JP2839635B2 - Estradiol-containing patch - Google Patents
Estradiol-containing patchInfo
- Publication number
- JP2839635B2 JP2839635B2 JP2117050A JP11705090A JP2839635B2 JP 2839635 B2 JP2839635 B2 JP 2839635B2 JP 2117050 A JP2117050 A JP 2117050A JP 11705090 A JP11705090 A JP 11705090A JP 2839635 B2 JP2839635 B2 JP 2839635B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- estradiol
- sensitive adhesive
- adhesive layer
- patch
- 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 - Fee Related
Links
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 title claims description 57
- 229960005309 estradiol Drugs 0.000 title claims description 25
- 229930182833 estradiol Natural products 0.000 title claims description 25
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 36
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 32
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 32
- 239000010410 layer Substances 0.000 claims description 28
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 19
- 230000001070 adhesive effect Effects 0.000 claims description 16
- 239000000853 adhesive Substances 0.000 claims description 15
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012510 hollow fiber Substances 0.000 claims description 2
- 239000004744 fabric Substances 0.000 claims 1
- 229920006267 polyester film Polymers 0.000 claims 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 19
- 239000003814 drug Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 229940011871 estrogen Drugs 0.000 description 9
- 239000000262 estrogen Substances 0.000 description 9
- -1 polyethylene Polymers 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 229920000139 polyethylene terephthalate Polymers 0.000 description 6
- 239000005020 polyethylene terephthalate Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 206010040880 Skin irritation Diseases 0.000 description 5
- 239000012790 adhesive layer Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000009245 menopause Effects 0.000 description 5
- 231100000475 skin irritation Toxicity 0.000 description 5
- 230000036556 skin irritation Effects 0.000 description 5
- 239000003522 acrylic cement Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 206010015150 Erythema Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 231100000321 erythema Toxicity 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000003405 preventing effect Effects 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000005068 transpiration Effects 0.000 description 2
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- 229920001342 Bakelite® Polymers 0.000 description 1
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 208000019300 CLIPPERS Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- JQIYNMYZKRGDFK-RUFWAXPRSA-N Estradiol dipropionate Chemical compound C1CC2=CC(OC(=O)CC)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 JQIYNMYZKRGDFK-RUFWAXPRSA-N 0.000 description 1
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000004637 bakelite Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229950002007 estradiol benzoate Drugs 0.000 description 1
- 229950010215 estradiol dipropionate Drugs 0.000 description 1
- 229960004766 estradiol valerate Drugs 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Description
【発明の詳細な説明】 ＜産業上の利用分野＞ 本発明は更年期障害，骨粗鬆症，アルツハイマー痴呆
症等の閉経後の女性に多く観察される障害の予防、及び
改善に有用なエストラジオール含有貼付剤に関する。Description: TECHNICAL FIELD The present invention relates to an estradiol-containing patch useful for preventing and improving disorders often observed in postmenopausal women such as menopause, osteoporosis, and Alzheimer's dementia. .
＜従来の技術＞ 閉経後の女性に多く観察される更年期障害，骨粗鬆
症，アルツハイマー痴呆症等の原因として閉経に伴う卵
胞ホルモンの減少が重要視されており、エストラジオー
ル，エストリオール及びそれらの誘導体が主として経口
剤，注射剤として臨床に応用されている。<Prior art> Estrogen, estriol and derivatives thereof are mainly regarded as a cause of menopause, osteoporosis, Alzheimer's dementia, etc. due to menopause, a decrease in estrogen associated with menopause, which is often observed in postmenopausal women. It is used clinically as an oral preparation and injection.
しかしながら卵胞ホルモンは多用すると子宮体癌の増
加等の副作用があるために使用に際しては必要最少限の
投与量で可能な限り生物学的利用率（以下BAと略す）を
高め、しかも薬物血中濃度が安定的に維持されることが
望まれている。However, if estrogen is used extensively, it will cause side effects such as an increase in endometrial cancer. When used, eosin hormone will increase the bioavailability (hereinafter abbreviated as BA) as much as possible with the minimum dosage required, and the drug concentration in the blood Is desired to be stably maintained.
臨床応用されている各種の卵胞ホルモン中、エストラ
ジオールは本来生体内で合成され利用されている、いわ
ゆる天然型卵胞ホルモンの１つであり、薬理的にも活性
が高く安全性の面からも医薬品として使用するのに最も
適した卵胞ホルモンと考えられているにもかかわらず、
ほとんど使用されていない。その理由はエストラジオー
ルは経口投与したときには消化管及び肝臓ですみやかに
代謝されてしまうためBAが低くなることによる。必要な
薬物血中濃度を維持するためには多量のエストラジオー
ルの投与を必要とするが、その場合同時に多量の有害な
代謝物を血中に副生することを意味しており好ましくな
い。Among the various estrogen hormones that have been clinically applied, estradiol is one of the so-called natural estrogen hormones that are originally synthesized and used in vivo, and are highly pharmacologically active and safe as pharmaceuticals. Despite being considered the best estrogen to use,
Hardly used. The reason for this is that estradiol is rapidly metabolized in the digestive tract and liver when administered orally, resulting in a low BA. Administration of a large amount of estradiol is necessary in order to maintain a necessary drug blood concentration, but in that case, it means that a large amount of harmful metabolites are simultaneously produced in the blood, which is not preferable.
エストラジオールは経皮投与することによりBAを著し
く改善でき、しかも安定した薬物血中濃度を維持でき
る。Estradiol can remarkably improve BA by transdermal administration and can maintain a stable drug concentration in blood.
