TW200400048A - Hydrous gel and production process and use of the hydrous gel - Google Patents
Hydrous gel and production process and use of the hydrous gel Download PDFInfo
- Publication number
- TW200400048A TW200400048A TW092116564A TW92116564A TW200400048A TW 200400048 A TW200400048 A TW 200400048A TW 092116564 A TW092116564 A TW 092116564A TW 92116564 A TW92116564 A TW 92116564A TW 200400048 A TW200400048 A TW 200400048A
- Authority
- TW
- Taiwan
- Prior art keywords
- acid
- hydrogel
- item
- patent application
- ascorbic acid
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 90
- -1 aluminum compound Chemical class 0.000 claims abstract description 90
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 45
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 45
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 39
- 239000004584 polyacrylic acid Substances 0.000 claims abstract description 37
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 23
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 claims abstract description 17
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 claims abstract description 17
- 229920000642 polymer Polymers 0.000 claims abstract description 15
- 239000008213 purified water Substances 0.000 claims abstract description 13
- 239000000017 hydrogel Substances 0.000 claims description 61
- 239000000499 gel Substances 0.000 claims description 59
- 239000000126 substance Substances 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 20
- 239000000853 adhesive Substances 0.000 claims description 16
- 230000001070 adhesive effect Effects 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 10
- 150000005846 sugar alcohols Polymers 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000010998 test method Methods 0.000 claims description 8
- MIJPAVRNWPDMOR-ZAFYKAAXSA-N L-ascorbic acid 2-phosphate Chemical group OC[C@H](O)[C@H]1OC(=O)C(OP(O)(O)=O)=C1O MIJPAVRNWPDMOR-ZAFYKAAXSA-N 0.000 claims description 6
- 150000000996 L-ascorbic acids Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000002537 cosmetic Substances 0.000 claims description 5
- RJZNFXWQRHAVBP-UHFFFAOYSA-I aluminum;magnesium;pentahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Al+3] RJZNFXWQRHAVBP-UHFFFAOYSA-I 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000000052 vinegar Substances 0.000 claims description 3
- 235000021419 vinegar Nutrition 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 238000012360 testing method Methods 0.000 claims 1
- 229920000058 polyacrylate Polymers 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract 1
- 229920001577 copolymer Polymers 0.000 description 26
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 17
- 229940047670 sodium acrylate Drugs 0.000 description 16
- 239000008279 sol Substances 0.000 description 16
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 description 15
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 14
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 14
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 14
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 14
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
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- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 10
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- 238000009472 formulation Methods 0.000 description 10
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- 239000007864 aqueous solution Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
