JP3066515B2 - Transdermal formulation for treatment of urinary incontinence - Google Patents
Transdermal formulation for treatment of urinary incontinenceInfo
- Publication number
- JP3066515B2 JP3066515B2 JP4327460A JP32746092A JP3066515B2 JP 3066515 B2 JP3066515 B2 JP 3066515B2 JP 4327460 A JP4327460 A JP 4327460A JP 32746092 A JP32746092 A JP 32746092A JP 3066515 B2 JP3066515 B2 JP 3066515B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- parts
- molecular weight
- oxybutynin
- polyisobutylene
- 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.)
- Expired - Lifetime
Links
Description
【０００１】[0001]
【産業上の利用分野】本発明は尿失禁，尿意切迫感，頻
尿などの膀胱機能障害に適用される経皮投与製剤に関す
るものである。更に詳しく述べると、オキシブチニンを
有効成分として含有する事を特徴とする尿失禁治療用経
皮投与製剤に関するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for transdermal administration applied to bladder dysfunction such as urinary incontinence, urgency and urinary frequency. More specifically, the present invention relates to a transdermal administration preparation for treating urinary incontinence, which comprises oxybutynin as an active ingredient.
【０００２】[0002]
【従来の技術】近年、高齢化が進行するに伴い、失禁患
者は２００万人を優に越えるものと予想され、国内での
寝たきり、もしくは寝たり起きたりの痴呆老人の約５０
％が失禁を起こすと言われており、将来的にはさらに増
加するものと予想される。このような状況の中で，頻尿
や尿失禁等の排尿以上を治療するための試みも数多くな
され，例えば、前記のごとき排尿異常を治療するための
経口投与型の排尿異常改善薬として、多くの種類の医薬
が既に市販されている。2. Description of the Related Art With the aging of the population in recent years, it is expected that the number of incontinent patients will exceed 2 million.
% Are said to cause incontinence and are expected to increase further in the future. In such a situation, many attempts have been made to treat urination such as pollakiuria and urinary incontinence. For example, as an orally administered urination disorder improving drug for treating urination disorders as described above, many attempts have been made. Are already commercially available.
【０００３】しかしながら、例えばこれらの頻尿をきた
す原因疾患の内脳脊随外傷、脳血管障害、各所腫瘍手術
後の患者などは、寝たきりで過ごす時間を必要とする。
これらの患者の場合、経口投与における施薬において
は、一定時間毎に薬を服用しなければならないので、施
薬が難しい場合も多く見受けられる。一方、近年効果的
薬物投与経路即ちドラッグデリバリーシステムの概念よ
り、経皮投与経路が注目されている。従来の経口投与に
より腸管から吸収された薬物は必然的に門脈を経て肝臓
に送られて代謝を受ける、いわゆる初回通過効果が生
じ、生物学的利用率が甚だしく低下する。そこで有効血
中濃度を保つためには、比較的多量の薬物を投与する必
要があり、当然副作用発現率も増大する。その点、経皮
投与によると、薬物は直ちに皮下毛細血管に入り、殆ど
分解を受ける事無く、静脈、心臓を経て目的部位に到達
する。即ち、薬物の生物学的利用率は最大限に近く、薬
物は比較的少量を持って足りる。ゆえに、副作用の強い
薬物や経口叉は注射による投与が主に行われてきた薬物
及び有効血中濃度保持時間が短く１日数回の投与が必要
な薬物を、副作用を軽減し且つ苦痛を伴わずに皮膚から
徐々に持続的に吸収させる事が出来る。このため、経皮
投与は薬物の徐放化方法として有効であり、前記排尿異
常改善薬としても経皮投与型のものが期待されている。
この様な実状から、デロジリン、オキシブチニン等尿失
禁治療剤の長時間にわたって持続的に血中濃度を維持す
る製剤の開発が望まれており、近年その例としてこれら
の薬物を経皮的に吸収させる外用剤について提案されて
いる。（特開平４−２６６８２１号公報、特開平４−２
７３８１８号公報）[0003] However, for example, patients suffering from intracerebrospinal trauma, cerebrovascular disorders, and various places after surgery for tumors that cause urinary frequency require bedridden time.
In the case of these patients, in the case of oral administration, it is often difficult to administer the drug because the drug must be taken at regular intervals. On the other hand, in recent years, transdermal administration routes have attracted attention from the concept of effective drug administration routes, that is, drug delivery systems. Drugs absorbed from the intestinal tract by conventional oral administration are necessarily sent to the liver via the portal vein for metabolism, a so-called first-pass effect, and the bioavailability is significantly reduced. Therefore, in order to maintain the effective blood concentration, it is necessary to administer a relatively large amount of the drug, and the incidence of side effects naturally increases. In this regard, according to transdermal administration, the drug immediately enters the subcutaneous capillaries and reaches the target site via the vein and heart without undergoing any substantial degradation. That is, the bioavailability of the drug is near maximal and the drug needs to be in relatively small amounts. Therefore, drugs with strong side effects, drugs that have been mainly administered orally or by injection, and drugs that have a short effective blood concentration holding time and need to be administered several times a day can reduce side effects without causing pain. Can be gradually and continuously absorbed from the skin. For this reason, transdermal administration is effective as a method for sustained release of a drug, and a transdermal administration type is expected as the urinary abnormalities improving drug.
