CN1671393A - 靶向氧化性治疗制剂 - Google Patents
靶向氧化性治疗制剂 Download PDFInfo
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- CN1671393A CN1671393A CNA028087038A CN02808703A CN1671393A CN 1671393 A CN1671393 A CN 1671393A CN A028087038 A CNA028087038 A CN A028087038A CN 02808703 A CN02808703 A CN 02808703A CN 1671393 A CN1671393 A CN 1671393A
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- pharmaceutical preparation
- alkene
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- penetrating solvent
- oxygen
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Abstract
药物制剂、它的制备方法和它的用途。药物制剂含有烯烃、例如香叶醇被含氧氧化剂、例如臭氧氧化所得过氧化属或反应产物;渗透溶剂,例如二甲基亚砜;染剂,含有螯合金属,例如血卟啉;和芳族氧化还原化合物,例如苯醌。药物制剂用于治疗被肉孢子虫属原虫感染的马。
Description
背景和概述
本发明涉及含有过氧化属或氧化产物的组合物、它的制备方法和它的用途。更具体地,本发明涉及药物组合物或制剂,它含有:烯属化合物被含氧氧化剂氧化所得过氧化属或反应产物,为液体形式或溶液;渗透溶剂;含有螯合金属的染剂;和芳族氧化还原化合物。本发明还涉及该药物制剂的制备及其用途。
臭氧是一种三原子的气体分子,是氧的同素异形体。可以借助放电或强紫外光从纯氧获得之。Christian Friedrich Schonbein于1840年发现臭氧后,六十年内没有关注过它的医药应用。在第一次世界大战开始时,Albert Wolf第一次使用该气体进行治疗,用于感染伤口的局部愈合。不过,在二十世纪二十年代,抗生素药物(磺胺类和青霉素类)的发现以及有关在医药领域中内服臭氧气体的怀疑阻碍了其医药应用的发展。六十年间,臭氧的临床研究仅限于欧洲私人行医,零散的材料没有发表在行业杂志上。而且,人们关于臭氧是严重的污染物的误解、疾病的“自由基”理论和抗氧化剂添加剂市场都为它的使用带来偏见,这也是可以理解的。
臭氧疗法是一种误称。臭氧是一种极具反应性的和不稳定的气体,作用机理直接涉及副产物,它通过与存在于血浆和细胞膜中的有机化合物的选择性相互作用而生成。臭氧与不饱和烯烃的选择性反应发生在碳-碳双键上,生成臭氧化物。臭氧本身是毒性的,它的反应产物臭氧化物是不稳定的,本身也不是治疗性的。
于1818年发现的过氧化氢(H2O2)仅以痕量存在于自然界中。过氧化氢是不稳定的,在与有机膜和特定物质直接接触时剧烈分解(泡沫)。光、搅拌、加热和铁都加速过氧化氢在溶液中的分解速率。过氧化氢的来自体内直接接触杀死过氧化物破坏性酶、即过氧化氢酶水平低的微生物。例如,在将过氧化氢注入被过氧化物敏感性大肠杆菌感染的兔子血液中时,没有细菌效应。而且,增加含有大肠杆菌的兔或人血液中的过氧化物的来自体内浓度没有产生直接的细菌活动的迹象。高浓度过氧化氢的效应的缺乏直接涉及过氧化物破坏性酶、即过氧化氢酶的存在。为了具有任何效应,高浓度过氧化氢将不得不与细菌接触相当长的时间。正常存在于血液中的大量过氧化氢破坏性酶、例如过氧化氢酶使过氧化物不可能在血液中存在超过几秒钟。必须承认,通过注射或输注引入到血流中的过氧化氢不会在血液或细胞外液中直接充当细胞外杀菌剂。