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- 239000004745 nonwoven fabric Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 8
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 8
- 239000000347 magnesium hydroxide Substances 0.000 description 8
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 8
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000004743 Polypropylene Substances 0.000 description 7
- 229940024545 aluminum hydroxide Drugs 0.000 description 7
- 235000019437 butane-1,3-diol Nutrition 0.000 description 7
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 7
- 229920001155 polypropylene Polymers 0.000 description 7
- 229960004889 salicylic acid Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
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- 239000002585 base Substances 0.000 description 5
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- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 5
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Landscapes
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200400048 Ο) 玖、發明說明 【發明所屬之技術領域】 本發明有關含有抗壞血酸(asc〇rbic acid)或其衍生 物,且在保持該酸等之下能用爲外用醫藥製劑(例如貼敷 劑用基劑)、敷臉劑等之化粧品、創傷保護劑等之自己保 型性高而容易製作的含水凝膠體,該含水凝膠體之製造方 法及其用途。 【先前技術】 抗壞血酸或其衍生物,周知有特別是對肌膚之膠原之 生物合成有關係,能維持有彈性且光滑的狀態,又能抑制 成爲老人斑、雀斑之原因的黑色素(melanin )之生成, 以維持美麗淸澈的肌膚的作用。然而.,如作爲應用此等酸 在肌膚上的手段而作成化粧水或雪花膏等之形態時,則由 於其塗工量不能作成一定之故以致效果不穩定,又因與衣 類等的接觸而從皮膚上脫落之故以致不能獲得充份效果。 爲解決此等方法而言,可舉:將抗壞血酸或其衍生物 含在有保型性之含水凝膠中以供應用的方法。一般用爲貼 敷劑或保冷劑的含水凝膠,係作爲其基劑而使用黃蓍膠、 阿拉伯膠、角叉萊膠、硬粒膠、藥酸鈉、甘露糖膠、白明 膠等之天然水溶性高分子;聚丙烯酸或聚甲基丙烯酸鹽、 聚乙烯醇、聚丙烯醯胺等之合成高分子,並對此調配多元 醇等之保濕劑或水所構成者。然而’特別是由於天然水溶 性高分子係得自天然物之故品質不夠穩定,如不實施高度 -4- (2) (2)200400048 精製時,則會產生因混合物的污染或因不純物的劣化等之 現象。 又,例如,在日本專利特開2〇〇 1 - 64 1 75號公報中, 揭示有藉由在矽酸鋁酸鎂、乾燥氫氧化鋁凝膠、氯化鋁中 之2種化合物之使用以調整含有抗壞血酸或其衍生物的含 水凝膠的方法。然而,此等方法仍然在凝膠之保型性之維 持方面不足夠,尤其在氣溫高的夏季時,含水凝膠中產生 塌邊而有發生所謂背面掏空的情形,故極待解決。 · 【發明內容】 〔發明擬解決的課題〕 本發明係鑑於如此情況下所開發者,本發明係以提供 能安定地保持抗壞血酸或其衍生物,凝膠強度高,在被貼 體上的粘接性良好,且不會產生離漿液,能以單純的組成 即可容易調整,凝膠之生成快速,可以工業規模生產的含 7jc凝膠爲其課題者。 β 〔爲解決課題的手段〕 本發明人等爲解決前述課題而專心硏究的結果,發現 實質上含有選自由聚丙烯酸、聚丙烯酸鈉以及聚丙烯酸部 份中和物而成的群中之至少2種聚合物,並因此等聚合物 含有交聯劑,特別是用含有鋁化合物而被交聯,當以精製 水稀釋爲100倍時之pH値在6.5至8.5之範圍的含水凝 膠體,能安定地保持抗壞血酸或其衍生物,且具有優異的 -5- (3) 200400048 凝膠特性之現象,終於完成本發明。本發明係下述(1 ) 至(1 3 )所示的含水凝膠體,該含水凝膠體之製造方法及 其用途。 (1 ) 一種含水凝膠體,係含有選自聚丙烯酸、聚丙 烯酸鈉以及聚丙烯酸部份中和物而成的群中之至少2種聚 合物經以鋁化合物所交聯的凝膠體、水、以及抗壞血酸或 其衍生物的含水凝膠體,而其特徵爲:當以精製水稀釋爲 100倍時之pH値在6.5至8.5之範圍。 _ (2 )如上述(1 )所記載之含水凝膠體,其中前述 、 pH値在7.0至8.0之範圍。 (3 )如上述(1 )或(2 )所記載之含水凝膠體,其 中鋁化合物係氫氧化鋁鎂。 (4 )如上述(1 )或(2 )所記載之含水凝膠體,其 中鋁化合物之含量係對前述含水凝膠體100質量份爲0.01 至1 〇質量份。 (5 )如上述(1 )或(2 )所記載之含水凝膠體,其 β 中抗壞血酸或其衍生物之含量係對前述含水凝膠體1 〇 〇質 量份爲〇 . 〇 1至1 〇質量份。 (6 )如上述(1 )或(2 )所記載之含水凝膠體,其 中抗壞血酸衍生物係抗壞血酸一 2 -磷酸酯或其鹽。 (7 )如上述(1 )或(2 )所記載之含水凝膠體,其 中前述含水凝膠體含有多元醇。 (8 )如上述(1 )或(2 )所記載之含水凝膠體,其 中將前述含水凝膠體成型爲具有0.5 mm厚度的膜片,並 -6 - (4) (4)200400048 在 2 5 °C,相對濕度6 0 %下曝露2 4小時後,準照Π S Z 02 3 7之膠粘(tack)試驗法試驗其表面之粘接性時之傾斜 角30度之球膠粘値(ball tack value )爲10以上。 (9 ) 一種含水凝膠體之製造方法,其特徵爲:調製 含有選自聚丙烯酸、聚丙烯酸鈉以及聚丙烯酸部份中和物 而成的群中之至少2種聚合物、鋁化合物、水以及抗壞血 酸或其衍生物的混合物,並將該混合物加熱爲2 5 °C至6 5 〇C。 (1 〇 )如上述(9 )所記載之含水凝膠體之製造方法 ’其中將前述含水凝膠體調整爲以精製水稀釋爲1 00倍時 pH値爲6.5至8.5之範圍。 (1 1 )如上述(1 0 )所記載之含水凝膠體之製造方法 ’其中將前述pH値調整爲7.0至8.0之範圍。 (1 2 ) —種化粧料,其特徵爲:使用上述(1 )至(8 )中之任一項所記載之含水凝膠體。 (1 3 ) —種外用製劑,其特徵爲··使用上述(1 )至 (8 )中之任一項所記載之含水凝膠體。 【實施方式】 〔發明之實施形態〕 以下,就本發明加以詳細說明。 本發明之含水凝膠體,係含有選自聚丙烯酸、聚丙烯 酸鈉以及聚丙烯酸部份中和物而成的群中之至少2種聚合 物經以鋁化合物所交聯的凝膠體、水以及抗壞血酸或其衍 (5) (5)200400048 生物的含水凝膠體,而其特徵爲:當以精製水稀釋爲1 0 0 倍時之pH値在6 · 5至8 .5之範圍。 本發明之含水凝膠體,能安定地保持抗壞血酸或其衍 生物,且具有優異的凝膠特性。又,無流動性且具有強力 彈性,即使指壓仍不會容易崩壞。由於本發明之含水凝膠 體具有如此優異的性質之故,可應用在例如經皮層吸收用 製劑、經粘膜吸收用製劑等之貼敷劑等之醫藥品、化粧品 或者例如敷臉劑、曬黑用品、青春痘用品等醫藥之外用藥 等的種種用途。 