Under such circumstances, it has been desired to develop a preparation for maintaining urinary incontinence such as delodiline, oxybutynin and the like in the blood for a long period of time, and in recent years, for example, these drugs have been transdermally absorbed. Topical preparations have been proposed. (JP-A-4-266821, JP-A-4-2
No. 73818)
【０００４】[0004]
【発明が解決しようとする課題】しかしながら、これら
の提案の中では、製剤化において重要な薬物安定性、及
び製剤の物性安定性、皮膚刺激性、持続放出性について
は十分な検討がなされていない。例えば、特開平４−２
６６８２１号公報の中の実施例においては、テロジリ
ン、オキシブチニンを塩酸塩として用い水性基剤で検討
を行っており、処方中の多くの添加剤及び水との相互作
用により十分な薬物安定性は期待できない。また、実際
の薬剤投与においては１日１回もしくは２日に１回の薬
剤の投与が望まれており、その点、水性基剤では長時間
の貼付における貼着安定性について不十分である。特開
平４−２７３７１８号公報においても同様に薬物の安定
性及び皮膚刺激性等の要件を満足していない。However, in these proposals, sufficient studies have not been made on drug stability, which is important in formulation, and on physical stability, skin irritation, and sustained release of the formulation. . For example, Japanese Patent Laid-Open No. 4-2
In the examples in JP-A-66821, terodiline and oxybutynin are used as hydrochloride salts and an aqueous base is studied. Sufficient drug stability is expected due to interaction with many additives and water in the formulation. Can not. Further, in actual drug administration, it is desired to administer the drug once a day or once every two days. In this respect, the aqueous base is insufficient in the application stability in long-time application. Japanese Patent Application Laid-Open No. 4-273718 similarly does not satisfy requirements such as drug stability and skin irritation.
【０００５】[0005]
【問題を解決するための手段】本発明は、上記従来から
のオキシブチニン製剤の問題点を解決するためのもので
あってその目的とするところは、有効成分であるオキシ
ブチニンを安定に保持し、持続的に，且つ効果的に経皮
吸収させて優れた薬効を発現させうる経皮投与用医薬製
剤を提供することにある。本発明者らは、上記目的を達
成すべく鋭意検討を重ねた結果、合成ゴムであるポリイ
ソブチレンを主体とした基剤がオキシブチニンの薬物の
安定性、薬物の持続放出性及び長時間の皮膚貼着性にお
いて優れた性能を有する事を見いだし、本発明を完成す
るに至った。Means for Solving the Problems The present invention is intended to solve the problems of the above-mentioned conventional oxybutynin preparations, and aims at stably retaining oxybutynin as an active ingredient, It is an object of the present invention to provide a transdermally administrable pharmaceutical preparation which can be effectively and effectively transdermally absorbed to exhibit excellent drug efficacy. The present inventors have conducted intensive studies to achieve the above object, and as a result, it has been found that a base mainly composed of a synthetic rubber, polyisobutylene, has a drug stability of oxybutynin, a sustained release property of the drug, and a long-term skin patch. They have found that they have excellent performance in terms of adhesion, and have completed the present invention.
【０００６】さらに、徐放性に優れるポリイソブチレン
を主体とする感圧性接着剤は、鉱油または鮫肝油及び熱
可塑性樹脂、または化学的に安定な充填剤を含有するこ
とにより、薬物放出性をさらに効率よくコントロールす
るものである。本発明における感圧性接着剤は，ポリイ
ソブチレンを主基剤として構成するものであり粘度平均
分子量４０００００〜１８０００００を有する高分子量
ポリイソブチレン及び粘度平均分子量１００００〜２０
００００の低分子量ポリイソブチレンを必須成分とす
る。また、その含量に付いては製剤の物性及び薬物放出
性を考慮し、高分子量ポリイソブチレンについて１０〜
８０重量％、好ましくは２０〜５０重量％を含有する。
また低分子量ポリイソブチレンについては１０〜８０重
量％，好ましくは１５〜５０重量％の範囲で配合する事
が好ましい。また、本感圧性接着剤に含有する鉱油及び
鮫肝油は、粘度が５〜１００ｃｐの範囲のものが適当で
あり使用する鮫肝油の例としては、天然及び合成のスク
ワラン、スクワレン等がある。配合量としては５〜７０
％、好ましくは２０〜６０％含有することができる。ま
た、スクワランについては安定な飽和炭化水素であるこ
とが公知であり、しかも低皮膚刺激性の点から化粧品と
しても繁用されているものであり、本発明の製剤におい
ても同様に皮膚刺激性を低減させる効果を有するもので
ある。又、本発明の製剤においてこれらの鉱油及び鮫肝
油等の油性の添加剤は、その含有量を増加することによ
り放出性を向上させることが出来るが、５０％を越える
と製剤としての凝集力が不足し、製剤の粘着性及び安定
性に支障をきたすことがある。また、この様な基剤中
に、熱可塑性樹脂及び化学的に安定な充填剤を含有する
ことにより、基剤の粘着性及び凝集力を損なうこと無く
安定な持続放出性を長時間にわたって達成できるもので
ある。ここで使用できる熱可塑性樹脂としては、例えば
常温で結晶状態で軟化点が５０〜２５０℃のものが好ま
しく、具体的にはロジン叉はその誘導体、テルペン樹
脂、テルペン、フェノール樹脂、石油樹脂、アルキル・
フェノール樹脂、キシレン樹脂などの粘着付与性樹脂な
どが挙げられる。これらの樹脂は、１種もしくは２種以
上を５０重量％以下、好ましくは５〜４０重量％の範囲
で配合する。また、充填剤としては化学的に安定なもの
が好適であり、具体的には、酸化チタン、酸化亜鉛、タ
ルク、無水珪酸、珪酸マグネシウム、ポリエチレンビー
ズ、ポリスチレンビーズなどが挙げられその粒子系は２
０μｍ以下好ましくは０．５〜１０μｍのものが望まし
い。これらの充填剤は１種もしくは２種配合する事が出
来、１０％以下、好ましくは０．１〜５％の範囲で配合
することができる。[0006] Further, the pressure-sensitive adhesive mainly composed of polyisobutylene having excellent sustained-release properties further improves drug release by containing mineral oil or shark liver oil and a thermoplastic resin, or a chemically stable filler. It controls efficiently. The pressure-sensitive adhesive in the present invention comprises polyisobutylene as a main base, and has a high-molecular-weight polyisobutylene having a viscosity-average molecular weight of 400,000 to 1800000 and a viscosity-average molecular weight of 10,000 to 20.