エストラジオール又はそのエステル等の誘導体が経皮
吸収されることは公知であり、特公昭46−5427号公報，
特開昭57−154122号公報等に開示されている。特に、特
開昭57−154122号公報に示された貼付剤はBAの向上，薬
物血中濃度の安定化という点で秀れている。しかしなが
らエストラジオール含有貼付剤は閉経に伴って起る卵胞
ホルモンの減少を補うものであり、治療期間は数ケ月乃
至数年に及ぶものであるから、患者のコンプライアンス
が高いこともまた必須の要件である。特に貼付剤の場
合、貼付時の違和感，皮膚カブレの発生が最も大きな問
題点であるにもかかわらず、従来の技術ではこの点に対
する配慮が不十分であった。It is known that a derivative such as estradiol or an ester thereof is transdermally absorbed, and Japanese Patent Publication No. 46-5427,
It is disclosed in JP-A-57-154122. In particular, the patch disclosed in JP-A-57-154122 is excellent in improving BA and stabilizing drug blood concentration. However, since estradiol-containing patches compensate for the decrease in estrogen that occurs with menopause, and the treatment period extends for several months to several years, high patient compliance is also an essential requirement. . In the case of patches, in particular, although the unpleasant sensation at the time of application and the occurrence of skin irritation are the most serious problems, conventional techniques have insufficiently considered this point.
＜発明が解決しようとする課題＞ 上述のように、従来技術においては、患者のコンプラ
イアンスの比較的高い経口剤の場合にはBAが低く、副作
用発生が深刻であり、BAが高く、薬物血中濃度も安定し
ている経皮吸収型貼付剤においては違和感があり、皮膚
カブレが発生するという問題があった。<Problems to be Solved by the Invention> As described above, in the prior art, in the case of an oral preparation having relatively high patient compliance, BA is low, side effects are serious, BA is high, and drug There is a problem that a transdermal patch having a stable concentration has an uncomfortable feeling and causes skin irritation.
本発明の目的はBAが高く、薬物血中濃度も安定してお
り、かつ従来のエストラジオール経皮吸収型貼付剤の欠
点である違和感，皮膚カブレを顕著に改善して患者コン
プライアンスの高いエストラジオール含有貼付剤を提供
することにある。It is an object of the present invention to provide an estradiol-containing patch having a high BA, a stable drug blood concentration, and a remarkable improvement in discomfort and skin fogging, which are disadvantages of conventional estradiol transdermal patches, and having high patient compliance. To provide an agent.
従来技術の欠点のひとつである違和感を改善するため
には、貼付剤の柔軟性を出来るだけ高め、そのサイズを
小さくすることが望ましい。しかしながら、柔軟性をあ
まりに大きくすると貼付剤の取扱いが著しく困難となり
実用性に欠けることとなる。また、貼付剤のサイズは薬
物の吸収量即ち、薬物血中濃度と比較関係にあるから、
必要な薬物血中濃度が決まっている場合、貼付剤のサイ
ズを小さくするためには何らかの薬物の経皮吸収性を高
める手段が必要となる。そして、そのために薬物の経皮
吸収性を高める目的で吸収促進剤を使用すると、かえっ
て皮膚カブレを助長することが多いという問題がある。
一方、皮膚カブレを改善するためには、従来から粘着剤
の種類を適宜選択し、粘着剤中の残留モノマーや残留溶
媒を少なくすることなどが検討されているが、根本的に
は、貼付剤の水分蒸散性や酸素，炭酸ガス等の通気性を
高めることが望ましい。しかしながら、単に水分蒸散性
や酸素等の気体透過性を高めることも貼付剤の密封性を
減少させ、結果として薬物の経皮吸収性を減少すること
がある。In order to improve the feeling of discomfort, which is one of the disadvantages of the prior art, it is desirable to increase the flexibility of the patch and reduce its size. However, if the flexibility is too high, the handling of the patch becomes extremely difficult, and the utility is lacking. In addition, since the size of the patch has a comparative relationship with the drug absorption amount, that is, the drug blood concentration,
When the required blood concentration of the drug is determined, some means for increasing the transdermal absorbability of the drug is required to reduce the size of the patch. When an absorption enhancer is used for the purpose of enhancing the transdermal absorbability of a drug, there is a problem in that skin fogging is often promoted.
On the other hand, in order to improve skin irritation, it has been conventionally studied to appropriately select the type of adhesive and to reduce residual monomers and residual solvent in the adhesive, but basically, a patch is used. It is desirable to increase the moisture transpiration and the permeability of oxygen, carbon dioxide gas and the like. However, simply increasing the moisture transpiration or the gas permeability of oxygen or the like may also decrease the hermeticity of the patch, and consequently reduce the transdermal absorbability of the drug.
本発明らは、かかる課題に対して様々な角度より鋭意
検討した結果本発明に到達した。The present inventors have intensively studied such problems from various angles, and have reached the present invention.
＜課題を解決するための手段＞ 即ち、本発明は水分不透過性又は水分半透過性のフイ
ルムと、厚みが10乃至200μの粘着剤層であって、該粘
着剤層中に粘着剤に対して、0.5乃至10重量％のエスト
ラジオールと0.5乃至15重量％の分子量100,000以上のポ
リビニルピロリドンを含有するアクリル系粘着剤層から
なり、かつ中空繊維からなる編物を構成要素としないエ
ストラジオール含有貼付剤である。<Means for Solving the Problems> That is, the present invention is directed to a water-impermeable or semi-permeable film and a pressure-sensitive adhesive layer having a thickness of 10 to 200 μm. And an estradiol-containing patch comprising an acrylic pressure-sensitive adhesive layer containing 0.5 to 10% by weight of estradiol and 0.5 to 15% by weight of a polyvinylpyrrolidone having a molecular weight of 100,000 or more, and having no knitted material composed of hollow fibers as a component. .
