CN1852721B - 用于治疗、预防和/或改善癌症、癌症发病或癌症症状的组合物和方法 - Google Patents
用于治疗、预防和/或改善癌症、癌症发病或癌症症状的组合物和方法 Download PDFInfo
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- CN1852721B CN1852721B CN2004800264983A CN200480026498A CN1852721B CN 1852721 B CN1852721 B CN 1852721B CN 2004800264983 A CN2004800264983 A CN 2004800264983A CN 200480026498 A CN200480026498 A CN 200480026498A CN 1852721 B CN1852721 B CN 1852721B
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Abstract
本发明公开了用于治疗、预防和/或改善癌症如乳腺癌、结肠癌、卵巢癌、肺癌、白血病、皮肤癌、前列腺癌、咽喉癌、食管癌等的症状的组合物及方法,其中该组合物包括非甾体抗炎药物(NSAID)与磷脂的缔合复合物,且该方法包括在癌症鉴定之前或之后,给予抗癌量的该组合物。
Description
相关申请
本申请要求2003年7月31日提交的美国临时申请系列号60/491,676的临时优先权。
发明背景
1.发明领域
本发明涉及用于治疗、预防和/或改善癌症、癌症发病或与癌症如乳腺癌、结肠癌、皮肤癌、肺癌、咽喉癌、食管癌、胃癌、胰腺癌、前列腺癌、膀胱癌等有关的症状的组合物和方法。
更具体而言,本发明涉及用于治疗、预防和/或改善癌症、癌症发病或与癌症如乳腺癌、结肠癌、皮肤癌、肺癌、咽喉癌、食管癌、胃癌、胰腺癌、前列腺癌、膀胱癌等有关的症状的组合物和方法,其中该组合物包含非甾体抗炎药物(NSAID)和磷脂,其中该磷脂可提高NSAID的抗癌功效,且该方法包括在癌症鉴定之前或之后给予人或动物该组合物,且其中给药方法可以是口服、局部、静脉内、动脉内或直接给予到组织部位中。
2.相关技术描述
癌症是导致美国和全世界大多数死亡的疾病。虽然新化疗方案的出现增加了被诊断为癌症的患者的存活率,但不会降低该疾病的总体发病率或严重程度。
基于流行病学研究,非甾体抗炎药物(NSAID)已被建议用于乳腺癌;结肠癌和其它癌症的化学预防,其中所述研究显示NSAID的使用与癌症危险之间的逆关联(1,2)。有支持性临床前期和临床数据表明NSAID可提供有效且便宜的化学预防策略。使用NSAID的主要限制性副作用是它们倾向引起易感患者的胃肠(GI)出血和损害。
NSAID目前细分为两类:1)常规药物像阿司匹林、布洛芬(Advil或Motrin)、或甲氧萘丙酸(Aleve),其分别抑制组成型环加氧酶-1(COX-1)和诱导型环加氧酶-2(COX-2)酶同工型,所述酶同工型在花生四烯酸向前列腺素的转化中起限速酶的作用,和2)近来研制的且商品化的选择性COX-2抑制剂像塞来昔布(Celebrex)和洛芬昔布(Vioxx)(3)。
COX抑制可影响癌症的机理正在研究中且可能涉及多种因素。COX-2的高水平表达导致前列腺素,即刺激细胞增殖的分子的形成提高(4-5)。COX-2和前列腺素还涉及通过因子如血管内皮生长因子的产生而诱导血管生成(6)。因此,对前列腺素这些增殖性质的NSAID抑制可清楚地促进抗-肿瘤活性。此外,NSAID近来已经显示出通过诱导NSAID活化基因(NAG-1),一种促编程性细胞死亡和抗肿瘤发生因子,具有不依赖于COX的抗-癌活性(7-10)。NSAID还可通过诱导促编程性细胞死亡BAX基因并抑制抗编程性细胞死亡Bcl-XT蛋白(13),并通过蛋白激酶G和c-Jun激酶的激活诱导编程性细胞死亡(14),而抑制NFκB激活(11-12),进而影响癌症生长。
虽然在癌症化学预防中施用常规或COX-2选择性NSAID具有重大希望,但是这些药物的长期服用并不是没有危险和/或问题的。与这些药物的长期使用有关的主要问题是30-40%的消费者对NSAID具有GI不耐受性,且患有从消化不良到消化性溃疡病的多种症状,其可能与威胁生命的出血发作有关(15)。其中一项临床研究证实30%的长期NSAID使用者在内窥镜检查下具有至少一处胃十二指肠溃疡(15-16)。此外,限于美国类风湿性关节炎患者的一项回顾性研究总结出由于NSAID使用导致的GI并发症导致该单独患者群体中每年400,000例住院和16,000例死亡(15)。还应注意不是必须在较高抗-关节炎剂量下给予NSAID才会诱导严重的GI副作用,有证据表明拥有最大数目需要住院的NSAID-相关GI并发症的群体中有数百万人摄取低剂量阿司匹林用于预防心血管疾病和/或癌症(17-18)。
因此,本领域仍然需要新的预防性组合物来预防癌性生长的发生、用于治疗已经鉴定的癌性生长和/或用于改善与癌性生长、肿瘤有关的症状。
发明概述
本发明提供一种用于治疗、预防或改善与癌症或癌性生长有关的症状的组合物,其中该组合物包括磷脂和抗炎药物,包括非甾体抗炎药物(NSAID)、COX-2抑制剂及其混合物或组合,优选磷脂与抗炎药物的缔合复合物。本发明的组合物可包括一种或多种磷脂和抗炎药物组合物,其中磷脂和抗炎药物均可变。这种组合物可以是分开制备的磷脂和抗炎药物组合物或包括一种或多种磷脂和/或一种或多种磷脂和抗炎药物的组合物的混合物。
本发明还提供一种用于治疗、预防或改善癌症或癌性生长的过滤除菌的组合物,其中该组合物包括磷脂与非甾体抗炎药物或NSAID的缔合复合物。
本发明提供用于治疗、预防和/或改善癌症或癌性生长的症状的方法,包括口服、局部、静脉内、动脉内、直接向人或动物组织部位中给予包括磷脂与非甾体抗炎药物的缔合复合物的组合物或包括磷脂与非甾体抗炎药物或NSAID的缔合复合物的过滤除菌组合物的步骤或这种给药方案的组合。
本发明提供用于制备无菌制剂的方法,包括下列步骤:在搅拌条件、一定pH范围下,使含水磷脂组合物与抗炎药物接触而形成搅拌的磷脂/抗炎药物制剂,并使该搅拌制剂通过具有足够小孔径的膜滤器,产生过滤除菌的磷脂/抗炎药物制剂。关于可无菌过滤的磷脂/抗炎药物组合物制备的进一步详述,读者可参考使用快信标记EV 405 879 065
US与本申请同时在2004年8月2日提交的共同未决的美国专利申请No.,其引入此处作为参考。
本发明提供一种洗手皂或肌体用肥皂,它包括有效量的含磷脂和非甾体抗炎药物或NSAID的组合物,优选磷脂与非甾体抗炎药物的缔合复合物,其中有效量足以防止皮肤癌发病、治疗皮肤癌或改善皮肤癌症状。
本发明提供一种防晒品,它包括有效量的含磷脂和非甾体抗炎药物或NSAID的组合物,优选磷脂与非甾体抗炎药物的缔合复合物,其中有效量足以防止皮肤癌发病、治疗皮肤癌或改善皮肤癌症状。
本发明提供一种身体乳霜(body cream),它包括有效量的含磷脂和非甾体抗炎药物或NSAID的组合物,优选磷脂与非甾体抗炎药物的缔合复合物,其中有效量足以防止皮肤癌发病、治疗皮肤癌或改善皮肤癌症状。
本发明提供一种面霜,它包括有效量的含磷脂和非甾体抗炎药物或NSAID的组合物,优选磷脂与非甾体抗炎药物的缔合复合物,其中有效量足以防止皮肤癌发病、治疗皮肤癌或改善皮肤癌症状。
定义
除非另有说明,下列术语具有下列含义:
术语“流体”是指液体和液体的任意混合物以及具有流体性质的固体,例如,在标准温度和压力下是可流动的或具有适当流动性,包括但不限于,固体在液体中的分散液、乳液、浆液、微乳、胶态混悬液、混悬液等。
术语“分子缔合或缔合复合物”是指经由任何已知的稳定化原子或分子水平相互作用或其任意组合而缔合的两种或更多分子种类的组合,其中的相互作用包括但不限于,键合相互作用,如共价键合、离子键合、氢键合、配位键合、或任何其它分子键合相互作用、静电相互作用、极性或疏水相互作用,或任何其它经典或量子机械稳定化原子或分子相互作用。
术语“动物”被定义为动物界中的任何物种,包括哺乳动物。
术语“哺乳动物”被定义为包括人类在内的、任何种炎的温血高等脊椎动物。
术语“磷脂”是指在分子结构中具有共价连接的磷酸基团的任何脂类或脂肪酸。
术语“两性离子磷脂”是指在分子结构中具有质子受体的磷脂,这样磷酸基团就可带负电荷,质子受体可以是正电荷,这是由于分子内的酸-碱反应。
术语“杂环基”是指具有1或2个环和独立选自N、O或S的1-3个杂原子的饱和或不饱和5-7元杂环基团。
术语“芳基”表示取代或未取代的苯基、呋喃基、噻吩基或吡啶基,或任何这些基团的稠环系统,如萘基。
术语“取代芳基”表示如上面所定义的芳基,其被一个或多个烷基、烷氧基、卤素、氨基、巯基、硝基、羟基、酰基、芳基或氰基取代。
术语“胶态金属”表示可形成胶态混悬液或分散液的任何金属或含金属的化合物。
术语“金属复合物”表示元素周期表中照这样分类的任何金属的复合物,且优选非-碱金属的复合物。
术语“多价金属复合物”表示金属的任何复合物,其中该金属可具有、携带或带有超过1且通常为2-6的正电荷。
术语“两性离子”表示同时具有正电基团和负电基团的分子。
术语“两性离子形式”表示具有正电基团和负电基团的分子。通常,对反应条件进行调节,从而可发生分子内的氢离子转移。
术语“药学有效量”表示引起受NSAID影响的症状的可测量减轻,如疼痛减轻、发热减轻、炎症减轻等所需的NSAID量。
附图简述
参考下列详细描述以及附图可更好地理解本发明,其中相似元素编号相同:
图1描述布洛芬与磷脂-布洛芬抑制TPA-激活的HUVEC的COX-2活性的效力比较;
图2描述ASA对MCF-7细胞生长的剂量-反应[对照值(0mM ASA)与1.25mM ASA相同];