0000 low molecular weight polyisobutylene is an essential component. In addition, regarding the content, considering the physical properties of the preparation and the drug release, the
It contains 80% by weight, preferably 20-50% by weight.
It is preferable that the low-molecular-weight polyisobutylene is added in an amount of 10 to 80% by weight, preferably 15 to 50% by weight. The mineral oil and shark liver oil contained in the pressure-sensitive adhesive are suitably those having a viscosity in the range of 5 to 100 cp. Examples of the shark liver oil to be used include natural and synthetic squalane and squalene. 5 to 70
%, Preferably 20 to 60%. Further, squalane is known to be a stable saturated hydrocarbon, and is widely used as a cosmetic in terms of low skin irritation. It has the effect of reducing. In addition, in the preparation of the present invention, the oily additives such as mineral oil and shark liver oil can improve the releasability by increasing the content thereof. Insufficiency, which may affect the adhesiveness and stability of the formulation. In addition, by including a thermoplastic resin and a chemically stable filler in such a base, stable sustained release can be achieved for a long time without impairing the adhesiveness and cohesion of the base. Things. As the thermoplastic resin that can be used here, for example, those having a softening point of 50 to 250 ° C. in a crystalline state at ordinary temperature are preferable, and specifically, rosin or a derivative thereof, terpene resin, terpene, phenol resin, petroleum resin, alkyl resin・
Tackifying resins such as phenolic resins and xylene resins are exemplified. One or more of these resins are blended in an amount of 50% by weight or less, preferably 5 to 40% by weight. As the filler, those which are chemically stable are preferable, and specific examples thereof include titanium oxide, zinc oxide, talc, silicic anhydride, magnesium silicate, polyethylene beads, and polystyrene beads.
0 μm or less, preferably 0.5 to 10 μm is desirable. One or two of these fillers can be blended, and can be blended in an amount of 10% or less, preferably 0.1 to 5%.
【０００７】即ち、本発明は徐放性に優れたポリイソブ
チレンを主基剤とした感圧性接着剤に薬物の拡散移動を
促進するための鉱油及びスクワラン等の鮫肝油を含有
し、さらに、熱可塑性樹脂並びに化学的に安定な充填剤
を配合することにより、物性的にも安定な持続放出性に
優れた尿失禁治療用経皮投与製剤を提供することにあ
る。また、上記添加剤はすべて化学的に安定なものであ
り、オキシブチニンとの相互作用がなく、経時的な薬物
の安定性についても優れた性能を有するものである。本
発明の経皮投与用医薬製剤において有効成分として用い
るオキシブチニンは基剤中に１〜５０重量％、好ましく
は５〜２０重量％の範囲で溶解もしくは分散状態にて含
有する事が望ましい。含有量が１重量％に満たない場合
は、オキシブチニンによる薬効が十分に期待できなかっ
たり持続的な薬効の発現が望めない場合がある。また、
５０重量％を越えて含有させた場合は増量による薬効及
び持続性の向上が望めないばかりでなく、基剤層の皮膚
接着性が低下する傾向を示し好ましくない。That is, the present invention comprises a polyisobutylene-based pressure-sensitive adhesive excellent in sustained release containing a mineral oil for promoting the diffusion and transfer of drugs and a shark liver oil such as squalane. It is an object of the present invention to provide a transdermal preparation for treating urinary incontinence which is stable in physical properties and excellent in sustained release by blending a plastic resin and a chemically stable filler. In addition, all of the above additives are chemically stable, have no interaction with oxybutynin, and have excellent performance in drug stability over time. Oxybutynin used as an active ingredient in the pharmaceutical preparation for transdermal administration of the present invention is desirably contained in a base in an amount of 1 to 50% by weight, preferably 5 to 20% by weight in a dissolved or dispersed state. When the content is less than 1% by weight, the drug effect by oxybutynin may not be sufficiently expected or a continuous drug effect may not be expected. Also,
If the content exceeds 50% by weight, not only is it not possible to expect an improvement in drug efficacy and sustainability by increasing the amount, but also the skin adhesion of the base layer tends to decrease, which is not preferable.
【０００８】また、本発明は所望により皮膚透過促進剤
も含有することができる。本感圧性接着剤に用いる皮膚
透過促進剤としては特に限定されないが、例えばｌ−メ
ントール，ハッカ油，ｄ−リモネン等のテルペン油、グ
リセリルモノラウレート，グリセリルモノオレエート，
セバシン酸ジエチル等の脂肪酸エステル、エイゾン及び
１−〔２−（デシルチオ）エチル〕アザシクロペンタン
−２−オン等のアザシクロアルカン類、その他、オレイ
ン酸、ラウリン酸、ミリスチン酸、オレイルアルコール
等の脂肪酸もしくは脂肪族アルコールから選ばれる１種
もしくは２種の混合物を０〜１５％、好ましくは０．５
〜５％の範囲で配合することができる。本発明に用いる
支持体としては特に限定されないが、皮膚面に貼付した
際に著しい違和感を生じない程度に柔軟性を有するもの
が好ましく、例えば、ポリエチレン，ポリプロピレン，
ポリエステル，ポリ酢酸ビニル，エチレン−酢酸ビニル
共重合体，ポリ塩化ビニル，ポリウレタンなどのプラス
チックフィルム，アルミニウム箔，鈴箔などの金属箔、
不織布，布，紙などからなる単層フィルムやこれらの積
層フィルムが使用できる。またこれらの担持体は、前記
基剤層との密着性，接着性を向上させるために基剤層形
成面にコロナ放電処理やプラズマ処理，酸化処理などを
施す事が望ましい。本発明の経皮投与医薬製剤は、上記
支持体の表面に前記基剤層を形成してなるものであるが
皮膚面への貼着の直前までは、基剤層の露出面にシリコ
ーン樹脂やフッ素樹脂などの塗布によって剥離処理を施
した紙やプラスチックフィルムなどの剥離ライナーにて
被覆保護する事が好ましい。[0008] The present invention can also optionally contain a skin permeation enhancer. The skin permeation enhancer used in the present pressure-sensitive adhesive is not particularly limited. Examples thereof include terpene oils such as l-menthol, peppermint oil, d-limonene, glyceryl monolaurate, glyceryl monooleate, and the like.