本発明の粘着剤層の粘着剤としては、従来から貼付剤
等に用いられる公知のアクリル系粘着剤を用いることが
できるが、なかでも生物学的安全性の高い（１）炭素数
４以上のアルキル基の（メタ）アクリル酸アルキルエス
テルを少くとも80〜98モル％，（２）アクリル酸及び／
又はメタアクリル酸又はそれらのアルキルエステル２〜
20モル％を主成分として共重合したアクリル系粘着剤が
好ましい。As the pressure-sensitive adhesive of the pressure-sensitive adhesive layer of the present invention, known acrylic pressure-sensitive adhesives conventionally used for patches and the like can be used, and among them, biological safety is high (1) having 4 or more carbon atoms. At least 80 to 98 mol% of (meth) acrylic acid alkyl ester of alkyl group, (2) acrylic acid and / or
Or methacrylic acid or their alkyl esters
An acrylic pressure-sensitive adhesive copolymerized with 20 mol% as a main component is preferable.
本発明においては、かかるアクリル系粘着剤層中に、
特定量のエストラジオールとポリビニルピロリドンを含
有せしめる。In the present invention, in such an acrylic pressure-sensitive adhesive layer,
A specific amount of estradiol and polyvinylpyrrolidone are included.
かかるエストラジオールとは、天然型卵胞ホルモンと
合成卵胞ホルモンおよびそれらの誘導体をいい、例えば
エストラジオール、安息香酸エストラジオール，ジプロ
ピオン酸エストラジオール，吉草酸エストラジオール，
エチニルエストラジオール等があげられる（以下、本発
明においてはこれらエストラジオールをE2と略称す
る）。Such estradiol refers to natural estrogen, synthetic estrogen, and derivatives thereof, such as estradiol, estradiol benzoate, estradiol dipropionate, estradiol valerate,
Ethinyl estradiol, and the like (hereinafter, abbreviated these estradiol and E 2 in the present invention).
本発明においては、かかるE2をアクリル系粘着剤層中
に、粘着剤に対して0.5乃至10重量％含有せしめる。こ
こで粘着剤とは、溶媒等を除外した粘着剤の固形分をい
う。In the present invention, such a E 2 in the acrylic pressure-sensitive adhesive layer, allowed to contain 0.5 to 10% by weight relative to the adhesive. Here, the adhesive means a solid content of the adhesive excluding a solvent and the like.
アクリル系粘着剤層中のE2の濃度は最後に得られるE2
含有貼付剤の経皮吸収性に重要な要因であり、0.5重量
％未満では十分に高い経皮吸収性を得ることができず、
0.5重量％以上、濃度が高まるにつれてほとんど比例的
に経皮吸収性は高くなる。しかし、10重量％より大きい
濃度となると経皮吸収性はほとんど高まらず、むしろ粘
着剤層中でのE2の結晶化が顕著に起るようになり、その
結果経皮吸収性は小さくなる傾向があり、従って10重量
％より大では経皮吸収性も小さく、また得られた製剤の
粘着力も不十分となるため好ましくない。なかでも１乃
至５重量％の濃度が好ましい。The concentration of E 2 of the acrylic pressure-sensitive adhesive layer is obtained at the end E 2
It is an important factor in the transdermal absorbability of the contained patch, and if it is less than 0.5% by weight, a sufficiently high transdermal absorbability cannot be obtained.
Above 0.5% by weight, the transdermal absorbability increases almost proportionally with increasing concentration. However, percutaneous absorption becomes 10 wt% greater than the concentration hardly Takamara, rather look like crystallization of E 2 in the pressure-sensitive adhesive layer occurs significantly, the smaller the tendency resulting transdermal absorbability Therefore, if it is more than 10% by weight, the transdermal absorbability is low, and the adhesive strength of the obtained preparation is not sufficient, which is not preferable. Particularly, a concentration of 1 to 5% by weight is preferable.
本発明のE2を含有するアクリル系粘着剤層には、ポリ
ビニルピロリドンを用いることが必須である。すなわ
ち、アクリル系粘着剤層にE2を含有させてE2濃度を経皮
吸収性がほぼ最適となる約３重量％としても、その経皮
吸収性は不十分であり、さらにより重要なことは経時す
るに従って粘着剤層中でE2が結晶となって析出し、これ
に伴って経皮吸収性が変化することである。本発明者ら
は、E2の経皮吸収性を高め、かかる経時変化を防ぐ手段
について鋭意検討した結果、ポリビニルピロリドンを所
定量含有せしめることが有効であることを見出した。The acrylic pressure-sensitive adhesive layer containing the E 2 of the present invention, the use of polyvinyl pyrrolidone is essential. That is, even about 3 wt% of percutaneous absorbability E 2 concentrations contain a E 2 in acrylic pressure-sensitive adhesive layer is substantially optimal, the transdermal absorbability is insufficient and that even more importantly is that E 2 with an adhesive layer is deposited as crystals in accordance with time, it changes transdermal absorbability accordingly. The present inventors have enhanced percutaneous absorbability of E 2, a result of intensive studies for means for preventing such aging, it was found that the polyvinylpyrrolidone be allowed to contain a predetermined amount is effective.
本発明のポリビニルピロリドンとは、分子量約100,00
0以上のＮ−ビニル−２−ピロリドンの重合体をいう
（以下、本発明においてPVPと略称する）。The polyvinylpyrrolidone of the present invention has a molecular weight of about 100,00
A polymer of 0 or more N-vinyl-2-pyrrolidone (hereinafter abbreviated as PVP in the present invention).