图3描述ASA和磷脂-ASA制剂对MCF-7细胞生长的作用;
图4描述ASA和磷脂-ASA制剂对MCF-7细胞的乳酸脱氢酶(LDH)释放(细胞溶解-坏死)的作用;和
图5描述ASA和磷脂-ASA制剂对正常乳腺细胞生长的作用。
发明详述
本发明人发现相对于在没有磷脂存在的条件下给药的抗炎药物而言,包括磷脂与抗炎药物的组合物可提高抗炎药物的抗癌效果。这些结果提供一种通过使癌症或癌性生长的细胞与本发明组合物单独接触或与其它抗癌治疗联合,用于治疗、预防或改善与癌症或癌性生长有关的症状的组合物和方法。此外,本发明组合物可作为治疗性和/或预防性预防药物口服、局部、和/或内部给药。此外,可将本发明组合物加入到洗手皂、防晒品、或其它化妆品中,作为针对皮肤损害和皮肤癌最终发病的预防性预防药物。
非甾体抗炎药物(NSAID)预防癌症的预防性用途对于有患结肠直肠癌危险的患者已得到公认。NSAID在乳腺癌预防中的可能用途正在考虑之中,且得到许多体外和体内研究支持。NSAID长期使用的主要限制性副作用是它们在易感个体中诱导出血和胃肠道溃疡形成的倾向。向NSAID中加入磷脂如磷脂酰胆碱(PC)导致在动物和人中短期或长期给药后很少或没有GI损伤;此外,磷脂如PC与NSAID的组合,所谓的PC-NSAID,较之未修饰的NSAID显示出更强大的减轻疼痛、发热和炎症的能力。
本发明广泛涉及一种用于预防、治疗或改善癌症或癌性生长的症状的方法,包括按照给药方案,给予动物包括人含有磷脂与NSAID的缔合复合物的组合物的步骤,其中该给药方案包括一次或多次给药,包括口服给药、局部给药、静脉内给药、动脉内给药、或直接给药到组织部位中。
虽然本发明的组合物可单独分开使用,但它们也可与其它化学疗法、免疫疗法和放射疗法联合使用。因此,本发明的组合物可在放射疗法之前、之后或过程中给药。本发明的组合物还可在用其它化疗剂给药之前、过程中或之后给药。
适宜的放射疗法包括但不限于,源自x-射线、γ-射线、中子、和其它来源的高能辐射,以杀死癌细胞并使肿瘤萎缩。放射可来自肌体外的机器(外线束放射疗法),或它可来自放置于肌体中靠近癌细胞处的放射性物质(内部放射疗法、植入放射、或近程放射疗法)。全身放射疗法使用放射性物质,如放射性标记的单克隆抗体,其在整个肌体中循环。也称作放射疗法。
适宜的免疫疗法包括但不限于,癌症疫苗(主动特异性免疫疗法)、单克隆抗体疗法(被动免疫疗法)和非特异性免疫疗法及佐剂。
适宜的化学疗法包括但不限于,烷化剂、通过阻断DNA复制而干扰癌细胞生长的药剂;抗代谢剂,阻断癌细胞存活和生长所需的酶;抗肿瘤的抗生素,其干扰DNA、阻断特定的酶和细胞分裂并改变细胞膜,和有丝分裂抑制剂,其抑制细胞分裂或阻碍细胞再生过程中必需的特定的酶。
用于本发明中的适宜磷脂包括但不限于,以下通式的磷脂:
其中R’是H、OH或Cl且R是:(a)具有1-6个碳原子的烷基,任选被氨基、烷氨基、二烷氨基或杂环基取代,其中烷氨基和二烷氨基取代基中的烷基具有1-5个碳原子且在二烷氨基取代烷基的情况下相同或不同;(b)卤素;(c)芳硫基,优选氯取代;(d)具有5-7个碳原子的环烷基氨基;或(e)具有1或2个杂原子的饱和5或6元含氮杂环基;且R1和R2是8-32个碳原子的饱和或不饱和取代;R3是H或CH3,且X是H或COOH;且R4是=O或H2。还可使用通式的两性离子磷脂的混合物及组合和NSAID的混合物及组合。
上式的两性离子磷脂的例子包括但不限于,磷脂酰胆碱如磷脂酰胆碱(PC)、二棕榈酰磷脂酰胆碱(DPPC)、其它二饱和磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇、磷脂酰丝氨酸鞘磷脂或其它神经酰胺、或各种其它两性离子磷脂、含磷脂的油如来源于大豆的卵磷脂油、二肉豆蔻酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二亚油酰(linoleoyl)磷脂酰胆碱(DLL-PC)、二棕榈酰磷脂酰胆碱(DPPC)、大豆磷脂酰胆碱(大豆-PC或PCS)和卵磷脂酰胆碱(卵-PC或PCE)。在DPPC-一种饱和磷脂中,饱和脂族取代R1和R2是CH3-(CH2)14,R3是CH3且X是H。在DLL-PC-一种不饱和磷脂中,R1和R2是CH3-(CH2)4--CH=CH--CH2--CH=CH-(CH2)7,R3是CH3且X是H。在卵PC中,其是不饱和磷脂的混合物,R1主要含有饱和脂族取代(例如,棕榈酸或硬脂酸),且R2主要是不饱和脂族取代(例如,油酸或花生四烯酸)。在大豆-PC中,其除饱和磷脂(棕榈酸和硬脂酸)外是不饱和磷脂的混合物,[油酸、亚油酸和亚麻酸]。优选的两性离子磷脂包括但不限于,二棕榈酰磷脂酰胆碱、磷脂酰胆碱或其混合物。
适宜的NSAID包括但不限于,丙酸药物如非诺洛芬钙(Nalfon.RTM.)、氟比洛芬(Ansaid.RTM.)、舒洛芬、苯噁洛芬、布洛芬(处方Motrin.RTM.)、布洛芬(200mg.非处方药Nuprin,Motrin 1B.RTM.)、酮洛芬(Orduis,Oruvall.RTM.)、甲氧萘丙酸(Naprosyn.RTM.)、甲氧萘丙酸钠(Aleve,Anaprox,Aflaxen.RTM.)、奥沙普嗪(Daypro.RTM.)等;乙酸药物如双氯芬酸钠(Voltaren.RTM.)、双氯芬酸钾(Cataflam.RTM.)、依托度酸(Lodine.RTM.)、吲哚美辛(Indocin.RTM.)、酮咯酸氨丁三醇(Acular,Toradol.RTM.肌内)、酮咯酸(口服,Toradol.RTM.)等;酮类药物如萘丁美酮(Relafen.RTM.)、舒林酸(Clinoril.RTM.)、托美汀钠(Tolectin.RTM.)等;芬那酯类药物如甲氯芬那酸钠(Meclomen.RTM.)、甲芬那酸(Ponstel.RTM.)等;昔康类药物如吡罗昔康(Dolibid.RTM.)等;水杨酸类药物如二氟尼柳(Feldene.RTM.)、阿司匹林等;吡唑啉酸类药物如羟保松(Tandearil.RTM.)、保泰松(Butazolidin.RTM.)等;对乙酰氨基酚(Tylenol.RTM.)等,或其混合物或组合。
用于本发明中的适宜COX-2抑制剂包括但不限于塞来昔布、美洛昔康、双氯芬酸、美洛昔康、吡罗昔康、或新批准的COX-2抑制剂或其混合物或组合。
一般而言,NSAID与两性离子磷脂的重量比为约1∶0.01-约1∶100、优选约1∶0.02-1∶50,特别优选1∶0.1-1∶10,尤其优选约1∶1-约1∶5。用于本发明组合物中的NSAID有效量为约1mg/剂-约1000mg/剂,这取决于组合物中所用的NSAID和磷脂,优选约50mg/剂-约1000mg/剂,特别优选83mg/剂(就ASA而言),或约100mg/剂、约200mg/剂、约400mg/剂、约500mg/剂、约600mg/剂、约800mg/剂和约1000mg/剂。足量磷脂通常为约0.1mg/剂-约5000mg/剂的磷脂量,优选约1mg/剂-2500mg/剂,且特别优选2mg/剂-约250mg/剂,且尤其优选约2mg/剂-约100mg/剂。
本发明的缔合复合物可按照下列美国专利Nos.5,955,451;5,763,422;5,260,287;5,260,284;5,134,129;5,043,329;5,032,464;4,950,658和4,918,063和共同未决的美国专利申请号No.:10/433454中提出的方法制备;它们引入此处作为参考。
通常,将本发明的组合物配制成根据癌症的性质和建议的单独或与其它抗癌治疗方案联合的治疗方案,按照一定的给药方案摄取。
本发明的组合物可以是任何所需形式,包括但不限于,固体如粉剂、颗粒剂、片剂、丸剂、胶囊剂、凝胶涂覆的片剂或丸剂等,半-固体如糊剂等,混悬液、分散液、乳液、或溶液。分散液或混悬液是指本发明组合物的固体形式与适宜的溶剂混合,该组合物在该溶剂中不溶或具有相对较低的溶解度,即,少于约10重量%、优选少于约5重量%且特别是少于约1重量%的溶解度。乳液是指分别在水溶液或油中乳化本发明组合物的含油或含水形式,即,水包油乳液或油包水乳液。此外,该乳液可以是标准乳液,或微乳,其中乳化还加上使该混合物通过喷口,或按照产生微乳的其它方法而乳化。溶液是指本发明的组合物溶于适宜溶剂中,其中该组合物是可溶的或溶解度较高。本发明还包括其中NSAID混悬于和/或溶于富含PC的油如大豆油中的制剂。
用于制备NSAID/磷脂组合物的方法
本发明其中一类优选的组合物是包括NSAID和磷脂的组合物,其通常是通过在促进两性离子形式的NSAID与磷脂分子缔合的条件下使NSAID与磷脂接触而制备的。这种条件通常包括使用溶剂和/或缓冲液,使用促进分子相互作用和缔合的混合过程,以及受控的温度、压力和时间,从而允许进行所需程度的分子间相互作用和缔合。因为这两类化学物质可在极性溶剂中以两性离子形式存在,因此这两类化合物之间的分子间相互作用和缔合可通过使用溶剂或通过使用低离子强度的缓冲液,即所谓的低渗缓冲液而促进。在某些情况下,可将NSAID加入到有机溶剂中的PC或去油卵磷脂中,然后蒸发除去有机溶剂。
通常,低渗缓冲液包括含有加入缓冲化合物的水,形成具有约1mM-约100mM的体积摩尔浓度的缓冲液。这些离子强度较低的缓冲液可通过降低NSAID与缓冲液和磷脂与缓冲液之间的相互作用而促进两性离子形式的NSAID与磷脂之间的分子间相互作用和/或缔合。