在本發明之含水凝膠體中所用的抗壞血酸或其衍生物 之含量係對含水凝膠體100質量份爲0.01至10質量份, 較佳爲0.5至5.0質量份。 抗壞血酸衍生物或其鹽,係在生物體內能接受酵素性 或非酵素性的分解,其結果會游離抗壞血酸者較爲有效。 具有如此性質的抗壞血酸衍生物或其鹽而言,可舉:抗壞 血酸一 2 -磷酸酯、抗壞血酸一 2 -焦磷酸酯、抗壞血酸一 2 —三磷酸酯、抗壞血酸一 2 -多磷酸、抗壞血酸—2,3 -二磷酸酯、抗壞血酸一 2,6 -二磷酸酯、抗壞血酸一 2 一 硫酸酯、抗壞血酸一 6 -棕櫚酸酯、抗壞血酸一 2,6 -棕 櫚酸酯、抗壞血酸-2 -葡糖苷、抗壞血酸- 2-鄰一葡糖 苷一 6-棕櫚酸酯、抗壞血酸一 5,6-亞苄、抗壞血酸一 5 ,6-亞丙基或此等之金屬鹽、銨鹽、烷基或羥烷基所代 銨鹽等。 此等抗壞血酸衍生物之中,從效果功能之觀點來看, -8- (6) (6)200400048 較佳的化合物爲抗壞血酸- 2 -磷酸酯及其鹽類,例如較 佳爲抗壞血酸- 2-隣酸酯鎂鹽、抗壞血酸- 2 -隣酸醋鈉 鹽。抗壞血酸- 2 -磷酸酯較其他已知之抗壞血酸衍生物 爲被生物體內之吸收速度高,又在生物體內之抗壞血酸之 游離速度較快速。此等鹽可依例如日本專利特開昭 44 - 3 1 23 7號公報所記載之方法製造,亦能利用市售品。 本身爲基劑的水溶性高分子之聚丙烯酸、聚丙烯酸鈉 、聚丙烯酸部份中和物對皮膚的刺激性較低,又粘接性亦 高。此中,聚丙烯酸部份中和物係聚丙烯酸中之一部份被 鹼所中和者,鹼而言,可舉:氫氧化鈉、氫氧化鉀等之鹼 金屬鹽、氨、氨水、三乙醇胺、二甲胺、二乙胺、三甲胺 、三乙胺、三異丙醇胺、單乙醇胺、二乙醇胺、二異丙醇 胺、多乙醇胺等之一級、二級或三級烷基胺、或者一級、 二級或三級烷醇胺等。 製造聚丙烯酸部份中和物的方法,有從後面進行聚丙 烯酸之一部份中和的方法、及在聚合時之單體之飼給時將 丙烯酸之一部份中和後進行聚合的方法。所得聚丙烯酸部 份中和物中的丙烯酸與丙烯酸鹽之莫耳比,較佳爲在80 :20至20: 80之範圍,更佳爲在65: 35至35: 65之範 圍。如超過此範圍,則有凝膠化(與鋁離子之離子結合: 交聯反應)之速度顯著遲慢的傾向。聚丙烯酸部份中和物 之例而言,可舉:丙烯酸鈉/丙烯酸共聚物、丙烯酸鉀/ 丙烯酸共聚物、丙烯酸銨/丙烯酸共聚物等,惟並不限定 在此等。 -9- (7) (7)200400048 本發明之含水凝膠體,由於使用選自聚丙烯酸、聚丙 烯酸鈉以及聚丙烯酸部份中和物而成的群中之至少2種聚 合物之故,可容易進行凝膠化。雖然其機構不甚明瞭,可 能是在此等高分子中之游離之羧基與羧酸酯間進行鈉鹽之 鹽交換的過程中,因介在有鋁離子而進行離子交聯之故。 作爲交聯劑所添加的鋁化合物,當凝膠之保型性維持 起見,對含水凝膠體100質量份爲0.01至10質量份,較 佳爲〇 · 5至5 · 0質量份。如添加量在0 · ο 1質量份以下時, 則交聯變成不充份而凝膠強度不足,以致所得含水凝膠體 之保型性可能會顯著惡化。又,如超過1 0質量份時,則 凝膠體變硬,以致可能柔軟性會變差及成型加工變成困難 。在此’如改變交聯劑之量即可自由控制凝膠體之彈力或 柔軟性’而改變與皮膚間之適應用(粘接性)。 鋁化合物而言,包含有氯化鋁、鉀明礬、銨明礬、硝 酸鋁、硫酸鋁、EDTA (乙二胺四乙酸)一鋁、氫氧化鋁 •鐵酸氫鈉共沈澱物(例如,協和化學工業(股)製「估 姆萊特」等)、合成矽酸鋁、硬脂酸鋁、尿囊酸鋁、合成 水滑石(例如協和化學工業(股)製「阿爾佳邁克」「阿 爾佳邁沙」「裘瓦特」等)、氫氧化鎂·氧化鋁(例如, 協和化學工業(股)製「莎拿爾明」等)、氫氧化鋁(例 如’協和化學工業(股)製「乾燥氫氧化鋁凝膠s — 1〇〇 」等)、乙酸鋁、二氫氧化鋁胺基乙酸酯(例如,協和化 學工業(股)製「葛利西那爾」等)、高嶺土、合成水滑 石、偏砂酸錯酸鎂(例如,富士化學(股)製「伊諾西琳 -10- (8) (8)200400048 」)、砂酸銘酸鎂等。此等銘化合物可爲水溶性者,亦可 爲難溶性者。此中特別是使用氫氧化鎂氧化鋁時,由於凝 膠化能迅速進行,且均勻並能製作保型性優異的凝膠體之 故’較理想。在此,此等鋁化合物可使用1種或2種以上 〇 又’本發明之含水凝膠體亦能添加鋁化合物以外之交 聯橋’此等交聯劑而言,可舉:鈣、錫、鐵、鎂、錳、鋅 、鋇等之無機酸鹽(例如,氯化鈣、氯化鎂、鐵明礬、硫 酸鐵、硫酸鎂、EDTA -鈣、EDTA —鎂、氯化亞錫、碳酸 鈣、磷酸鈣、磷酸氫鈣、碳酸鎂、硫酸鋇、矽酸鎂、硬脂 酸鎂、檸檬酸鎂)、氫氧化物(例如,氫氧化鈣、氫氧化 鋇、氫氧化鎂(例如,協和化學工業(股)製「奇士馬」 等)、氫氧化鐵、氫氧化亞錫等)、氧化物(例如,氧化 鎂(例如,協和化學工業(股)製「協和馬刻」「馬刻沙 拉特」等))甲醛、乙二醇二縮水甘油醚、甘油二縮水甘 油醚、聚乙二醇二縮水甘油醚、丙二醇二縮水甘油醚、聚 丙二醇二縮水甘油醚等之環氧化合物,而可使用此等交聯 劑之1種或2種以上。 本發明之含水凝膠體中’爲提升含水凝膠體之保濕性 及抗壞血酸或其衍生物之效果起見,較佳爲添加多元醇。 多元醇而言,可舉:乙二醇、丙二醇、1,3 — 丁二醇、二 乙二醇、三乙二醇、1,4 一 丁二醇(二元醇)、甘油、三 羥基異丁烷(三元醇)、赤藻糖醇、異戊四醇(四元醇) 、木糖醇、側金盞花醇(五元醇)、阿洛糖醇、山梨糖醇 -11 - (9) (9)200400048 、雙脫水山梨糖醇液、甘露糖醇(六元醇)等,惟並不限 定在此等。 本發明之含水凝膠體之pH値,係當以精製水將含水 凝膠體按質量稀釋爲100倍時之pH値爲在6.5至8·5之 範圍,較佳爲pH値在7.0至8.0之範圍。如超過此範圍 ,則抗壞血酸或其衍生物之安定性將顯著惡化,以致難於 獲得所期待的效果。測定pH値的方法並不特別限定,而 可使用一般所用的pH計。 φ pH値之調整係以確保抗壞血酸或其衍生物之安定性 之外,尙以控制交聯速度爲目的而所實施者。能用爲製造 本發明之含水凝膠體的pH調整劑而言,可使用:氫氧化 鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、氯、氨水、三乙胺 、二甲胺、二乙胺、三甲胺、三乙胺、三異丙醇胺、磷酸 三鈉、磷酸氫二銨、磷酸氫二鉀、單乙醇胺、二乙醇胺、 二異丙醇胺、多乙醇胺等之鹼金屬氫氧化物、鹼土類金屬 氫氧化物、一級、二級或三級之烷基胺、或者一級、二級 ® 或三級之烷醇胺等之鹼。再者,可使用:檸檬酸、酒石酸 、乳酸、乙醇酸、鹽酸、硝酸、蘋果酸、磷酸、柳酸、反 丁烯二酸、甲磺酸、順丁烯二酸、乙酸、EDTA — 2鈉、 脲、三乙胺、氨等對金屬離子具有鉗合結構或配位作用的 有機酸、有機酸鹽、有機鹼性等之外,尙可使用有鹽酸、 磷酸、硫酸、硝酸、溴化氫酸等之無機酸等。 又,亦可使用能呈現酸性或鹼性的高分子,可例舉: 海藻、聚麩胺酸、聚天冬胺酸、澱粉-丙烯酸接枝聚合物 -12- (10) (10)200400048 、聚丙烯酸鹽(例如’聚丙烯酸鉀)、羧基乙烯基聚合物 、乙酸乙烯酯/巴豆酸共聚物、乙酸乙烯酯/(甲基)丙 烯酸共聚物、乙酸乙烯酯/巴豆酸共聚物、聚乙烯磺酸、 聚衣康酸、苯乙烯/順丁烯二酸酐共聚物、丙烯醯胺/丙 烯酸共聚物等,惟並不限定於此等化合物。 本發明之含水凝膠中,爲提升含水凝膠體之保濕性及 抗壞血酸或其衍生物之效果起見,可添加溶劑等。溶劑而 言,可使用:醇類;丙酮、甲基乙基甲酮等之酮類;溶纖 素、二哼烷、二甲基甲醯胺、N —甲基吡咯烷酮、二甲基 亞硕等能與水混和的有機溶劑之外,尙可使用乙酸乙酯、 克化米頓(crotamiton )等不能與水混和的有機溶劑。 醇而言,可例舉:甲醇、乙醇、丙醇、苯甲醇、苯乙 醇、異丙醇、異丁醇、己醇、2 —乙基己醇、環己醇、辛 醇、丁醇、乙二醇一丁醚、戊醇等之一元醇、乙二醇、丙 二醇、1,3 — 丁二醇、二乙二醇、三乙二醇、1,4一丁二 醇(二元醇)、甘油、三羥基異丁烷(三元醇)、赤藻糖 醇、異戊四醇(四元醇)、木糖醇、側金盞花醇(五元醇 )、阿洛糖醇、山梨糖醇、雙脫水山梨糖醇液、甘露糖醇 (六元醇)等多元醇,惟並不限定在此等。此中,特別是 從對皮膚之刺激性或保濕性之觀點而看,較佳爲多元醇。 