PVPの重合度がこれより小さくなると、アクリル系粘
着剤層をつくるためにいわゆるドープ（粘着剤を有機溶
媒に溶解したもの）にPVPを溶解したとき、ドープがゲ
ル化して均一な厚みの粘着剤層をつくるのが困難とな
り、また得られるアクリル系粘着剤層中にゲル状となっ
たPVPが斑らとなって多数存在するようになり、またE2
の経皮吸収促進効果も少くなる傾向がある。If the degree of polymerization of PVP is lower than this, when PVP is dissolved in a so-called dope (a solution in which the adhesive is dissolved in an organic solvent) to form an acrylic adhesive layer, the dope gels and the adhesive with a uniform thickness It becomes difficult to form a layer, and in the obtained acrylic pressure-sensitive adhesive layer, a large number of gelled PVPs are dispersed and present, and E 2
Also tend to have less transdermal absorption promoting effect.
本発明のPVPは、PVP以外に少量の他のモノマーやポリ
マーが共重合されていても、本発明の効果を得られる限
り本発明の範囲内に含まれる。The PVP of the present invention is included in the scope of the present invention even if a small amount of other monomer or polymer other than PVP is copolymerized, as long as the effects of the present invention can be obtained.
かかるPVPはアクリル系粘着剤層中の粘着剤に対して
0.5乃至15重量％含有せしめる。15重量％より大となる
と得られる粘着剤層の粘着力が不十分となる。0.5重量
％未満では、十分な経皮吸収促進効果およびE2の結晶化
防止効果が得られない。Such PVP is used for the adhesive in the acrylic adhesive layer.
0.5 to 15% by weight. If it exceeds 15% by weight, the resulting pressure-sensitive adhesive layer will have insufficient adhesion. Is less than 0.5 wt%, sufficient percutaneous absorption promoting effect and crystallization prevention effect of E 2 was obtained.
経皮吸収促進効果、及びE2の結晶化防止効果、即ち経
時安定性の向上効果は、粘着剤層中のE2濃度と無関係で
はないが、PVPの濃度が高い程得られる効果は大きくな
る傾向にある。10重量％以上ではその増加傾向は少な目
であり、好ましい範囲は１乃至５重量％である。Transdermal absorption promoting effect, and E 2 of the crystallization preventing effect, i.e. effect of improving stability with time is not independent of the E 2 concentration in the adhesive layer, the effect obtained higher concentrations of PVP is increased There is a tendency. At 10% by weight or more, the increasing tendency is small, and a preferable range is 1 to 5% by weight.
本発明においては、このように特定量のE2及びPVPと
アクリル系粘着剤を溶媒存在下に混合し、得られたアク
リル系粘着剤ドープを通常のコーティングマシーンで塗
布，乾燥し、溶媒を除いてその厚みが10乃至200μで特
定量のE2およびPVPを含有するアクリル系粘着剤層を得
る。In the present invention, such a specific amount of E 2 and PVP and acrylic adhesive was mixed in the presence of a solvent, the coating the resulting acrylic pressure-sensitive adhesive doped with conventional coating machine, dried, and the solvent removed To obtain an acrylic pressure-sensitive adhesive layer having a thickness of 10 to 200 μm and containing specific amounts of E 2 and PVP.
該粘着剤層の厚みは貼付剤の柔軟性、及び気体透過性
と関係する。また得られた粘着剤層の粘着力とも関係す
る。ヒトの皮膚に貼付する時、十分な粘着力を付与する
ためには該粘着剤層の厚みは最低10μは必要であり、好
ましくは20μ以上である。一方、この粘着剤層の厚みが
増加するとまず残留溶媒が増加して皮膚刺激性が悪化す
る。また気体や水分蒸発性が減少するので、この点でも
皮膚カブレの原因となりやすい。さらに貼付剤としてヒ
トの皮膚に貼付した時に、この粘着剤層の断面にゴミが
粘着し外見上好ましくない。かかる理由から粘着剤層の
厚みは200μ以下である。好ましくは100μ以下である。The thickness of the pressure-sensitive adhesive layer is related to the flexibility of the patch and the gas permeability. It also relates to the adhesive strength of the obtained adhesive layer. When applied to human skin, the pressure-sensitive adhesive layer must have a thickness of at least 10 μm, preferably 20 μm or more, in order to impart sufficient adhesive strength. On the other hand, when the thickness of the pressure-sensitive adhesive layer increases, the residual solvent first increases, and the skin irritation deteriorates. In addition, since gas and water evaporation are reduced, skin irritation is likely to occur in this respect as well. Further, when applied to human skin as a patch, dust adheres to the cross section of the pressure-sensitive adhesive layer, which is not preferable in appearance. For this reason, the thickness of the pressure-sensitive adhesive layer is 200 μm or less. Preferably it is 100 μm or less.
かかる粘着剤層の皮膚に接する面と反対側の面に水分
不透過性又は半透過性のフイルムを圧着して本発明のエ
ストラジオール含有貼付剤とすることができる。The estradiol-containing patch of the present invention can be obtained by pressing a water-impermeable or semi-permeable film against the surface of the pressure-sensitive adhesive layer opposite to the surface in contact with the skin.