Fatty acid esters such as diethyl sebacate, azacycloalkanes such as Azone and 1- [2- (decylthio) ethyl] azacyclopentan-2-one, and other fatty acids such as oleic acid, lauric acid, myristic acid, and oleyl alcohol Alternatively, one or two kinds of mixtures selected from aliphatic alcohols are added in an amount of 0 to 15%, preferably 0.5 to 15%.
It can be blended in the range of ５5%. The support for use in the present invention is not particularly limited, but is preferably flexible enough to not cause a significant discomfort when applied to the skin surface. Examples thereof include polyethylene, polypropylene, and the like.
Plastic films such as polyester, polyvinyl acetate, ethylene-vinyl acetate copolymer, polyvinyl chloride, and polyurethane; metal foils such as aluminum foil and bell foil;
A single-layer film made of non-woven fabric, cloth, paper, or the like, or a laminated film thereof can be used. In addition, it is desirable that these support members be subjected to a corona discharge treatment, a plasma treatment, an oxidation treatment, or the like on the surface on which the base layer is formed in order to improve the adhesion and the adhesion to the base layer. The pharmaceutical preparation for percutaneous administration of the present invention is obtained by forming the base layer on the surface of the support, but until immediately before sticking to the skin surface, a silicone resin or the like is exposed on the exposed surface of the base layer. It is preferable to cover and protect with a release liner such as paper or plastic film that has been subjected to a release treatment by applying a fluorine resin or the like.
【０００９】[0009]
【実施例】以下、実施例においてさらに具体的に説明す
る。 実施例１ 高分子量ポリイソブチレン １５．６重量部 （粘度平均分子量１，１１０，０００，Ｏｐｐａｎｏｌ Ｂ−１００） 低分子量ポリイソブチレン １６．４重量部 （粘度平均分子量４０．０００，Ｏｐｐａｎｏｌ Ｂ−１０） 流動パラフィン ４６．３重量部 水添ロジンエステル（ＫＥ−３１１） １０．２重量部 酸化チタン １．５重量部 からなる組成物を、ヘキサンに溶解してできたポリイソ
ブチレン溶液（固形分濃度２５．０％）にオキシブチニ
ンを乾燥時の含有量が１０％となるように添加混合し，
離型ライナー上に乾燥後の厚みが５０μｍとなるように
塗布，乾燥して基剤層を形成した。次に，ポリエステル
フィルム（厚み２５μｍ）に上記にて得た基剤層を転着
して本発明の尿失禁治療用経皮投与用製剤を得た。The present invention will be described more specifically with reference to the following examples. Example 1 High molecular weight polyisobutylene 15.6 parts by weight (viscosity average molecular weight 1,110,000, Oppanol B-100) Low molecular weight polyisobutylene 16.4 parts by weight (viscosity average molecular weight 40.000, Oppanol B-10) Paraffin 46.3 parts by weight Hydrogenated rosin ester (KE-311) 10.2 parts by weight A composition comprising 1.5 parts by weight of titanium oxide was dissolved in hexane to obtain a polyisobutylene solution (solid content: 25.0%). %) And mixed with oxybutynin so that the content when dried is 10%.
The composition was coated on a release liner so that the thickness after drying became 50 μm, and dried to form a base layer. Next, the base layer obtained above was transferred to a polyester film (thickness: 25 μm) to obtain a preparation for transdermal administration for treating urinary incontinence of the present invention.
【００１０】実施例２ 高分子量ポリイソブチレン １２．３重量部 （粘度平均分子量１，１１０，０００，Ｏｐｐａｎｏｌ Ｂ−１００） 低分子量ポリイソブチレン １３．７重量部 （粘度平均分子量４０，０００，Ｏｐｐａｎｏｌ Ｂ−１０） 流動パラフィン ５４．５重量部 水添ロジンエステル（ＫＥ−３１１） ６．０重量部 酸化チタン ４．５重量部 からなる組成物を、以下実施例１と同様にして本発明の
尿失禁治療用経皮投与製剤を得た。Example 2 12.3 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 13.7 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) 54.5 parts by weight of liquid paraffin Hydrogenated rosin ester (KE-311) 6.0 parts by weight A composition comprising 6.0 parts by weight of titanium oxide was treated in the same manner as in Example 1 to treat urinary incontinence according to the present invention. A transdermal preparation was obtained.
【００１１】実施例３ 高分子量ポリイソブチレン １４．６重量部 （粘度平均分子量１，１１０，０００，Ｏｐｐａｎｏｌ Ｂ−１００） 低分子量ポリイソブチレン ２０．４重量部 （粘度平均分子量４０，０００，Ｏｐｐａｎｏｌ Ｂ−１０） スクワラン ４０．５重量部 アエロジル ３．８重量部 水添ロジンエステル（ＫＥ−３１１） １０．７重量部 からなる組成物を、以下実施例１と同様にして本発明の
尿失禁治療用経皮投与製剤を得た。Example 3 14.6 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 20.4 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) Squalane 40.5 parts by weight Aerosil 3.8 parts by weight Hydrogenated rosin ester (KE-311) 10.7 parts by weight The composition for treating urinary incontinence of the present invention was treated in the same manner as in Example 1 below. A skin administration formulation was obtained.
