CN1838969A - 经皮和经粘膜制剂 - Google Patents
经皮和经粘膜制剂 Download PDFInfo
- Publication number
- CN1838969A CN1838969A CNA2005800001253A CN200580000125A CN1838969A CN 1838969 A CN1838969 A CN 1838969A CN A2005800001253 A CNA2005800001253 A CN A2005800001253A CN 200580000125 A CN200580000125 A CN 200580000125A CN 1838969 A CN1838969 A CN 1838969A
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- Prior art keywords
- agent
- hydrochloride
- percutaneous
- preparation
- sodium
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Abstract
经皮和经粘膜制剂常常不能充分地吸收。因此,需要能提高各种药物的经皮和/或经粘膜吸收的添加剂。本发明提供用于提高经皮和/或经粘膜吸收的组合物,其含有羟基磷灰石和必要组分。羟基磷灰石具有1μm或更小的最大粒径,优选0.1μm或更小,并且羟基磷灰石的含量相对于将要被配制的药物计在重量百分数为0.1至1000的范围。
Description
技术领域
本发明涉及应用于皮肤或粘膜的经皮和经粘膜制剂,其中它提高了必要组分的经皮和/或经粘膜吸收。
背景技术
用于对身体循环系统给药的主要剂型是口服方式、注射方式等等。近年来,许多药物已经采用经皮的和经粘膜的制剂形式,其可通过经皮或经粘膜吸收应用于皮肤和/或粘膜例如口腔、鼻、直肠、阴道、和眼粘膜。由于其血液浓度易于长期维持或高于某一水平,并且当必要时能容易地中止给药,因此这样的制剂形式是有利的并且便于药物应用。另外,这样的方式不像注射那样疼痛而且其药效几乎不会由于胃肠道环境或肝脏新陈代谢而降低。
然而,经过皮肤角质层或粘膜的经皮/经粘膜的药物给药通常具有低效的药物吸收效果,其中皮肤角质层或粘膜起着预防杂质侵入的阻挡层作用,因此难以以药物的治疗有效剂型给药。
因此,已经公开了用于增强经皮/经粘膜吸收的各种方法和组合物:通过与已酸香叶酯混合以削弱表皮细胞层屏障功能来增强吸收的方法(日本专利申请公开号NO.(JP-A)H5-178762(未审查,已公开的日本专利申请));通过粘膜吸收的基于右旋糖酐的药学载体(JP-A H5-238956);由粘合剂、增粘剂、药物、经皮吸收增强剂以及释放激发剂组成的粘合层压制成经皮贴剂用作经皮吸收增强剂(JP-A H7-101864);含有10-20重量百分比油酸单甘油酯、30-60重量百分比乙醇和30-60重量百分比水的外用制剂以用于提高药学活性物质的经皮吸收((授权的)日本专利NO.3471840);用于改善经皮/经粘膜吸收的微乳剂制剂(JP-A H7-2689);含甘油基变性硅树脂的经皮吸收增强剂((授权的)日本专利No.3417744);含有不易吸收的物质和精氨酸、其聚合物或聚合物盐的经粘膜制剂组合物(JP-A H10-95738);含有用于提高药物经皮吸收和/或经粘膜吸收的砂砾颗粒的外用制剂(JP-A H11-80031);通过用外用贴剂结合4至15μm的陶瓷用于提高经皮药物吸收的方法(RinshoYakuri(临床药理和治疗)23(1)Mar.1992);经皮吸收增强剂,其含有作为活性成分的在一定范围具有溶解性参数的油剂;含有唇形科植物提取物的经皮吸收增强剂;含有作为活性成分的多元醇脂肪酸酯或硫酸烷基酯的经皮吸收增强剂;含有中等链长的脂肪酸盐以及甘草次酸盐的经粘膜吸收增强剂;含有精氨酸、精氨酸聚合物、精氨酸盐或等等的经粘膜吸收增强剂;含有丙二醇、多元醇脂肪酸酯或聚桂醇的提高经皮吸收的组合物;提高药物浓度的方法,等等,还公开了使药剂与磷酸钙细粒结晶相混合用作血管内羟基磷灰石注射剂的方法。在这种方法中,药剂的血管内给药增强或延缓了药剂的效果,并且使药剂选择性地粘附于各种细胞例如癌细胞和病毒例如AIDS、ATL和肝炎病毒。当药效保持时可就此调节这些癌细胞或病毒的分化和生长(JP-A H5-255095)。
然而,经皮和经粘膜制剂常常不能很好的吸收,因此需要发展用于提高各种药剂经皮和经粘膜吸收的添加剂。
专利文献1:JP-A H5-178762
专利文献2:JP-A H5-238956
专利文献3:JP-A H7-101864
专利文献4:(授权的)日本专利No.3471840
专利文献5:JP-A H7-2689
专利文献6:(授权的)日本专利No.3417744
专利文献7:JP-A H10-95738
专利文献8:JP-A H11-80031
专利文献9:JP-A H5-255095
非专利文献1:Rinsho Yakuri(临床药理和治疗)23(1),Mar.1992
发明公开
本发明的目的在于提供当施加于皮肤或粘膜时具有提高必要组分经皮和/或经粘膜吸收的优良效果的经皮和经粘膜制剂。
本发明者为了获得上述目的进行了彻底的研究。结果本发明者发现通过对皮肤或粘膜施加含有必要组分和羟基磷灰石的经皮或经粘膜组合物能提高必要组分的经皮和经粘膜吸收,并就此完成了本发明。
典型地是本发明所使用的羟基磷灰石具有Ca10(PO4)6(OH)2的化学计量比组成,即使当它们是不具有1.67Ca/P摩尔比例的非化学计量比成份时,其也具有羟基磷灰石特征和磷灰石结构。
在本发明中所使用的羟基磷灰石所具有的化学计量或非化学计量的Ca/P摩尔比例在1.4-1.8的范围。
能通过改变盐组分的混合比例和合成条件来控制羟基磷灰石的Ca/P摩尔比率。例如,在湿的羟基磷灰石合成法中,能通过用氨水碱化水溶液来增加Ca/P的摩尔比例。可供选择的是,通过用稀酸中和或弱酸化水溶液能降低Ca/P摩尔比例。
以上提到的在本发明中使用的羟基磷灰石包括结晶的和弱结晶的羟基磷灰石。优选弱结晶的或无定形的羟基磷灰石。
在这里,术语“弱结晶的”是指在X-射线衍射图谱中比高度粉晶显示出更宽峰的晶体粉末。
术语“无定形”是指含有X-射线衍射图案显示出延伸晕的细微颗粒和无典型特征的晶体。在下文中,弱结晶的羟基磷灰石和无定形的羟基磷灰石是指分别作为“弱结晶的磷灰石”和“无定形的磷灰石”。
本发明中所使用的弱结晶的磷灰石和无定形的磷灰石包括,例如,通过上述的湿合成法制备磷灰石,然后冷冻干燥,或在低于100℃的温度下干燥,或在低于300℃的温度下烘焙。
弱结晶的磷灰石和无定形磷灰石包括尺寸小于高度结晶的羟基磷灰石的颗粒(以下简称“结晶磷灰石”)。
在本发明中,羟基磷灰石的最大粒径优选1.0μm或更小,更优0.1μm或更小,和仍然更优选0.05μm或更小。
平均粒径优选0.6μm或更小,更优选0.07μm或更小,和仍然更优选0.04μm或更小。
由于获得更小的平均粒径,比面积变得更大,从而导致药剂吸收的增强。因此,并不限制特别限制平均粒径的下限;但是,优选的是,例如,大约为0.01μm。
能通过粉碎调节羟基磷灰石的最大粒径,优选1.0μm或更小,更优选对皮肤或粘膜施加含有必要组分和羟基磷灰石的经皮或经粘膜组合物能提高必要组分的经皮和经粘膜吸收,并就此完成了本发明。
典型地是本发明所使用的羟基磷灰石具有Ca10(PO4)6(OH)2的化学计量比组成,即使当它们是不具有1.67Ca/P摩尔比例的非化学计量比成份时,其也具有羟基磷灰石特征和磷灰石结构。
可在本发明中所使用的化学计量或非化学计量的羟基磷灰石Ca/P摩尔比例在1.4-1.8的范围。
能通过改变盐组分的混合比例和合成条件来控制羟基磷灰石的Ca/P摩尔比率。例如,在湿的羟基磷灰石合成法中,能通过用氨水碱化水溶液来增加Ca/P的摩尔比例。可供选择的是,通过用稀酸中和或弱酸化水溶液能降低Ca/P摩尔比例。
以上提到的在本发明中使用的羟基磷灰石包括结晶的和弱结晶(poorlycrystalline)的羟基磷灰石。优选弱结晶的或无定形的羟基磷灰石。
在这里,术语“弱结晶的”是指在X-射线衍射图谱中比高度结晶的粉末显示出更宽峰的晶体粉末。
术语“无定形”是指含有细微颗粒的粉末,其X-射线衍射图案显示出宽的晕,这不是晶体的特征。在下文中,弱结晶的羟基磷灰石和无定形的羟基磷灰石是分别指“弱结晶的磷灰石”和“无定形的磷灰石”。
本发明中所使用的弱结晶的磷灰石和无定形的磷灰石包括,例如,通过上述的湿合成法制备、然后冷冻干燥、或在低于100℃的温度下干燥、或在低于300℃的温度下烘焙的磷灰石。
弱结晶的磷灰石和无定形磷灰石包括尺寸小于高度结晶的羟基磷灰石的颗粒(以下简称“结晶磷灰石”)。
在本发明中,羟基磷灰石的最大粒径优选1.0μm或更小,更优选0.1μm或更小,和仍然更优选0.05μm或更小。
平均粒径优选0.6μm或更小,更优选0.07μm或更小,和仍然更优选0.04μm或更小。
平均粒径越小,比面积越大,从而导致药剂吸收的增强。因此,并不限制特别限制平均粒径的下限;但是,优选的是,例如,大约为0.01μm。
能通过粉碎调节羟基磷灰石的最大粒径至粒径优选1.0μm或更小,更优选0.1μm或更小,和仍然更优选0.05μm或更小。粉碎至具有1.0μm或更小的最大尺寸、优选0.1μm或更小和更优选0.05μm或更小的细微粒子后,羟基磷灰石可与必要组分和其它组分以及基料组合,用于经皮/经粘膜制剂。然而,为提高经皮和经粘膜吸收,更优选的是首先通过粉碎的羟基磷灰石携带必要组分,接着将混合物与其他组分和基料结合,用于经皮/经粘膜制剂。
在经皮/经粘膜制剂中羟基磷灰石含量随必要组分变化,因此难以使所有制剂都具有固定量的羟基磷灰石。以必要组分为基准其含量优选在0.1到1000重量百分比的范围,为获得足够的经皮或经粘膜吸收效果,更优选的是含量在1至500重量百分比范围,和仍然更优选的是在10至200重量百分比范围。
当经皮/经粘膜制剂中含有本发明的羟基磷灰石时能显著提高各种经皮/经粘膜制剂中必要组分的皮肤或粘膜渗透性。
在本发明中,不特别限制通过皮肤或粘膜吸收的组分类型。这种成份包括各种药剂和化妆品组分,条件是只要它们能用于经皮和/或经粘膜吸收。
具体地是,这种组分包括但不局限于:止痛剂、退热剂、或消炎剂、抗痛风或抗高尿酸血症剂、与非类固醇抗炎剂、类固醇抗炎剂、伤口愈合剂、抗癌剂、安眠或止痛剂、抗焦虑剂、抗精神病剂、抗抑郁剂、抗躁狂症、抗组胺剂、抗癫病剂、局部麻醉剂、用于外周循环紊乱的治疗剂、抗帕金森剂、肌肉松弛剂、自律或抗痉挛剂、抗发汗剂、脑循环或新陈代谢改善剂、强心剂、抗心绞痛剂、β阻断剂、Ca拮抗剂、抗心律失常剂、抗高血压剂、血管扩张剂、减充血剂、毛细管稳定剂、抗高脂血症剂、血管加压剂、呼吸刺激剂、支气管扩张剂或止喘剂、止咳剂、祛痰剂、消化性溃疡治疗剂、促吞咽剂、抗吐剂、止泻剂(obstipants)或抗气胀剂、健胃或助消化剂、泻剂、痔制剂、神经原性膀胱治疗剂、良性前列腺肥大或尿频治疗剂、肾石病或尿石病治疗剂、利尿剂、促胆汁分泌剂、抗糖尿病剂、脑垂体激素制剂、肾上腺皮质激素制剂、性激素制剂、前列腺素、甲状腺机能障碍治疗剂、抗骨质疏松症或骨骼新陈代谢改善药物、氨基酸、维生素制剂、止血剂、抗血栓剂、抗生素、磺胺药、抗真菌剂、抗病素剂、抗HIV剂、抗寄生虫剂或抗原虫剂、抗风湿药、免疫抑制剂、防晒(sunscreen)剂、抗过敏剂、眼药制剂、抗癣剂、皮肤软化剂或润滑剂、湿润组分、秃顶治疗剂或毛发生长促进剂、肽激素制剂、戒烟助剂、节食(diet)组分、皮肤漂白组分、抗老化组分、多糖、植物提取物或提炼油、酶和疫苗。它们可以单独使用或联合便用。
在另一个具体实施方案中,本发明提供羟基磷灰石和经皮和/或经粘膜吸收的组分用于制备经皮和经粘膜制剂的用途。优选使用具有上述粒径的羟基磷灰石。
本发明预防或治疗疾病的方法包括施用有效剂量的含有上述羟基磷灰石和经皮或经粘膜吸收的组分的经皮或经粘膜制剂的步骤。此外,本发明用于促进美丽和健康的方法包括施用有效剂量的上述经皮和/或经粘膜制剂步骤。
在本发明中所使用的“经皮和/或经粘膜吸收的组分”在下面作了详细地描述,但这决不是对它的限制。本发明的预防或治疗方法所针对的疾病或通过本发明方法用于增进美丽和健康所针对的疾病是与上面所描述的组分相对应的。
[止痛剂、退热剂和消炎剂]
阿斯匹林、醋氨酚(acetaminophen)、布洛芬(ibuprofen)、消炎痛(indomethacin)、酮洛芬(ketoprofen)、双氯芬酸钠(diclofenac sodium)、二氟苯水杨酸、吡罗昔康(piroxicam)、非那西汀(phenacetin)、非诺洛芬钙(fenoprofen calcium)、联苯乙酸、氟比洛芬(flurbiprofen)、马来酸氯苯吡胺、水杨酸、水杨酸甲酯等等。