接触也是在有混合存在的情况下进行的,且优选强力或剧烈混合。这种混合过程包括声处理或其它分子水平的混合过程、涡旋混合或其它高剪切混合过程等。混合的时间和温度应设计为使两性离子形式的NSAID和磷脂之间的分子间相互作用达到最大,而不会引起对分子本身的热损害或剪切损害。通常,混合时间为约5分钟-若干小时,优选10分钟-1小时。通常,混合温度为室温-低于所混合的NSAID或磷脂的最低分解温度至少10%的温度,或低于最低沸点溶剂的沸点至少10%的温度或低于缓冲液开始分解或丧失其缓冲能力的温度10%的温度。优选,该温度为室温-约70℃。
缓冲液的pH也可在促进NSAID与磷脂之间的分子间相互作用和/或缔合方面发挥作用。通常,对于大多数NSAID和COX-2抑制剂而言,pH为约3-约10,优选约4-8。优选,调节pH至NSAID或COX-2抑制剂的pKa值或接近该值(在2个pH单位内)。
在制备本发明制剂时,可将NSAID与纯化的天然来源的或合成的磷脂混合或可与各种级别的卵磷脂(从Americall Lecithin Co的大豆卵磷脂提取)或磷脂含量较高的其它天然油混合。特别有用的卵磷脂具有约15-约93重量%PC的磷脂浓度。此外,该制剂可使用去油的和含油的卵磷脂制剂。
与磷脂的形式无关,通常NSAID与磷脂的比例为约1.0∶0.01-约1∶100,优选约1.0∶0.5-约1∶25,且特别是约1.0∶1.0-约1.0∶10.0。
在使用去油卵磷脂的制剂中,最初将去油卵磷脂溶于有机溶剂如乙醇中,其中该有机溶剂通过在氮气或真空下蒸发除去或冷冻干燥,然后重悬于含NSAID的溶液中,接着在适度加热条件(高于室温-约75℃)下(如果需要)混合如涡旋和/或声处理混合。在使用卵磷脂的制剂中,将含油的卵磷脂与NSAID化合物简单合并,且如果需要,通过涡旋和/或声处理混合。
用于制备本发明组合物的另一优选方法是将NSAID溶于低渗水溶液或具有约1-约100毫摩尔(mM)体积摩尔浓度的缓冲液中。适宜的溶液和/或缓冲液包括但不限于,NaCl溶液、Tris缓冲液、碳酸氢盐缓冲液、HEPES缓冲液、MOPS缓冲液等。
声处理或混合温度优选在高于磷脂的转变温度Tm的温度下进行,所述转变温度Tm即磷脂经历从液晶态向凝胶态相转变的温度,如本领域熟知。在PC的情况下,混合可在室温下进行,而就DPPC而言,混合是在高于42℃的温度下进行的。
用于制备本发明组合物的另一优选方法包括将磷脂和NSAID溶于极性溶剂中。适宜的溶剂包括但不限于,含氯烃如氯仿等,低级醇如甲醇、乙醇、异丙醇等,或任何其它溶剂,其中磷脂和NSAID在上述溶剂中具有一定的溶解度,附加的条件是可通过蒸发等很容易除去该溶剂。
当使用金属复合物时,可将复合物直接加入到磷脂和NSAID溶液中。可选择性且优选地,该复合物和NSAID可在低渗缓冲液中制备,其中加入预形成的磷脂膜,正如此处所述。
包括NSAID/磷脂组合物的化妆组合物
一种包含化妆用可接受组合物的皮肤护理组合物,其中该化妆用可接受的组合物包括约0.001-约25重量%磷脂与NSAID的缔合复合物,其中重量%是相对于组合物成分的总重量而言的,优选,约0.1-约25重量%磷脂与NSAID的缔合复合物,特别是,约1-约25重量%磷脂与NSAID的缔合复合物,更特别是约2-约20重量%,且甚至更特别是约2-约10重量%磷脂与NSAID的缔合复合物。
该化妆用可接受的组合物进一步包含阴离子、阳离子、非离子型表面活性剂或其混合物或组合。该化妆用可接受的组合物进一步包含一种或多种赋形剂,其选自水、糖类、表面活性剂、湿润剂、矿脂、矿物油、脂肪醇、脂肪酯润肤剂、蜡剂和含硅氧烷的蜡剂、硅油、硅酮液、硅氧烷表面活性剂、挥发性烃油、季氮化合物、胺官能化的硅氧烷、调节(conditioning)聚合物、流变改性剂、抗氧剂、防晒活性剂、约C10-C22的二长链胺、约C10-C22的长链脂肪胺、脂肪醇、乙氧基化脂肪醇和二-尾磷脂。
化妆用可接受的组合物选自香波、须后水、防晒品、润手乳液、护肤霜、液体肥皂、条皂、浴油条、剃须膏、洗碗液、调理剂、沐浴凝胶、泡泡浴等。
化妆用可接受的组合物选自香波、须后水、防晒品、润手乳液、护肤霜、液体肥皂、条皂、浴油条、剃须膏、洗碗液、调理剂、烫发剂、头发松散剂、头发漂白剂、头发去缠绕洗剂、定型凝胶、定型釉、喷雾泡沫、定型膏、定型蜡、定型洗剂、摩丝、喷雾凝胶、发蜡、沐浴凝胶、泡泡浴、头发着色制剂、临时和永久性头发染色剂、色彩调理剂、头发亮泽剂、着色和无着色的护发素、头发染色剂、卷发定型剂、持久卷发剂、卷发剂、直发剂、头发修饰剂、生发油、头发整理剂和氧化产品、喷雾、定型蜡和香脂。
化妆用可接受的组合物还包含一种或多种选自阴离子、阳离子、非离子或其混合物或组合的表面活性剂,一种或多种选自水、糖类、表面活性剂、湿润剂、矿脂、矿物油、脂肪醇、脂肪酯润肤剂、蜡剂和含硅氧烷的蜡剂、硅油、硅酮液、硅氧烷表面活性剂、挥发性烃油、季氮化合物、胺官能化的硅氧烷、调节聚合物、流变改性剂、抗氧剂、防晒活性剂、约C10-C22的二长链胺、约C10-C22的长链脂肪胺、脂肪醇、乙氧基化脂肪醇和二-尾磷脂的赋形剂。
代表性糖类包括非离子或阳离子糖类,如琼脂糖、支链淀粉、直链淀粉、阿拉伯聚糖、阿拉伯半乳聚糖、arabinoxylens、鹿角菜胶、阿拉伯胶、羧甲基瓜尔胶、羧甲基(羟丙基)瓜尔胶、羟乙基瓜尔胶、羧甲基纤维素、阳离子瓜尔胶、纤维素醚包括甲基纤维素、软骨素、壳多糖、脱乙酰壳多糖、脱乙酰壳多糖吡咯烷酮羧酸盐、羟乙酸脱乙酰壳多糖、乳酸脱乙酰壳多糖、羟丙基乙氧基纤维素椰油基二甲基季铵盐、多聚乙酰神经氨酸([聚-N乙酰基-神经氨酸])、玉米淀粉、凝胶多糖、硫酸皮肤素、葡聚糖、丹麦琼脂、葡聚糖、交联葡聚糖、糊精、脂肪乳剂、乙基羟乙基纤维素、亚麻子糖类(酸性)、半乳葡甘露聚糖、半乳甘露聚糖、葡甘露聚糖、糖原、瓜尔胶、羟乙基淀粉、羟丙基甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基淀粉、羟丙基化瓜尔胶、凝胶糖胶、凝胶糖、阔叶榆绿木胶、刺梧桐胶、黄芪胶(黄芪质)、肝素、透明质酸、菊粉、硫酸角蛋白、konjac mannan、改性淀粉、昆布糖、羟丙基乙氧基纤维素月桂基二甲基季铵盐、秋葵胶、氧化淀粉、果胶酸、果胶、聚葡萄糖、季化羟乙基纤维素(Polyquaternium)-4、季化羟乙基纤维素-10、季化羟乙基纤维素-28、马铃薯淀粉、原果胶、车前子胶、芽霉菌糖、透明质酸钠、淀粉二乙氨基乙醚、羟乙基纤维素硬脂基二甲基季铵盐、棉子糖、rhamsan、木薯淀粉、whelan、果聚糖、硬葡聚糖、藻酸钠、stachylose、琥珀酰聚糖、小麦淀粉、黄原胶、木聚糖、xyloglucan、及其混合物。微生物糖类可在Kirk-Othmer Encyclopedia of Chemical Technology,Fourth Edition,Vol.16,John Wiley and Sons,NY pp.578-611(1994)中找到,其全部引入此处作为参考。复合糖可在Kirk-OthmerEncyclopedia of Chemical Technology,Fourth Edition,Vol.4,John Wiley and Sons,NY pp.930-948,1995中找到,其引入此处作为銮考。
本发明化妆用可接受的组合物可包括表面活性剂。表面活性剂包括表面活化剂,其通常为制剂提供清洁功能或简单发挥湿润剂的作用。表面活性剂通常可分为阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂、两性表面活性剂和两性离子表面活性剂,以及分散聚合物。
此处可用阴离子表面活性剂包括在美国专利US5,573,709中公开的那些,其引入此处作为参考。例子包括烷基和烷基醚硫酸盐。可用于本发明的烷基醚硫酸盐的具体例子是月桂基硫酸盐的钠盐和铵盐、月桂醚硫酸盐、椰子烷基三乙二醇醚硫酸盐;牛油烷基三乙二醇醚硫酸盐、和牛油烷基六氧乙烯硫酸盐。十分优选的烷基醚硫酸盐是含有各化合物的混合物的那些,所述混合物具有约12-约16个碳原子的平均烷基链长度和约1-约6摩尔环氧乙烷的平均乙氧基化程度。
另一适宜种类的阴离子表面活性剂是烷基硫酸盐。重要的例子是按照已知的磺化方法包括漂白和水解获得的具有约8-约24个碳原子,优选约12-约18个碳原子的甲烷系列的烃,包括异-、新-、ineso-和正-链烷烃与磺化剂,例如SO3、H2SO4、发烟硫酸的有机硫酸反应产物。优选碱金属和铵硫酸化的C12-38正-链烷烃。
其它合成的阴离子表面活性剂包括烯属磺酸酯、β-烷氧基链烷磺酸酯、和用羟乙磺酸酯化并用氢氧化钠中和的脂肪酸的反应产物,以及琥珀酰胺酸盐。琥珀酰胺酸盐的具体例子包括N-十八烷基磺基琥珀酰胺酸二钠;N-(1,2-二羧乙基)-N-十八烷基磺基琥珀酰胺酸四钠;磺基琥珀酸钠的二戊酯;磺基琥珀酸钠的二己酯;磺基琥珀酸钠的二辛酯。
用于本发明化妆用可接受的组合物中的优选阴离子表面活性剂包括月桂基硫酸铵、月桂基醚(laureth)硫酸胺、三乙胺月桂基硫酸盐、三乙胺月桂基醚硫酸盐、三乙醇胺月桂基硫酸盐、三乙醇胺月桂基醚硫酸盐、一乙醇胺月桂基硫酸盐、一乙醇胺月桂基醚硫酸盐、二乙醇胺月桂基硫酸盐、二乙醇胺月桂基醚硫酸盐、月桂一甘油酯硫酸钠、月桂基硫酸钠、月桂基醚硫酸钠、月桂基硫酸钾、月桂基醚硫酸钾、月桂基肌氨酸钠、月桂酰肌氨酸钠、月桂基肌氨酸、椰油基肌氨酸、椰油基硫酸铵、月桂酰硫酸铵、椰油基硫酸钠、月桂酰硫酸钠、椰油基硫酸钾、月桂基硫酸钾、三乙醇胺月桂基硫酸盐、三乙醇胺月桂基硫酸盐、一乙醇胺椰油基硫酸盐、一乙醇胺月桂基硫酸盐、十三烷基苯磺酸钠和十二烷基苯磺酸钠。
可用于本发明化妆用可接受组合物中的两性表面活性剂包括脂族仲胺和叔胺的衍生物,其中脂族取代基含有约8-18个碳原子和阴离子水增溶基团,例如,羧基、磺酸、硫酸、磷酸、或膦酸;代表性例子包括3-十二烷基-氨基丙酸钠、3-十二烷基氨基丙磺酸钠、月桂基肌氨酸钠、N-烷基牛磺酸(如按照美国专利US2,658,072中所述通过使十二烷胺与羟乙基磺酸钠反应制备的),如美国专利US2,438,091描述的N-高级烷基天门冬氨酸,及美国专利US2,528,378所述、商品名为MIRANOL.TM的产品。其它肌氨酸盐和肌氨酸盐衍生物可在CTFACosmetic Ingredient Handbook,Fifth Edition,1988,第42页中找到,其引入此处作为参考。