本発明の水分不透過性又は半透過性のフイルムとは、
例えばそのようなフイルムの材質としては、ポリエチレ
ン，ポリプロピレン，塩化ビニル，ナイロン,EVA等があ
げられるが、アクリル系粘着剤に対する圧着性の点か
ら、ポリエステル、なかでも主としてポリエチレンテレ
フタレートからなるフイルム等が好ましい。The water-impermeable or semi-permeable film of the present invention,
For example, examples of the material of such a film include polyethylene, polypropylene, vinyl chloride, nylon, EVA, etc., and from the viewpoint of the pressure-sensitive adhesive property to an acrylic adhesive, polyester, especially a film mainly composed of polyethylene terephthalate, is preferred. .
また、かかるフイルムの厚みは、0.5乃至６μが好ま
しく、なかでも厚みが1.0乃至４μのポリエチレンテレ
フタレートのフイルムを用いた場合には安定性及び安全
性に秀れ、適度な引張り強さ，柔軟性と適度な気体及び
水分透過性を持ち好ましい。Further, the thickness of such a film is preferably 0.5 to 6 μm, and in particular, when a film of polyethylene terephthalate having a thickness of 1.0 to 4 μm is used, the film has excellent stability and safety, and has an appropriate tensile strength and flexibility. It is preferable because it has appropriate gas and moisture permeability.
かくして、本発明の特定の厚みで、かつ特定量のE2と
PVPを含有するアクリル系粘着剤層からなるエストラジ
オール貼付剤が提供される。Thus, in particular the thickness of the present invention, and a specific amount of E 2
An estradiol patch comprising an acrylic pressure-sensitive adhesive layer containing PVP is provided.
本発明により得られたエストラジオール含有貼付剤
は、例えば大きさ5cm2乃至100cm2で、正方形，長法形，
円形，楕円形状に裁断したのち医薬品として使用でき
る。Estradiol-containing patch obtained by the present invention, for example, a size 5 cm 2 to 100 cm 2, square, long method form,
It can be used as a pharmaceutical after being cut into circular and elliptical shapes.
医薬品は通常調剤後３年間位は安定して使用できるこ
とが望ましい。It is usually desirable that drugs can be used stably for about three years after preparation.
本発明のエストラジオール含有貼付剤には、特定量の
PVPを含有せしめることにより、E2の結晶化を防止し、
優れた経皮吸収性が得られているが、本発明者らはさら
に、この貼付剤中の水分含有率を一定以下に低く保つこ
とによって、より長期安定な貼付剤が得られることを知
見した。The estradiol-containing patch of the present invention contains a specific amount of
By including PVP, crystallization of E 2 is prevented,
Although excellent transdermal absorbability has been obtained, the present inventors have further found that a long-term stable patch can be obtained by keeping the moisture content in the patch low below a certain level. .
アクリル系粘着剤にPVPを含有させた場合の平均水分
率は外気の温湿度によって変化するが、医薬品が通常貯
蔵される室温条件では１〜２重量％となる。しかし、E2
含有貼付剤は貯蔵中に１度でも、かかる水分率となると
経皮吸収率が著しく低下する。The average moisture content when PVP is contained in the acrylic pressure-sensitive adhesive changes depending on the temperature and humidity of the outside air, but is 1 to 2% by weight under room temperature conditions where pharmaceuticals are usually stored. But E 2
The percutaneous absorption rate of the patch containing the percutaneous absorption decreases significantly even if it is once during storage.
従って、本発明の貼付剤においては、貼付剤中の水分
含有率が貼付剤の粘着剤に対して１重量％以下、好まし
くは0.7重量％以下であることが好ましい。かかる所定
の量の水分含有率は貼付剤製造の際の乾燥温度，時間等
を制御することによってなされるが、長期的に維持する
ためには、更に貼付剤の水分含有率が0.2重量％以下と
なるように製造し、例えば防湿性のある包装材料中に、
乾燥状態となるように密封することによって、前記１重
量％以下の水分含有率となるようにすることができる。
かかる場合には、シリカゲル等の乾燥剤を介在させるこ
とも効果的である。Therefore, in the patch of the present invention, it is preferable that the water content in the patch is 1% by weight or less, preferably 0.7% by weight or less based on the pressure-sensitive adhesive of the patch. Such a predetermined amount of water content is controlled by controlling the drying temperature, time, and the like during the production of the patch, but in order to maintain it for a long period of time, the water content of the patch must be 0.2% by weight or less. Manufactured to be, for example, in a moisture-proof packaging material,
By sealing so as to be in a dry state, the moisture content can be adjusted to 1% by weight or less.
In such a case, it is effective to interpose a desiccant such as silica gel.
本発明のかかる製剤が十分に経皮吸収性を与えるため
には患者に製剤を貼付したときには製剤中の水分率が早
急に0.9％以上、好ましく1.0％以上になるように密封性
を保たれることが望ましい。In order for such a preparation of the present invention to give sufficient transdermal absorbability, when the preparation is applied to a patient, the hermeticity is maintained so that the water content in the preparation becomes 0.9% or more, preferably 1.0% or more immediately. It is desirable.
以下に実施例をあげて、本発明をさらに詳細に説明す
る。実施例及び参考例中の部は重量部を示している。Hereinafter, the present invention will be described in more detail with reference to Examples. Parts in Examples and Reference Examples indicate parts by weight.
参考例１ アクリル系粘着剤溶液 ２−エチルヘキシルアクリレート97.4部，メタアクリ
ル酸2.5部，ポリエチレングリコール（重合度14）ジメ
タクリレート0.1部，過酸化ベンゾイル1.0部および酢酸
エチル100部を還流冷却機，かきまぜ機を有する反応容
器に仕込み窒素雰囲気下60℃でゆっくり撹拌しながら９
時間重合を続けた。重合転化率は99.9％であった。Reference Example 1 Acrylic pressure-sensitive adhesive solution 97.4 parts of 2-ethylhexyl acrylate, 2.5 parts of methacrylic acid, 0.1 part of polyethylene glycol (degree of polymerization: 14) dimethacrylate, 1.0 part of benzoyl peroxide and 100 parts of ethyl acetate were reflux-cooled and stirred. Into a reaction vessel having a temperature of 9 ° C. while stirring slowly at 60 ° C. under a nitrogen atmosphere.