[抗痛风和抗高尿酸血症剂]
秋水仙碱(Colchicine)、苯溴马隆(benzbromarone)、丙磺舒(probenecid)、苯磺唑酮(sulfinpyrazone)、别嘌呤醇(allopurinol)等等。
[非类固醇消炎剂]
阿斯匹林、醋氨酚、布洛芬、消炎痛、依托度酸(etodolac)、水杨酸、水杨酸乙二醇酯、双氯芬酸钠、二氟苯水杨酸、舒洛芬(suprofen)、舒林酸(sulindac)、酮洛芬(ketoprofen)、甲苯酰吡酸钠(tolmetin sodium)、氟比洛芬(flurbiprofen)、非诺洛芬(fenoprofen)、非诺洛芬钙(fenoprofen calcium)、扎托洛芬(zaltoprofen)、吡罗昔康(piroxicam)、氨基比林(aminopyrine)、氨替比林(antipyrine)、安乃近(sulpyrine)、羟保泰松(oxyphenbutazone)、萘普生(naproxen)、依托芬那酯(etofenamate)、水杨酰胺、舒林酸(sulindac)、氨基水杨酸三乙醇酯、甲灭酸(mefenamic acid)、氟灭酸(flufenamic acid)、甲氯灭酸(meclofenamic acid)、秋水仙碱(colchicine)、丁苯羟酸(bufexamac)、联苯乙酸、氯索洛芬(loxoprofen)、芬布芬(fenbufen)、二氟苯水杨酸、阿氯芬酸(alclofenac)、苯丁唑酮(phenylbutazone)、苄达酸(bendazac)等等。
[类固醇消炎剂]
安西奈德(Ameinonide)、强的松龙戊酸酯(prednisolone valerate)、双氟皮甾松(diflucortolone)戊酸酯、倍他米松(betamethasone)戊酸酯、倍他米松乙酸酯、醋酸氟美松(dexamethasone acetate)、二丙酸倍他米松、地塞米松(dexamethasone)、二氟美松(flumethasone)特戊酸酯、倍氯米松(beclomethasone)丙酸酯、倍他米松、去炎松(triamcinolone)缩丙酮、哈西缩松(halcinonide)、氟轻松醋酸酯(fluocinonide)、氟轻松(fluocinolone acetonide)缩酮、氟氢缩松(fluorometholone)、氟氢缩松(fludroxycortide)、氢化泼尼松(prednisolone)、甲基强的松龙(methylprednisolone)、醋酸甲基强的松龙(methylprednisolone acetate)、氢化可的松(hydrocortisone)、氢化可的松(hydrocortisone)丁酸酯、丙酸氯氟美松(clobetasol propionate)等等。
[伤口愈合促进剂]
尿囊素(allantoin)及其衍生物、甘草甜素(glycyrrhizin)酸及其衍生物、甘草次酸(glycyrrhetic acid)及其衍生物、ε-氨基己酸、甘草根(GlycyrrhizaRadix)、紫草根(Lithospermum Radix)、甘葡环烃(azulene)、甘葡环烃磺酸钠、氯化小檗碱、硫酸小檗碱、氯化溶菌酶、扁柏酚(hinokitiol)、芦荟(aloe)等等。
[抗癌剂]
环磷酰胺(Cyclophosphamide)、5-氟尿嘧啶、盐酸伊达比星(idarubicin)、盐酸表柔比星(epirubicin)、盐酸博来霉素(bleomycin)、盐酸道诺霉素(daunorubicin)、盐酸阿霉素(doxorubicin)、盐酸吡柔比星(pirarubicin)、放线菌素C(actinomycin C)、阿霉素、丝裂霉素C、吉非替尼(gefitinib)、干扰素(interferon)β,溶链菌(Picibanil),6-巯基嘌呤、鬼臼乙叉苷(etoposide)、顺铂、卡铂、奈达铂(nedaplatin)、奥沙利铂(oxaliplatin)、卡巴醌(carboquone)、净司他丁(zinostatin)stimalamer、阿霉素(doxorubicin)、盐酸尼莫司汀(nimstine)、新制癌菌素(neocarzinostatin)、紫杉醇(paclitaxel)、米尔法兰(melphalan)、维甲酸(tretinoin)、雌莫司汀(estramustine)磷酸钠、道诺霉素、羟基脲、替加氟(tegafur)、巯基嘌呤、L-天冬酰胺酶、氨甲喋呤(methotrexate)、索布佐生(sobuzoxane)、白消安(busulfan)、枸橼酸它莫西芬(tamoxifen citrate)、氟他胺(flutamide)、UFT、硫酸培洛霉素(peplomycin)、硫酸长春碱(vinblastinesulfae)、长春新碱(vincristine)、硫酸长春新碱(vincristine sulfae)、阿糖胞苷(cytarabine)ocfosfate、脱氧氟尿苷(doxifluridine)、色霉素A、醋葡醛内酯(aceglatone)、阿纳托唑(anastrozole)、乌苯美司(ubenimex)、盐酸法倔唑(fadrozole)水合物、盐酸甲基苄肼、柠檬酸托瑞米芬(toremifene)、比卡鲁胺(bicalutamide)、伊马替尼(imatinib)甲磺酰酯、等等。
[安眠剂和止痛剂]
溴异戊酰脲(Bromvalerylurea)、烯丙基异丙基乙酰脲、艾司唑仑(estazolam)、三唑仑(triazolam)、咪达唑仑(midazolam)、氟硝基安定(flunitrazepam)、硝甲西泮(nimetazepam)、硝基安定(nitrazepam)、氟西泮(flurazepam)、卤沙唑仑(haloxazolam)、夸西泮(quazepam)、吡嗪哌酯(zopiclone)、唑吡旦(zolpidem)、环己烯巴比妥(hexobarbital)、戊巴比妥(pentobarbital)、异戊巴比妥(amobarbital)、巴比妥(barbital)、半琥珀酸布酰胺(butoctamide semisuccinate)、水合氯醛(chloral hydrate)、溴异戊酰脲(bromvalerylurea)、三氯乙基钠、哌拉平(perlapine)、吗啡、硫酸吗啡、羟基吗啉、氧吗啡酮、可待因(codeine)、二氢可待因(dihydrocodeine)、纳洛酮(naloxone)、纳洛芬(nalorphine)、戊唑星(pentazocine)、美沙酮、盐酸美沙酮(methadone)、溴替唑仓(brotizolam)、卤沙唑仑(haloxazolam)、苯巴比妥(phenobarbital)、盐酸利马扎封(rilmazafone)等等。
[抗焦虑剂]
溴异戊酰脲(Bromvalerylurea)、异戊巴比妥(amobarbital)、地西泮(diazepam)、硝基安定(nitrazepam)、氟西泮(flurazepam)、氯噻西泮(clotiazepam)、氟托西泮(flutoprazepam)、氯羟去甲安定(lorazepam)、环丙二氮卓(prazepam)、美达西泮(medazepam)、溴西泮(bromazepam)、去甲羟基安定(oxazepam)、托非索泮(tofisopam)、氯氮卓二钾(dipotassium clorazepate)、氟地西泮(fludiazepam)、阿普唑仑(alprazolam)、依替唑仑(etizolam)、奥沙唑仑(oxazolam)、氯唑安定(cloxazolam)、美沙唑仑(mexazolam)、氟他唑仑(flutazolam)、羟嗪(hydroxyzine)、盐酸羟嗪、盐酸甲硫哒嗪、甲氨二氮卓(chlordiazepoxide)、双羟萘酸噻嘧啶(pyrantel pamoate)、盐酸氯丙嗪(chlorpromazine hydrochloride)、马来酸甲氧异丁嗪(levomepromazinemaleate)、ethyl loflazepate等等。
[抗精神病剂]
阿莫沙平(Amoxapine)、盐酸阿米替林(amitriptyline)、盐酸去甲替林(nortriptyline)、盐酸马普替林(maprotiline)、盐酸丙咪嗪(imipramine)、氯卡比咪嗪(clocapramine)、氯丙嗪(chlorpromazine)、止呕灵(sulpiride)、硫利达嗪(thioridazine)、替米哌隆(timiperone)、三氟拉嗪(trifluoperazine)、尼莫纳地(nemonapride)、氟哌啶醇(haloperidol)、庚酸氟非那嗪(fluphenazineenanthate)、癸氟奋乃静(fluphenazine decanoate)、癸氟哌啶醇(decanoatehaloperidol)、佐替平(zotepine)、利哌利酮(risperidone)、喹硫平延胡索酸酯(quetiapine fumarate)、奥氮平(olanzapine)、马来酸三甲丙咪嗪(trimipraminemaleate)、马来酸甲氧异丁嗪(levomepromazine maleate)等等。
[抗抑郁剂]
阿莫沙平(Amoxapine)、盐酸阿米替林(amitriptyline)、盐酸丙咪嗪(imipramine)、盐酸氯丙咪嗪(clomipramine)、盐酸哌异丙肼(safrazine)、盐酸洛非帕明(lofepramine)、盐酸度硫平(dosulepin)、盐酸曲唑酮(trazodone)、盐酸去甲替林(nortriptyline)、盐酸马普替林(maprotiline)、盐酸米安色林(mianserin)、盐酸米那普仑(milnacipran)、马来酸三甲丙咪嗪(trimipraminemaleate)、顺丁烯二酸司普替林(setiptiline)、马来酸三氟戊肟胺(fluvoxaminemaleate)等等。
[抗躁狂剂]
碳酸锂等等。
[抗组胺剂]
可他敏(Diphenhydramine)、盐酸苯海拉明(diphenhydraminehydrochloride)、丹宁酸可他敏(diphenhydramine tannate)、硫酸月桂烷基可他敏(diphenhydramine lauryl sulfae)、马来酸氯苯吡胺(chlorpheniraminemaleate)、酒石酸阿利马嗪(alimemazine tartrate)、盐酸苯丙烯啶(triprolidinehydrochloride)、盐酸敏可静(meclizine hydrochloride)、异丙嗪(promethazine)、盐酸异丙嗪(promethazine hydrochloride)、盐酸高氯环嗪(homochlorcyclizinehydrochloride)、美喹他嗪(mequitazine)、富马酸氯马斯汀(clemastine)、盐酸异丙海汀(iproheptine)、盐酸塞庚啶(cyproheptadine)、8-氯茶碱二苯拉林(diphenylpyraline teoclate)、萘二磺酸美海洛林(mebhydrolin napadisylate)、盐酸二苯拉林、乘晕宁(dimenhydrinate)、盐酸异西喷地(isothipendyl)、顺丁烯二酸二甲吡茚胺(dimethindene)等等。
[抗癫痫剂]
苯巴比妥、苯巴比妥钠、美沙比妥(metharbital)、扑痫酮(primidone)、苯妥英(Hydantol)D、E和F、酰胺咪嗪(carbamazepine)、丙戊酸钠(sodiumvalproate)、乙妥英(ethotoin)、苯妥英(phenytoin)、三甲双酮(trimethadione)、乙酰苯丁脲(acetylpheneturide)、舒噻嗪(sultiame)、氯硝西泮(clonazepam)、地西泮、硝基安定、乙琥胺、唑尼沙胺(zonisamide)、乙酰唑胺(acetazolamide)、ACTH、维生素B6等等。
[局部麻醉剂]
可卡因、氨基苯甲酸乙酯、盐酸丁卡因(tetracaine hydrochloride)、普鲁卡因(procaine)、盐酸普鲁卡因、待布卡因(dibucaine)、盐酸待布卡因、利多卡因(lidocaine)、盐酸利多卡因、盐酸奥布卡因(oxybuprocaine)、盐酸丁吡卡因(bupivacaine)、T-卡因、盐酸甲哌卡因(mepivacaine)、盐酸丙胺卡因(propitocaine)、奥昔卡因(oxethazaine)等等。
[用于外周循环紊乱的治疗剂]
烟酸肌醇酯(Inositol hexanicotinate)、灭胆灵(hepronicate)、盐酸妥拉唑林(tolazoline hydrochloride)、盐酸异克舒令(isoxsuprine)等等。
[抗帕金森剂]