當藥物之給藥用媒介體而使用本發明之含水凝膠體時 ,藥劑係含水凝膠體組成物尙在溶膠(sol )狀態時即可 加以混合,或可在熟成後使藥劑內含在凝膠體內。較合適 的方法,可視其藥劑之物性,給藥部位以及對釋放速度的 -13- (11) (11)200400048 初期之目的而加以選擇。 可使用本發明之含水凝膠體以給藥的藥劑有很多種, 可例舉:柳酸、柳酸乙二醇酯、柳酸甲酯、1 —薄荷醇、 樟腦、舒林達酸(Sulindac )、妥美鎭鈉(Τ ο 1 m e t i η Sodium )、那普洛辛(Naproxen)、芬布芬(Fenbufen) 、匹洛西卡(Piroxicam)、特安皮質醇(Triamcinolone )、副腎皮質荷爾蒙乙酸酯(Hydrocortisone acetate)、 D引晚美酒辛(Indomethacin)、凱妥普洛芬(Ketoprofen )、乙醯胺酣 (Acetaminophen)、邁菲那密酸( Mefenamic acid)、富爾菲那密酸(Fulfenamic acid)、 異布菲那克(Ibufenac)、羅索普洛芬(Loxoprofen)、 替亞普洛芬(Tiaprofen )、普拉諾普洛芬(Pranoprofen )、芬普芬(Fenpufen)、二克氯吩(Dichlofenac)、二 克氯吩鈉 (Dichlofenac Sodium )、阿爾克氯吩 ( Alchlofenac)、經基保泰松(Qxyphenbutazone)、異布 普洛芬(Ibuprofen)、菲爾比那克(Felpinac)、凱妥羅 拉克(Ketolac)、白莫普洛芬(Bermoprofen)、那布美 頓(Napmeton)、那普洛辛(Naproxen)、氟爾比普洛芬 (Flurbiprofen)、氛歐西乃特(Fluocinonide)、氯倍多 松丙酸酯(Clobetasol propinate)等之消炎鎭痛劑。 此外,尙可舉:皮質類固醇、抗黴菌、抗組織胺類劑 '催眠鎭靜劑、精神神經安定劑、血壓降下劑、降壓利尿 劑、抗生素、麻醉藥品、抗微生物藥物、維生素、抗癲癎 劑、冠狀動脈擴張劑、抗組織胺類劑、鎭咳劑、性荷爾蒙 -14- (12) (12)200400048 、抗憂鬱劑、狹心症治療劑、麻藥性鎭痛劑、中藥等之外 ,尙可舉:5—氣基脈密Π定(5 — fluorourasil)、二氯麥角 胺(dihydroergotamin) ' 芬太尼(Fentanyl)、德斯摩普 列辛(Desmopressin)、異羥基毛地黃毒苷(digoxin)、 美多普胺(Metoclopramide )、酮倍利多(D o mp e r i d )、 東莨菪鹼(scopolamin)、氫溴酸柬莨菪鹼(S c ο p ο 1 am i η HBr )、動物用醫藥品、催眠劑、循環器系治療藥、腦代 謝改善劑、殺菌劑、酵素製劑、抗酶劑、生理醫藥(多肽 )、角質症治療劑、麻藥、抗惡性腫瘍劑、全身麻醉劑、 抗不安劑、氣喘·鼻過敏劑、抗帕金森氏症劑、化學療化 劑、驅蟲劑、抗原蟲劑、通風治療劑、止血劑、強心劑、 興奮劑·淸醒劑、習慣性中毒用劑、中藥劑、放射性醫藥 品、泌尿生殖系統及肛門用劑、血糖降下劑、抗潰瘍劑、 頭髮用劑、金屬離子螯隔劑、發赤發泡劑、發汗防止劑、 鎭靜劑、抗凝血劑、抗風濕、抗痛風以及抗凝固藥等,惟 並不限定在此等而依需要可倂用此等藥物之2種以上。 又’本發明之含水凝膠體中,可添加促進抗壞血酸或 其衍生物之吸收之用的補助劑,可調配例如:乙醇、異丙 醇、丁醇、1,3-丁二醇、丙二醇、聚乙二醇井400、甘 油、克樂他米頓(CrcTtamiton)、苄醇、苯乙醇、碳酸丙 烯酯、己基十二烷醇、丙醇、脲基海因(Allantoin)、二 甲基亞碾、二甲基乙醯胺、二甲基甲醯胺、二異丙基己二 酸酯、二甲基癸二酸酯、乙基月桂酸酯、含水羊毛脂、埃 松(Eison) 、1—香葉草基(geranyl)、氮雜環庚烷—2 -15- (13) (13)200400048 一酮(GACH )、脂肪酸二烷基醇醯胺、柳酸、柳酸衍生 物、脲、硫黃等之角質軟化劑、吡咯烷酮羧酸等之保濕劑 、丙二醇一油酸酯、聚氧化乙烯山梨糖醇酐一硬脂酸酯、 山梨糖醇酐一硬脂酸酯、甘油一硬脂酸酯等之表面活劑、 肉豆蔻酸二丙酯、癸二酸二酯等之酯類,油醇、硬脂醇、 月桂醇等之高級醇類、硬脂酸、己酸、壬酸、癸酸、十二 烷酸、十四烷酸、十六烷酸、十八烷酸、油酸、亞油酸等 之脂肪酸、薄荷醇、盖烷、檸檬烯、蒎烯、對Μ烯酮、萜 品烯、萜品二烯、萜品烯醇、黃蒿萜醇等之萜烯系化合物 、杏仁油、山茶子油、羅勒油(basiloil )、薄荷油、芝 麻油、大豆油、貂皮油、綿實油、玉蜀黍油、紅花子油、 椰子油、尤加利油、箆蔴子油、流動石臘、凡士林油、角 鯊烯、三十碳烷、含水羊毛脂等之1種以上。如考慮對皮 膚的剌激性時,此等補助劑之調配量對含水凝膠體1 〇〇質 量份較佳爲0.1至5質量份。 本發明之含水凝膠體中,作爲其他有效成份,而可任 意添加:抗青春痘劑、抗男性荷爾蒙、抗菌劑、消炎劑、 抗氧化劑、自由基洗除劑、美白劑等作爲有效成份而一般 所採用者。可倂用的抗男性荷爾蒙劑有效成份而言,可舉 ••塞浦得隆乙酸酯(Cyp rot er one Acetate )、螺環固醇丙 酮(Spironolactone)、卵胞荷爾蒙(estrogen)、糖皮質 激素(glucocorticoid )等,可倂用的抗菌有效成份而言 ,紅絲菌素(Erythromyein )、氯林絲菌素(Clindamycin )、紫菌素 (Gentanycin )、盤尼西林、氯黴素 ( -16- (14) (14)200400048
Chloramphenicol )、四環黴素(Tetracycline)等之抗生 素、過氧化苯甲醯基、那西羅其洒辛(Nadifloxacin) 、氯化苯甲院錢(benzalkonium chloride)、磺黃、對經 基苯甲酸酯類、柳酸、日柏醇(hinokitol )、三氯散( trichlosan,三氯經基二苯醚)、高磺胺(homosulfamine )等之抗菌成份等,可倂用的消炎劑有效成份而言,可舉 :異布普洛芬皮考醇(Ibuprofenpiconol )、甘其利晶(
Glycyrrhizine)、樟腦、D引噪美洒辛(Indomethacin)等 〇 可倂用的抗青春痘有效成份而言,可舉:維生素A 酸(tretinoin )、間苯二酚(r e s o r c i η )、異丙基甲酚、 維生素 Ε ( tocopherol )、抗壞血酸等。又,可倂用的美 白劑成份而言,可舉:胎盤素精(placenta ext.)、曲酸 (Kojic acid)、錄花酸(ellagic acid)、熊果苷( arbutin)、凝血酸(tranexamic acid)酯等。又,此外, 尙可倂用:母菊精、山白竹精、薔薇精、蜂花精、龍膽( gentiana)精、甘草精、油采(j〇j〇ba)精、迷迭香( rosemary )精、鼠尾草(sage )精、百里香(thyme )精 、薰衣草(lavender)精、牡丹精、人蔘精、蘆薈精、黃 豆精、紫蘇精、艾蒿精、鬱金精、扁柏精、日柏精、大黃 精、迎春花精、黃蓮精(c opt is)、銀杏精、桑精、茶精 、葡萄皮精、暇夷松精、土常山藤精(hydrangea leaves )以及各種海藻精等,源自植物之抗菌、抗氧化、消炎成 份。此等可倂用的有效成份,視其種類及用途而有所不同 -17- (15) (15)200400048 ,惟可在對含水凝膠體之0 · 0 1質量%至5 0質量%之範圍 添力口。 本發明之含水凝膠體,爲能顯現更多特性起見,或以 提升加工·成型性及品質,提升凝膠體中的抗壞血酸或其 衍生物之分散性及安定性等目的,在不影響含水凝膠體之 性能的程度,再可任意調配按照目的所選擇的化合物。 該添加劑包含 (1 )濕潤劑可舉舉:甘油、丙二醇、雙脫水山梨糖 醇、1,3 -丁二醇、dl -吡咯烷酮羧酸、乳酸鈉等。 (2 )收斂劑可例舉:檸檬酸、酒石酸、乳酸、氯化 鋁、硫酸鋁、脲基海因氯代氫氧化鋁、脲基海因二氫氧化 鋁、苯基磺酸鋁、對苯基磺酸鋅、硫酸鋅、氯化氫氧化鋁 等。 (3 )保濕劑可例舉:甘油、丙二醇、1,3 - 丁二醇 、山梨糖醇、聚甘油、聚乙二醇、二丙二醇等之多元醇類 、乳酸鈉等之NMF成份、透明質酸(hyaluronic acid)、 膠原(collagen)、粘多糖(mucopolysaccharide)類、軟 骨素(chondoitin)硫酸等之水溶性高分子等。 (4 )增粘劑可例舉:阿拉伯膠、黃蓍膠、槐樹豆膠 (locust bean gum )、瓜膠(guar gum ) 、ecogum、朿[J 梧 桐樹膠(kar ay a gum )、瓊脂(agar )、澱粉、角叉聚糖 (carrageenan )、藻酸(alagic acid)、藻酸鹽(例如, 藻酸鈉)、藻酸丙二醇酯、葡聚糖(dextran )、糊精( dextrin )、直鏈澱粉(amylose )、明膠、膠原、支鏈澱 -18- (16) (16)200400048 粉 (pullulan )、果膠 (pectin )、直鏈果膠 ( amylopectin )、澱粉、直鏈果膠半羥基乙酸鈉( amylopectin semi sodium glycolate )、幾 丁質(chitin) 、淸蛋白(albumin)、酪蛋白(casein)等之天然高分子 、聚谷胺酸(poly glutamic acid)、聚天冬胺酸(poly aspartic acid)、甲基纖維素、乙基纖維素、丙基纖維素 、乙基甲基纖維素、羥基乙基纖維素、羥基丙基纖維素、 羥基丙基甲基纖維素、羧甲基澱粉、鹼金屬羧甲基纖維素 、鹼金屬纖維素硫酸鹽、纖維素接枝聚合物、交聯明膠、 纖維素乙酸酯酞酸酯、澱粉一丙烯酸接枝聚合、酞酸酐改 明膠、琥珀酸改性明膠等之半合成高分子、聚乙烯醇、聚 乙烯基吡咯烷酮、聚乙烯基甲醚、羧基乙烯聚合物、乙烯 基吡咯烷酮/丙烯酸酯共聚物、乙烯基吡咯烷酮/苯乙烯 共聚物、乙烯基吡咯烷酮-乙酸乙烯酯共聚物、乙酸乙烯 酯/(甲基)丙烯酸共聚物、乙酸乙烯酯/巴豆酸共聚物 、N-乙烯基乙醯胺/丙烯酸鈉共聚物等之N-乙烯基乙 醯胺系共聚物、聚乙烯磺酸、N —乙烯基乙醯胺交聯物、 聚衣康酸、聚羥基甲基丙烯酸酯、聚丙烯醯胺、苯乙烯/ 順丁烯二酸酐共聚物、丙烯醯胺/丙烯酸共聚物等之合成 高分子等。 (5 )粘接性賦與物質可例舉:矽酮橡膠、聚異戊二 烯橡膠、苯乙烯-嵌段共聚物橡膠、丙烯酸橡膠、天然橡 膠等之各粘接性物質等。 (6 )止癢劑可例舉:樟腦、百里酚、薄荷醇、聚氧 -19- (17) (17)200400048 化乙烯月桂醚、抗組織胺劑、胺基安息香酸酯等。 (7 )角質軟化剝離劑可例舉:硫黃、吉歐奇索隆( T h i ο X ο 1 ο n e )、硫化硒、柳酸、間苯二酣。 (8 )誤食防止劑可例舉:辣椒、辣椒油等。 (9 )粉體原料可例舉:蒙脫石、焦水矽酸、石膏、 碳黑、矽藻土、鐵紅、碳酸鈣、水滑石、滑石、玻璃、高 嶺土、膨潤土、金屬肥皂、埃勒薩爾防蝕鋁(Eloxal )、 雲母欽、經基氯化鉍、珠光粉、鋅白、二氧化欽等。 · (1 〇 )油性原枓可例舉:杏仁油、橄欖油、硬化油、 山茶油、篦蔴子油、漆脂(vegetable wax)、椰子油、蜂 臘' 羊毛脂、巴豆棕櫚臘、小燭樹臘、流動石臘、凡士林 、微晶臟、純地獵(c e r e s i n e )、魚黨嫌(s q u a 1 e lx e )、 月桂酸、肉豆M酸(myristic acid)、棕櫚酸、硬脂酸、 異硬脂酸、油酸、月桂醇、鯨臘醇(cetanol )、硬脂醇、 油醇、辛棊十二烷醇、膽固醇、顯花植物固醇( phanerosterol )、乳酸鯨臘酯、肉豆蔻酸異丙酯、月桂酸 β 己酯、肉豆蔻酸肉豆蔻酯、棕櫚酸異丙酯、肉豆蔻酸辛基 十一 fci:醇醋、硬脂酸丁醋、可可脂、樹臓、j 〇 j 〇 b a油、葡 甸種子油、鳄梨油(a v o c a d ο o i 1 )、水貂油、蛋黃油、蜂 臘、鯨臘、羊毛脂、巴西棕櫚臘、小燭樹臘、流動石臘、 純地臘、石臘、蘿酸(behenic acid )、己二酸異丙酯、 肉丑宼酸辛基十二院酯、油酸辛基十二院醋、油酸膽固醇 (1 1 )表面活性劑可例舉:硫酸月桂酯鹽、聚氧化乙 -20- (18) (18)200400048 烯烷基醚硫酸鹽、苯基磺酸烷基酯鹽、磷酸聚氧化乙烯烷 基醚、磷酸聚氧化乙烯烷基苯基醚、N-醯基胺基酸鹽、 硬脂酸鈉、棕櫚酸鉀、鯨臘基硫酸鈉、月桂基硫酸鈉、棕 櫚酸三乙胺、聚氧化乙烯月桂基磷酸鈉、醯基谷胺酸鈉、 撒發叮(Surfacten)等之陰離子表面活性劑;烷基二甲基 平基氯化鏡 (benzalkomium Chloride )、干乙鞍 ( beazethonium chloride)、硬脂醯氯三甲基錢、二硬脂醯 氯二甲基銨、硬脂醯氯二甲基苄基銨等之陽離子表面活性 劑;鹽酸烷基二胺基乙基甘胺酸、2 —烷基一 N -羧甲基 —N —羥乙基咪唑鑰甜菜鹼、月桂二甲基胺基乙酸甜菜鹼 、卵磷脂等之兩性表面活性劑;多元醇脂肪酸酯、單硬脂 酸甘油、親油型單油酸甘油、單硬脂酸乙二醇、單硬脂酸 丙二醇、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯脂肪酸 酯、聚氧乙烯烷基醚、聚氧乙烯烷基苯基醚、聚氧乙烯山 梨糖醇脂肪酸酯、N -醯基胺基酸酯、蔗糖脂肪酸酯、脂 肪酸烷基醇醯胺、聚氧乙烯化固醇、聚氧乙烯化羊毛脂、 聚氧乙烯硬化箆騄子油等之非離子性表面活性劑等。 (1 2 )著色劑可例舉:黃色氧化鐵、鐵紅、黑色氧化 鐵、群青、碳黑、氫氧化鉻、氧化鉻、煤焦油色素、色澱 (lake )、紅色2號、紅色3號、紅色102號、紅色201 號、黃色4號、黃色5號、藍色1號、藍色2號等。 (1 3 )香料可例筚:罌粟籽油橙皮油、胡椒油、茉莉 油、日本柳杉油、松油、橙花油、薔薇油、尤加利油、梨 莓油(lime oil )、檸檬油、日本薄荷油、迷迭香油等之 -21 - (19) (19)200400048 植物性香料;麝香(musk )、香猫香(civet )、海狸香 (castroreum )、龍涎香(am b e r g r i s )等之動物性香料; 漠苯乙燒(bromostyrole)、苹嫌(pinene)、棒檬嫌( limonene )等之烴系香料;苄醇、1 —薄荷醇等之醇系香 料、乙酸乙酯、柳酸甲酯等之酯類系香料;苯甲醛( benzaldehyde)、柳醛(Salcylaldehyde)等之醛類系香料 ,棒腦、麝香酮(muscone)、酮麝香(musk ketone)、 1 —篕酮(menthone )等之酮類系香料;黃樟腦(Safr〇le )等之醚類系香料、瑞香草酚(thymol )等之酚類系香料 ;內酯(lactone )類系香料;乙酸苯酯(phenyiacetate ) 等之酸系香料;Η丨D朵(i n d ο 1 e )等之酸系香料、巧丨D朵等之 氮化合物系香料等。 (1 4 )糸外線遮斷劑可例舉·· ASL - 24、塞亞索布(
Cyasorb) UV — 9、優費奴盧(Uvinul Μ - 40)等之二苯 基甲_系、沙羅盧(Salol )等之安息香酸系、替奴彬( Tinuvin) P等之吡咯(az〇le)系、優費奴盧(Uvinul N — 35)等之腈系、安可爾(Anc〇ur ) UA等之脲系、新亥利 δλ 潘·吉虽唐(Neo Heliopan Give Tan) F、2 —經基—4 一甲氧二苯基甲酮、辛基二甲基對胺基安息香酸酯、甲基 己基對甲氧桂皮酸酯等之對胺基酸系、柳酸系、苯并呋喃 系、薰草系、吡咯系等。 (1 5 )防腐殺菌劑可例舉:安息香酸、柳酸、脫氫乙 酸、山梨酸、硼酸等之酸類及其鹽類、苯酚、氯代甲苯酚 、氯代二甲苯酚、異丙基甲酚、間苯二酚、鄰苯基苯酚、 -22- (20) 200400048 對羥基安息酸酯、苯氧基乙醇、瑞香草酚、日扁柏醇、 吉歐奇索隆(Thioxolone)等之酚類;六氯代二酣基甲院 、2,4,4 _二氣代—2 -經基一本基酸寺之歯化雙酣 類;二氯代均—►苯胺(trichloro carbanilide)、鹵碳隨苯 胺(Halo car ban )、癸烯醯一乙醇胺等之醯胺化合物類; 烷基二甲基苄基氯化銨、溴化烷基異喹啉鏺、氯代节乙氧 銨、鯨臘基吡啶_等之四級銨化合物類;月桂基二(胺乙 基)甘胺酸等之兩性表面活性劑;2 -吡啶硫醇一 i _氧化 馨 物鋅鹽、氯核西辛(Chlorhexidine)、奇拉姆(Tyram) 、N —三氯代甲基硫一 4一環己烯一1,2 -二羧基醯胺、 氯丁醇等。 (1 6 )氧化防止劑可例舉:降二氫愈瘡木酸、愈瘡木 脂(guajac )、沒食子酸丙酯、丁基羥基茴香腦( Butylhydroxy anethole)、二丁基經基甲苯、生育酸(維 生素 E) (tocopherol) 、2,2' — 甲嫌雙(4 一 甲基一 6 —第三丁基)酚等。 _ (17 )鉗合劑可例舉:俟德特酸鹽(Edetate )、焦 磷酸鹽、六偏磷酸鹽、檸檬酸、酒石酸、葡萄酸等、 (1 8 )紫外線散射劑可例舉:氧化鐵、高嶺土、滑石 等。 (1 9 )溶劑可例舉:丙酮、甲基乙基甲酮等之酮類; 溶纖素、二噚烷、二甲基甲醛、N —甲基吡咯烷酮、二甲 基亞硕等能與水混合的有機溶劑之外,尙可舉:乙酸乙酯 、克樂他米頓(C r 〇 t a m i t ο η )等不能與水混和的有機溶劑 -23- (21) (21)200400048 。醇而言,可舉:甲醇、乙醇、丙醇、苄醇、苯乙醇、異 丙醇、異丁醇、己醇、2—乙基己醇、環己醇、辛醇、丁 醇、戊醇等之醇類等。 此外尙有:安定劑、塡充劑、保存劑、可塑劑、軟化 劑' 劣化防止劑等,而此等添加劑可在不影響所得含水凝 膠體之特的範圍內任意添加。 又’本發明之含水凝膠體,係將含水凝膠成型爲具有 0.5 mm之厚度的薄膜,在25 π,相對濕度6〇%下曝露24 小時後’將其表面之粘接性作成準照JIS Ζ 023 7之膠粘試 驗法實施時的傾斜角3 0度之球膠粘値爲1 0以上者。 其次,就本發明之含水凝膠體之製造方法加以說明。 本發明之含水凝膠體之製造方法之特徵爲··調製含有 選自聚丙烯酸、聚丙烯酸鈉以及聚丙烯酸部份中和物而成 的群中的至少2種聚合物、鋁化合物、水以及抗壞血酸或 其衍生物的混合物,並將該混合物加熱爲25至65 °C。 加熱溫度較佳爲35°C至55°C,更佳爲40°C至50°C。 如加熱溫度低於2 5 °C,則凝膠化所需時間即拖長,而如 加熱溫度高於6 5 °C,則難於獲得抗壞血酸或其衍生物之 安定性。 當製作本發明之凝膠體時,可採用例如將抗壞血酸或 其衍生物、鋁化合物、水以及聚丙烯酸等分散在多元醇中 ,在將其分散液添加於含有pH調整劑的水中之下進行混 練,需要時再加添加物以加熱的方法。 本發明之製造方法中’含水凝膠體係以交聯劑混合後 -24- (22) (22)200400048 之溶膠狀態進行成型,需要時加溫’並使其交聯。將交聯 後之含水凝膠體直接使用適當的成型機、打錠機以調製爲 各種成型物。在此,如予以加熱,則可加快凝膠化之速度 〇 當將含水凝膠體進行片材化時,則可在紙、木材、金 屬、玻璃纖維、布(絨布、織布、不織布等)、合成樹脂 (聚胺酯、乙烯/乙酸乙烯共聚物、聚氯化乙烯、聚酯( 例如聚對苯二甲酸乙二醇酯)、聚烯烴(例如聚乙烯、聚 丙烯等)、聚醯胺(例如尼龍6、尼龍66等)、聚二氯 亞乙烯、聚四氟乙烯等、鋁等之金屬箔、橡膠或纖維素衍 生物以及此等與塑膠薄膜之積層薄膜等之成型品、片材( 箔)、或帶子等的支持體之1面或兩面上適量塗佈含水凝 膠體即可。爲使所得片材狀之含水凝膠體容易保存,較佳 爲在塗佈有含水凝膠的面上貼合經以矽或其他適當方法所 處理的剝離片材、或者將未塗佈有粘接劑的面使用矽或其 他適當方法加以處理而作成剝離面,然後與未塗佈有凝膠 的面重疊之方式加以捲繞或重疊。在此,剝離片材可使用 :聚乙烯薄膜、聚丙烯薄膜、剝離紙、賽璐玢( cellophane)、聚氯化乙烯、聚酯等。 〔實施例〕 以下’藉由實施例及比較例而將更詳細說明本發明, 惟本發明並不因此等實施例而有所限定。另外,各實施例 中之份分別表示質量份。 -25- (23) 200400048 實施例1 ) 按照下列原料調配比及配方,調製含水凝膠 原料調配比〕 聚丙烯酸鈉 丙烯酸/丙烯酸鈉 甘油 氫氧化銘鎂 水 二異丙醇胺 2份 50/50 (莫耳比))共聚物2份 30份 1份 61份 份 抗壞血酸- 2-磷酸鎂鹽 份 〔配方〕 在二異丙醇胺之水溶液中徐徐添加:抗壞血酸一 2〜 聚 磷酸鎂鹽(「抗壞血酸P Μ」:昭和電工(股)製) 丙烯酸鈉(「俾斯可美特F 4 8 0 S S」:昭和電工(股)製 )與丙烯酸/丙烯酸鈉(50/50(莫耳比)共聚物(聚丙 烯酸部份中和物)(「俾斯可美特N P - 7 0 0」:昭和電工 (股份)製)以及氫氧化鋁鎂(「沙那爾明」:協和化學 工業(股)製)之甘油分散液並加以混練。使用刮刀塗佈 機(Knife coater)在聚丙烯製之襯布上將所得溶膠按0.5 mm之餘隙(clearance )進行塗工,然後在溶膠上貼合不 織布,並裝入鋁層合袋中加以熱封後進行熟成3天以製得 貼敷劑。如用手指接觸不織布上之凝膠,即感覺到稍有伸 -26- (24) 200400048 張,並有強反彈力。使用精製水稀釋凝膠爲i 〇 0倍並測定 pH之結果’ pH値爲8.2。又,將所得貼敷劑在25 °C,相 對濕度6 0 %下曝露2 4小時後,準照J I s Z 0 2 3 7之膠粘試 驗法所進行的傾斜角3 0度之球膠粘値爲1 4。 (實施例2 ) 按照下列原料調配比及配方,調製含水凝膠。
〔原料調配比〕 聚丙烯酸鈉 2份 丙烯酸/丙烯酸鈉(70/3 0 (莫耳比))共聚物2份 右旋雙脫水山梨糖醇液 3 0份 精製水 6 1 . 5份 氫氧化鋁 〇 . 5份 二羥基鋁胺基乙酸酯 〇 · 5份
二異丙醇胺 0 · 5份 抗壞血酸- 2 —磷酸鋅鹽 3份 〔配方〕 在二異丙醇胺之水溶液中一口氣添加:抗壞血酸- 2 一磷酸鹽、聚內烯酸鈉及丙烯酸/丙烯酸鈉(70 / 3 0 (莫 耳比))共聚物(聚丙烯酸部份中和物)及二羥基鋁胺基 乙酸酯(「葛利西那爾」:協和化學工業(股)製)以及 氫氧化鋁(「乾燥氫氧化鋁凝膠S - 1 〇〇」:協和化學工 -27- (25) (25)200400048 業(股)製)之右旋雙脫水山梨糖醇液(右旋山梨糖醇之 70 w / v %水溶液)之分散液並加以混練。使用刮刀塗佈 機在聚丙烯製之離模紙上將所得溶膠按〇 . 5 mm之餘隙進 行塗工’然後在溶膠上貼合不織布,並裝入鋁層合袋中加 以熱封後進行熟成3天以製得貼敷劑。如用手指接觸不織 布上之凝膠,即感覺到稍有伸張,並有強反彈力。按與實 施例1同樣方式測定凝膠體之pH結果,pH値爲8.5。又 ’將所得貼敷劑在25。(:,相對濕度60%下曝露24小時後 ’準照JIS Z 0237之膠粘試驗法所進行的傾斜角30度之 球膠粘値爲2 2。 (實施例3 ) 按照下列原料調配比及配方,調製含水凝膠。 〔原料調配比〕 聚丙烯酸鈉 2份 丙烯酸/丙烯酸鈉(80/20 (莫耳比) )共聚物2份 氫氧化鋁鎂 0.5份 氫氧化錦 0.5份 丙二醇 0.5份 精製水 61份 抗壞血酸一 2 -磷酸鈉鹽 4份 〔配方〕 -28- (26) (26)200400048
在水中徐徐添加:抗壞血酸- 2 -磷酸鈉鹽(「抗壞 血酸PS」:昭和電工(股)製)、聚丙烯酸鈉(「俾斯 可美特F480 SS」:昭和電工(股)製)及丙烯酸/丙烯 酸鈉(8 0 / 2 0 (莫耳比))共聚物(聚丙烯酸部份中和物 )及氫氧化鎂(「沙那爾明」:協和化學工業(股)製) 以及氫氧化鋁(「乾燥氫氧化鋁凝膠S - 1 00」:協和化 學工業(股)製)之甘油分散液並加以混練。將所得溶膠 按0 · 5 mm之餘隙進行成型並密封後,在5 〇艺下熟成1天 ’然後從容器取出以製得凝膠狀之敷臉劑。如用手指接觸 ,即感覺到伸張,並有強反彈力。又,按與實施例1同樣 方式測定凝膠體之p Η結果,p Η値爲7 · 4。又,將所得敷 臉劑在25 °C,相對濕度60%下曝露24小時後,準照JIS Z 023 7之膠粘試驗法所進行的傾斜角30度之球膠粘値爲 18° (實施例4 ) 按照下列原料調配比及配方,調製含水凝膠。 〔原料調配比〕 丙烯酸鈉/丙烯酸(80/20 (莫耳比))共聚物 1〇份 聚丙烯酸鈉 1 〇份 聚丙烯酸 1 〇份 N-甲基-N-乙烯基乙醯胺/丙烯酸鉀(60/4〇(wt比)共聚 物 1份 -29- (27) (27)200400048 偏矽酸鋁酸鎂鹽 5份 硫酸鉀鋁 5份 氫氧化鈉 0.5份 乙醇 30份 水 28份 抗壞血酸- 2 -磷酸苷 〇·5份 〔配方〕 在氫氧化鈉及硫酸鉀鋁之水溶液中一口氣添加抗壞血 酸一 2 —葡萄苷、聚丙烯酸鈉(「俾斯可美特F480 SS」 :昭和電工(股)製)及丙烯酸鈉/丙烯酸(8 0 / 2 0 (莫 耳比))共聚物(聚丙烯酸部份中和物)、聚丙烯酸、N 一甲基一 N—乙烯基乙醯胺共聚合物以及偏矽酸鋁酸鎂( 「諾異西林」:富士化學工業(股)製)之乙醇分散液並 加以混練。