【００１２】比較例１ 高分子量ポリイソブチレン １８．５重量部 （粘度平均分子量１，１１０，０００，Ｏｐｐａｎｏｌ Ｂ−１００） 低分子量ポリイソブチレン ２７．５重量部 （粘度平均分子量４０．０００，Ｏｐｐａｎｏｌ Ｂ−１０） 流動パラフィン ４９．０重量部 からなる組成物を、ヘキサンに溶解してできたポリイソ
ブチレン溶液（固形分濃度２５．０％）にオキシブチニ
ンを乾燥時の含有量が１０％となるように添加混合し、
離型ライナー上に乾燥後の厚みが５０μｍとなるように
塗布、乾燥して基剤層を形成した。次に、ポリエステル
フィルム（厚み２５μｍ）に上記にて得た基剤層を転着
して従来技術のテープ製剤を得た。Comparative Example 1 18.5 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 27.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40.000, Oppanol B-) 10) Add a composition consisting of 49.0 parts by weight of liquid paraffin to a polyisobutylene solution (solid content: 25.0%) prepared by dissolving in hexane so that the content of oxybutynin when dried becomes 10%. Mix,
It was applied on a release liner so that the thickness after drying was 50 μm, and dried to form a base layer. Next, the base layer obtained above was transferred to a polyester film (thickness: 25 μm) to obtain a conventional tape preparation.
【００１３】比較例２ スチレン−イソプレン−スチレンブロック共重合体 ２０．０重量部 （ＫＲＡＴＯＮ Ｄ １１１１、以下ＳＩＳと略記） 水添ロジンエステル（ＫＥ−３１１） ３０．０重量部 流動パラフィン ３２．０重量部 ジブチルヒドロキシトルエン １．０重量部 を、１７０℃で加熱溶融した後、オキシブチニン含量が
１０％となるように添加混合し、シリコン処理したライ
ナー上に塗膏し室温まで冷却した後、ポリエステルフィ
ルム（厚さ２５μｍ）上に転着し、オキシブチニン１０
％含有ＳＩＳ系テープ製剤を得た。Comparative Example 2 Styrene-isoprene-styrene block copolymer 20.0 parts by weight (KRATON D 1111; hereinafter abbreviated as SIS) 30.0 parts by weight of hydrogenated rosin ester (KE-311) 32.0 parts by weight of liquid paraffin 1.0 part by weight of dibutylhydroxytoluene was heated and melted at 170 ° C., added and mixed so that the oxybutynin content became 10%, applied on a silicon-treated liner, cooled to room temperature, and then cooled with a polyester film ( 25 μm thick) and transferred to oxybutynin 10
% SIS tape preparation was obtained.
【００１４】比較例３ ゼラチン １５．０重量部 ニッカゾール ＴＳ−６２０ ５．０重量部 （８８％部分ケン化）ポリビニルアルコール １０．０重量部 グリセリン ２５．６重量部 パラオキシ安息香酸メチル ０．２重量部 アルミニウムグリシネート ０．２重量部 精性水 ４０．０重量部 オキシブチニン ４．０重量部 からなる組成物を、７０℃に加熱した精性水に、ゼラチ
ン、ポリビニルアルコール及びニッカゾールＴＳ−６２
０を順次溶解し（Ｉ）、次に同じく７０℃に加熱したグ
リセリンにパラオキシ安息香酸メチル、オキシブチニン
を溶解させた後、無水マレイン酸−メチルビニルエーテ
ル共重合体及びアルミニウムグリシネートを均一に分散
させたものを、（Ｉ）に加え混合した後、シリコン処理
した離型ライナー上に基剤層の厚さが、３００μｍとな
るように塗布し、片面をＰＥＴ処理した不織布の処理面
上に転着し、オキシブチニン含有パップ製剤を得た。Comparative Example 3 Gelatin 15.0 parts by weight Nicazole TS-620 5.0 parts by weight (88% partially saponified) polyvinyl alcohol 10.0 parts by weight Glycerin 25.6 parts by weight Methyl parahydroxybenzoate 0.2 parts by weight A composition consisting of 0.2 parts by weight of aluminum glycinate, 40.0 parts by weight of purified water, and 4.0 parts by weight of oxybutynin was added to purified water heated to 70 ° C. in gelatin, polyvinyl alcohol and Nicazole TS-62.
0 was sequentially dissolved (I), and then methyl paraoxybenzoate and oxybutynin were dissolved in glycerin also heated to 70 ° C., and then a maleic anhydride-methyl vinyl ether copolymer and aluminum glycinate were uniformly dispersed. The mixture was added to (I), mixed and then applied onto a silicon-treated release liner so that the thickness of the base layer was 300 μm, and one side was transferred to the treated surface of a PET-treated nonwoven fabric. And an oxybutynin-containing cataplasm.
【００１５】試験例１ 経時安定性試験 なお、本実施例及び比較例にて試作した製剤について、
薬物の残存量及び物性面での経時的な安定性試験を実施
した。保存条件は４０℃でアルミ包剤中に密封した形で
行った。オキシブチニンの薬物残存量はＨＰＬＣ法によ
り測定した。また、物性面では外観及び粘着性について
観察を行った。粘着性は、リガクプローブタックテスタ
ーを用い経時的な粘着力の変化を観察した。本実施例の
尿失禁治療用経皮投与製剤中のオキシブチニンは安定で
あったのに対し、比較例２および３における製剤中のオ
キシブチニンの安定性は不十分であった。（表１に試験
結果を示す。）また実施例１〜３の尿失禁治療用経皮投
与製剤はいずれも製品化にたえる十分な物性安定性を示
したのに対し、比較例の製剤では不十分であった。（表
２に試験結果を示す。）Test Example 1 Stability test over time The preparations prepared in Examples and Comparative Examples were
Stability tests over time were performed on the residual amount of the drug and physical properties. The storage was performed at 40 ° C. in a form sealed in an aluminum packaging. The residual amount of oxybutynin was measured by the HPLC method. Further, in terms of physical properties, appearance and adhesion were observed. The adhesiveness was observed by using a Rigaku probe tack tester and the change in adhesive force over time was observed. Oxybutynin in the transdermal formulation for treating urinary incontinence of this example was stable, whereas the stability of oxybutynin in the formulations in Comparative Examples 2 and 3 was insufficient. (The test results are shown in Table 1.) In addition, all of the transdermal administration preparations for treating urinary incontinence of Examples 1 to 3 exhibited sufficient physical stability for commercialization, whereas the preparations of the comparative examples did not. It was not enough. (Table 2 shows the test results.)