左旋多巴(Levodopa)、屈昔多巴(droxidopa)、甲磺酸培高利特(pergolide)、甲磺酸溴麦角环肽(bromocriptine)、盐酸苯海索(trihexyphenidylhydrochloride)、盐酸他利克索(talipexole)、盐酸金刚烷胺(amantadinehydrochloride)、盐酸安克痉(biperiden)、盐酸吡咯庚汀(piroheptine)、盐酸普鲁芬胺(profenamine)、盐酸马扎替可(mazaticol)、盐酸甲哌噻吨(methixene)等等。
[肌肉松弛药]
地西泮、氯化筒箭毒碱(tubocurarine chloride)、氯化琥珀酰胆碱(suxamethonium)、溴化双哌雄双酯(pancuronium bromide)、维库溴铵(vecuronium bromide)、丹曲林钠(dantrolene sodium)、氟喹酮(afloqualone)、盐酸乙哌立松(eperisone)、盐酸甲苯哌丙酮(tolperisone)、氨基甲酸氯酚醚(chlorphenesin)、氯苯氨丁酸(baclofen)、盐酸替托尼定(tizanidine)、甲磺酸二苯哌丙醇(pridinol)、苯丙氨酯(phenprobamate)、美索巴莫(methocarbamol)等等。
[自律和抗痉挛剂]
氯化氨甲酰甲胆碱(Bethanechol chloride)、氯化三甲胺丁酸甲酯(carpronium chloride)、氯化乙酰胆碱(acetylcholine chloride)、新斯的明(neostigmine)、溴化吡啶斯的明(pyridostigmine bromide)、溴地斯的明(distigmine bromide)、氯化阿伯农(ambenonium chloride)、氯化滕西隆(edrophonium chloride)、吡芬溴铵(prifinium bromide)、格隆溴铵(glycopyrronium bromide)、硫酸阿托品(atropine sulfate)、甲溴辛托品(anisotropine methylbromide)、氢溴酸莨菪胺(scopolamine)、溴丁基莨菪胺、N-甲基莨菪胺硫酸甲酯、盐酸罂粟碱(papaverine bydrochloride)、碘化环宁(oxapium iodide)、苯戊溴铵(valethamate bromide)、盐酸乙哌苯乙酯(piperidolate)、东莨菪属(scopolia)提取物、溴化丁托品(butropium bromide)、曲匹布通(trepibutone)、依托多林(etomidoline)、噻哌溴铵(timepidiumbromide)、替喹溴铵(tiquizium bromide)、溴化乙基哌沙酯(pipethanate)、替莫碘铵(tiemonium iodide)、溴双苯酯铵(methylbenactyzium bromide)、溴化丙胺太林(propantheline bromide)、盐酸双环胺(dicyclomine hydrochloride)、夫洛丙酮(flopropione)、马来酸麦角新碱(ergometrine maleate)、托非索泮(tofisopam)等等。
[抗发汗剂]
莨菪胺、溴化丙胺太林(propantheline bromide)、quaternary alloxyammonium salts等等。
[改善大脑循环和新陈代谢的药物]
胞磷胆碱(Citicoline)、腺苷三磷酸二钠、γ-氨基丁酸盐、γ-氨基β-羟基丁酸盐、γ-阿魏酸脂(γ-orizanol)、高泛酸钙(calcium hopantenate)、艾地苯醌(idebenone)、盐酸氯酯醒(meclofenoxate)、盐酸二苯美仑(bifemelane)、盐酸茚氯嗪、马来酸麦角乙脲(马来酸麦角乙脲)、阿尼西坦(aniracetam)、盐酸硫必利(tiapride)、酒石酸艾芬地尔(ifenprodil)、盐酸法舒地尔(fasudil)、麦角溴烟酯(nicergoline)、异丁地特(ibudilast)、富马酸溴长春胺(brovincamine)、己酮可可豆碱(pentoxifylline)、盐酸氟桂嗪(flunarizine)、盐酸莫西赛利(moxisylyte)、甲磺酸二氢麦角碱(dihydroergotoxine)、奥扎格雷(ozagrel)钠、富马酸尼唑苯酮(nizofenone)等等。
[心脏刺激剂]
地高辛(Digoxin)、毛地黄毒苷(digitoxin)、甲基地高辛、毛花甙C(lanatoside C)、去乙酰毛花甙(deslanoside)、前海葱甙原(proscillaridin)、盐酸多巴胺、盐酸多巴酚丁胺、多卡巴胺(docarpamine)、肾上腺素(epinephrine)、去甲肾上腺素(norepinephrine)、盐酸异丙肾上腺素(isoprenalinehydrochloride)、氨利酮(amrinone)、盐酸奥普力农(olprinone)、甲氰吡酮(milrinone)、卡培立肽(carperitide)、氨茶碱(aminophylline)、甘油茶碱(diprophylline)、维司力农(vesnarinone)、匹莫苯(pimobendan)、山楂属(crataegus)提取物、反式-π-氧化樟脑(trans-π-oxocamphor)、癸稀醌(ubidecarenone)、氨乙基磺酸酯、卡培立肽(carperitide)等等。
[抗心绞痛剂]
硝化甘油、亚硝酸戊酯、硝酸异山梨醇酯、单硝酸异山梨醇酯、二硝酸异山梨醇酯、硝苯吡啶(nifedipine)、尼卡地平(nicardipine)、尼伐地平(nilvadipine)、尼索地平(nisoldipine)、尼群地平、盐酸马尼地平、盐酸贝尼地平、盐酸巴尼地平、氨氯地平苯磺酸酯、盐酸依福地平(efonidipine)、非洛地平(felodipine)、西尼地平(cilnidipine)、盐酸异博定(verapamil)、盐酸地尔硫卓(diltiazem)、盐酸依他苯酮(etafenone)、双嘧哌胺醇(dipyridamole)、曲匹地尔(trapidil)、尼可地尔(nicorandil)、盐酸三甲氧苄嗪、盐酸地拉齐普(dilazep)等等。
[β阻断剂]
盐酸普萘洛尔(Propranolol)、盐酸布非洛尔(bufetolol)、盐酸氯甲苯心安(bupranolol)、盐酸心得舒(alprenolol)、盐酸茚诺洛尔(indenolol)、盐酸心得平(oxprenolol)、盐酸布尼洛尔(bunitrolol)、硫酸环戊丁心安(penbutolol)、丙二酸波吲洛尔(bopindolol)、心得静(pindolol)、盐酸卡替洛尔(carteolol)、酒石酸美托洛尔(metoprolol)、氨酰心安(atenolol)、富马酸比索洛尔(bisoprolol)、盐酸倍他索洛尔(betaxolol)、盐酸醋丁洛尔(acebutolol)、盐酸塞利洛尔(celiprolol)、盐酸柳氨苄心定(labetalol)、卡维地洛(carvedilol)、盐酸贝凡洛尔(bevantolol)、盐酸氨磺洛尔(amosulalol)、盐酸阿罗洛尔(arotinolol)、尼普地洛(nipradilol)、盐酸替利洛尔(tilisolol)等等。
[Ca拮抗剂]
硝苯吡啶(Nifedipine)、盐酸硝吡胺甲酯(nicardipine)、尼伐地平(nilvadipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、盐酸美尼地平(manidipine)、盐酸比尼地平(benidipine)、盐酸巴尼地平(barnidipine)、盐酸依福地平(efonidipine)、非洛地平(felodipine)、西尼地平(cilnidipine)、阿雷地平(aranidipine)、苯磺酸氨氯地平(amlodipine besilate)、盐酸异博定(verapamil)、盐酸地尔硫卓(diltiazem)等等。
[抗心律失常剂]
盐酸心得平(Oxprenolol)、硫酸奎尼定(quinidine sulfate)、盐酸普鲁卡因酰胺(procaineamide)、达舒平(disopyramide)、磷酸双异丙吡胺、阿吗灵(ajmaline)、琥珀酸西苯唑啉、盐酸苄普地尔(bepridil)、盐酸吡美诺(pirmenol)、盐酸普萘洛尔、盐酸利多卡因、盐酸尼非卡兰(nifekalant)、盐酸索他洛尔(sotalol)、盐酸慢心利(mexiletine)、盐酸安博律定(aprindine)、醋酸氟卡胺(flecainide acetate)、盐酸匹西卡地(pilsicainide)、盐酸丙胺苯丙酮(propafenone)、盐酸胺碘达隆(amiodarone)、溴苄铵(bretylium)、盐酸布非洛尔(bufetolol)、盐酸氯甲苯心安(bupranolol)、盐酸布库洛尔(bucumolol)、马来酸噻吗洛尔(timolol)、萘羟心安(nadolol)、心得静(pindolol)、丙二酸波吲洛尔(bopindolol)、盐酸心得舒(alprenolol)、盐酸茚诺洛尔(indenolol)、盐酸卡替洛尔(carteolol)、硫酸环戊丁心安(penbutolol)、盐酸布尼洛尔(bunitrolol)、酒石酸美托洛尔(metoprolol)、醋丁洛尔(acebutolol)、氨酰心安(atenolol)、富马酸比索洛尔(bisoprolol)、盐酸倍他索洛尔(betaxolol)、盐酸塞利洛尔(celiprolol)、盐酸柳氨苄心定(labetalol)、盐酸阿罗洛尔(arotinolol)、盐酸氨磺洛尔(amosulalol)、卡维地洛(carvedilol)、尼普地洛(nipradilol)、盐酸替利洛尔(tilisolol)、盐酸贝凡洛尔(bevantolol)等等。
[抗高血压药]
甲基多巴(Methyldopa)、乙酸胍那苄(guanabenz)、利血平(reserpine)、萝芙木碱(rescinnamine)、盐酸胍法辛(guanfacine)、硫酸胍法辛(guanfacine)、盐酸哌唑嗪(prazosin)、盐酸布那唑嗪(bunazosin)、盐酸特拉唑嗪(terazosin)、呱胺甲尿啶(urapidil)、甲磺酸多沙唑嗪(doxazosin)、甲磺酸氢化麦角碱(dihydroergotoxine)、哌唑嗪(prazosin)、阿拉普利(alacepril)、甲巯丙脯酸(captopril)、马来酸依那普利(enalapril)、盐酸地拉普利(delapril)、西拉普利(cilazapril)、赖诺普利(lisinopril)、盐酸贝那普利(benazepril)、盐酸咪达普利(imidapril)、盐酸喹那普利(quinapril)、盐酸替莫西林(temocapril)、群多普利(trandolapril)、可乐宁(clonidine)、盐酸可乐宁(clonidine hydrochloride)、胍乙啶(guanethidine)、二甲苄胍(betanidine)、硫酸胍乙啶(guanethidine sulfate)、盐酸肼苯哒嗪(hydralazine)、布酞嗪(budralazine)、盐酸托屈嗪(todralazine)、卡屈嗪(cadralazine)、硝普酸钠(sodium nitroprusside)、溴化六烃己胺、樟脑磺酸曲美芬、美替克仑、甲基多巴等等。
[血管扩张剂]
乙酯黄酮(Efloxate)、依他苯酮(etafenone)、安蒙痛(oxyfedrine)、延痛心(carbocromen)、二盐酸地拉齐普(dilazep)、盐酸地尔硫卓(diltiazem)、盐酸比尼地平(benidipine)、盐酸异搏定(verapamil)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、苯磺酸氨氯地平(amlodipine)、四硝基季戊四醇、尼可地尔(nicorandil)、潘生丁(dipyridamole)、异山梨醇硝酸酯、曲匹地尔(trapidil)、硝苯地平、心可定(prenylamine)、脉导敏(molsidomine)、三硝酸三乙醇胺磷酸酯、烟酸肌醇酯、异克舒令(isoxsuprine)、布酚宁(nylidrin)、柠檬酸烟胺乙酯、烟醇、环扁桃酯、灭胆灵(hepronicate)、盐酸三甲氧苄嗪(trimetazidine)、肉桂苯哌嗪(cinnarizine)、布酞嗪(budralazine)、盐酸肼苯哒嗪、盐酸托屈嗪(todralazine)、卡屈嗪、硝普酸钠、盐酸异克舒令、硫酸丁酚胺等等。
[减充血剂]
肾上腺素、盐酸肾上腺素、盐酸麻黄碱、盐酸四氢唑啉、盐酸萘唑啉等等。
