excellent. It is understood that this is a highly safe formulation.
試験例３．付着性試験
まず、実施例１の製造方法に従い、下記組成を用いて、薬物であるエストラジオールを含有しない以外はそれぞれ実施例１および比較例４と全く同じ成分を含有するプラセボ貼付剤（プラセボ製剤１および２）を製造した。 Test Example 3 Adhesion Test First, according to the production method of Example 1, a placebo patch (placebo formulation 1) containing exactly the same components as in Example 1 and Comparative Example 4 except that it does not contain estradiol, which is a drug, using the following composition. And 2) were produced.
プラセボ製剤１
プラセボ製剤２
次に、プラセボ製剤１および２についてそれぞれ２０ｃｍ２を、被験者１８人の左右の下腹部へ１枚ずつ貼付し、４日間（９６時間）にわたり２４時間毎の入浴前および入浴後に以下の判定基準に従って付着性を評価し、その平均値を図２に示した。
＜判定基準＞
１０：全く剥がれていない
８：端の部分（１／１０程度）剥離
６：１／５程度剥離
４：１／３程度剥離
２：１／２程度剥離
０：剥がれ落ちたThen, each 20 cm 2 for the
<Criteria>
10: not peeled at all 8: edge part (about 1/10) peeling 6: about 1/5 peeling 4: about 1/3 peeling 2: about 1/2 peeling 0: peeling off
図２の結果から明らかなとおり、本発明の貼付剤である実施例１と同じ粘着剤成分のプラセボ製剤１は、毎日入浴するという状況下で４日間貼付しても、製剤の端の部分が１／１０程度剥離しただけであったのに対し、比較例４と同じ粘着剤成分のプラセボ製剤２は、１日後にはすでに１／５程度は剥離してしまっており、４日後には１／２まで剥離した。 また、プラセボ製剤１、２ともに、貼付した被験者にはカブレ等の皮膚刺激は観察されず、皮膚刺激性においてはプラセボ製剤１と２で差はなかった。一方、プラセボ製剤２を貼付した被験者では、６名で製剤が剥がれ落ち、脱落が認められたのに対し、プラセボ製剤１を貼付した被験者ではいずれも脱落は観察されなかった。したがって、本発明の貼付剤は長期間にわたる皮膚への付着性に特に優れたものでありながら、皮膚への安全性にも優れたものであることが理解される。
As is clear from the results of FIG. 2, the
以上の試験例の結果から、比較例の貼付剤は、製剤の結晶化が起こるもしくは薬物の皮膚透過性が低いといった欠点を有しているか、または薬物の皮膚透過性が良好であっても、製剤中に含まれる薬物の安定性に欠けるもしくは長期間の適用に耐える十分な付着性を有していないなどの問題点を有しており、実際に医薬品として患者に提供されるために十分なものとはいえないのに対し、本願発明の貼付剤は、優れた薬物の皮膚透過性、含有薬物の高い安定性、長期間の貼付に耐える十分な付着性、皮膚への高い安全性、良好な製剤物性といった効果全てを同時に実現することができるものであり、臨床の場において、少なくとも３日以上という長期間にわたって薬効を十分に発揮できる安全な製剤として使用し得るものである。 From the results of the above test examples, the patch of the comparative example has a defect that crystallization of the preparation occurs or the skin permeability of the drug is low, or even if the drug has good skin permeability, It has problems such as lack of stability of drugs contained in the formulation or insufficient adhesion to withstand long-term application, and is sufficient to be actually provided to patients as pharmaceuticals In contrast, the patch of the present invention has excellent skin permeability of the drug, high stability of the contained drug, sufficient adhesion to withstand long-term application, high safety to the skin, good All the effects such as physical properties of the preparation can be realized at the same time, and can be used as a safe preparation capable of sufficiently exerting the medicinal effect for a long period of at least 3 days or more in the clinical field.
以上説明した通り、本発明によれば、少なくとも１日間以上、さらには３日間以上貼付しても、皮膚への付着性が十分でありながら、皮膚への安全性に優れ、また、薬物の結晶析出がなく、含有薬物の安定性に優れ、製剤物性および経皮吸収性が非常に良好な薬物含有貼付剤を提供することができる。そしてまた、本発明によれば、３日間以上という長期間にわたって、持続的に体内に十分な量の薬物を供給することが可能なエストラジオール含有貼付剤を提供することができる。 As described above, according to the present invention, even when affixed for at least 1 day or even 3 days or more, the adhesion to the skin is sufficient, and the safety to the skin is excellent. It is possible to provide a drug-containing patch that does not precipitate, has excellent stability of the contained drug, and has very good physical properties and transdermal absorbability. In addition, according to the present invention, it is possible to provide an estradiol-containing patch capable of continuously supplying a sufficient amount of drug into the body for a long period of 3 days or longer.