季铵化合物也可用于本发明化妆用可接受的组合物中,只要它们在本发明组合物中是相容的,其中该结构在CTFA CosmeticIngredient Handbook,Fifth Edition,1988,第40页中提供。阳离子表面活性剂通常包括但不限于,含约8-约18个碳原子的脂肪季铵化合物。季铵化合物的阴离子可以是普通离子如氯化物、硫酸二乙酯、硫酸二甲酯、醋酸盐、溴化物、乳酸盐、硝酸盐、磷酸盐或甲苯磺酸盐及其混合物。长链烷基可包括附加或替代碳原子或氢原子或醚键。季氮上的其它取代可以是氢、氢、苄基或短链烷基或羟烷基,如甲基、乙基、羟甲基或羟乙基、羟丙基或其组合。
季铵化合物的例子包括但不限于:二十二烷基三甲基氯化铵、椰油基三甲基氯化铵、十六烷基二甲基乙基溴化铵、二(二十二烷基)二甲基氯化铵、二(氢化牛油基)苄基甲基氯化铵、二(豆油基)二甲基氯化铵、二(牛油基)二甲基氯化铵、羟十六烷基羟乙基二甲基氯化铵、羟乙基山萮酰胺丙基二甲基氯化铵、羟乙基十六烷基二甲基氯化铵、羟乙基牛油基二甲基氯化铵、十四烷基二甲基苄基氯化铵、PEG-2油基甲基氯化铵、PEG-5硬脂基甲基氯化铵、PEG-15椰油基quaternium4、PEG-2stearalkonium 4、月桂基三甲基氯化铵;Quaternium-16;Quaternium-18、月桂基苄基二甲基氯化铵、油基二甲基苄基氯化铵、氯化十六烷基吡啶鎓、季化羟乙基纤维素-5、季化羟乙基纤维素-6、季化羟乙基纤维素-7、季化羟乙基纤维素-10、季化羟乙基纤维素-22、季化羟乙基纤维素-37、季化羟乙基纤维素-39、季化羟乙基纤维素-47、十六烷基三甲基氯化铵、二(月桂基)二甲基氯化铵、十六烷基二甲基苄基氯化铵、二(十六烷基)二甲基氯化铵、豆油基三甲基氯化铵、硬脂基辛基二甲基硫酸甲酯铵、及其混合物。其它季铵化合物在CTFACosmetic Ingredient Handbook,First Edition,第41-42页中列出,其引入此处作为参考。
该化妆用可接受的组合物可包括约C10-C22的二-长链胺,约C10-C22的长链脂肪胺及其混合物。具体例子包括二-十六胺、月桂酰胺基丙基二甲基、硬脂酰胺基丙基二甲胺。本发明化妆用可接受的组合物还可包括脂肪醇(通常是一元醇)、乙氧基化脂肪醇、和二-尾磷脂,其可用于使乳液或分散液形式的化妆用可接受组合物稳定。它们还提供化妆用可接受的粘度。对脂肪醇的选择并不严格,通常可使用那些特征为具有C10-C32,优选C14-C22脂肪链的醇,它们是基本上饱和的链烷醇。例子包括硬脂醇、鲸蜡醇、鲸蜡硬脂醇、肉豆蔻醇、山萮醇、花生醇、异硬脂醇和异鲸蜡醇。鲸蜡醇是优选的且可单独使用或与其它脂肪醇联合使用,优选与硬脂醇联合使用。使用时,脂肪醇优选以约1-约8重量%,更优选约2-约6重量%的浓度包括在本发明制剂中。还可将脂肪醇乙氧基化。具体例子包括cetereth-20、steareth-20、steareth-21及其混合物。还可包括磷脂如磷脂酰丝氨酸和磷脂酰胆碱及其混合物。使用时,脂肪醇组分可以约1-约10重量%,更优选约2-约7重量%的浓度包括在制剂中。
可用于本发明化妆用可接受的组合物中的非离子表面活性剂包括被广泛定义为通过烯氧化物基团(亲水)与有机疏水化合物(其可以是脂族或烷基芳香性质的)缩合产生的那些化合物,优选的非离子表面活性剂种类的例子是:长链链烷醇酰胺;烷基苯酚的聚环氧乙烷缩合物;具有约8-约18个碳原子的脂族醇(直链或支链构型)与环氧乙烷的缩合产物;长链氧化叔胺;长链氧化叔膦;长链二烷基亚砜,其含一个约1-约3个碳原子的短链烷基或羟烷基;和烷基多糖(APS)表面活性剂如烷基聚糖苷;聚乙二醇(PEG)甘油基脂肪酯。
两性离子表面活性剂如甜菜碱也可用于本发明化妆用可接受的组合物中。此处可用甜菜碱的例子包括高级烷基甜菜碱,如椰油二甲基羧甲基甜菜碱、椰油酰胺基丙基甜菜碱、椰油甜菜碱、月桂基酰胺基丙基甜菜碱、油基甜菜碱、月桂基二甲基羧甲基甜菜碱、月桂基二甲基α-羧乙基甜菜碱、鲸蜡基二甲基羧甲基甜菜碱、月桂基双-(2-羟乙基)羧甲基甜菜碱、硬脂基双-(2-羟丙基)羧甲基甜菜碱、油基二甲基γ-羧丙基甜菜碱和月桂基双-(2-羟丙基)α-羧乙基甜菜碱。磺基甜菜碱的代表可以是椰油二甲基磺丙基甜菜碱、硬脂基二甲基磺丙基甜菜碱、月桂基二甲基磺丙基甜菜碱、月桂基双-(2-羟乙基)磺丙基甜菜碱等;酰胺基甜菜碱和酰胺基磺基甜菜碱,其中RCONH(CH2)3与甜菜碱的氮原子相连,它们也可用于本发明中。
用于本发明化妆用可接受的组合物中的阴离子、阳离子、非离子、两性或两性离子表面活性剂通常以约0.1-50重量%、优选约0.5-约40重量%,更优选约1-约20重量%的量使用。
本发明化妆用可接受的组合物可包括湿润剂,其发挥吸湿剂的作用,增加所吸收、容纳、保留的水量。用于本发明制剂的适宜湿润剂包括但不限于:乙酰胺MEA、乳酸铵、脱乙酰壳多糖及其衍生物、胶态燕麦片、半乳阿拉伯聚糖、葡萄糖谷氨酸盐、甘油聚氧乙烯(7)醚、甘油聚氧乙烯(12)醚、甘油聚氧乙烯(26)醚、甘油聚氧乙烯(31)醚、甘油、乳酰胺MEA、乳酰胺DEA、乳酸、甲基葡糖聚氧乙烯(10)醚、甲基葡糖聚氧乙烯(20)醚、泛醇、丙二醇、山梨糖醇、聚乙二醇、1,3-丁二醇、1,2,6-己三醇、氢化淀粉水解产物、肌醇、甘露糖醇、PEG-5季戊四醇醚、聚甘油基山梨糖醇、木糖醇、蔗糖、透明质酸钠、PCA钠及其组合。甘油是特别优选的湿润剂。该湿润剂可以约0.5-约40重量%,优选约0.5-约20重量%且更优选约0.5-约12重量%的浓度存在于组合物中。
本发明化妆用可接受的组合物可包括矿脂或矿物油组分,通常选择USP或NF级。矿脂可以是白色或黄色的。对矿脂粘度或稠度的级别没有严格限制。矿脂可以用烃物质的混合物部分替代,其可被配制成在外观和稠度方面与矿脂类似。例如,也可将矿脂或矿物油与不同蜡等的混合物组合。优选的蜡包括蜡果杨梅蜡、小烛树蜡、地蜡、希蒙得木脂、羊毛脂蜡、褐煤蜡、石蜡、聚甘油基-3-蜂蜡、聚甘油基-6-五硬脂酸酯、微晶蜡、石蜡、异链烷烃、凡士林固体石蜡、角鲨烯、低聚烯烃、蜂蜡、合成小烛树蜡、合成巴西棕榈蜡、合成蜂蜡等,可将它们混合在一起。具有不同程度取代的烷基甲基硅氧烷可用于增加皮肤保持的水分。硅氧烷如硬脂基聚二甲基硅氧烷,称作2503Wax,C30-45烷基methicone,称作AMS-C30蜡,和硬脂氧基三甲基硅烷(和)硬脂醇,称作580蜡,分别从Dow Corning.RTM.,Midland,Mich.,USA得到。其它烷基和苯基硅氧烷可用于提高保湿性。树脂如聚二甲基硅氧烷(和)三甲基甲硅烷氧基硅酸酯,称作Dow Corning.RTM.593或环状聚二甲基硅氧烷(和)三甲基甲硅烷氧基硅酸酯,称作DowCorning.RTM.749流体,可用于提高皮肤护理产品的膜形成。使用时,矿脂、蜡或烃或油组分可以约1-约20重量%、更优选约1-约12重量%的浓度包括在制剂中。使用时,硅树脂可为约0.1-约10.0重量%的浓度。
润肤剂被定义为帮助维持皮肤的柔软、平滑及圆润的外观的物质。润肤剂通过它们停留在皮肤表面上或角质层中的能力而发挥作用。本发明化妆用可接受的组合物可包括脂肪酯润肤剂,它们在International Cosmetic Ingredient Dictionary,Eighth Edition,2000,p.1768-1773中列出。用于本发明制剂中的适宜脂肪酯的具体例子包括肉豆蔻酸异丙酯、棕榈酸异丙酯、辛酸/癸酸甘油三酯、乳酸十六酯、棕榈酸十六酯、氢化蓖麻油、甘油酯、异硬脂酸羟十六酯、磷酸羟十六酯、异硬脂酸异丙酯、异硬脂酸异硬脂醇酯、癸二酸二异丙酯、PPG-5-Ceteth-20、2-乙基己基异壬酸酯、2-乙基己基硬脂酸酯、C2-C16脂肪醇乳酸酯、羊毛脂酸异丙酯、2-乙基-己基水杨酸酯及其混合物。目前优选的脂肪酯是肉豆蔻酸异丙酯、棕榈酸异丙酯、PPG-5-Ceteth-20、和辛酸/癸酸甘油三酯。使用时,该脂肪酯润肤剂优选以约1-约8重量%、更优选约2-约5重量%的浓度包括在本发明制剂中。
本发明的组合物还可包括硅氧烷化合物。优选,硅氧烷组分在25℃温度下的粘度为约0.5-约12,500cps。适宜物质的例子是二甲基聚硅氧烷、二乙基聚硅氧烷、二甲基聚硅氧烷-二苯基聚硅氧烷、环状聚二甲基硅氧烷、三甲基聚硅氧烷;二苯基聚硅氧烷及其混合物。聚二甲基硅氧烷,一种用三甲基单元封端的二甲基聚硅氧烷,是其中一个优选的例子。具有50-1,000cps粘度的聚二甲基硅氧烷是特别优选的。使用时,该硅氧烷油优选以0.1-5重量%,更优选1-2重量%的浓度包括在本发明的制剂中。
本发明化妆用可接受的组合物可包括挥发性和非-挥发性硅氧烷油或硅酮液。硅氧烷化合物可以是具有约0.5-约100厘沱粘度的线形或环状聚二甲基硅氧烷。最优选的线形聚二甲基硅氧烷化合物具有约0.5-约50厘沱。线形、低分子量、挥发性聚二甲基硅氧烷的其中一个例子是八甲三硅氧烷,商品名Dow Corning.RTM.200流体,具有约1厘沱粘度。使用时,硅氧烷油优选以0.1-30重量%、更优选1-20重量%的浓度包括在本发明制剂中。