[毛细管稳定剂]
芸香甙(Rutin)等等。
[抗高血脂剂]
氯苯丁酯(Clofibrate)、克利贝特(clinofibrate)、双贝特(simfibrate)、苯扎贝特(bezafibrate)、非诺贝特(fenofibrate)、烟酸环己醇酯(nicomol)、烟酸戊四醇酯(niceritrol)、生育酚(tocopherol)烟酸酯、考来烯胺(colestyramine)、丙丁酚、普伐他汀(pravastatin)钠、斯伐他汀(simvastatin)、氟伐他汀(fluvastatin)钠、阿伐他汀(atorvastatin)钙水合物、氯贝酸铝(aluminium clofibrate)、非皂化豆油、精制的大豆卵磷脂、γ-阿魏酸脂(γ-orizanol)、康复龙(oxymetholone)、乙基亚油酸、右旋糖苷硫酸钠、多烯磷脂酰胆碱、酯酶(estarase)、乙基二十碳五烯酯(icosapentate)、考来酰胺(colestimide)、甲亚油酰胺(melinamide)等等。
[血管加压药]
盐酸多巴胺、盐酸多巴酚丁胺、多卡巴胺(docarpamine)、地诺帕明(denopamine)、盐酸苯肾上腺素、肾上腺素、去甲肾上腺素(norepinephrine)、盐酸去甲苯福林(norphenepbrine)、盐酸乙苯福林(etilefrine)、盐酸异丙肾上腺素(isoprenaline hydrochloride)、盐酸米多君(midodrine)、布拉地辛钠(bucladesine sodium)、酒石酸氢阿拉明(metaraminol)、盐酸甲氧胺、甲硫酸氨甲氧苯嗪(amezinium)等等。
[呼吸刺激剂]
盐酸吗啉吡酮、甲羟基孕酮(medroxyprogesterone)、莱瓦洛芬(levallorphan)、盐酸纳洛酮(naloxone hydrochloride)、茶碱(theophylline)、甘油茶碱(diprophylline)、盐酸回苏灵(dimefline)、盐酸异丙肾上腺素(isoprenaline hydrochloride)、硫酸间羟异丙肾上腺素(orciprenaline)、盐酸邻氯喘息定(clorprenaline)、硫酸叔丁喘宁(terbutaline)、硫酸己双肾上腺素(hexoprenaline)、盐酸麻黄碱、盐酸甲基麻黄碱、DL-甲基麻黄碱糖精酯、盐酸喘咳宁(methoxyphenamine hydrochloride)、地莫拉明(dimorphoramine)、盐酸三甲氧醇(trimethoxynol)、硫酸柳丁氨醇(salbutamol)、富马酸福莫特罗(formoterol)、盐酸妥洛特罗(tulobuterol)、妥洛特罗、氢溴酸非诺特罗(fenoterol)、盐酸异丙喹喘宁(procaterol)、盐酸克仑特罗、盐酸马布特罗、硫酸异丙肾上腺素、地高辛、洋地黄毒甙、甲地高辛、毛花甙C、去乙酰毛花甙、海葱次甙等。
[支气管扩张和止喘剂]
茶碱(Theophylline)、氨茶碱(aminophylline)、胆茶碱(cholinetheophylline)、甘油茶碱(diprophylline)、盐酸麻黄碱、盐酸甲基麻黄碱、DL-甲基麻黄碱糖精酯、盐酸喘咳宁(methoxyphenamine hydrochloride)、硫酸间羟异丙肾上腺素(orciprenaline)、盐酸邻氯喘息定(clorprenaline)、盐酸三甲氧醇(trimethoxynol)、硫酸柳丁氨醇(salbutamol)、硫酸叔丁喘宁、硫酸己双肾上腺素、盐酸异丙肾上腺素、富马酸福莫特罗(formoterol)、妥洛特罗、盐酸妥洛特罗(tulobuterol)、氢溴酸非诺特罗(fenoterol)、盐酸异丙喹喘宁(procaterol)、盐酸氨双氯喘通(clenbuterol hydrochloride)、盐酸马布特罗(mabuterol)、柳丁氨醇、叔丁喘宁(terbutaline)、妥洛特罗、非诺特罗、异丙喹喘宁、克喘素、硫酸异丙肾上腺素、色甘酸钠(cromoglicate sodium)、曲尼司特(tranilast)、哌罗来斯(pemirolast)、富马酸甲哌噻庚酮(ketotifen)、氮卓斯汀(azelastine)、丙酸倍氯米松、溴化异丙托铵(ipratropium)、氟托溴铵(flutropium bromide)、oxitropium bromide、心痛定、尼群地平、盐酸马尼地平、盐酸比尼地平、盐酸巴尼地平(barnidipine)、氨氯地平(amlodipine)、盐酸依福地平(efonidipine)、非洛地平(felodipine)、西尼地平(cilnidipine)、盐酸异搏定(verapamil)、盐酸地尔硫卓(diltiazem)等等。
[止咳剂]
那可汀(Noscapine)、磷酸二甲吗喃(dimemorfan)、羟苯酰苯酸双噻哌啶(tipepidine hibenzate)、柠檬酸奥昔拉定(oxeladin)、愈创木酚甘油醚(guaifenesin)、氢溴酸美沙芬(dextromethorphan)、枸橼酸维静宁(pentoxyverinecitrate)、盐酸依普拉酮(eprazinone)、盐酸福米诺苯(fominoben)、氯哌啶(chloperastine)、盐酸氯苯胺丙醇(clofedanol)、磷酸苯丙哌林(benproperine)、那可汀(noscapine)、樱木皮提取物、车前草、杏仁等等。
[祛痰药]
盐酸美司坦、乙酰半胱氨酸、盐酸溴己新、羧甲半胱氨酸、弗多司坦(fudosteine)、盐酸氨溴索(ambroxol)、茴香氨醑(foeniculated aμmonia spirit)、美远志(senega)等等。
[消化性溃疡治疗剂]
甲腈咪胍(Cimetidine)、盐酸雷尼替丁(ranitidine)、法莫替丁(famotidine)、奥美拉唑、奥美拉唑(omeprazole)钠、兰索拉唑(lansoprazole)、雷贝拉唑(rabeprazole)钠、盐酸罗沙替丁乙酯(roxatidine acetate)、尼扎替丁(nizatidine)、拉呋替丁(lafutidine)、盐酸哌仑西平(pirenzepine)、丙谷胺(proglumide)、分泌素(secretin)、尿抑胃素(urogastrone)、氧化镁、沉淀碳酸钙、干燥的氢氧化铝凝胶、硅酸铝镁、合成硅酸铝、铝碳酸镁、硫糖铝、甘葡环烃(azulene)、乙哌仑(egualen)钠、尿囊素铝(aldioxa)、吉法酯(gefarnate)、替普瑞酮(teprenone)、奥诺前列素(ornoprostil)、盐酸西曲酸酯(cetraxate)、止呕灵(sulpiride)、马来酸伊索格拉定(irsogladine)等等。
[促吞咽剂]
硫酸镁、硫酸钠、柠檬酸镁、人造卡尔斯泉盐(carlsbad salt)、羧甲醚纤维素钠、蓖麻油、比沙可啶(bisacodyl)、匹可硫酸(picosulfate)钠、乙戊酚酞(phenovalin)、番泻叶提取物、番泻苷等等。
[止呕剂]
氯丙嗪(Chlorpromazine)等等。
[止泻剂(Obstipants)和抗气胀药]
盐酸洛哌丁胺(loperamide)、次硝酸铋(bismuth subnitrate)、鞣酸白蛋白(albumin tannate)、氯化小檗碱、硫酸小蘖碱、鞣酸黄连素、天然硅酸铝、半乳糖苷酶(tilactase)、β-半乳糖苷酶(galactosidase)、溴美喷酯(mepenzolatebromide)、聚卡波非(polycarbophil)钙、野梧桐(Mallotus japonicus)、水杨酸偶氮磺胺吡啶(salazosulfapyridine)、美沙拉嗪(mesalazine)、双歧乳杆菌(Lactobacillus bififdus)、干酪乳杆菌(Lactobacillus casei)、酪酸梭状芽胞杆菌(Clostridium butyricum)、乳酶生(lactomin)、抗生素抗性乳酸菌、干酵母、二甲硅油等等。
[健胃药和助消化剂]
胃复安(Metoclopramide)、吗丁啉(domperidone)、西沙比得(cisapride)、盐酸伊托必利(itopride)、柠檬酸莫沙必利(mosapride)、马来酸曲美布汀、淀粉酶、胰酶等等。
[泻剂]
羧甲醚纤维素钠、蓖麻油、比沙可啶(bisacodyl)、匹可硫酸钠(picosulfatesodium)、乙戊酚酞(phenovalin)、番泻叶提取物、番泻苷等等。
[痔制剂]
三苄葡甙、Hemolingual、草木犀提取物、痔根断(Circanetten)、苯酚等等。
[神经原性膀胱治疗剂]
盐酸奥昔布宁(Oxybutynin hydrochloride)、盐酸丙哌维林(propiverine)、盐酸黄酮哌酯(flavoxate)等等。
[良性前列腺肥大和尿频治疗剂]
奥生多龙(Oxendolone)、己酸孕诺酮(gestonorone)、乙酸氯地孕酮(chlormadinone acetate)、Paraprost、尿通(Eviprostat)、烯丙雌烯醇、盐酸坦舒洛辛(tamsulosin hydrochloride)、萘哌地尔(Naftopidil)、cernitin花粉提取物、等等。
[肾石病和尿石病治疗剂]
Quercus salicina提取物、等等。
[利尿剂]
三氯噻嗪、双氢氯噻嗪、苄氢氯噻嗪、吲达帕胺(indapamide)、曲帕胺(tripamide)、氯噻酮、美替克仑(meticrane)、强速尿灵(mefruside)、呋喃苯胺酸(furosemide)、布美他尼(bumetanid)、利尿酸(ethacrynic acid)、吡咯他尼(piretanide)、阿佐塞米(azosemide)、托拉塞米(torasemide)、螺甾内酯(spironolactone)、三氨蝶啶(triamterene)、坎利酸钾(canrenoate potassium)、乙酰唑胺、异山梨醇、等等。
[利胆药剂]
羟甲香豆素(Hymecromone)、茴三硫(anetholtrithion)、柳氨酚(osalmide)、等等。
[抗糖尿病药剂]
胰岛素、甲糖宁(tolbutamide)、氯磺丙脲(chlorpropamide)、醋磺环己脲(acetohexamide)、格列吡脲(glyclopyramide)、甲磺吖庚脲(tolazamide)、格列本脲(glibenclamide)、格列齐特(gliclazide)、格列美脲(glimepiride)、格列丁唑(glybuzole)、盐酸丁双胍(buformin)、盐酸二甲双胍(metformin)、盐酸匹格列酮(pioglitazone)、那格列奈(nateglinide)、阿卡波糖(acarbose)、伏格列波糖(voglibose)、依帕司他(epalrestat)、等等。
[脑垂体激素制剂]
促生长激素(Somatropin)、美卡舍明(mecasermin)、乙酸替可克肽(tetracosactide)、垂体促性腺激素(pituitary gonadotropin)、血清促性腺激素(serum gonadotropin)、胎盘促性腺激素(placental gonadotropin)、抗利尿激素(vasopressin)、乙酸去氨加压素(desmopressin)、催产素(oxytocin)、等等。
[肾上腺皮质激素制剂]
醋酸可的松(Cortisone acetate)、氢化可的松、醋酸氢化可的松、氢化可的松磷酸钠、氢化可的松琥珀酸钠、醋酸氟氢可的松、强的松龙(prednisolone)、醋酸强的松龙、强的松龙醋酸丁酯、强的松龙琥珀酸钠酯、强的松龙磷酸钠酯、卤泼尼松(halopredone)乙盐酸、甲基强的松龙、醋酸甲基强的松龙、甲基脱氢皮质甾醇(methyl prednisolone)琥珀酸钠、氟羟脱氢皮醇(triamcinolone)、乙酸氟羟脱氢皮醇、氟羟脱氢皮醇缩酮、地塞米松(dexamethasone)、醋酸氟美松(dexamethasone acetate)、地塞米松(dexamethasone)磷酸钠、棕榈酸地塞米松、倍他米松(betamethasone)和磷酸倍他米松的混合物、倍他米松、倍他米松磷酸钠、乙酸泼拉米松(paramethasone)、丙酸倍氯米松(beclomethasone)、等等。
[性激素制剂]