【００１６】[0016]
【表１】 [Table 1]
【００１７】[0017]
【表２】 [Table 2]
【００１８】実施例４ 高分子量ポリイソブチレン １３．５重量部 （粘度平均分子量１，１１０，０００，Ｏｐｐａｎｏｌ Ｂ−１００） 低分子量ポリイソブチレン ２２．５重量部 （粘度平均分子量４０，０００，Ｏｐｐａｎｏｌ Ｂ−１０） スクワラン ４７．０重量部 タルク ４．０重量部 からなる組成物を、ヘキサンに溶解してできたポリイソ
ブチレン溶液（固形分濃度３０．０％酸化チタンは分散
状態）に、乾燥時のオキシブチニン含量が１０％となる
ように添加混合した後、シリコン処理した離型ライナー
上に乾燥後の厚みが５０μｍとなるように塗布乾燥して
基剤層を形成させた。次にポリエステルフィルム（厚さ
２５μｍ）上に基剤層を転着させて、本発明の尿失禁治
療用経皮投与用製剤を得た。Example 4 13.5 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 22.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) A composition comprising 47.0 parts by weight of squalane and 4.0 parts by weight of talc was dissolved in hexane to give a polyisobutylene solution (solid content concentration: 30.0% titanium oxide in a dispersed state). After adding and mixing so as to have a content of 10%, the resultant was coated and dried on a silicon-treated release liner so as to have a thickness of 50 μm after drying to form a base layer. Next, the base layer was transferred onto a polyester film (25 μm in thickness) to obtain a preparation for transdermal administration for treating urinary incontinence of the present invention.
【００１９】実施例５ 高分子量ポリイソブチレン １４．５重量部 （粘度平均分子量１，５００，０００，Ｏｐｐａｎｏｌ Ｂ−１２０） 低分子量ポリイソブチレン ２２．５重量部 （粘度平均分子量４０，０００，Ｏｐｐａｎｏｌ Ｂ−１０） 流動パラフィン ４５．５重量部 水添ロジンエステル（ＫＥ−３１１） １５．５重量部 からなる組成物を、以下実施例４と同様にして本発明の
尿失禁治療用経皮投与製剤を得た。Example 5 14.5 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,500,000, Oppanol B-120) 22.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B- 10) A composition comprising 45.5 parts by weight of liquid paraffin and 15.5 parts by weight of hydrogenated rosin ester (KE-311) was prepared in the same manner as in Example 4 to obtain a transdermal administration preparation for treating urinary incontinence of the present invention. Was.
【００２０】実施例６ 高分子量ポリイソブチレン １６．０重量部 （粘度平均分子量１，１１０，０００，Ｏｐｐａｎｏｌ Ｂ−１００） 低分子量ポリイソブチレン １７．５重量部 （粘度平均分子量４０，０００，Ｏｐｐａｎｏｌ Ｂ−１０） 流動パラフィン ４７．５重量部 水添ロジンエステル（ＫＥ−３１１） １７．０重量部 アエロジル ４．０重量部 からなる組成物を、以下実施例４と同様にして本発明の
尿失禁治療用経皮投与製剤を得た。Example 6 16.0 parts by weight of high molecular weight polyisobutylene (viscosity average molecular weight 1,110,000, Oppanol B-100) 17.5 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 40,000, Oppanol B-) 10) Liquid paraffin 47.5 parts by weight Hydrogenated rosin ester (KE-311) 17.0 parts by weight Aerosil 4.0 parts by weight was treated in the same manner as in Example 4 for the treatment of urinary incontinence of the present invention. A transdermal formulation was obtained.
【００２１】実施例７ オキシブチニン含量を２０％とした以外は、実施例４と
同様にして、本発明の尿失禁治療用経皮投与製剤を得
た。Example 7 A transdermal preparation for treating urinary incontinence of the present invention was obtained in the same manner as in Example 4, except that the oxybutynin content was changed to 20%.
【００２２】比較例４ アクリル酸２−エチルヘキシル ７５．０重量部 メタクリル酸メチル １５．０重量部 アクリル酸 １０．０重量部 アゾビスイソブチロニトリル ０．０２重量部 からなる組成物を、酢酸エチル／トルエン（１／１）溶
媒中で、固形分濃度が４０％となるように６０℃、４８
時間重合反応を行い、出来たポリマー溶液にイソシアネ
ート系架橋剤を０．１部、及びオキシブチニンの乾燥時
の含量が１０％となるように、オキシブチニンを添加
し、シリコン処理したライナー上に乾燥時の厚さが５０
μｍとなるように塗膏し、乾燥後、ポリエステルフィル
ム（厚さ２５μｍ）上に転着しオキシブチニン含有アク
リル系テープ製剤を得た。Comparative Example 4 75.0 parts by weight of 2-ethylhexyl acrylate 15.0 parts by weight of methyl methacrylate 10.0 parts by weight of acrylic acid 0.02 parts by weight of azobisisobutyronitrile was treated with ethyl acetate. / Toluene (1/1) solvent at 60 ° C., 48
The polymerization reaction was carried out for a period of time, 0.1 part of an isocyanate-based crosslinking agent was added to the resulting polymer solution, and oxybutynin was added so that the dry content of oxybutynin was 10%. 50 thickness
After coating, drying and transfer onto a polyester film (thickness 25 μm), an oxybutynin-containing acrylic tape preparation was obtained.