不过,过氧化氢的确参与活化巨噬细胞内的杀菌过程。细胞内过氧化作用的关键治疗标准是过氧化载体分子的选择性释放、吸收和活化,仅进入患病的巨噬细胞,而这据信不能提升过氧化氢酶和谷胱甘肽还原酶的活性。所注入的过氧化氢是一种泛化的毒素,而靶向细胞内过氧化作用是一种选择性治疗工具。
De Villez的美国专利No.4,451,480教导了治疗痤疮的组合物和方法。该方法包括用臭氧化材料局部治疗病患区域,该材料源于臭氧化各种不挥发油和不饱和酯、醇、醚与脂肪酸。
De Villez的美国专利No.4,591,602提示了用于控制微生物感染的霍霍巴油的臭氧化物。
Herman的美国专利No.4,983,637公开了肠胃外治疗局部与全身病毒感染的方法,该方法在药学上可接受的载体中给以萜烯的臭氧化物。
Herman的美国专利No.5,086,076提示了含有载体和萜烯臭氧化物的抗病毒组合物。该组合物适合于全身给药或局部用药。
Herman的美国专利No.5,126,376描述了局部治疗哺乳动物病毒感染的方法,该方法在载体中使用萜烯的臭氧化物。
Herman的美国专利No.5,190,977教导了含有非水性载体和萜烯臭氧化物的抗病毒组合物,适合于全身注射。
Herman的美国专利No.5,190,979描述了肠胃外治疗哺乳动物病症的方法,该方法在载体中使用萜烯的臭氧化物。
Herman的美国专利No.5,260,342教导了肠胃外治疗哺乳动物病毒感染的方法,该方法在载体中使用萜烯的臭氧化物。
0Herman的美国专利No.5,270,344提示了治疗哺乳动物全身疾患的方法,该方法向哺乳动物肠道应用不饱和烃的三氧戊环或二过氧化物衍生物,该衍生物是通过臭氧化溶于非极性溶剂的不饱和烃而制备的。
Herman的美国专利No.5,364,879描述了治疗哺乳动物病症的组合物,该组合物含有非萜烯类不饱和烃的二过氧化物或三氧戊环衍生物,该衍生物是通过在35℃下、在载体中臭氧化不饱和烃而制备的。
尽管有关于萜烯臭氧化物用于不同适应症的报道,萜烯臭氧化物仍然显示多种缺陷。例如,单萜、如月桂烯和柠檬烯的臭氧化物在实验室中突然起火。所以,它们太危险,无法配制或贮存。
此外,一种直链单萜醇、香叶醇的臭氧化物在水或DMSO中对三例水痘-带状疱疹(带状疱疹)病毒和两例单纯疱疹性皮炎都不显示任何临床功效。
因而,需要安全有效的采用烯烃化合物氧化反应产物的药物制剂或组合物。
详细说明
本发明涉及组合物,包含不饱和有机化合物被含氧氧化剂氧化所得过氧化属或反应产物,为液体形式或溶液;渗透溶剂;螯合染剂;和芳族氧化还原化合物。在本发明的一种实施方式中,必要组分包括由不饱和醇的臭氧分解作用所生成的过氧化产物、稳定溶剂、金属卟啉和醌。
用于本发明的不饱和有机化合物或不饱和烯属烃可以是没有羟基的烯烃或含有羟基的烯烃。因而,没有羟基的烯烃可以是开链不饱和烃、单环不饱和烃或二环不饱和烃。含有羟基的烯烃可以是开链不饱和醇、单环不饱和醇或二环不饱和醇。
不饱和有机化合物可以是直链的、支链的、环状的、螺旋的或与其他分子配合的,具有一定的构型。在与“活化氧”键合之前,不饱和有机化合物可以以气态、液态或固态形式天然存在。
开链不饱和烃可以是:CnH2n,一条双键,n=2-20;CnH2n-2,两条双键,n=4-20;CnH2n-4,三条双键,n=6-20;CnH2n-6,四条双键,n=8-20;C25H40,二倍半萜烃;或C30H48,三萜烃。