The polymerization was continued for hours. The polymerization conversion was 99.9%.
得られた重合体溶液に酢酸エチル500部を加えて固形
分濃度を約20％に調節して粘着剤溶液を得た。500 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20% to obtain a pressure-sensitive adhesive solution.
実施例１ エストラジオール（E2）0.5部をメタノール15部に溶
解した液（Ａ液）と、分子量1,200,000のPVP（G.A.F.社
Ｋ−90）0.2部をクロロホルム30部に溶解した液（Ｂ
液）、及び参考例１で得たアクリル系粘着剤溶液10部に
酢酸エチル55部を加えて強く撹拌して均一なドープとし
た後、シリコンコートした離型紙の上に乾燥後の厚みが
40μとなるように塗工し、90℃で20分間乾燥してE2（2.
5重量％）及びPVP（１重量％）を含有したアクリル系粘
着剤層を得た。Example 1 A solution prepared by dissolving 0.5 part of estradiol (E 2 ) in 15 parts of methanol (solution A) and a solution prepared by dissolving 0.2 part of PVP having a molecular weight of 1,200,000 (GAF K-90) in 30 parts of chloroform (B)
Liquid) and 10 parts of the acrylic pressure-sensitive adhesive solution obtained in Reference Example 1, 55 parts of ethyl acetate was added, and the mixture was vigorously stirred to obtain a uniform dope.
Coated to 40μ, dried at 90 ° C for 20 minutes and E 2 (2.
5% by weight) and an acrylic pressure-sensitive adhesive layer containing PVP (1% by weight).
得られた粘着剤層中の水分率は0.16％であった。 The water content in the obtained pressure-sensitive adhesive layer was 0.16%.
得られたアクリル系粘着剤層の片面全面に厚さ3.5μ
のポリエチレンテレフタレートフイルム（バッキングフ
イルム）を圧着したのち大きさ5cm2に裁断して得た貼付
剤を電気バリカンで除毛した７週令、雄のヘアレスラッ
トの背部に貼付し（ｎ＝５）、貼付後２時間,4時間,8時
間に採血して血清を分離し血清中のE2をラジオイムノア
ッセイ法で測定した。結果をベークライト板に対する粘
着力（180゜剥離力）と共に表−１に示した。3.5μ thickness on the entire surface of one side of the obtained acrylic pressure-sensitive adhesive layer
A 7-week-old male hairless rat whose polyethylene terephthalate film (backing film) was crimped and then cut into a size of 5 cm 2 and dehaired with an electric clipper, was attached to the back of a male hairless rat (n = 5). 2 hours after application, 4 hours, to measure the E 2 in the serum was separated and serum were bled 8 hours radioimmunoassay. The results are shown in Table 1 together with the adhesive strength (180 ° peel force) to the bakelite plate.
表−１に示す通り良好なE2血中濃度を達成し、また持
続性も良好であった。Table 1 through to achieve good E 2 blood concentration shown in, also was also sustained good.
実施例２〜４ 実施例１においてPVPの量をそれぞれ0.4部,1.0部,2部
と変更した以外は総て実施例１と同じ要領で貼付剤（実
施例２ E2（2.5重量％）,PVP（２重量％），実施例３
E2（2.5重量％）,PVP（５重量％），実施例４ E
2（2.5重量％）,PVP（10重量％））を得、ヘアレスラッ
トでの経皮吸収試験を行った結果を表−１に示した。Examples 2 to 4 Patches (Example 2 E 2 (2.5% by weight), all in the same manner as in Example 1 except that the amount of PVP was changed to 0.4 part, 1.0 part, and 2 parts, respectively) PVP (2% by weight), Example 3
E 2 (2.5% by weight), PVP (5% by weight), Example 4 E
2 (2.5% by weight), PVP (10% by weight)), and the results of a percutaneous absorption test performed on hairless rats are shown in Table 1.
本実施例で使用した製剤の粘着剤中水分率はいずれも
0.4％以下であった。The moisture content in the adhesive of the preparation used in this example was all
It was 0.4% or less.
比較例１〜３ 実施例１においてPVPの量を０部,0.05部,4.0部とした
以外は総て実施例１と同じ要領で貼付剤（比較例１ E2
（2.5重量％）,PVP（０重量％），比較例２ E2（2.5重
量％）,PVP（0.25重量％），比較例３ E2（2.5重量
％）,PVP（17重量％））を得、試験した結果を表−１に
示した。Comparative Examples 1-3 Patches (Comparative Example 1 E 2) were prepared in the same manner as in Example 1 except that the amount of PVP was changed to 0, 0.05, and 4.0 parts.
(2.5% by weight), PVP (0% by weight), Comparative Example 2 E 2 (2.5% by weight), PVP (0.25% by weight), Comparative Example 3 E 2 (2.5% by weight), PVP (17% by weight) The results obtained and tested are shown in Table 1.
本比較例で使用した製剤の粘着剤中の水分率は0.4％
以下であった。The water content in the adhesive of the preparation used in this comparative example is 0.4%
It was below.