本发明化妆用可接受的组合物可包括挥发性、环状、低分子量聚二甲硅氧烷(环状聚二甲基硅氧烷)。优选的环状挥发性硅氧烷可以是具有4-6个平均重复单元和约2.0-约7.0厘沱粘度的聚二甲基环状硅氧烷及其混合物。优选的环状聚二甲基硅氧烷从Dow Corning,Midland,Mich.,USA得到,商品名Dow Corning.RTM.244流体,Dow Corning.RTM.245流体,Dow Corning.RTM.246,Dow CorninG.RTM.344流体和Dow Corning.RTM.345流体,和Silicone SF-1173及Silicone SF-1202,来源于General Electric,Waterford,N.Y.,USA。使用时,硅氧烷油优选以0.1-30重量%,更优选1-20重量%的浓度包括在本发明制剂中。
具有聚氧乙烯或聚氧丙烯侧链的硅氧烷表面活性剂或乳化剂也可用在本发明的组合物中。优选的例子包括聚二甲基硅氧烷copolyol,Dow Corning.RTM.3225C和5225C Formulation Aids,从Dow Corning,Midland,Mich.,USA得到,和Silicone SF-1528,从General Electric,Waterford,N.Y.,USA得到。侧链还可包括烷基,如月桂基或鲸蜡基。优选月桂基methicone copolyol,称作Dow Corning.RTM.5200Formulation Aid,和鲸蜡基聚二甲基硅氧烷copolyol,称作AbilEM-90,从Goldschmidt Chemical Corporation,Hopewell,Va得到。还优选月桂基聚二甲基硅氧烷,称作Belsil LDM 3107VP,从Wacker-Chemie,Munchen,GER得到。使用时,硅氧烷表面活性剂优选以0.1-30重量%(wt/%),更优选1-15重量%的浓度包括在本发明制剂中。
胺官能性硅氧烷和乳液可用于本发明中。优选例子包括DowCorning.RTM.8220、Dow Corning.RTM.939、Dow Corning.RTM.949、Dow Corning.RTM.2-8194,所有均从Dow Corning,Midland,Mich.,USA得到。从General Electric,Waterford,N.Y.,USA得到的Silicone SM 253也是优选的。使用时,胺官能性硅氧烷优选以0.1-5重量%、更优选0.1-2.0重量%的浓度包括在本发明制剂中。
本发明化妆用可接受的组合物可包括挥发性烃油。该挥发性烃含约C6-C22个原子。优选的挥发烃是具有约C6-C16个碳原子链长的脂族烃。这类化合物的例子包括异十六烷,商品名为Permethyl 101A,从Presperse,South Plainfield,N.J.,USA得到。优选挥发烃的另一个例子是C12-C14异链烷烃,商品名Isopar M,从Exxon,Baytown,Tex.,USA得到。使用时,挥发烃优选以0.1-30重量%,更优选1-20重量%的浓度包含在本发明的制剂中。
本发明化妆用可接受的组合物可包括阳离子和两性调节聚合物。这类的例子包括但不限于由International Cosmetic IngredientDictionary列出的那些,由Cosmetic,Toiletry,and FragranceAssociation(CTFA),110117.sup.th Street,N.W.,Suite 300,Washington,D.C.20036出版。一般的例子包括纤维素醚的季铵衍生物、瓜尔胶的季铵衍生物、DADMAC的均聚物和共聚物、MAPTAC的均聚物和共聚物及淀粉的季铵衍生物。具体例子,使用CTFA命名,包括但不限于,季化羟乙基纤维素-10、瓜耳羟丙基三甲基氯化铵、淀粉羟丙基三甲基氯化铵、季化羟乙基纤维素-4、季化羟乙基纤维素-5、季化羟乙基纤维素-6、季化羟乙基纤维素-7、季化羟乙基纤维素-14、季化羟乙基纤维素-15、季化羟乙基纤维素-22、季化羟乙基纤维素-24、季化羟乙基纤维素-28、季化羟乙基纤维素-32、季化羟乙基纤维素-33、季化羟乙基纤维素-36、季化羟乙基纤维素-37、季化羟乙基纤维素-39、季化羟乙基纤维素-45、季化羟乙基纤维素-47和聚甲基丙烯酰胺丙基三甲基氯化铵及其混合物。使用时,本发明化妆用可接受的组合物中优选包括0.1-10重量%、优选0.2-6重量%、且最优选0.2-5重量%浓度的调节聚合物。
本发明化妆用可接受的组合物可包括一种或多种流变改性剂。可用于本发明中的流变改性剂包括但不限于丙烯酸的高分子量交联均聚物,和丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物,如Carbopol.RTM.和Pemulen.RTM.系列,均可从B.F.Goodrich,Akron,Ohio,USA获得;阴离子丙烯酸酯聚合物如Salcare.RTM.AST和阳离子丙烯酸酯聚合物如Salcare.RTM.SC96,从Ciba Specialties,High Point,N.C.,USA得到;丙烯酰胺丙基三甲基氯化铵/丙烯酰胺;羟乙基甲基丙烯酸酯聚合物、Steareth-10烯丙基醚/丙烯酸酯共聚物;丙烯酸酯/Beheneth-25甲基丙烯酸酯共聚物,称作Aculyn.RTM.28,从International Specialties,Wayne,N.J.,USA得到;甘油基聚甲基丙烯酸酯、丙烯酸酯/Steareth-20甲基丙烯酸酯共聚物、膨润土;胶如藻酸盐、鹿角菜胶、阿拉伯胶、阿拉伯树胶、阔叶榆绿木胶、刺梧桐胶、黄芪胶、瓜尔胶;瓜耳羟丙基三甲基氯化铵、黄原胶或凝胶糖胶;纤维素衍生物如羧甲基纤维素钠、羟乙基纤维素、羟甲基羧乙基纤维素、羟甲基羧丙基纤维素、乙基纤维素、硫酸纤维素、羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、微晶纤维素;琼脂;果胶;明胶;淀粉及其衍生物;脱乙酰壳多糖及其衍生物如羟乙基脱乙酰壳多糖;聚乙烯醇、PVM/MA共聚物;PVM/MA癸二烯交联聚合物、基于聚(环氧乙烷)的增稠剂、sodium carbomer及其混合物。使用时,本发明化妆用可接受的组合物中优选包括0.01-12重量%、优选0.05-10重量%且最优选0.1-6重量%浓度的流变学改性剂。
本发明化妆用可接受的组合物可包括一种或多种抗氧剂,其包括但不限于抗坏血酸、BHT、BHA、异抗坏血酸盐、酸式亚硫酸盐、巯基乙醇酸盐、生育酚、焦亚硫酸钠、醋酸维生素E和棕榈酸抗坏血酸酯。抗氧剂以占化妆用可接受的组合物0.01-5重量%,优选0.1-3重量%,最优选0.2-2重量%存在。
本发明化妆用可接受的组合物可包括一种或多种防晒活性剂。防晒活性剂的例子包括但不限于甲氧基肉桂酸辛酯(乙基己基对-甲氧基肉桂酸酯)、水杨酸辛酯羟苯甲酮(二苯甲酮(benzophenone)-3)、二苯甲酮-4、邻氨基苯甲酯、二羟苯宗、对氨基苯甲酸、戊基二甲基PABA、二乙醇胺对-甲氧基肉桂酸盐、4-双(羟丙基)氨基苯甲酸乙酯、2-乙基己基1-2-氰基-3,3-二苯基丙烯酸酯、高基水杨酸酯、甘油基氨基苯甲酸酯、二羟基丙酮、辛基二甲基PABA、2-苯基苯并咪唑-5-磺酸、三乙醇胺水杨酸盐、氧化锌、和氧化钛及其混合物。用于本发明化妆用可接受的组合物中的防晒品的量将根据所用具体防晒活性剂的特异性UV吸收波长而改变,且可以是0.1-10重量%,2-8重量%。
本发明化妆用可接受的组合物可包括一种或多种防腐剂。可使用的防腐剂的例子包括但不限于1,2-二溴-2,4-二氰基丁烷(甲基二溴戊二腈,称为MERGUARD.RTM.,ONDEO Nalco Chemical Company,Naperville,I11.,USA)、苯甲醇、咪唑烷基脲、1,3-双(羟甲基)-5,5-二甲基-2,3-咪唑烷二酮(例如,DMDM Hydantoin,称为GLYDANT.RTM.,Lonza,Fairlawn,N.J.,USA.)、甲基氯异噻唑啉酮和甲基异噻唑啉酮(例如,Kathon.RTM.,Rohm & Haas Co.,Philadelphia,Pa.,USA)、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯氧基乙醇和苯甲酸钠,及其混合物。
本发明化妆用可接受的组合物可包括通常用于化妆品中的任何其它成分,这类成分的例子包括但不限于缓冲剂、芳香成分、螯合剂、色彩添加剂或染料(其可使组合物本身或角蛋白着色)、多价螯合剂、软化剂、增泡剂、泡沫稳定剂、阳光过滤剂和胶溶剂。
可用此处所述的不饱和季铵化合物处理颜料,如二氧化钛、氧化锌、滑石粉、碳酸钙或高岭土的表面,然后用于本发明化妆用可接受的组合物中。则处理过的颜料作为防晒活性成分更有效,并可用于彩妆如粉底和睫毛油中。
本发明化妆用可接受的组合物可以各种形式存在。这种形式的例子包括但不限于溶液、液体、霜剂、乳液、分散液、凝胶、粘稠洗液。
本发明化妆用可接受的组合物可含有水,且还可含有任何化妆用可接受的溶剂。可接受溶剂的例子包括但不限于一元醇,如具有1-8个碳原子的链烷醇(像乙醇;异丙醇、苯甲醇和苯乙醇),多元醇,如烷撑二醇(像丙三醇、乙二醇和丙二醇)和乙二醇醚如单-、二-、和三-乙二醇一烷基醚,例如乙二醇单甲基醚和二甘醇单甲基醚,其单独使用或以混合物的形式使用。这些溶剂可以相对于组合物总重至多多达70重量%,例如0.1-70重量%的比例存在。
还可将本发明化妆用可接受的组合物包装成气雾剂,其中它可以气溶胶喷雾的形式或气溶胶泡沫的形式应用。作为用于这些气雾剂的推进气体,可使用,特别是,二甲醚、二氧化碳、氮气、一氧化氮、空气和挥发性烃,如丁烷、异丁烷和丙烷。
本发明化妆用可接受的组合物还可包含电解质,如水合氯化铝、碱金属盐如钠、钾或锂盐,这些盐优选是卤化物,如氯化物或溴化物,和硫酸盐或有机酸盐,如醋酸盐或乳酸盐,且还有碱土金属盐,优选钙、镁和锶的碳酸盐、硅酸盐、硝酸盐、醋酸盐、葡萄糖酸盐、泛酸盐和乳酸盐。