Claims (4)
１種または２種以上の液状成分、
粘着剤層全体の質量を基準として５〜１５質量％のポリビニルピロリドン、
ならびに、アクリル酸、アクリル酸２−エチルヘキシルおよび酢酸ビニルからなる、粘着剤層全体の質量を基準として６０〜８０質量％のアクリル系粘着剤
を含有する粘着剤層を含み、
液状成分が
Ｉ）プロピレングリコールモノラウレート、
ＩＩ）グリセリルモノオレエートとメチルラウレートとの組み合わせ、または
ＩＩＩ）グリセリルモノオレエートとイソプロピルパルミテートとの組み合わせである、
貼付剤。 Drugs,
One or more liquid components,
5 to 15% by weight of polyvinylpyrrolidone based on the weight of the entire pressure-sensitive adhesive layer,
And, acrylic acid, consisting of 2-ethylhexyl acrylate and vinyl acetate, seen containing a pressure-sensitive adhesive layer containing an acrylic pressure-sensitive adhesive of 60 to 80% by weight, based on the weight of the total adhesive layer,
Liquid component
I) propylene glycol monolaurate,
II) A combination of glyceryl monooleate and methyl laurate, or
III) A combination of glyceryl monooleate and isopropyl palmitate.
Patch.
液状成分を合計で１〜２５質量％含有することを特徴とする、請求項１に記載の貼付剤。 Based on the mass of the entire adhesive layer ,
Characterized in that it contains 1 to 25 wt% of the liquid-like components in total, patch according to claim 1.
The patch according to any one of claims 1 to 3, wherein the drug is estradiol.
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| JP2007552906A JP5285279B2 (en) | 2005-12-28 | 2006-12-20 | Transdermal preparation |
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| JP2005378796 | 2005-12-28 | ||
| PCT/JP2006/325399 WO2007077741A1 (en) | 2005-12-28 | 2006-12-20 | Transdermally absorbable preparation |
| JP2007552906A JP5285279B2 (en) | 2005-12-28 | 2006-12-20 | Transdermal preparation |
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| JP5209433B2 (en) * | 2007-10-19 | 2013-06-12 | 日東電工株式会社 | Patch preparation |
| CN102099020B (en) | 2008-05-30 | 2013-09-18 | 迈兰股份有限公司 | Stabilized transdermal drug delivery system |
| US20130338122A1 (en) * | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
| CN104487072B (en) * | 2012-07-26 | 2017-08-04 | 久光制药株式会社 | Adhesive preparation and its manufacture method |
| CN104955516B (en) | 2012-12-28 | 2019-01-22 | 帝国制药美国公司 | Extend buprenorphine percutaneous delivering compositions and its application method |
| JP2014148492A (en) * | 2013-02-04 | 2014-08-21 | Asanuma Corporation | Shampoo composition |
| KR101564434B1 (en) | 2013-04-04 | 2015-10-29 | 현대약품 주식회사 | A topical composition having enhanced skin penetration |
| MA41266A (en) * | 2014-12-22 | 2017-10-31 | Hisamitsu Pharmaceutical Co | POULTICE |
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| WO2000051575A1 (en) * | 1999-03-01 | 2000-09-08 | Amarin Technologies S.A. | Transdermal device comprising non-steroidal anti-inflammatory drugs incorporated in acrylic adhesive polymer matrix |
| US6267984B1 (en) * | 1997-12-22 | 2001-07-31 | Alza Corporation | Skin permeation enhancer compositions comprising a monoglyceride and ethyl palmitate |
| JP2002542277A (en) * | 1999-04-22 | 2002-12-10 | エルティエス ローマン テラピー−ズュステーメ アーゲー | Transdermal therapeutic system with neutralized acrylic adhesive patch |
| JP2003533471A (en) * | 2000-05-16 | 2003-11-11 | サムヤン コーポレイション | Hydrogel compositions for transdermal drug delivery |
| JP2004512356A (en) * | 2000-11-06 | 2004-04-22 | サムヤン コーポレイション | Transdermal agent with improved water absorption and adhesion |
| WO2005002482A1 (en) * | 2002-05-23 | 2005-01-13 | Agile Therapeutics, Inc. | Transdermal hormone delivery system: compositions and methods |
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| US6267984B1 (en) * | 1997-12-22 | 2001-07-31 | Alza Corporation | Skin permeation enhancer compositions comprising a monoglyceride and ethyl palmitate |
| WO2000051575A1 (en) * | 1999-03-01 | 2000-09-08 | Amarin Technologies S.A. | Transdermal device comprising non-steroidal anti-inflammatory drugs incorporated in acrylic adhesive polymer matrix |
| JP2002542277A (en) * | 1999-04-22 | 2002-12-10 | エルティエス ローマン テラピー−ズュステーメ アーゲー | Transdermal therapeutic system with neutralized acrylic adhesive patch |
| JP2003533471A (en) * | 2000-05-16 | 2003-11-11 | サムヤン コーポレイション | Hydrogel compositions for transdermal drug delivery |
| JP2004512356A (en) * | 2000-11-06 | 2004-04-22 | サムヤン コーポレイション | Transdermal agent with improved water absorption and adhesion |
| WO2005002482A1 (en) * | 2002-05-23 | 2005-01-13 | Agile Therapeutics, Inc. | Transdermal hormone delivery system: compositions and methods |
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