【００２３】比較例５ スチレン−イソプレン−スチレンブロック共重合体 ２０．０重量部 （ＫＲＡＴＯＮ Ｄ １１０７Ｐ、以下ＳＩＳと略記） 水添ロジンエステル（ＫＥ−３１１） ３０．０重量部 流動パラフィン ３２．０重量部 ジブチルヒドロキシトルエン １．０重量部 からなる組成物を、１７０℃で加熱溶融した後、オキシ
ブチニン含量が１０％となるように添加混合し、シリコ
ン処理したライナー上に塗膏し室温まで冷却した後、ポ
リエステルフィルム（厚さ２５μｍ）上に転着し、オキ
シブチニン１０％含有ＳＩＳ系テープ製剤を得た。Comparative Example 5 Styrene-isoprene-styrene block copolymer 20.0 parts by weight (KRATON D 1107P, hereinafter abbreviated as SIS) Hydrogenated rosin ester (KE-311) 30.0 parts by weight Liquid paraffin 32.0 parts by weight A composition consisting of 1.0 part by weight of dibutylhydroxytoluene was heated and melted at 170 ° C., added and mixed so that the oxybutynin content became 10%, applied on a silicon-treated liner, and cooled to room temperature. And transferred onto a polyester film (thickness: 25 μm) to obtain an SIS tape preparation containing 10% oxybutynin.
【００２４】比較例６ ゼラチン ３．０重量部 無水マレイン酸−メチルビニルエーテル共重合体 ３．０重量部 （ＧＡＮＴＲＥＺ １６９） 部分ケン化ポリビニルアルコール ５．０重量部 ポリアクリル酸ナトリウム ２．０重量部 グリセリン ３１．０重量部 バラオキシ安息香酸メチル ０．２重量部 精性水 ４９．６重量部 オキシブチニン ４．０重量部 からなる組成物を、７０℃に加熱した精性水に、ゼラチ
ン、ポリアクリル酸ナトリウム、無水マレイン酸−メチ
ルビニルエーテル共重合体を順次溶解さる（Ｉ）。次に
同じく７０℃に加熱したグリセリン部分ケン化ポリビニ
ルアルコール、パラオキシ安息香酸メチル、オキシブチ
ニンを溶解させた後、（Ｉ）に加え混合した後、シリコ
ン処理した離型ライナー上に、基剤層の厚さが、３００
μｍとなるように塗布し、片面をPET処理した不織布の
処理面上に転着し、オキシブチニン含有パップ製剤を得
た。Comparative Example 6 Gelatin 3.0 parts by weight Maleic anhydride-methyl vinyl ether copolymer 3.0 parts by weight (GANTREZ 169) Partially saponified polyvinyl alcohol 5.0 parts by weight Sodium polyacrylate 2.0 parts by weight Glycerin 31.0 parts by weight Methyl balaoxybenzoate 0.2 parts by weight Essential water 49.6 parts by weight A composition consisting of 4.0 parts by weight oxybutynin was added to gelatinous water and sodium polyacrylate heated to 70 ° C. And a maleic anhydride-methyl vinyl ether copolymer are sequentially dissolved (I). Next, glycerin partially saponified polyvinyl alcohol, methyl paraoxybenzoate, and oxybutynin, which were also heated to 70 ° C., were dissolved, added to (I) and mixed, and then the thickness of the base layer was formed on a silicon-treated release liner. Saga, 300
It was applied so as to have a thickness of μm, and was transferred onto the treated surface of a nonwoven fabric that had been PET-treated on one side to obtain an oxybutynin-containing cataplasm.
【００２５】試験例２ 皮膚刺激性試験 実施例４〜６及び比較例４〜６の製剤について、健康人
男性におけるパッチテスト（４８時間貼付）を実施し
た。実施例４〜６の尿失禁治療用経皮投与製剤は、低刺
激性の面で優れた性能を有する。（試験結果を表３に示
す。）Test Example 2 Skin Irritation Test A patch test (applying for 48 hours) on healthy men was carried out on the preparations of Examples 4 to 6 and Comparative Examples 4 to 6. The transdermal administration preparations for treating urinary incontinence of Examples 4 to 6 have excellent performance in terms of low irritation. (Test results are shown in Table 3.)
【００２６】[0026]
【表３】 [Table 3]
【００２７】試験例３ ラットによる経皮吸収実験 ラット インビボにて、経皮吸収性の検討を行った。実
験は直径２ｃｍの円形に調整した製剤を、除毛したラッ
ト腹部に適応し、経時的な血中濃度をガスクロマトグラ
フィーにより測定した。実施例６および７の本発明尿失
禁治療用経皮投与製剤は、優れた持続放出性を有してい
る。（実験結果を図１に示す）Test Example 3 Percutaneous Absorption Experiments with Rats Percutaneous absorption was examined in vivo in rats. In the experiment, a preparation adjusted to a circular shape having a diameter of 2 cm was applied to the abdomen of a dehaired rat, and the blood concentration over time was measured by gas chromatography. The transdermal preparations for treating urinary incontinence of the present invention of Examples 6 and 7 have excellent sustained release properties. (The experimental results are shown in FIG. 1.)