用于处理皮肤的组合物包括留存或洗掉的皮肤护理产品,如洗液、手/身体用霜剂、剃须凝胶或剃须膏、沐浴乳、防晒品、液体肥皂、除臭剂、止汗剂、晒黑乳液、晒后凝胶、泡泡浴、手或机械洗碗组合物等。除聚合物外,皮肤护理组合物可包括通常用于皮肤护理制剂中的组分。这类组分包括,例如:(a)湿润剂、(b)矿脂或矿物油、(c)脂肪醇、(d)脂肪酯润肤剂、(e)硅油或硅酮液、和(f)防腐剂。这些组分通常用于人的皮肤必须是安全的且必须与制剂中的其它组分相容。这些组分的选择通常在本领域技术人员的能力范围之内。该皮肤护理组合物还可包括用于化妆用皮肤护理制剂中的其它常规添加剂。这类添加剂包括美容增强剂、芳香油、染料和药物如甲醇等。
可将本发明的皮肤护理组合物制备成水包油、油包水乳液、三重乳液、或分散液。
优选的水包油乳液是通过首先形成水溶性组分,例如不饱和季铵化合物、湿润剂、水溶性防腐剂的含水混合物,接着加入水不溶性组分而制备的。水不溶性组分包括乳化剂、水不溶性防腐剂、矿脂或矿物油组分、脂肪醇组分、脂肪酯润肤剂、和硅油组分。混合能的输入应较高并维持一段时间,从而足以形成具有平滑外观的油包水乳液(表明在乳液中存在相对较小的胶束)。优选的分散液通常通过形成水溶性组分的含水混合物,接着加入增稠剂以混悬力用于水不溶性物质而制备。
就清洁制剂,如洗发香波、或液体洗手皂、或清洁皮肤的沐浴凝胶而言,该组合物含有通常约3-约50重量%,优选约3-约20重量%的阴离子、阳离子、非离子、两性离子或两性表面活性剂,它们的pH通常为约3-约10。
化妆用制剂是通过广泛熟知的混合及掺和技术制备的。本发明的PC-NSAID组合物可预先制备或在制造过程中现场制备,条件是PC与NSAID可形成缔合复合物。
其中可加入磷脂与NSAI D的缔合复合物的其它肥皂及化妆制剂和组合物在美国专利Nos.:6,767,878;6,696,397;6,696,067;6,613,866;6,613,755;6,610,315;6,586,590;6,583,181;6,555,708;6,518,229;6,517,846;6,440,908;6,429,180;6,383,997;6,312,703;6,271,187;6,187,728;6,147,039;6,121,214;6,087,400;6,060,808;6,025,312;5,994,383;5,994,286;5,962,399;5,942,478;5,854,197;5,490,955;5,419,908;5,395,541;5,338,541;5,136,093;5,075,042;5,041,236;4,959,171;4,617,148;和4,548,810中公开,其引入此处作为参考。
实验部分
首先参考图1,显示布洛芬相对于与磷脂缔合的布洛芬(PC-IBU)抑制TPA-激活的HUVEC的COX-2活性的效能的比较。数据证实,与单独的布洛芬相比,PC可提高布洛芬抑制12-O-四癸酰基佛波醇-13-醋酸酯(TPA)激活的人脐静脉内皮细胞(HUVEC)的COX-2活性的效能。
首先使用培养生长的MCF-7乳腺癌细胞进行对阿司匹林的剂量-反应(1.25-20mM)。与各种浓度阿司匹林(乙酰基水杨酸,ASA)接触48小时后,进行线粒体溴化3-(4,5-二甲噻唑-2-基)-2,5-二苯基四唑鎓(MTT)测定。MTT测定可产生细胞数的测量值并用于监测MCF-F乳腺癌细胞的生长或生长抑制,即,测量组合物的相对生长抑制剂活性。如图2所示,当以毫摩尔(mM)的对数标度绘制ASA浓度曲线,发现ASA在这些条件下,在2.5mM和更高的浓度下,对细胞生长具有抑制剂活性或效应。
如图2所示,为了试验与磷脂缔合的阿司匹林(PC-ASA)制剂的相对生长抑制剂活性,制备其中ASA浓度不会导致超过50%生长抑制(例如,2.5和5mM)的PC-ASA制剂。在本实施例和随后所有实施例中,通过测量线粒体溴化3-(4,5-二甲噻唑-2-基)-2,5-二苯基四唑鎓(MTT)活性评价细胞生长。选择那些ASA浓度,这样就可很容易地观察到任何PC作用。在制备PC-ASA制品后,使MCF-7乳腺癌细胞与ASA或具有相同ASA浓度的PC-ASA接触48小时。现在参考图3,与单独的ASA制剂相比,PC-ASA制剂在抑制乳腺癌细胞的生长方面明显更有效。还应注意在这些相对较低的浓度下,单独的PC不会不利地影响细胞的生长(比较空心和阴影条的对照细胞)。这些结果证实在体外PC-ASA较之未修饰的ASA在抑制乳腺癌细胞生长,且甚至促进细胞死亡方面更有效。
PC-ASA制剂对MCF-7细胞的生长抑制剂活性可以是通过增加的编程性细胞死亡或坏死或细胞增殖抑制。为了区别前两种可能性,进行PC-ASA制剂对作为坏死量度的胞质酶乳酸脱氢酶(LDH)释放的作用的研究。进行该研究时,使MCF-7细胞与2.5和5mM ASA或PC-ASA制剂接触48小时,如前所述。收集培养基并测定LDH活性(该测定是一种从Sigma Chemical Co.,St.Louis,MO得到的试剂盒)。为了作为阳性对照,在LDH测定前,使一些细胞与一种胆汁酸-0.6mM脱氧胆酸钠(DOC)接触5小时。本发明人发现与该浓度DOC接触该时间周期对于培养细胞是有毒的。正如从图4中所见,DOC引起细胞LDH释放,而NSAID则不会。无论是单独的ASA,还是PC-ASA制剂的处理均未导致这些细胞的任意坏死迹象。然而,在这些浓度下,ASA和PC-ASA制剂很明显降低MCF-7细胞数。这些发现的最可能的解释是NSAID诱导编程性细胞死亡而不是坏死。这种可能性与文献中的报道相一致(见,例如,Xiaojun L,Xie W,Reed D,Bradshaw WS,Simmons DL.非甾体抗炎药物在鸡胚胎成纤维细胞中引起编程性细胞死亡并诱导环加氧酶,Proc Nat1 Acad Sci USA 1995;92:7961-7965)。另外一种可能性是PC-NSAID通过抑制细胞增殖而起作用。
还研究了ASA和PC-ASA制剂对正常乳腺细胞系MCF-10A的作用。如图5所示,较之未修饰的ASA,PC-ASA制剂对该非-癌细胞系具有明显更少的生长抑制活性。该发现连同我们其它的数据表明磷脂-NSAID制剂对癌细胞和正常细胞可能具有不同的作用,与未修饰的NSAID相比,在抑制癌细胞生长方面更有效,且对正常细胞作用较小,因此通过保存正常组织而较之未修饰的NSAID提供附加益处。
MCF-7乳腺癌细胞在培养中生长并以等摩尔浓度与阿司匹林(乙酰基水杨酸,ASA)和PC-ASA接触。进行测定以评估细胞数。表1显示PC-ASA较之单独的ASA在抑制乳腺癌细胞生长方面明显更有效。
表1
阿司匹林(ASA)和与磷脂酰胆碱缔合的阿司匹林(PC-ASA)对MCF-7乳腺癌细胞数和DNA合成的作用
细胞处理 | 细胞数(%对照) | DNA合成(%对照) |
对照 | 100±22 | 100±4 |
5mM ASA | 55±3 | 85±8 |
5mM PC-ASA | 45±3*# | 9±0.2*# |
5mM PC | 114±3 | 41±1*# |
值以平均值±平均值的标准误差表示
*与对照相比p<0.05
#与单独的ASA相比p<0.05
还应注意单独的PC(在该剂量下)在抑制细胞生长方面无效。该体外发现证实PC-NSAID制剂较之未修饰的NSAID制剂在抑制乳腺癌细胞的生长,甚至促进细胞死亡方面更有效。进一步进行研究以确定ASA和PC-ASA降低细胞数的机理。在没有或有ASA和PC-ASA存在的条件下,使MCF-7细胞再次生长,并通过测量滴定胸苷掺入到细胞DNA中而评价细胞增殖。表1表明PC-ASA复合物较之单独的ASA在降低细胞生长方面明显更有效,正如通过滴定胸苷掺入所测量的。
还测试了PC-NSAID对另外一种癌症类型-结肠癌细胞系SW-480的作用。如表2所见,发现PC-ASA和PC-布洛芬(PC-IBU)较之单独的ASA或IBU在降低SW-480细胞数方面更为有效得多。
表2
NSAID和PC-NSAID对SW-480结肠癌细胞数和DNA合成的作用
细胞处理 | 细胞数(%对照) | DNA合成(%对照) |
对照 | 100±4 | 100±2 |
5mM ASA | 68±3* | 102±4 |
5mM PC-ASA | 58±1*# | 50±1*# |
5mM PC | 106±7 | 65±4* |
1mM IBU | 81±2* | 79±1* |
1mM PC-IBU | 66±5* | 53±4*# |
1mM PC | 106±13 | 97±5 |
值以平均值±平均值的标准误差表示。ASA=阿司匹林;IBU=布洛芬;PC=磷脂酰胆碱
*与对照相比p<0.05
#与单独的ASA或IBU相比p<0.05
且如表2所见,PC-NSAID较之单独的ASA或IBU,可较大程度地降低SW-480细胞的细胞增殖。因此,在两种不同的癌细胞系中,PC-NSAID较之单独的NSAID在抑制癌细胞生长方面更有效,且PC-NSAID似乎通过抑制癌细胞增殖而发挥作用。
为了证实PC-NSAID也具有体内抗癌活性,对家猫进行了研究。如表3所概括的,该动物在2003年12月被诊断患有膀胱平滑肌肉瘤-一种特别具侵袭性形式的癌症。
表3
猫中膀胱癌和对癌症的PC-吡罗昔康治疗的概述
日期 | 超声波检查结果 | 处理 |
12/11/1003 | 膀胱的平滑肌肉瘤 | 手术切除和每周长春新碱×3 |
12/31/2003 | 膀胱肿瘤的生长(肿瘤宽度=3.5cm) | 每日,卵磷脂 |
02/17/2004 | 与先前比没有改变(肿瘤宽度=3.0cm) | 每日,卵磷脂 |