將所得溶膠按〇· 5 mm之餘隙進行成型並密封 後,在室溫下熟成7天,然後從容器取出以製得凝膠狀之 貼敷劑。如用手指接觸,即感覺到伸張,並有強反彈力。 按與實施例1同樣方式測定凝膠體之pH結果,pH値爲 8 · 5。又,將所得則貼敷劑在2 5 °C,相對濕度6 0 %下曝露 24小時後,準照JIS Z 023 7之膠粘試驗法所進行的傾斜 角3 0度之球膠粘値爲1 5。 (實施例5 ) 〔原料調配比〕 -30- (28) (28)200400048 丙烯酸鈉/丙烯酸(7 0/3 0 (莫耳比))共聚物 1份 聚丙烯酸 1份 N-乙烯基乙醯胺/丙烯酸鈉(9/l(wt比))共聚物 3份 精製水 6 4.8 8份 氫氧化鋁凝膠·碳酸氫鈉共沈物 〇.〇5份 乳酸鋁 0.0 5份 1,3 — 丁二醇 3 0 份 氯1 0 %水溶液 0.0 1份 抗壞血酸一 2-磷酸鎂鹽 0.01份 〔配方〕 在氨及乳酸鋁之水溶液中添加:抗壞血酸- 2 -磷酸 鎂(「抗壞血酸P Μ」:昭和電工(股)製)、丙烯酸鈉 /丙烯酸(70/ 3 0 (莫耳比))共聚物(聚丙烯酸部份中 和物)(「俾斯可美特 ΝΡ - 600」:昭和電工(股)製 、聚丙烯酸、Ν-乙烯基乙醯胺/丙烯酸鈉(9/1 (wt比 ))共聚物以及氫氧化鋁凝膠*碳酸氫鈉共沈物(「苦姆 萊特」:協和化學工業(股)製)之1,3 -丁二醇分散 液並加以混練。使用刮刀塗佈機在聚丙烯製之襯布上將所 得溶膠按〇·5 mm之餘隙進行塗工,然後在溶膠上貼合不 織布,並裝入鋁層合袋中加以熱封後進行熟成3天以製得 貼敷劑。如用手指接觸貼敷劑上之凝膠,即感覺到稍有伸 張,並有強反彈力。按與實施例1同樣方式測定凝膠體之 pH結果,pH値爲6.5。又,將所得貼敷劑在25 °C,相對 -31 - 200400048 (29) 濕度60%下曝露24小時後,準照JIS Z 02 3 7之膠粘試驗 法所進行的傾斜角3 0度之球膠粘値爲 10° (比較例1 ) 〔原料調配比〕 聚丙烯酸鈉 4份 甘油 30份 精製水 61份 氫氧化銘鎂 1份 二異丙醇胺 1份 抗壞血酸一 2 -磷酸鎂鹽 3份 〔配方〕 在二異丙醇胺水溶液中徐徐添加:抗壞血酸一 2 -磷 酸鎂鹽(「抗壞血酸Ρ Μ」:昭和電工(股)製)、聚內 烯酸鈉(「俾斯可美特F 4 8 0 S S」:昭和電工(股)製) 及氫氧化鋁鎂(「沙那爾明」:協和化學工業(股)製之 甘油分散液並加以混練。使用刮刀塗佈機在聚丙烯製之襯 布上將所得溶膠按0.5 mm之餘隙進行塗工,然後在溶膠 上貼合不織布,並裝入鋁層合袋中加以熱封後進行熟成3 天以製得貼敷劑。如用手指接觸不織布上之凝膠時,未感 覺到彈性而附著在手指上,又不織布整體被溶膠所潤濕。 (比較例2 ) -32- (30) (30)200400048 〔原料調配比〕 丙烯酸鈉/丙烯酸(70/3 0 (莫耳比))共聚物 4份 精製水 6 1 · 5份 二羥基鋁胺基乙酸酯 0 · 5份 乾燥氫氧化鋁凝膠 0 · 5份 右旋雙脫水山梨糖醇液 3 〇份 二異丙醇胺 〇 · 5份 抗壞血酸—2 -磷酸鋅鹽 3份 〔配方〕 在二異丙醇胺水溶液中添加:抗壞血酸- 2 -磷酸鋅 鹽、丙烯酸鈉/丙烯酸(7 0 / 3 0 (莫耳比))共聚物(聚 丙烯酸部份中和物)以及二羥基鋁胺基乙酸酯(「葛利西 那爾」:協和化學工業(股)製)、氫氧化鋁(「乾燥氫 氧化鋁凝膠 S — 1 00」:協和化學工業(股)製)之右旋 雙脫水山梨糖醇液(右旋雙脫水山梨糖醇之70w/v水溶 液)之分散液並加以混練。使用刮刀塗佈機在聚內烯製之 襯布上將所得溶膠按0.5 mm之餘隙進行塗工,然後在溶 膠上貼合貼敷劑’並裝入鋁層合袋中加以熱封後進行熟成 3天以製得貼敷劑。如用手指接觸貼敷劑上之凝膠時,未 感覺到彈性而附著在手指上’又不織布整體被溶膠所潤濕 〔發明效果〕 -33- (31) 200400048 如上所說明,本發明之含水凝膠體,係一種能安定地 保持抗壞血酸或其衍生物,而凝膠強度高,對被粘體上之 粘接性良好,且不致於產生離漿液,組成單純且容易調整 的含水凝膠體。使用本發明之含水凝膠體,即可提供能以 最大限度發揮抗壞血酸或其衍生物對肌膚等之效果的化粧 料等。 -34 -
Claims (1)
- 200400048 (1) 拾、申請專利範圍 1· 一種含水凝膠體,係含有選自聚丙烯酸、聚丙烯 酸鈉以及聚丙烯酸部份中和物而成的群中之至少2種聚合 物經以鋁化合物所交聯的凝膠體、水、以及抗壞血酸或其 衍生物的含水凝膠體,而其特徵爲:當以精製水稀釋爲 100倍時之pH値在6.5至8.5之範圍。 2 ·如申請專利範圍第1項之含水凝膠體,其中該pH 値爲7.0〜8.0的範圍。 3.如申請專利範圍第1項或第2項之含水凝膠體, 其中鋁化合物爲氫氧化鋁鎂。 4 ·如申請專利範圍第1項或第2項之含水凝膠體, 其中鋁化合物的含有量爲,對100質量份的該含水凝膠體 而言爲0.01至10質量份者。 5·如申請專利範圍第1項或第2項之含水凝膠體, 其中抗壞血酸或其衍生物之含量係對該含水凝膠體1〇〇質 量份爲0.01至10質量份。 6·如申請專利範圍第1項或第2項之含水凝膠體, 其中抗壞血酸衍生物係抗壞血酸- 2-磷酸醋或其鹽。 7·如申請專利範圍第1項或第2項之含水凝膠體, 其中該含水凝膠體含有多元醇。 8.如申請專利範圍第1項或第2項之含水凝膠體’ 其中將該含水凝膠體成型爲具有〇· 5 mm厚度的膜片’並 在25 °C,相對濕度60%下曝露24小時後,準照 JIS Z 023 7之膠粘試驗法試驗其表面之粘接性時之傾斜角 -35- (2) (2)200400048 3 〇度之球膠粘値爲1 〇以上。 9· 一種含水凝膠體之製造方法,其特徵爲:調製含 有選自聚丙烯酸、聚丙烯酸鈉以及聚丙烯酸部份中和物而 成的群中之至少2種聚合物、鋁化合物、水以及抗壞血酸 或其衍生物的混合物,並將該混合物加熱爲25 t至65 °C 〇 1 〇 ·如申請專利範圍第9項之含水凝膠體之製造方法 ’其中將該含水凝膠體調整爲以精製水稀釋爲100倍時之 pH値爲6.5至8.5之範圍。 1 1 .如申請專利範圍第i 〇項之含水凝膠體之製造方 法’其中將前述PH値調整爲7.0至8.0之範圍。 12· —種化粧料,其特徵爲:使用申請專利範圍第1 項至第8項中之任〜項之含水凝膠體。 1 3 · —種外用製劑,其特徵爲:使用申請專利範圍第1 項至第8項中之任〜項之含水凝膠體。 -36- 200400048 柒、(一)、本案指定之代表圖為··無 (二)、本代表圖之元件代表符號簡單說明:無 捌、本案若有化學式時,請揭示最能顯示發明特徵的化學式: 無
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| KR101901386B1 (ko) * | 2018-03-06 | 2018-09-28 | 비엘테크 주식회사 | 하이드로겔의 제조방법 |
| CN108382120A (zh) * | 2018-03-21 | 2018-08-10 | 合肥师范学院 | 一种植物标本软化制作工艺 |
| US10813889B2 (en) | 2018-09-04 | 2020-10-27 | Babak Ghalili | Cannabinoid and menthol compositions and methods |
| US10987321B2 (en) | 2018-09-04 | 2021-04-27 | Babak Ghalili | Cannabinoid and anesthetic compositions and methods |
| CN112888743A (zh) * | 2018-10-26 | 2021-06-01 | 住友精化株式会社 | 凝胶状组合物和分散液以及凝胶状组合物的制造方法 |
| CN110010337B (zh) * | 2019-05-07 | 2021-08-31 | 深圳市金泰德五金电子有限公司 | 一种高效的扁平状漆包线去漆皮方法 |