雌二醇(Estradiol)、17β-雌二醇、雌二醇苯甲酸酯、雌二醇丙酸酯、雌二醇戊酸酯、乙炔雌二醇、雌三醇(estriol)、雌三醇丙酸酯、乙酸雌三醇苯甲酸酯、结合雌激素(conjugated estrogen)、磷雌酚(fosfestrol)、黄体酮(progesterone)、去甲睾酮(nortestosterone)、己酸孕诺酮(gestonorone)、诺塞甾酮(norethisterone)、诺塞甾酮乙酸酯、孕二醇(pregnanediol)、丙酸睾酮(testosterone propionate)、庚酸睾酮(testosterone enanthate)、胰舒血管素(kallidinogenase)、普拉睾酮(prasterone)硫酸钠、前列地尔(alprostadil)、贝前列素(beraprost)钠、依前列醇(epoprostenol)钠、前列甲酯(gemeprost)、地诺前列素(dinoprost)、地诺前列素缓血酸胺(dinoprost tromethamine)、地诺前列酮倍他环糊精(dinoprostone betadex)、乙酸环丙孕酮(cyproterone acetate)、甲基睾甾酮(methyltestosterone)、氟羟甲睾酮(fluoxymesterone)、丙酸屈他雄酮(dromostanolone propionate)、柠檬酸氯底酚胺(clomiphene citrate)、环芬尼(cyclofenil)、达那唑(danazol)、醋酸戈舍瑞林(goserelin acetate)、乙酸布舍瑞林(buserelin acetate)、乙酸那法瑞林(nafarelin)、甲磺酸溴麦角环肽、特麦角脲(terguride)、等等。
[前列腺素制剂]
前列腺素F2α、前列环素、前列腺素E1、前列腺素E2、前列地尔(alprostadil)、贝前列素钠(beraprost sodium)、吉美前列素(gemeprost)、地诺前列酮(dinoprostone)、地诺前列素(dinoprost)、地诺前列素缓血酸胺、5-氟环前列腺素、7-氟环前列腺素、等等。
[用于甲状腺机能障碍的治疗剂]
左旋甲状腺素钠、三碘甲腺原氨酸钠(liothyronine sodium)、干甲状腺制剂、甲巯咪唑(thiamazole)、丙硫氧嘧啶(propylthiouracil)、等等。
[抗骨质疏松和改善骨骼新陈代谢的药物]
阿法骨化醇(Alfacalcidol)、钙三醇(calcitriol)、四烯甲萘醌(menatetrenone)、益钙宁(elcatonin)、鲑降钙素(salmon calcitonin)、二膦酸盐氢氧化钠(alendronate sodium hydrate)、羟乙二磷酸二钠、氨羟二磷酸二钠(disodium pamidronate)、英卡膦酸二钠(disodium incadronate)、异丙氧黄酮(ipriflavone)、等等。
[氨基酸]
L-天冬氨酸及其盐、氨基乙基硫酸、等等。
[维生素制剂]
维生素A棕榈酸酯、阿法骨化醇(alfacalcidol)、盐酸维生素B1、核黄素、泛酰醇(panthenol)、维生素B12(cyanocobalamin)、盐酸吡哆醇、烟酸、叶酸、泛酸钙、抗坏血酸、乙酸维生素E、烟酸维生素E、维生素H、维生素K1、复合维生素、等等。
[止血剂]
肾上腺色素缩氨脲(Carbazochrome)磺酸钠、肾上腺素红丙脒腙(adrenochrome guanylhydrazone)甲磺酸酯、ε-氨基己酸、凝血酸、聚多卡醇(polidocanol)、油酸单乙醇胺、蛇毒促凝血酶(hemocoagulase)、凝血酶、等等。
[抗血栓形成剂]
结合雌激素、尿激酶、替索激酶、阿太普酶(alteplase)、那沙普酶(nasaruplase)、那替普酶(nateplase)、孟替普酶(monteplase)、帕米普酶(pamiteplase)、巴曲酶(baroxobin)、盐酸噻氯匹定(ticlopidine)、西洛他唑(cilostazol)、利马前列素阿法环糊精(limaprost alfadex)、奥扎格雷(ozagrel)钠、阿加曲班(argatroban)、乙基二十碳五烯酸酯(icosapentate)、盐酸沙格雷酯(sarpogrelate)、肝素(heparin)钙、肝素钠、硫酸精蛋白、达特肝素钠(dalteparin sodium)、华法令(warfarin)、华法令钙、柠檬酸钠、抗凝血酶III(基因重组的)、依泊丁α(epoetin alfa)(基因重组体)、依泊丁β(基因重组体)、来诺拉提(lenograstim)、非格司亭(filgrastim)、那托司亭(natograstim)、等等。
[抗生素]
青霉素G、青霉素V、苄基青霉素钙、苄基青霉素苄星青霉素(benzylpenicillin benzathine)、苯氧乙基青霉素钾、邻氯苯唑青霉素钠(cloxacillin sodium)、氟氯青霉素钠、氨苄青霉素(ampicillin)、阿莫西林(amoxicillin)、海他西林(hetacillin)、环己西林(ciclacillin)、羧苄青霉素(carbenicillin)、盐酸酞氨青霉素(talampicillin hydrochloride)、羧噻吩青霉素钠(ticarcillin sodium)、磺苄西林(sulbenicillin)、磺苄青霉素钠(sulbenicillinsodium)、羧茚青霉素钠(carindacillin sodium)、哌拉西林钠(piperacillinsodium)、盐酸氮卓脒青霉素(pivmecillinam hydrochloride)、对甲苯磺酸舒他西林(sultamicillin tosilate)、克拉维酸钾(clavulanate potassium)、苯氧甲基青霉素钾、苯氧甲基青霉素、双氯青霉素钠、恶西林(oxacillin)、氯唑西林(cloxacillin)、克拉维酸钾或替卡西林钠(ticarcillin sodium)、舒巴坦钠(sulbactam sodium)、氨必西林(ampicillin)、氨必西林钠、头孢噻啶(cefaloridine)、头孢唑啉(cefazolin)、头孢甘酸(cephaloglycin)、苄星青霉素、头孢菌素钠(cephalothin sodium)、先锋霉素(cefalexin)、头孢羟唑钠(cefamandole sodium)、头孢氨呋肟钠(cefuroxime sodium)、氨噻肟头孢菌素钠(cefotaxime sodium)、头孢去甲噻肟钠(ceftizoxime sodium)、头孢他啶(ceftazidime)、头孢拉宗钠(cefbuperazone sodium)、拉氧头孢钠(latamoxefsodium)、氟氧头孢钠(flomoxef sodium)、氨曲南(aztreonam)、卡芦莫南(carumonam)钠、米诺配能(meropenem)、亚胺培南(imipenem)、西司他丁(cilastatin)钠、帕尼培南(panipenem)、贝他扑隆(betamipron)、硫酸艮他霉素(gentamicin sulfate)、硫酸卡那霉素(kanamycin sulfatte)、托普霉素(tobramycin)、链霉素(streptomycin)、地贝卡星(dibekacin)、硫酸新霉素(fradiomycin)、磷霉素(fosfomycin)、盐酸万古霉素(vancomycinhydrochloride)、盐酸四环素(tetracycline hydrochloride)、土霉素(oxytetracycline)、二甲基氯四环素、脱氧土霉素(doxycycline)、米诺环素(minocycline)、红霉素、柱晶白霉素(leucomycin)、交沙霉素(josamycin)、吉他霉素(kitasamycin)、罗红霉素(roxithromycin)、盐酸林肯霉素(lincomycinhydrochloride)、氯林肯霉素(clindamycin)、氨基丁卡霉素(amikacin)、短杆菌肽(gramicidin)、缠霉素(capreomycin)、环丝氨酸、恩维霉素(enviomycin)、利福平(rifampicin)、制霉菌素(nystatin)、曲古霉素(trichomycin)、磷霉素(phosphonomycin)、两性霉素B(amphotericin B)、氯霉素(chloramphenicol)、甲砜霉素(thiamphenicol)、灰黄霉素(griseofulvin)、变曲霉素(variotin)、吡咯尼林(pyrrolnitrin)、干蠕孢菌素(siccanin)、呋喃妥因(nitrofurantoin)、头孢唑啉钠(cefamezin)、等等。
[磺胺类药物]
乙酸磺胺米隆(Mafenide acetate)、磺胺嘧啶(sulfadiazine)、磺胺嘧啶银(sulfadiazine silver)、磺胺甲基异唑钠磺胺二甲氧嘧啶(sulfadimethoxine)、磺胺甲基唑、磺胺莫托辛(sulfamonomethoxine)、磺胺索嘧啶(sulfisomidine)、磺胺索嘧啶钠、等等。
[抗真菌剂]
Naftiomate、克霉唑(clotrimazole)、盐酸氯康唑(cloconazolehydrochloride)、硝酸异康唑(isoconazole nitrate)、硝酸硫康唑(sulconazolenitrate)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、咪康唑(miconazole)、酮康唑(ketoconazole)、硫康唑(thioconazole)、联苯苄唑(bifonazole)、灰黄霉素(griseofulvin)、干蠕孢菌素(siccanin)、曲古霉素(trichomycin)、匹马菌素(pimaricin)、两性霉素B、制霉菌素、吡咯尼林、依沙酰胺(exalamide)、托西拉酯(tolciclate)、变曲霉素(variotin)、卤普罗近(haloprogin)、phenyliodoundecynoate、氟胞嘧啶、盐酸特比萘芬(terbinafine hydrochloride)、萘替芬(naftifine)、octpirox、环吡司(ciclopirox)、环匹罗司乙醇胺(olamine)、无环鸟苷(acyclovir)、碘苷(idoxuridine)、等等。
[抗病毒剂]
无环鸟苷(Acyclovir)、盐酸伐昔洛韦(valacyclovir)、阿糖腺苷(vidarabine)、更昔洛韦(ganciclovir)、氨基三环癸烷(amantadine)、阿糖腺苷、inosine pranobex、盐酸金刚烷胺、磷酸奥塞米韦(oseltamivir phosphate)、病毒唑(ribavirin)、等等。
[抗HIV试剂]
叠氮胸苷(Zidovudine)、叠氮胸腺嘧啶(azidothymidine)、sanilvudine、扎西他宾(zalcitabine)、双脱氧腺苷(didanosine)、拉米夫定(lamivudine)、硫酸阿巴卡韦(abacavir sulfae)、依法韦仑(efavirenz)、诺维平(nevirapine)、地拉夫定(delavirdine)甲磺酸酯、沙奎那维(saquinavir)、沙奎那维甲磺酸酯、那非那韦(nelfinavir)甲磺酸酯、里托那维(ritonavir)、硫酸印地那韦(indinavirsulfate)、安普那韦(amprenavir)、等等。
[抗寄生虫药和抗原虫药]
奎宁、甲硝哒唑、磺甲硝咪唑、磺胺多辛(sulfadoxine)、乙胺嘧啶、盐酸甲氟喹、双羟萘酸喹嘧啶(pyrantel pamoate)、甲苯咪唑(mebendazole)、噻苯达唑(tiabendazole)、柠檬酸二乙碳酰嗪(diethylcarbamazine citrate)、吡喹酮(praziquantel)、依西酸戊烷脒(pentamidine isothionate)等等。
[抗风湿药]
布西拉明(Bucillamine)、水杨酸偶氮磺胺吡啶(salazosulfapyridine)、青霉胺、阿克他利(actarit)、氯苯扎利(lobenzarit)、硫代苹果酸金钠(aurothiomalate)、金诺芬(auranofin)、D-青霉胺、法呢酸强的松龙、等等。
[免疫抑制剂]
环孢菌素(Ciclosporin)、咪唑硫嘌呤(azathioprine)、咪唑立宾(mizoribine)、莫罗莫那-CD3(muromonab-CD3)、他克莫司(tacrolimus)水合物、盐酸胍立莫司(gusperimus)、吗乙麦考酚酯(mycophenolate mofetil)、氨甲喋呤(methotrexate)、环磷酰胺、等等。
[防晒剂]
p-氨基苯甲酸酯、p-二甲基氨基苯甲酸酯、等等。
[抗过敏药]