04/06/2004 | 肿瘤大小降低(肿瘤宽度=1.9cm) | 每日,卵磷脂 |
05/20/2004 | 膀胱肿瘤的生长(肿瘤占据膀胱壁的75%) | 每日,PC-吡罗昔康α |
07/15/2004 | 肿瘤大小降低(肿瘤宽度=1.0cm) | 每日,PC-吡罗昔康α |
α于5/20/04每隔一天以0.3mg/kg剂量开始吡罗昔康治疗
对猫进行手术治疗,从而切除肿瘤,然后进行标准长春新碱化疗3周。长春新碱没有阻止剩余肿瘤的生长,然后用大豆卵磷脂(磷脂酰胆碱)对该猫进行口服处理若干周。卵磷脂处理似乎最初阻止甚至降低肿瘤大小。最终,肿瘤开始再次生长并开始用卵磷脂与NSAID-吡罗昔康联合治疗。根据超声波评价,PC-吡罗昔康似乎可限制肿瘤生长,且猫仍然保持健康并自PC-吡罗昔康给药起体重增加。到本申请提交之日,继续用PC-吡罗昔康对猫进行治疗。
总之,本发明获得的数据表明,与磷脂缔合的NSAID制剂,除了它降低的GI毒性外,在抑制乳腺癌和结肠癌细胞系的生长和/或诱导细胞死亡方面具有功用。该PC-NSAID制剂较之未修饰的NSAID在体外更有效。
参考文献
上述公开中引证下列参考文献:
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所有引证的参考文献均引入此处作为参考。当已经充分且完全描述了本发明时,应了解,在本发明权利要求的范围内,可以除特别描述以外的方式实施本发明。虽然已经参考优选实施方案公开了本发明,但通过阅读本说明书,本领域技术人员可认识到在不背离上面所述以及之后权利要求所要求保护的范围和精神的前提下,可对本发明进行改变和改进。
Claims (9)
1.含有磷脂和抗炎药物的缔合复合物的水性组合物在制备用于治疗、预防和/或改善癌症或癌性生长的症状的药物中的用途,其中所述磷脂和抗炎药物存在于具有或接近NSAID的pKa值的2个pH单位内的pH的含水缓冲液中,其中该药物给予患有癌症或癌性生长的动物的机体或直接给予到癌性生长的癌症部位,其中该药物预防或改善癌症的症状,其中所述磷脂是两性离子磷脂,所述抗炎药物是选自丙酸药物、昔康类药物或水杨酸类药物的NSAID。
2.权利要求1的用途,其中所述动物为人。
3.权利要求1或2的用途,其中该药物是口服给药、局部给药、静脉内给药、动脉内给药、直接向组织中给药的,或作为给药方案的一部分给药,其中该给药方案包括一次或多次口服、局部、静脉内、动脉内或直接组织给药步骤。
4.权利要求1或2的用途,其中该磷脂是具有下式的化合物或其混合物:
其中R1和R2是8-32个碳原子的饱和或不饱和取代;R3是H或CH3,且X是H或COOH;且R4是=O或H2。
5.权利要求1或2的用途,其中该磷脂选自磷脂酰胆碱、二棕榈酰磷脂酰胆碱、其它二饱和磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇、磷脂酰丝氨酸、鞘磷脂、含磷脂的油、二肉豆蔻酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二亚油酰磷脂酰胆碱、大豆磷脂酰胆碱和卵磷脂酰 胆碱。
6.权利要求5的用途,其中所述含磷质的油为来源于大豆的卵磷脂油。
7.权利要求5的用途,其中该磷脂选自二棕榈酰磷脂酰胆碱、磷脂酰胆碱或其混合物。
8.权利要求1或2的用途,其中所述癌症是乳腺癌、结肠癌或膀胱癌。
9.权利要求1或2的用途,其中所述丙酸药物是布洛芬;所述昔康类药物是吡罗昔康;所述水杨酸类药物是阿司匹林。
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Application Number | Title | Priority Date | Filing Date |
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CN2004800264983A Expired - Fee Related CN1852721B (zh) | 2003-07-31 | 2004-08-02 | 用于治疗、预防和/或改善癌症、癌症发病或癌症症状的组合物和方法 |
CN2013100537924A Pending CN103143031A (zh) | 2003-07-31 | 2004-08-02 | 用于治疗、预防和/或改善癌症、癌症发病或癌症症状的组合物和方法 |
Family Applications After (1)
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CN2013100537924A Pending CN103143031A (zh) | 2003-07-31 | 2004-08-02 | 用于治疗、预防和/或改善癌症、癌症发病或癌症症状的组合物和方法 |
Country Status (9)
Country | Link |
---|---|
US (1) | US7838511B2 (zh) |
EP (1) | EP1653975A4 (zh) |
KR (1) | KR20060054405A (zh) |
CN (2) | CN1852721B (zh) |
AU (1) | AU2004260696C1 (zh) |
CA (1) | CA2534241C (zh) |
HK (1) | HK1096298A1 (zh) |
IL (1) | IL173352A0 (zh) |
WO (1) | WO2005011708A1 (zh) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090232911A1 (en) * | 2005-03-25 | 2009-09-17 | Yoichi Kato | Use of sericin for improving feeling in use of denture |
EP1745788A1 (de) * | 2005-07-22 | 2007-01-24 | KTB Tumorforschungsgesellschaft mbH | Acylglycerophospholipide zur Behandlung von Krebs und Tumorkachexie |
US7597914B1 (en) * | 2007-10-02 | 2009-10-06 | Allen Jay Cohen | Ala-septic pre-cancerous liquid dissolving solution and method |
US8153171B1 (en) * | 2007-10-02 | 2012-04-10 | Allen Jay Cohen | Solution for dissolving pre-melanoma lesions and melanoma lesions including psoriasis, herpes simplex lesions and eczema lesions |
WO2010088924A1 (en) | 2009-02-06 | 2010-08-12 | Telormedix Sa | Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration |
JP5348784B2 (ja) | 2009-12-28 | 2013-11-20 | 株式会社 資生堂 | 化粧料 |
NZ603155A (en) * | 2010-04-30 | 2014-06-27 | Telormedix Sa | Phospholipid drug analogs |
US9050319B2 (en) | 2010-04-30 | 2015-06-09 | Telormedix, Sa | Phospholipid drug analogs |
US20120003298A1 (en) * | 2010-04-30 | 2012-01-05 | Alcide Barberis | Methods for inducing an immune response |
US9125899B1 (en) | 2010-06-17 | 2015-09-08 | Stc.Unm | Modulators of GTPases and their use |
EP2412792A1 (en) | 2010-07-29 | 2012-02-01 | The Procter & Gamble Company | Liquid detergent composition |
AU2015317330B2 (en) * | 2014-09-19 | 2021-01-14 | Memorial Sloan-Kettering Cancer Center | Methods for treating brain metastasis |
FR3038606B1 (fr) * | 2015-07-06 | 2018-10-05 | Institut National Des Sciences Appliquees De Lyon | Glycerophosphocholines, pour leur utilisation dans le traitement d'une inflammation intestinale ou d'un cancer intestinal |
MX2018016091A (es) | 2016-06-29 | 2019-09-16 | Machavert Pharmaceuticals Llc | Composiciones de fosfolipidos. |