| CN111066964A (zh) * | 2019-12-26 | 2020-04-28 | 湖北回盛生物科技有限公司 | 反刍动物用液体润滑剂及其制备方法 |
| US20210195865A1 (en) * | 2019-12-31 | 2021-07-01 | Yong Wang | Pet cooling Pad |
| WO2021177936A1 (en) * | 2020-03-02 | 2021-09-10 | Babak Ghalili | Cannabinoid and anesthetic compositions and methods |
| WO2021177937A1 (en) * | 2020-03-02 | 2021-09-10 | Babak Ghalili | Cannabinoid and menthol compositions and methods |
| US12421358B2 (en) * | 2020-09-08 | 2025-09-23 | Lg Chem, Ltd. | Polymer film, preparation method thereof, and polymer film laminate comprising the same |
| CN112521627B (zh) * | 2020-10-14 | 2022-05-03 | 浙江树人学院(浙江树人大学) | 一种具有缓释型净化杀菌功能的绿色复合水凝胶的制备方法 |
| CN112754957B (zh) * | 2021-01-29 | 2022-06-14 | 浙江芬尼奇工贸有限公司 | 一种免洗手凝胶 |
| CN112842678B (zh) * | 2021-02-03 | 2022-02-22 | 天津市肿瘤医院(天津医科大学肿瘤医院) | 一种用于预防手足综合征的贴片 |
| CN113173728B (zh) * | 2021-05-08 | 2023-08-22 | 四川铁科新型建材有限公司 | 抗骨料碱活性反应的无碱速凝剂及其制备方法 |
| KR20240141268A (ko) * | 2022-01-27 | 2024-09-26 | 데드 씨 브롬 컴퍼니 리미티드 | 마그네슘 하이드록사이드 페이셜 마스크 및 이의 제조 및 사용 방법 |
| CN115089767B (zh) * | 2022-05-25 | 2023-06-20 | 中山大学 | 一种大豆创伤修复材料及其制备方法与应用 |
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|---|---|---|---|---|
| JP3739100B2 (ja) | 1993-07-30 | 2006-01-25 | 救急薬品工業株式会社 | 低温架橋型ゲル剤 |
| JPH1147233A (ja) | 1997-07-30 | 1999-02-23 | Teikoku Seiyaku Co Ltd | 貼付剤および貼付剤の保存方法 |
| DE19860754B4 (de) * | 1998-06-24 | 2004-10-28 | Coty B.V. | Kosmetische Zubereitung |
| EP0993936A3 (en) * | 1998-10-13 | 2001-08-08 | Nitto Denko Corporation | Gel sheet for cosmetics and method for producing the same |
| JP2000143484A (ja) | 1998-11-06 | 2000-05-23 | Nitto Denko Corp | 化粧用ゲルシート |
| JP2000212074A (ja) | 1999-01-27 | 2000-08-02 | Sekisui Plastics Co Ltd | 多層ゲル構造生体用粘着シ―ト、これを用いた化粧品および医薬部外品 |
| JP3655781B2 (ja) * | 1999-08-25 | 2005-06-02 | 帝國製薬株式会社 | ビタミンc又はその誘導体を配合したパップ剤 |
| FR2805461B1 (fr) * | 2000-02-28 | 2003-01-31 | Snf Sa | Nouveaux agents de gommage cutane et nouvelles compositions cosmetiques |
-
2003
- 2003-06-18 TW TW092116564A patent/TW200400048A/zh not_active IP Right Cessation
- 2003-06-18 CN CNB038140586A patent/CN1301285C/zh not_active Expired - Lifetime
- 2003-06-18 AT AT03760885T patent/ATE391744T1/de not_active IP Right Cessation
- 2003-06-18 CN CN200610171440A patent/CN100577136C/zh not_active Expired - Lifetime
- 2003-06-18 DE DE60320251T patent/DE60320251T2/de not_active Expired - Lifetime
- 2003-06-18 AU AU2003243001A patent/AU2003243001A1/en not_active Abandoned
- 2003-06-18 EP EP03760885A patent/EP1513889B1/en not_active Expired - Lifetime
- 2003-06-18 KR KR10-2004-7020695A patent/KR20050013217A/ko not_active Ceased
- 2003-06-18 WO PCT/JP2003/007753 patent/WO2004000918A1/en not_active Ceased
- 2003-06-18 US US10/516,452 patent/US20060165801A1/en not_active Abandoned
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Also Published As
| Publication number | Publication date |
|---|---|
| US20060165801A1 (en) | 2006-07-27 |
| CN1301285C (zh) | 2007-02-21 |
| CN1662586A (zh) | 2005-08-31 |
| DE60320251D1 (de) | 2008-05-21 |
| KR20050013217A (ko) | 2005-02-03 |
| HK1072062A1 (zh) | 2005-08-12 |
| CN100577136C (zh) | 2010-01-06 |
| EP1513889A1 (en) | 2005-03-16 |
| US8580849B2 (en) | 2013-11-12 |
| WO2004000918A1 (en) | 2003-12-31 |
| CN101002722A (zh) | 2007-07-25 |
| EP1513889B1 (en) | 2008-04-09 |
| TWI349558B (zh) | 2011-10-01 |
| US20100099636A1 (en) | 2010-04-22 |
| DE60320251T2 (de) | 2009-05-14 |
| ATE391744T1 (de) | 2008-04-15 |
| AU2003243001A1 (en) | 2004-01-06 |
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