比較例４ 実施例１において分子量1,200,000ポリビニルピロリ
ドン（G.A.F.社 Ｋ−90）の代りに分子量40,000のポリ
ビニルピロリドン（G.A.F.社 Ｋ−30）を用いて均一な
ドープを得ようとしたが、混合物はゼリー状でありシリ
コンコートした離型紙に塗工することすら出来なかっ
た。Comparative Example 4 In Example 1, an attempt was made to obtain a uniform dope by using polyvinylpyrrolidone having a molecular weight of 40,000 (K-30 manufactured by GAF) instead of polyvinylpyrrolidone having a molecular weight of 1,200,000 (K-30 manufactured by GAF). And it was not even possible to apply it to the release paper coated with silicon.
比較例５ 実施例１においてE2 3部を用いた以外は、総て実施例
１と同じ要領で貼付剤（E2（13重量％）,PVP（１重量
％））を得、試験した結果を表−１に示した。Comparative Example 5 Patches (E 2 (13% by weight), PVP (1% by weight)) were obtained and tested in the same manner as in Example 1 except that 3 parts of E 2 were used in Example 1. Are shown in Table 1.
比較例６ 実施例１で得た製剤を厚み12μのポリエチレンからな
る袋に入れ通常の医薬品の加速試験条件である40℃で湿
度75％の雰囲気に３ケ月放置した製剤においては、粘着
層中に針状の結晶が無数に析出していた。本製剤中の水
分率を測定し、その値からバッキングフイルムの水分率
を差し引いて貼付層中の水分率を求めたところ、2.2％
であった。 Comparative Example 6 In the preparation obtained by placing the preparation obtained in Example 1 in a bag made of polyethylene having a thickness of 12 μm and leaving it for 3 months in an atmosphere of 75% humidity at 40 ° C., which is an accelerated test condition for ordinary pharmaceuticals, Countless needle-like crystals were precipitated. The moisture content of the preparation was measured, and the moisture content of the backing film was calculated by subtracting the moisture content of the backing film from the value.
Met.
また、この製剤を実施例１と同じ要領でヘアレスラッ
ト貼付試験を行った結果を表−２に示した。In addition, Table 2 shows the results of applying this preparation to a hairless rat sticking test in the same manner as in Example 1.
表−２に示した如く、本比較例の製剤の経皮吸収性は
大幅に低下していた。As shown in Table 2, the transdermal absorbability of the preparation of this comparative example was significantly reduced.
比較例７〜８ 実施例１で得た製剤を40℃で湿度75％の条件に異なる
期間放置したのち、その製剤中の水分率を測定し、粘着
層中での結晶析出状態を観察したのち、実施例１と同じ
要領でヘアレスラット貼付試験を行った結果を表−２に
示した。Comparative Examples 7 and 8 After the preparation obtained in Example 1 was left at 40 ° C. and a humidity of 75% for different periods of time, the moisture content in the preparation was measured, and the crystal precipitation state in the adhesive layer was observed. Table 2 shows the results of a hairless rat sticking test performed in the same manner as in Example 1.
試験例１ E2を使用しないこと、バッキングフイルムとして3.5
μポリエチレンテレフタレートの代りに４種の異なる厚
みのポリエチレンテレフタレートフイルムを用いたこと
を除いては実施例１と同じ要領で４種の製剤を作り、裁
断して3cm×3cmのプラセボ製剤を得た。該プラセボ製剤
を年令20〜35才，体重53〜68kgの健康な成人５名の背中
中央部にランダムに各人に各貼付剤２枚ずつ合計８枚を
貼付し、貼付２日後に取外した時の皮膚カブレ状態を判
定した。判定は無反応を０とし、わずかに紅斑となった
ものを１、明らかに紅斑となったものを２、丘疹等が発
生したものを３として５名の判定点の合計で判定した結
果を表−３に示した。 Not using Test Example 1 E 2, 3.5 as a backing film
Four preparations were prepared in the same manner as in Example 1 except that four kinds of polyethylene terephthalate films having different thicknesses were used instead of μ polyethylene terephthalate, and cut to obtain a placebo preparation of 3 cm × 3 cm. The placebo preparation was affixed at random to the center of the back of five healthy adults, aged 20 to 35 years and weighing 53 to 68 kg, with two patches each for each person, for a total of eight patches, and removed 2 days after application. The skin rash condition at that time was determined. The results are shown in the following table. The results are shown in the following table. The results are shown as 1 when the erythema was slightly unresponsive, 1 when the erythema was slightly evident, 2 when the erythema was apparent, and 3 when the papules etc. occurred. -3.
【図面の簡単な説明】 第１図は本発明の貼付剤であって、実施例１で得られた
貼付剤の断面図である。第１図において １……裏打ち部材（ポリエチレンテレフタレートフイル
ム） ２……粘着剤層 ３……離型紙（貼付剤使用時は剥して捨てる） を示す。BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional view of a patch of the present invention, which is obtained in Example 1. 1 shows a backing member (polyethylene terephthalate film) 2... An adhesive layer 3... A release paper (peeled off and discarded when using a patch).