CN106177976B (zh) * | 2016-07-11 | 2019-06-21 | 贵州医科大学 | 一种阿司匹林磷脂复合物及其制备方法 |
CN107760452A (zh) * | 2017-10-19 | 2018-03-06 | 蒋春霞 | 一种隐形眼镜护理液 |
Citations (2)
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US6120797A (en) * | 1996-10-15 | 2000-09-19 | The Liposome Company, Inc. | N-acyl phosphatidylethanolamine-mediated liposomal drug delivery |
WO2002085414A2 (en) * | 2000-12-19 | 2002-10-31 | The Board Of Regents Of The University Of Texas System | Nsaid formulations comprising lecithin oils for protecting the gastrointestinal tract and providing enhanced therapeutic activity |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US4421747A (en) * | 1978-12-27 | 1983-12-20 | A. Nattermann & Cie. Gmbh | Inflammation-preventing pharmaceutical composition of oral administration |
DE2914788A1 (de) * | 1979-04-11 | 1980-10-16 | Nattermann A & Cie | Parenteral applizierbare, stabile arzneimittelloesungen mit entzuendungshemmender wirkung |
US4847069A (en) | 1987-10-22 | 1989-07-11 | The Procter & Gamble Company | Photoprotection compositions comprising sorbohydroxamic acid and an anti-inflammatory agent |
FR2678929A1 (fr) * | 1991-07-11 | 1993-01-15 | Oreal | Compositions pour freiner la chute des cheveux et pour induire et stimuler leur croissance a base de derives de 2,4-diamino pyrimidine 3-oxyde, nouveaux derives 2,4-diamino pyrimidine 3-oxyde. |
US5505960A (en) * | 1992-02-12 | 1996-04-09 | Janssen Farmaceutici S.P.A. | Liposomal piroxicam formulations |
DE69621773T2 (de) | 1995-01-27 | 2003-01-02 | Board Of Regents, The University Of Texas System | Verfahren zur erhöhung der therapeutischen wirkung von nsaids und dazu verwendbare zwitterionische phospholipidhaltige zusammensetungen |
US5955451A (en) * | 1995-05-12 | 1999-09-21 | The University Of Texas System Board Of Regents | Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein |
US6231888B1 (en) * | 1996-01-18 | 2001-05-15 | Perio Products Ltd. | Local delivery of non steroidal anti inflammatory drugs (NSAIDS) to the colon as a treatment for colonic polyps |
US20040077604A1 (en) * | 2001-12-19 | 2004-04-22 | Lenard Lichtenberger | Method and compositions employing formulations of lecithin oils and nsaids for protecting the gastrointestinal tract and providingenhanced therapeutic activity |
-
2004
- 2004-08-02 KR KR1020067002187A patent/KR20060054405A/ko not_active Application Discontinuation
- 2004-08-02 US US10/909,751 patent/US7838511B2/en active Active
- 2004-08-02 CN CN2004800264983A patent/CN1852721B/zh not_active Expired - Fee Related
- 2004-08-02 EP EP20040779761 patent/EP1653975A4/en not_active Ceased
- 2004-08-02 AU AU2004260696A patent/AU2004260696C1/en not_active Ceased
- 2004-08-02 CN CN2013100537924A patent/CN103143031A/zh active Pending
- 2004-08-02 CA CA2534241A patent/CA2534241C/en not_active Expired - Lifetime
- 2004-08-02 WO PCT/US2004/024808 patent/WO2005011708A1/en active Application Filing
-
2006
- 2006-01-25 IL IL173352A patent/IL173352A0/en unknown
-
2007
- 2007-03-30 HK HK07103438.7A patent/HK1096298A1/xx not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6120797A (en) * | 1996-10-15 | 2000-09-19 | The Liposome Company, Inc. | N-acyl phosphatidylethanolamine-mediated liposomal drug delivery |
WO2002085414A2 (en) * | 2000-12-19 | 2002-10-31 | The Board Of Regents Of The University Of Texas System | Nsaid formulations comprising lecithin oils for protecting the gastrointestinal tract and providing enhanced therapeutic activity |
Also Published As
Publication number | Publication date |
---|---|
AU2004260696B2 (en) | 2007-11-08 |
IL173352A0 (en) | 2006-06-11 |
AU2004260696A1 (en) | 2005-02-10 |
US7838511B2 (en) | 2010-11-23 |
EP1653975A4 (en) | 2006-10-25 |
US20050064025A1 (en) | 2005-03-24 |
WO2005011708A1 (en) | 2005-02-10 |
CN1852721A (zh) | 2006-10-25 |
EP1653975A1 (en) | 2006-05-10 |
CN103143031A (zh) | 2013-06-12 |
KR20060054405A (ko) | 2006-05-22 |
HK1096298A1 (en) | 2007-06-01 |
AU2004260696C1 (en) | 2008-05-29 |
CA2534241A1 (en) | 2005-02-10 |
CA2534241C (en) | 2012-05-29 |
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