【００２８】[0028]
【発明の効果】本発明の経皮投与用医薬製剤は貼付剤形
態であり，含有するオキシブチニンが皮膚を経由して直
接循環血中に持続的に放出されるので，経口投与時に生
じる肝臓での初回通過効果による代謝を受けず，また一
時的な血中濃度の上昇による副作用も生じないものであ
り，製剤中に含有するオキシブチニンの生物学的利用率
が高まり，効率よく生体内へ投与できる。オキシブチニ
ンを含有する基剤層は、オキシブチニンがフリー体で液
状であることから従来のような薬物溶解用の担体を含有
せず、各種油性の基剤に容易に相溶させる事が出来、か
つ、それ自体で良好な経皮吸収性を示す。従って、ポリ
イソブチレンを主体とする感圧性接着剤基剤は添加剤と
して用いる熱可塑性樹脂、充填剤等はすべて化学的に安
定なものであり、オキシブチニンとの相互作用が少な
く、薬物の経時的な安定性が極めて良好である。また所
望により前記の皮膚透過促進剤を含有することにより、
更に良好な経皮吸収性を得ることができ優れた効果を発
揮する。さらに、本発明の感圧性接着剤中に熱可塑性樹
脂、充填剤などを配合する事により、基剤のもつ物性を
損なうこと無く、基剤中のオキシブチニンの拡散移動を
適度に阻害し持続的放出性をさらに向上するものとな
り、有効血中濃度の維持即ち効果の持続性に優れた性能
を発揮するものである。その結果、投与回数（単位時間
当たりの投与回数）を減少出来るので、皮膚刺激性をさ
らに減少させることができる。尚、本製剤の投与回数と
しては、１日１回もしくは２日に１回が適当であるが、
３日以上に１回の製剤とする事も可能であり、医薬品と
して有効である。The pharmaceutical preparation for transdermal administration of the present invention is in the form of a patch, and the oxybutynin contained therein is continuously released directly into the circulating blood via the skin, so that it is produced in the liver by oral administration. It does not undergo metabolism due to the first-pass effect and does not cause any side effects due to a temporary increase in blood concentration. The bioavailability of oxybutynin contained in the preparation is increased, and it can be efficiently administered to the living body. Since the base layer containing oxybutynin does not contain a conventional drug-dissolving carrier because oxybutynin is free and liquid, it can be easily compatible with various oily bases, and Shows good transdermal absorption by itself. Therefore, the pressure-sensitive adhesive base mainly composed of polyisobutylene is a thermoplastic resin used as an additive, fillers and the like are all chemically stable, have little interaction with oxybutynin, and the Very good stability. If desired, by containing the skin permeation enhancer,
Further, excellent transdermal absorbability can be obtained, and an excellent effect is exhibited. Furthermore, by blending a thermoplastic resin, a filler, and the like in the pressure-sensitive adhesive of the present invention, the diffusion and transfer of oxybutynin in the base are appropriately inhibited without impairing the physical properties of the base and sustained release. The performance of the composition is further improved, and the performance is excellent in maintaining the effective blood concentration, that is, maintaining the effect. As a result, the number of administrations (the number of administrations per unit time) can be reduced, so that skin irritation can be further reduced. The number of administrations of this formulation is appropriate once a day or once every two days.
It is possible to make the preparation once every three days or more, which is effective as a pharmaceutical.
【図１】ラットによる経皮吸収実験結果を示す。FIG. 1 shows the results of a percutaneous absorption experiment using rats.
□ 実施例６の製剤 ○ 実施例７の製剤 ▲ 比較例４の製剤 ■ 比較例５の製剤 □ Formulation of Example 6 ○ Formulation of Example 7 ▲ Formulation of Comparative Example 4 ■ Formulation of Comparative Example 5
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/216 A61K 9/70 A61P 13/10 ＣＡ（ＳＴＮ) ＥＭＢＡＳＥ（ＳＴＮ) ＭＥＤＬＩＮＥ（ＳＴＮ)────────────────────────────────────────────────── ─── Continued on the front page (58) Fields surveyed (Int. Cl. 7 , DB name) A61K 31/216 A61K 9/70 A61P 13/10 CA (STN) EMBASE (STN) MEDLINE (STN)
Claims (2)
イソブチレンを主基剤とした感圧性接着剤中に含有させ
てなる尿失禁治療用経皮投与製剤。1. A transdermal preparation for treating urinary incontinence, comprising oxybutynin as an active ingredient in a polyisobutylene-based pressure-sensitive adhesive.
００〜２０００００を有する低分子量ポリイソブチレン
と，粘度平均分子量４０００００〜１８０００００を有
する高分子量ポリイソブチレンの混合物及びポリブテン
からなる請求項１記載の尿失禁治療用経皮投与製剤。2. A pressure-sensitive adhesive having a viscosity average molecular weight of 100
The transdermal preparation for treating urinary incontinence according to claim 1, comprising a mixture of low molecular weight polyisobutylene having a molecular weight of 00 to 200,000, high molecular weight polyisobutylene having a viscosity average molecular weight of 400,000 to 1800000 and polybutene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4327460A JP3066515B2 (en) | 1992-11-11 | 1992-11-11 | Transdermal formulation for treatment of urinary incontinence |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4327460A JP3066515B2 (en) | 1992-11-11 | 1992-11-11 | Transdermal formulation for treatment of urinary incontinence |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06145052A JPH06145052A (en) | 1994-05-24 |
| JP3066515B2 true JP3066515B2 (en) | 2000-07-17 |
Family
ID=18199414
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4327460A Expired - Lifetime JP3066515B2 (en) | 1992-11-11 | 1992-11-11 | Transdermal formulation for treatment of urinary incontinence |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3066515B2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5677346A (en) * | 1995-01-31 | 1997-10-14 | Sepracor, Inc. | Treating urinary incontinence using (S)-desethyloxybutynin |
| US5674895A (en) * | 1995-05-22 | 1997-10-07 | Alza Corporation | Dosage form comprising oxybutynin |
| ES2281366T3 (en) * | 1999-12-15 | 2007-10-01 | Hisamitsu Pharmaceutical Co. Inc. | PREPARATIONS OF ADHESIVES. |
| US6436428B1 (en) * | 2000-03-21 | 2002-08-20 | Enhance Pharmaceuticals, Inc. | Device and method for treating urinary incontinence in females |
| US7988991B2 (en) | 2001-03-07 | 2011-08-02 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive patch |
| KR20130069764A (en) * | 2005-02-03 | 2013-06-26 | 교린 세이야꾸 가부시키 가이샤 | Percutaneous absorption preparation |
| JP4921739B2 (en) * | 2005-08-10 | 2012-04-25 | 久光製薬株式会社 | Patches with reduced skin irritation |
| EP2023907A1 (en) * | 2006-04-21 | 2009-02-18 | LABTEC GESELLSCHAFT FüR TECHNOLOGISCHE FORSCHUNG UND ENTWICKLUNG MBH | Transdermal delivery system comprising sufentanil and its analogues |
| US20090297591A1 (en) * | 2008-05-30 | 2009-12-03 | Orient Pharma Co., Ltd. | Compositions And Methods For The Transdermal Delivery Of Pharmaceutical Compounds |
-
1992
- 1992-11-11 JP JP4327460A patent/JP3066515B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06145052A (en) | 1994-05-24 |
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