盐酸二苯环庚啶、曲尼司特(tranilast)、色甘酸(cromoglicate)钠、氨来占诺(amlexanox)、瑞吡司特(repirinast)、他扎司特(tazanolast)、哌罗来斯(pemirolast)钾、富马酸甲哌噻庚酮(ketotifen)、奥沙米特(oxatomide)、美喹他嗪(mequitazine)、盐酸非索非那定(fexofenadine)、依巴斯汀(ebastine)、盐酸西替立嗪(cetirizine)、扎鲁司特(zafirlukast)、孟鲁司特(montelukast)钠、富马酸依美斯汀(emedastine)、等等。
[眼药制剂]
软骨素(Chondroitin)硫酸钠、甲基硫酸新斯的明(neostigmine methylsulfate)、谷胱甘肽(glutathione)、溴化的斯的明(distigmine)、色甘酸钠、等等。
[抗牛皮癣剂]
甲氧呋豆素(Methoxsalen)等等。
[皮肤软化剂和润滑剂]
氢醌、肝素、尿素、硫酸软骨素、等等。
[湿润剂]
神经酰胺(Ceramide)、透明质酸(hyaluronic acid)、辅酶Q10(coenzymeQ10)、异黄酮、LIPIDURE、丝胶蛋白、等等。
[秃发治疗和毛发生长伸进剂]
盐酸卡普铵(Carpronium)、米诺地尔(minoxidil)、西法安生(cepharanthine)、獐牙菜属草药提取物、维生素E衍生物、人参提取物、烟酰胺、烟酸苯甲基酯、槐属根提取物、竹节参(Panacis japonici rhizoma)、生物素(biotin)、十五酸甘油酯(pentadecanoate glyceride)、乙酰基甲硫氨酸、肌醇、L-丝氨酸、盐酸吡哆辛、泛酸钙、雌二醇苯甲酸酯、乙炔雌二醇、二乙基己烯雌酚(diethyl stilbestrol)、睾甾酮(testosterone)、甲基睾甾酮(methyltestosterone)、氢化可的松(hydrocortisone)、可他敏(diphenhydramine)、何首乌(Polygoni radix)、takanal、等等。
[肽激素制剂]
胰岛素、血管紧张素(angiotensin)、抗利尿激素(vasopressin)、苯赖加压素(felypressin)、普罗瑞林(protirelin)、促性腺激素释放激素(gonadotropin-releasing hormone)、促肾上腺皮质激素(corticotropin)、催乳激素(prolactin)、促生长激素(somatropin)、促甲状腺激素(thyrotropin)、促黄体生成激素(luteinizing hormone)、降钙素(calcitonin)、激肽释放酶(kallikrein)、甲状旁腺素(parathyrin)、胰高血糖素(glucagon)、催产素(oxytocin)、促胃泌素(gastrin)、分泌素(secretin)、血清促性腺激素(serum gonadotropin)、等等。
[抗烟助剂]
烟碱、盐酸丁氨苯丙酮、等等。
[食物配料]
藤黄属、辣椒素、柑桔属、武靴叶属、番石榴属、草木樨属、绿色番木瓜提取物、烟酸、车前草等等。
[皮肤增白组分]
氢醌、α熊果甙、维生素C、曲酸、鞣花酸、春黄菊属提取物、Rucinol、等等。
[抗衰老组分]
辅酶Q10、褪黑素(melatonin)、DHEA、维甲酸、阿焦烯(ajoene)、等等、
[多糖类]
肝素、软骨素硫酸钠、等等。
[植物提取物和提炼油]
茜草根(Rubia cordifolia root)、葡萄(Vitis vinifera)、伞菌属(Agaricus)、木通(Akebia quinata)、蓟属(thistle)、当归属(Angelica keiskei)、棕儿茶(gambir)、鳄梨(avocado)、药蜀葵(althea)、山金车属(arnica)、芦荟属(aloe vera)、淫羊藿属(Epimedium grandiflorum)、黄精属(Polygonatum officinale)、银杏叶(ginkgo leaves)、衣兰香精(Ylang Ylang)、茴香(fennel)、姜黄(curcuma)、墨鱼骨(cuttlebone)、梅果(Mume fructus)、钓樟素根(Linderae radix)、禹粮石(Limonite)、刺五加(Acanthopanax senticosus Harms)、延胡索块茎(CorydalisTuber)、黄芪根(Astragalus root)、黄芩根(Scutellaria root)、黄柏皮(Phellodendron Bark)、黄连根(coptis root)、车前草(plantain)、橄榄、橙、小连翘(Hypericum erectum)、鹧鸪菜(Digenea simplex)、刺桐(Erythrina indica)、夏枯草(prunellae spica)、白栎、蓼根(Polygoni radix)、水苏属(Stachysbetonica)、葛根(pueraria root)、滑石、黄春菊(chamolile)、日本榧(Torreyanucifera)、栝楼籽(trichosanthes seed)、甘草(licorice)、醴肠(Eclipta prostrata)、桔梗根(Platycodon root)、茼蒿属(Chrysanthemum morifolium)、枳实(orangepease)、金鸡纳树皮(cinchona)、樟脑草(catnip)、杏仁(apricot kernal)、黄瓜、黄精属(Polygonatum offcinalle)、金樱子、过路黄(Lysimachia christinae)、槐根(Sophora root)、柚(grapefruit)、裂叶荆芥草(schizonepeta herb)、肉桂芽(cassia buds)、桂皮(cassia bark)、芡实仔(seed of Euryale ferox Salisb)、决明子(cassia seed)、龙胆根(gentian)、天竺葵草(geranium herb)、莎草属根茎(Cyperus Rhizome)、厚朴(Magnolia Bark)、东方牛黄(oriental bezoar)、刺五加(Acanthopanax Senticosus Harms)、椰子、胡椒、牛蒡子(Arctii Fructus)、琥珀、麦芽、紫草科植物(comfrey)、细辛根(Asiasarum root)、柏(cypress)、藏红花(saffron)、山楂(hawthorn)、花椒属植物果实(Zanthoxyli Fructus)、地黄根(rehmanniae radix)、丝瓜(Luffa cylindrica)、绣线菊(Lithosermi Radix)、紫苏属(perilla)、紫苏灌木(Perillae frutescens)、香茅(citronella)、酸柚(lime)、肉桂(cinnamon)、绣线菊(Filipendula multijuga)、赤石脂(Halloysitum rubrum)、芍药(peony)、白桦(Betula alba)、问荆(Equisetum arvense)、撒尔维亚(Salviaofficinalis)、柑桔(Citrus reticulata)、赤芍(red Paeonia lactiflora)、芝麻(sesame)、杂色鲍(Haliotis diversicolor)、锦葵(mallow)、天竺葵(Geranium)、龙芽草(Agrimonia pilosa)、升麻(Cnidii Rhizoma)、金丝桃(St.John′s wort)、桑皮(Mulberry bark)、姜黄(Turmeric)、大黄(Rhubarb)、大豆提取物、发酵的大豆提取物、大枣(Zizyphi Fructus)、麝香草(thyme)、茶叶提取物、丁香(clove)、蜜柑皮(Citrus Unshiu Peel)、茶树、大节竹(Indosasa McClure)、甜茶(Rubussuavissimus)、三七(Panax notoginseng)、冬瓜(wax gourd)、日本当归根、金盏花(Calendula officinalis)、虫草(Cordyceps sinensis)、桃仁、酸橙皮、蕺菜(Houttuynia cordata)、菟丝子籽(Cuscuta chinensis seed)、杜仲(Eucommiaulmoides)、蕨麻(Potentilla anserina)、人参(ginseng)、蒜、日本女贞(Ligustrumjaponicum)、橙花油(neroli)、麦芽(malt)、白藓(Dictamnus dasycarpus)、白头翁(Pulsatilla chinensis)、沿阶草属块茎(Ophiopogon tuber)、罗勒(basil)、欧芹(parsley)、薏苡属(Coix lacryma-joli)、香子兰(vanilla)、北沙参(Glehnia root)、北美金缕梅(hamamelis)、蔷薇属(rose)、石南(heath)、碧萝芷(pycnogenol)、日本菱(Trapa japonica)、扁柏酚(hinokitiol)、檀香(sandalwood)、枇杷属(Eriobotrya)、槟榔(betel nut)、茯苓(hoelen)、乌头块茎(aconiti tuber)、越桔(blueberry)、甜菜碱(betaine)、红花(safflower)、胡椒薄荷(peppermint)、散沫花属(henna)、风仙花(Impatiens balsamina)提取物、防风属根(saposhnikoviaroot)、芍药(peony)、鸦片(hop)、西蒙德木(jojoba)、柑桔果实(Citrus reticulatafruit)、麻黄草(ephedra herba)、松针(pine needle)、morronnier、中国柑桔(mandarine)、薄荷、(Fomes yucatensis)、蜜蜂花属(Melissa officinalis)、木贼(Equisetum hiemale)、云木香根(Saussurea root)、桃树叶、矢车菊(centaury)、矢车菊蓝(cornflower)、桉树(eucalyptus)、虎耳草(Saxifraga)、香橙(Citrusjunos)、薏苡仁(coix seed)、艾蒿(mugwort)、罗汉果(Momordica grosvenori)、熏衣草(lavender)、洛依柏丝(Rooibos)、柠檬(lemon)、柠檬香草(lemongrass)、防臭木(lemon verbena)、连翘(forsythia)、紫檀(rosewood)、蔷微果(rose hip)、迷迭香(rosemary)、等等。
[酶]
胰蛋白酶、木瓜酶(papain)、蛋白酶、舍雷肽酶(serrapeptase)、溶菌酶(lysozyme)、菠萝蛋白酶(bromelain)、链激酶(streptokinase)、纤维蛋白溶酶(plasmin)、尿激酶(urokinase)、α-胰凝乳蛋白酶(chymotrypsin)、锯齿形肽酶(serratio peptidase)、半碱性肽酶、氯化溶菌酶、等等。
[疫苗]
黄热病(Yellow fever)、麻疹(measles)、风疹(rubella)、水痘(chickenpox)、肺结核(tuberculosis)、小儿麻痹症(polio)、霍乱(cholera)、伤寒(typhoid)、狂犬病(rabies)、日本脑炎(Japanese encephalitis)、肝炎(hepatitis)、白喉(diphtheria)、百日咳(pertussis)、破伤风(tetanus)、流感(influenza)、鼠疫(pest)、蜱传播的脑炎(tick-borne encephalitis)、脑膜炎(meningitis)、等等。
本发明所用剂型不特别受限制。能使用与皮肤或粘膜接触的任何常规剂型,例如包括,乳剂、软膏剂、液剂、涂沫剂、洗剂、乳化液、粉剂、泡沫、带、贴剂、糊剂、硬膏剂、栓剂、滴鼻剂、滴眼剂、阴道制剂、洁齿剂和口香糖。
下面将用实施例来描述本发明,然而,这不能就此被认为是对本发明的限制。
发明最佳实施方式
下面用实施例详细说明本发明。
[实施例1:具有不同粒径的羟基磷灰石(以下简称“HAP”)对粘膜渗透性的比较研究]
使用Fujii(2)改进的方法用具有不同粒径的HAPs进行皮肤渗透性实验。
自Saitama试验动物繁殖中心购进八周大雌性无毛鼠并用于本实验。切下鼠的腹部皮肤,小心去除油脂后将皮肤保存在-80℃以备使用。冷冻的皮肤在室温下解冻大约30分钟。所得完全厚度的皮肤用于渗透性研究。
在皮肤渗透性试验中使用由Fujii研究出的改良的Franz小室。将小室装好,以便使皮肤插入下室(受体区:真皮侧)和上室(供体区:角质层侧)之间。将样品加入到上室。使16ml等渗的磷酸盐缓冲液(pH7.1)在受体区中于37℃下保温,并同时用搅拌器搅拌。将0.5ml每种样品添加至供体区。在实验中,小室顶端用实验室膜密封住。