───────────────────────────────────────────────────── フロントページの続き (72)発明者 加藤 俊幸 東京都立川市高松町１―100 帝三製薬 株式会社立川工場内 (56)参考文献 特開 昭63−305873（ＪＰ，Ａ) 特開 昭62−153227（ＪＰ，Ａ) 特開 昭63−307819（ＪＰ，Ａ) 特開 昭59−199628（ＪＰ，Ａ) 特開 昭61−112015（ＪＰ，Ａ) (58)調査した分野(Int.Cl.6，ＤＢ名) A61K 31/565 A61K 9/70 369 A61K 9/70 324 A61K 47/32──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Toshiyuki Kato 1-100 Takamatsucho, Tachikawa-shi, Tokyo Teisan Pharmaceutical Co., Ltd. Tachikawa Plant (56) References JP-A-63-305873 (JP, A) JP-A Sho 62-153227 (JP, A) JP-A-63-307819 (JP, A) JP-A-59-199628 (JP, A) JP-A-61-112015 (JP, A) (58) Fields investigated (Int. Cl. 6, DB name) A61K 31/565 A61K 9/70 369 A61K 9/70 324 A61K 47/32
Claims (3)
と、厚みが10乃至200μの粘着剤層であって、該粘着剤
層中に粘着剤に対して0.5乃至10重量％のエストラジオ
ールと0.5乃至15重量％の分子量100,000以上のポリビニ
ルピロリドンを含有するアクリル系粘着剤層からなり、
かつ中空繊維からなる編物を構成要素としないエストラ
ジオール含有貼付剤。1. A moisture-impermeable or semi-permeable film, and a pressure-sensitive adhesive layer having a thickness of 10 to 200 μm, wherein 0.5 to 10% by weight of estradiol with respect to the pressure-sensitive adhesive is contained in the pressure-sensitive adhesive layer. An acrylic pressure-sensitive adhesive layer containing polyvinylpyrrolidone having a molecular weight of 0.5 to 15% by weight and a molecular weight of 100,000 or more,
An estradiol-containing patch which does not comprise a knitted fabric composed of hollow fibers as a component.
％以下であることを特徴とする請求項１記載のエストラ
ジオール含有貼付剤。2. The estradiol-containing patch according to claim 1, wherein the water content in the adhesive of the patch is 1.0% by weight or less.
リエステルフィルムであることを特徴とする請求項１記
載のエストラジオール含有貼付剤。3. The estradiol-containing patch according to claim 1, wherein the film is a polyester film having a thickness of 0.5 to 6 μm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2117050A JP2839635B2 (en) | 1990-05-07 | 1990-05-07 | Estradiol-containing patch |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2117050A JP2839635B2 (en) | 1990-05-07 | 1990-05-07 | Estradiol-containing patch |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1045178A Division JPH0791193B2 (en) | 1989-02-28 | 1989-02-28 | Estradiol-containing patch |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0334923A JPH0334923A (en) | 1991-02-14 |
| JP2839635B2 true JP2839635B2 (en) | 1998-12-16 |
Family
ID=14702187
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2117050A Expired - Fee Related JP2839635B2 (en) | 1990-05-07 | 1990-05-07 | Estradiol-containing patch |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2839635B2 (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59199628A (en) * | 1983-04-25 | 1984-11-12 | Sekisui Chem Co Ltd | Application drug |
| JPH0742228B2 (en) * | 1985-11-13 | 1995-05-10 | 日東電工株式会社 | Pharmaceutical formulation |
| JPH0753671B2 (en) * | 1985-12-26 | 1995-06-07 | 積水化学工業株式会社 | Transdermal / transmucosal preparation |
| JPS63305873A (en) * | 1987-06-05 | 1988-12-13 | Sekisui Chem Co Ltd | Medical adhesive composition and its preparation |
| JPS63307819A (en) * | 1987-06-08 | 1988-12-15 | Sekisui Chem Co Ltd | Patch for percutaneous absorption |
-
1990
- 1990-05-07 JP JP2117050A patent/JP2839635B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0334923A (en) | 1991-02-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3489831B2 (en) | Active ingredient patch | |
| US6231885B1 (en) | Composition for controlled and sustained transdermal administration | |
| JP2011252003A (en) | Transdermal therapeutic system containing tulobuterol hydrochloride for administering bronchodilator tulobuterol via skin | |
| JPS61280426A (en) | Anti-inflammatory and analgesic application agent | |
| JPH0684304B2 (en) | Transdermal system for timolol | |
| US20060088580A1 (en) | Hormone-containing transdermal therapeutic system with an active substance reservoir based on vinylacetate-vinylpyrrolidone copolymer with improved cohesion | |
| WO2005099766A1 (en) | Crosslinkable pressure-sensitive adhesive for the skin | |
| WO1993010772A1 (en) | Transdermal estradiol delivery system | |
| WO1989007951A1 (en) | Transdermal estradiol delivery system | |
| JPH04217919A (en) | Percutaneously eperisone or tolperisone-absorbing preparation | |
| WO1999062557A1 (en) | Composition for the transdermal administration of non-steroidal anti-inflammatory drugs | |
| JP2839635B2 (en) | Estradiol-containing patch | |
| JPH07103016B2 (en) | Patch and method for producing the same | |
| WO2021098791A1 (en) | Transdermal patch containing memantine | |
| JPH01233212A (en) | Plaster | |
| JPH0753671B2 (en) | Transdermal / transmucosal preparation | |
| KR950013448B1 (en) | Patch type pneparation | |
| JP4988080B2 (en) | Transdermal preparation | |
| AU2003254834B2 (en) | Female hormone-containing patch | |
| JPH1179979A (en) | Percutaneously absorbable type preparation | |
| JP2507068B2 (en) | Transdermal formulation | |
| JP3472359B2 (en) | Patch containing timiperone | |
| JP2596539B2 (en) | Transdermal and transmucosal preparations | |
| JP2774257B2 (en) | Method for producing a stable estradiol-containing patch | |
| US20030175330A1 (en) | Transdermal therapeutical system with a reduced tendency of the active substance to crystallize |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20081016 Year of fee payment: 10 |
|
| LAPS | Cancellation because of no payment of annual fees |