加至供体区的样品为:未处理的对照组-不含添加剂的等渗磷酸盐缓冲液(对照试验1);溶于等渗磷酸盐缓冲液的最大粒径为0.05μm或更小(平均粒径大约为0.03μm)的1重量百分比的HAP悬乳液(试验1-1);溶于等渗磷酸盐缓冲液的最大粒径为0.1μm或更小(平均粒径大约为0.06μm)的1重量百分比的HAP悬浮液(试验1-2);溶于等渗磷酸盐缓冲液的具有最大粒径为1μm或更小(平均粒径大约为0.5μm)的1重量百分比的HAP悬浮液(试验1-3);溶于等渗磷酸盐缓冲液的具有最大粒径为20μm或更小(平均粒径大约为8μm)的1重量百分比的HAP悬浮液(试验1-4)。用上述样品进行试验。
在实验中,24小时后测量并计算在受体区中每种样品的钙浓度;实验结果通过如表1中所示的经皮肤渗透的HAP量来表示。使用ICP进行离子测量。
表格1
HAP的皮肤渗透性 | |
试验1-1 | 98% |
试验1-2 | 94% |
试验1-3 | 75% |
试验1-4 | 32% |
对照试验1 | 0.7% |
如表1中所示,与具有较大粒径的HAPs相比较,最大粒径为1.0μm或更小的HAPs具有更好的皮肤渗透性,并且最大粒径为0.1μm或更小的HAPs的渗透性甚至更好。在不含HAP的对照试验1中,检测到了少量的钙。虽然该值在表1中记作HAP的量,但其说明了皮肤中内源的钙。
[实施例2:具有不同粒径的HAPs对粘膜渗透性的比较研究]
本实验中使用八周大的雌性金黄仓鼠。动物通过砍头来杀死从而避免麻醉的影响。然后立即切下口腔粘膜。切下包括粘膜至基底膜的口腔粘膜,极其小心不使它干燥。
在粘膜渗透性研究中使用改良的Franz小室。小室含有加入样品的上室(供体区)和下室(受体区);并且口腔粘膜置于两者之间。使16ml含有卡那霉素(kanamycin)的等渗的磷酸盐缓冲液(pH7.1)在受体区于37℃下保温,同时用搅拌器搅拌。将0.5ml每种样品添加至供体区。在实验期间,用实验室膜密封住小室顶端。
加至供体区的样品为:未处理的对照组-不含添加剂的等渗磷酸盐缓冲液(对照试验2);溶于等渗磷酸盐缓冲液的具有最大粒径为0.05μm或更小(平均粒径大约为0.03μm)的1重量百分比的HAP悬浮液(试验2-1);溶于等渗磷酸盐缓冲液的具有最大粒径为0.1μm或更小(平均粒径大约为0.06μm)的1重量百分比的HAP悬浮液(试验2-2);溶于等渗磷酸盐缓冲液的具有最大粒径为1μm或更小(平均粒径大约为0.5μm)的1重量百分比的HAP悬浮液(试验2-3);溶于等渗磷酸盐缓冲液的具有最大粒径为20μm或更小(平均粒径大约为8μm)的1重量百分比的HAP悬浮液(试验2-4)。
在实验中,24小时后测量并计算受体区中每种样品的钙浓度;实验结果通过如表2中所示的经粘膜渗透的HAP量来表示。使用ICP进行离子测量。
表2
HAP的粘膜渗透性 | |
试验2-1 | 95% |
试验2-2 | 89% |
试验2-3 | 68% |
试验2-4 | 22% |
对照试验2 | 0.9% |
如表2中所示,与具有较大粒径的HAPs相比较,最大粒径为1.0μm或更小的HAPs具有更好的粘膜渗透性,并且最大粒径为0.1μm或更小的HAPs的渗透性甚至更好。
[用于药物渗透性研究的组合物的制备]
表3显示了在药物渗透性比较研究中所使用的具有不同粒径HAPs的组合物。在含有不溶于水的消炎痛(indomethacin)的测试组合物的制备中使用乙醇。配制不含HAP的组合物作为对照(比较实施例1)。
表3
实施例3 | 实施例4 | 实施例5 | 对照实施例1 | |
消炎痛 | 1% | 1% | 1% | 1% |
乙醇 | 40% | 40% | 40% | 40% |
羟基磷灰石(最大粒径:0.1μm或更小) | 1% | - | - | - |
羟基磷灰石(最大粒径:1μm或更小) | - | 1% | - | - |
羟基磷灰石(最大粒径:20μm或更小) | - | - | 1% | - |
纯净水 | 剩余量 | 剩余量 | 剩余量 | 剩余量 |
总量 | 100% | 100% | 100% | 100% |
表4和5中显示了在药物渗透性比较研究中所使用的具有不同HAP含量的组合物(软膏)。在实施例9中,首先用搅拌器使消炎痛和HAP相混合,然后与剩余的试剂合并。在实施例10中,使所有的组分同时混合使用。作为对照,配制含有基于药物量的1500重量百分数(wt%)的HAP的组合物(比较实施例2)和不含HAP的组合物(比较实施例3)。
表4
实施例6 | 实施例7 | 实施例8 | 实施例9 | 实施例10 | |
消炎痛 | 1% | 1% | 1% | 1% | 1% |
白凡士林 | 25% | 25% | 25% | 25% | 25% |
硬脂醇 | 22% | 22% | 22% | 22% | 22% |
丙二醇 | 12% | 12% | 12% | 12% | 12% |
十二烷基硫酸钠 | 1% | 1% | 1% | 1% | 1% |
羟基磷灰石(最大粒径:0.1μm或更小) | 0.001% | 0.01% | 0.1% | 1% | 1% |
纯净水 | 剩余量 | 剩余量 | 剩余量 | 剩余量 | 剩余量 |
总量 | 100% | 100% | 100% | 100% | 100% |
表5
实施例11 | 实施例12 | 实施例13 | 比较实施例2 | 比较实施例3 | |
消炎痛 | 1% | 1% | 1% | 1% | 1% |
白凡士林 | 25% | 25% | 25% | 25% | 25% |
硬脂醇 | 22% | 22% | 22% | 22% | 22% |
丙二醇 | 12% | 12% | 12% | 12% | 12% |
十二烷基硫酸钠 | 1% | 1% | 1% | 1% | 1% |
羟基磷灰石(最大粒径:0.1μm或更小) | 2% | 5% | 10% | 15% | - |
纯净水 | 剩余量 | 剩余量 | 剩余量 | 剩余量 | 剩余量 |
总量 | 100% | 100% | 100% | 100% | 100% |
[试验3:具有不同粒径AHPs的消炎痛的皮肤渗透性比较研究]
使用无毛鼠的腹部皮肤进行实验。
使16ml等渗的磷酸盐缓冲液(pH7.1)在受体区(真皮侧)于37℃下保温,同时用搅拌器搅拌。将实施例3-5和比较实施例1的样品(各自1g)加入(应用面积,3.14cm2)至供体区(角质层侧)。顶端用实验室膜密封(试验3-1至3-3,以及对照试验3)。
在试验开始后的1、3、6、12和24小时后受体区的溶液进行采样。溶液中的药物浓度通过高效液相色谱法来定量从而测定经皮肤渗透的药物量。结果如表6中所示;其值代表皮肤的渗透性(μg/cm2)。
表6
时间 | 试验3-1(实施例3) | 试验3-2(实施例4) | 试验3-3(实施例5) | 对照试验3(比较实施例1) |
1 | 44.7 | 7.9 | 4.6 | 2.3 |
3 | 140.0 | 23.8 | 8.2 | 6.4 |
6 | 250.6 | 56.1 | 19.5 | 10.0 |
12 | 391.2 | 139.4 | 47.2 | 16.1 |
24 | 545.8 | 370.1 | 153.3 | 62.5 |
[试验4:具有不同粒径HAPs的消炎痛的粘膜渗透性比较研究]
使用金黄仓鼠的口腔粘膜进行实验。
使16ml等渗的磷酸盐缓冲液(pH7.1)在受体区(基底侧)于37℃下保温,同时用搅拌器搅拌。将实施例3-5和比较实施例1的样品(各自1g)加入(应用面积,3.14cm2)至供体区(粘膜侧)。顶端用实验室膜密封(试验4-1至4-3,和对照试验4)。
在试验开始后的1、3、6、12和24小时后从受体区进行溶液采样。溶液中的药物浓度通过高效液相色谱法来定量从而测定经皮肤渗透的药物量。结果如表7中所示;其值代表粘膜的渗透性(μg/cm2)。
表7
时间 | 试验4-1(实施例3) | 试验4-2(实施例4) | 试验4-3(实施例5) | 对照试验4(比较实施例1) |
1 | 30.6 | 5.4 | 2.8 | 1.2 |
3 | 95.5 | 19.9 | 4.3 | 2.5 |
6 | 186.3 | 48.7 | 11.9 | 6.3 |
12 | 332.8 | 127.2 | 33.0 | 11.1 |
24 | 512.7 | 311.6 | 98.1 | 37.4 |
[试验5:具有不同HAP含量的消炎痛的皮肤渗透性比较研究]
使用无毛鼠的腹部皮肤进行实验。
使16ml等渗的磷酸盐缓冲液(pH7.1)在受体区(真皮侧)于37℃下保温,同时用搅拌器搅拌。将实施例6-13以及比较实施例2和3中的样品(各自1g)加入(应用面积,3.14cm2)至供体区(角质层侧)。顶端用实验室膜密封(试验5-1至5-8,和对照试验5-1至5-2)。
试验开始24小时后从受体区进行溶液采样。溶液中的药物浓度通过高效液相色谱法来定量从而测定经皮肤渗透的药物量。结果如表8中所示;其值表示皮肤的渗透性(μg/cm2)。
表8
皮肤渗透性(μg/cm2) | |
试验5-1 | 189.2 |
试验5-2 | 237.4 |
试验5-3 | 275.7 |
试验5-4 | 315.8 |
试验5-5 | 280.1 |
试验5-6 | 284.3 |
试验5-7 | 279.0 |
试验5-8 | 270.5 |
对照试验5-1 | 251.4 |
对照试验5-2 | 21.9 |
当与不含HAP的对照试验5-2组合物相比较时,基于药物量含有0.1重量百分数的HAP含量的试验5-1组合物的皮肤渗透性得到了显著提高;以及在试验5-3至5-6组合物中的皮肤渗透性得到了显著提高,其中基于药物量计HAP的含量在重量百分数为10至200的范围(参见表4和5)。在试验5-4组合物中具有特别高的皮肤渗透性,其中这些组合物是通过将药物和HAP预先用搅拌器混合,然后将混合物与剩余的试剂合并来制备的。
[实施例14:各种药物的皮肤渗透性研究]
表9中显示了在各种药物的皮肤渗透性研究中所使用的组合物(实施例14-1至14-16)。配制不含HAP的组合物作为对照(比较实施例4-1至4-16)。
表9
组分 | 含量(%) | |
实施例14-1 | 盐酸纳洛酮(naloxone) | 1.0 |
HAP | 0.1 | |
甘油 | 10.0 | |
纯净水 | 剩余量 | |
实施例14-2 | 胰岛素 | 1.0 |
HAP | 0.01 | |
糊精 | 5.0 | |
纯净水 | 剩余量 | |
实施例14-3 | 叠氮胸苷(azidothymidine) | 1.0 |
HAP | 1.0 | |
乙醇 | 10.0 | |
纯净水 | 剩余量 | |
实施例14-4 | 盐酸乙哌立松(eperisone) | 1.0 |
HAP | 0.1 | |
纯净水 | 剩余量 | |
实施例14-5 | 盐酸麻黄碱 | 1.0 |
HAP | 0.01 | |
纯净水 | 剩余量 | |
实施例14-6 | 氟奋乃静(ffluphenazine)癸酸酯 | 1.0 |
HAP | 2.0 | |
乙醇 | 5.0 | |
纯净水 | 剩余量 | |
实施例14-7 | 秋水仙碱(colchicine) | 1.0 |
HAP | 0.1 | |
乙醇 | 2.0 | |
纯净水 | 剩余量 | |
实施例14-8 | 丙戊酸钠 | 1.0 |
HAP | 3.0 | |
纯净水 | 剩余量 | |
实施例14-9 | 硫酸阿托品(atropine) | 1.0 |
HAP | 1.0 | |
纯净水 | 剩余量 | |
实施例14-10 | 盐酸甲氯芬酯 | 1.0 |
(meclofenoxate) | ||
HAP | 0.01 | |
纯净水 | 剩余量 | |
实施例14-11 | 盐酸三甲氧苄嗪(hydrochloride) | 1.0 |
HAP | 0.1 | |
纯净水 | 剩余量 | |
实施例14-12 | 盐酸托屈嗪(todralazine) | 1.0 |
HAP | 1.0 | |
纯净水 | 剩余量 | |
实施例14-13 | 氯贝特(clofibrate) | 1.0 |
HAP | 5.0 | |
ethanol | 1.0 | |
纯净水 | 剩余量 | |
实施例14-14 | 地诺前列素(dinoprost) | 1.0 |
HAP | 0.5 | |
乙醇 | 2.0 | |
纯净水 | 剩余量 | |
实施例14-15 | 烟碱 | 1.0 |
HAP | 3.0 | |
纯净水 | 剩余量 | |
实施例14-16 | 烟酸 | 1.0 |
HAP | 0.1 | |
纯净水 | 剩余量 |
[试验6:各种药物的皮肤渗透性比较研究]
使用无毛鼠的腹部皮肤进行皮肤渗透性试验。
使16ml等渗的磷酸盐缓冲液(pH7.1)在受体区(真皮侧)于37?下保温,同时用搅拌器搅拌。将实施例14-1至14-16以及比较实施例4-1和4-16中的样品(各自1g)加入(应用面积,3.14cm2)至供体区(角质层侧)。顶端用实验室膜密封(试验6-1至6-16,和对照试验6-1至6-16)。
试验开始24小时后从受体区进行溶液采样。溶液中的药物浓度通过高效液相色谱法来定量从而测定经皮肤渗透的药物量。结果如表10中所示;其值代表皮肤的渗透性(μg/cm2)。
表10
皮肤渗透性(μg/cm2) | 皮肤渗透性(μg/cm2) | ||
试验6-1 | 373.9 | 对照试验6-1 | 35.1 |
试验6-2 | 43.7 | 对照试验6-2 | 7.3 |
试验6-3 | 614.1 | 对照试验6-3 | 41.8 |
试验6-4 | 405.6 | 对照试验6-4 | 32.0 |
试验6-5 | 541.0 | 对照试验6-5 | 47.2 |
试验6-6 | 136.5 | 对照试验6-6 | 14.6 |
试验6-7 | 250.7 | 对照试验6-7 | 20.2 |
试验6-8 | 898.3 | 对照试验6-8 | 64.7 |
试验6-9 | 82.4 | 对照试验6-9 | 11.4 |
试验6-10 | 359.2 | 对照试验6-10 | 30.5 |
试验6-11 | 309.0 | 对照试验6-11 | 25.6 |
试验6-12 | 671.8 | 对照试验6-12 | 43.4 |
试验6-13 | 634.9 | 对照试验6-13 | 45.9 |
试验6-14 | 310.6 | 对照试验6-14 | 24.8 |
试验6-15 | 1057.3 | 对照试验6-15 | 66.0 |
试验6-16 | 1296.1 | 对照试验6-16 | 69.3 |
在实施例14-1中所使用的盐酸纳洛酮(一种麻醉拮抗剂)具有类似于吗啡和可待因等麻醉止痛剂的结构。因此,这些麻醉止痛剂也可产生类似于在试验6-1和对照试验6-1中所获得的结果。
[实施例15-1:乳剂]
甲苯磺丁脲 10.0
HAP(最大粒径为0.1μm或更小) 1.0
鲸蜡醇 5.0
聚乙二醇 3.0
甘油 5.0
液体石蜡 10.0
HAP(最大粒径为0.1μm或更小) 1.0
纯净水 剩余量
总量 100.0
[实施例15-2:液剂]
米诺地尔 0.5
甘草酸二钾 0.1
泛酰乙酯 0.2
金鸡纳皮提取物 1.0
HAP(最大粒径为0.1μm或更小) 1.0
聚氧乙烯氢化蓖麻油 0.3
丙二醇 5.0
HAP(最大粒径为0.1μm或更小) 1.0
乙醇 60.0
纯净水 剩余量
总量 100.0
[实施例15-3:带]
烟碱 15.0
HAP(最大粒径为0.1μm或更小) 15.0
酯树胶 12.0
硅酮粘合剂(adhesive) 58.0
总量 100.0
[实施例15-4:贴剂]
硝酸甘油 14.0
HAP(最大粒径为0.1μm或更小) 5.0
酯树胶 13.0
硅酮粘合剂 68.0
总量 100.0
[实施例15-5:糊剂]
生长激素 0.5
HAP(最大粒径为0.1μm或更小) 5.0
L-组氨酸 0.1
聚丙烯酸钠 2.0
凝胶(gelatin) 5.0
聚乙烯醇 1.0
丙三醇 15.0
山梨醇 15.0
聚氧乙二醇 1.0
高岭土 2.0
单月桂酸聚乙二醇酯 1.5
蓖麻油 1.0
1,3-丁二醇 3.0
水杨酸乙二醇酯 1.0
纯净水 剩余量
总量 100.0
[实施例15-6:栓剂或阴道制剂]
地西泮(Diazepam) 1.0
HAP(最大粒径为0.1μm或更小) 0.01
聚氧乙烯聚氧丙二醇酯 剩余量
总量 100.0
[实施例15-7:滴鼻剂]
甘草酸二钾 0.2
马来酸氯苯吡胺 0.1
HAP(最大粒径为0.1μm或更小) 0.05
磷酸氢钾 0.01
洁尔灭(Benzalkonium chloride) 0.01
丙二醇 0.5
纯净水 剩余量
总量 100.0
[实施例15-8:滴眼剂]
甲硫酸新斯的明 0.005
d-?α-醋酸维生素E 0.02
硫酸软骨素钠 0.1
甲硫酸新斯的明 0.005
HAP(最大粒径为0.1μm或更小) 0.0002
EDTA钠(Sodium edentate) 0.1
聚丙二醇 0.5
山梨酸钾 0.1
氯化钠 0.3
纯净水 剩余量
总量 100.0
[实施例15-9:洁齿剂]
藤黄提取物 20.0
HAP(最大粒径为0.1μm或更小) 0.02
丙三醇 20.0
聚乙二醇 3.0
十二烷基磺酸钠 1.0
黄胞胶 0.5
羟乙基纤维素 0.5
薄荷醇 0.5
纯净水 剩余量
总量 100.0
[实施例15-10:口香糖]
脱氧氟尿苷(Doxifluridine) 5.0
HAP(最大粒径为0.1μm或更小) 0.5
胶基 28.0
木糖醇 30.0
Palatinite 21.0
麦芽糖醇 3.8
软化剂 0.8
香料 1.0
麦芽糖醇糖浆 剩余量
总量 100.0
[试验7:制备经皮和经粘膜组合物的各种剂型,及皮肤和粘膜的渗透性研究]
配制组合物的各种剂型。在实施例15-1至15-5中,通过在实施例14中所描述的同样方法进行组合物的皮肤渗透性研究(试验7-1至7-5)。在实施例15-6至15-10中,同实施例4中一样进行组合物的粘膜渗透性测试。实施例15-10中所描述的口香糖组合物的测试不使用胶基(试验7-6至7-10)。不含HAP的组合物作为实施例15-1至15-10的对照加以制备和测试(对照试验7-1至7-10)。
这些结果如表11中所示。
表11
皮肤渗透性(μg/cm2) | 皮肤渗透性(μg/cm2) | ||
试验7-1 | 1596.1 | 对照试验7-1 | 127.4 |
试验7-2 | 285.2 | 对照试验7-2 | 20.6 |
试验7-3 | 91.5 | 对照试验7-3 | 15.9 |
试验7-4 | 84.7 | 对照试验7-4 | 17.3 |
试验7-5 | 7.4 | 对照试验7-5 | 2.1 |
粘膜渗透性(μg/cm2) | 粘膜渗透性(μg/cm2) | ||
试验7-6 | 152.9 | 对照试验7-6 | 17.5 |
试验7-7 | 38.3 | 对照试验7-7 | 9.2 |
试验7-8 | 4.6 | 对照试验7-8 | 0.8 |
试验7-9 | 23.8 | 对照试验7-9 | 7.0 |
试验7-10 | 421.4 | 对照试验7-10 | 43.7 |
上述结果表明通过结合羟基磷灰石提高了各种组分的经皮吸收和经粘膜吸收。
工业实用性
本发明提供了经皮和经粘膜制剂,当其施加于皮肤或粘膜时提高了必要组分的经皮/经粘膜吸收。
Claims (6)
1.含有将要被经皮和/或经粘膜吸收的成份和羟基磷灰石的经皮和/或经粘膜制剂。
2.权利要求1的经皮和/或经粘膜制剂,其中羟基磷灰石具有1μm或更小的最大粒径。
3.权利要求1的经皮和/或经粘膜制剂,其中羟基磷灰石具有0.1μm或更小的最大粒径。
4.权利要求1-3任一项的经皮和/或经粘膜制剂,其中基于将要被结合的药物计,羟基磷灰石具有0.1%至1000%的含量。
5.权利要求1-4任一项的经皮和/或经粘膜制剂,其中将要被经皮和/或经粘膜吸收的成分含有选自下列的一种或多种:止痛剂、退热剂、或消炎剂、抗痛风或抗高尿酸血症剂、非类固醇消炎剂、类固醇消炎剂、伤口愈合剂、抗癌剂、安眠剂或止痛剂、抗焦虑剂、抗精神病剂、抗抑郁剂、抗躁狂症、抗组胺剂、抗癫痫剂、局部麻醉剂、外周循环紊乱治疗剂、抗帕金森剂、肌肉松弛剂、自律或抗痉挛剂、抗发汗剂、脑循环或新陈代谢改善药物、强心剂、抗心绞痛剂、β阻断剂、钙拮抗剂、抗心律失常剂、抗高血压剂、血管扩张剂、减充血剂、毛细管稳定剂、抗高脂血症剂、血管加压剂、呼吸刺激剂、支气管扩张剂或止喘剂、止咳剂、祛痰剂、消化性溃疡治疗剂、促吞咽剂、抗吐剂、止泻剂或抗气胀剂、健胃或助消化剂、泻剂、痔制剂、神经原性膀胱治疗剂、良性前列腺肥大或尿频治疗剂、肾石病或尿石病治疗剂、利尿剂、促胆汁分泌剂、抗糖尿病剂、脑垂体激素制剂、肾上腺皮质激素制剂、性激素制剂、前列腺素、甲状腺机能障碍治疗剂、抗骨质疏松症或骨骼新陈代谢改善药、氨基酸、维生素制剂、止血剂、抗血栓形成剂、抗生素、磺胺药、抗真菌剂、抗病毒剂、抗HIV剂、抗寄生虫或抗原虫剂、抗风湿药、免疫抑制剂、防晒剂、抗过敏剂、眼药制剂、抗牛皮癣剂、皮肤软化剂或润滑剂、湿润组分、秃顶治疗剂或毛发生长刺激剂、肽激素制剂、戒烟助剂、节食组分、皮肤漂白组分、抗老化组分、多糖、植物提取物或提炼油、酶或疫苗。
6.权利要求1-5任一项的经皮和/或经粘膜制剂,其中制剂的剂型是乳剂、软膏剂、液剂、带、贴剂、糊剂、栓剂、滴鼻剂、滴眼剂、阴道制剂、洁齿剂或口香糖。
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- 2005-02-22 JP JP2006539145A patent/JPWO2006038315A1/ja active Pending
- 2005-02-22 WO PCT/JP2005/002771 patent/WO2006038315A1/ja active Application Filing
- 2005-02-22 RU RU2005129267/15A patent/RU2357758C2/ru active
- 2005-02-22 EP EP05710502A patent/EP1797900A1/en not_active Withdrawn
- 2005-02-22 US US10/552,541 patent/US20070166362A1/en not_active Abandoned
- 2005-02-22 CA CA002522152A patent/CA2522152A1/en not_active Abandoned
- 2005-02-22 KR KR1020057017497A patent/KR20070060950A/ko not_active Application Discontinuation
- 2005-02-22 AU AU2005209706A patent/AU2005209706A1/en not_active Abandoned
- 2005-02-22 CN CNA2005800001253A patent/CN1838969A/zh active Pending
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US9068212B2 (en) | 2007-10-24 | 2015-06-30 | Chugai Seiyaku Kabushiki Kaisha | Method for producing a polypeptide using a cell that overexpresses a bicarbonate transporter |
US8741601B2 (en) | 2009-04-22 | 2014-06-03 | Chugai Seiyaku Kabushiki Kaisha | Method for producing a cell capable of high-yield production of heteroproteins |
CN107519182A (zh) * | 2016-06-20 | 2017-12-29 | 天津金耀集团有限公司 | 以丁酸氢化可的松为活性成分的皮肤药物组合物 |
CN114010575A (zh) * | 2021-10-22 | 2022-02-08 | 江苏谛奇医药科技有限公司 | 新斯的明及其衍生物的新制剂 |
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WO2006038315A1 (ja) | 2006-04-13 |
EP1797900A1 (en) | 2007-06-20 |
RU2005129267A (ru) | 2007-03-27 |
US20070166362A1 (en) | 2007-07-19 |
RU2357758C2 (ru) | 2009-06-10 |
AU2005209706A1 (en) | 2006-04-27 |
CA2522152A1 (en) | 2006-04-07 |
JPWO2006038315A1 (ja) | 2008-07-31 |
KR20070060950A (ko) | 2007-06-13 |
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