单环不饱和烃可以是:CnH2n-2,一条双键+一个环,n=3-20;CnH2n-4,两条双键+一个环,n=5-20;CnH2n-6,三条双键+一个环,n=7-20;C25H40,二倍半萜烃;或C30H48,三萜烃。
二环不饱和烃可以是:CnH2n-4,一条双键+两个环,n=4-20;CnH2n-6,两条双键+两个环,n=6-20;C25H40,二倍半萜烃;或C30H48,三萜烃。
开链不饱和醇可以是:CnH2nOm,一条双键,n=3-20,m=1-4;CnH2n-2Om,两条双键,n=5-20,m=1-4;CnH2n-4Om,三条双键,n=7-20,m=1-4;CnH2n-6Om,四条双键,n=9-20,m=1-4;C25H40Om,m=1-4,二倍半萜醇;或C30H48Om,三萜醇。
单环不饱和醇可以是:CnH2n-2Om,一条双键+一个环,n=3-20,m=1-4;CnH2n-4Om,两条双键+一个环,n=5-20,m=1-4;CnH2n-6Om,三条双键+一个环,n=7-20,m=1-4;C25H40Om,m=1-4,二倍半萜醇;或C30H48Om,m=1-4,三萜醇。
二环不饱和醇可以是:CnH2n-4Om,一条双键+两个环,n=5-20,m=1-4;CnH2n-6Om,两条双键+两个环,n=7-20,m=1-4;C25H40Om,m=1-4,二倍半萜醇;或C30H48Om,m=1-4,三萜醇。
可用的不饱和烯烃可以是未取代的、取代的、环状的或配合的烯烃、肼、类异戊二烯、类固醇、喹啉、类胡萝卜素、生育酚、异戊烯基化蛋白质或不饱和脂肪。本发明所优选的不饱和烃是烯烃和类异戊二烯。本发明更优选的不饱和烃是直链类异戊二烯醇,在线性链中具有二至四个重复的异戊二烯基,例如香叶醇、香叶基香叶醇、橙花醇或芫荽醇。
类异戊二烯主要见于植物,是精油的成分。尽管很多类异戊二烯是烃类,不过也存在含氧的类异戊二烯,例如醇、醛和酮。在正式意义上,类异戊二烯的构件可以被想象为异戊二烯烃CH2=C(CH3)-CH=CH2,不过已知异戊二烯本身是类异戊二烯生物合成的终产物,不是中间体。类异戊二烯烃是根据它们所含有的异戊二烯(C5H8)单元数而分类的。因而分别地,单萜具有2个、倍半萜具有3个、二萜具有4个、二倍半萜具有5个、三萜具有6个、四萜具有8个异戊二烯单元。四萜更普遍地称为类胡萝卜素。
柠檬烯和蒎烯是单萜的实例。法尼醇和橙花叔醇是倍半萜醇的实例。维生素A1和植醇是二萜醇的实例,角鲨烯是三萜的实例。维生素原A1、即已知的胡萝卜素,是四萜的实例。香叶醇是一种单萜醇,在氧键合与正常状态下都是液体,对活细胞是安全的。
基于药物制剂的总重量,烯烃可以占约0.001%至约30%,优选约0.1%至约5.0%,更优选约0.5%至约3.0%。
与不饱和烃反应的含氧氧化剂可以是单线态氧、三线态氧、超氧化物阴离子、臭氧、高碘酸盐、羟基原子团、过氧化氢、烷基过氧化物、过氧化氨甲酰、过氧化苯甲酰、或与过渡元素、例如钼键合的氧(例如MoO5)。
本发明优选的含氧氧化剂包括臭氧、单线态氧和超氧化物阴离子。臭氧是与不饱和烃键合所最优选的含氧氧化剂。它是从纯氧制备的。
我们发现,使“活化氧”与完整香叶醇键合的最好方法是在0-20℃之间的温度下,在黑暗中,在没有水或极性溶剂的存在下进行臭氧化。然后在黑暗中、在100%二甲基亚砜(DMSO)中溶解和稳定化香叶醇“臭氧化物”,以防止产物的过早分解。尽管不希望受任何理论所限,不过据信在超氧化物阴离子的存在下,在细胞内部发生香叶醇臭氧化的四噁烷过氧化二聚物副产物的催化分解,它不是臭氧化物。所释放的最终反应性治疗剂是过氧化氢和乙酸。
尽管不希望受任何理论所限,不过据信一般而言,本申请中烯烃与臭氧之间的反应是通过Criegee机理进行的。按照这种机理,最初的反应步骤是臭氧向烯烃的1,3-偶极环加成,得到伯臭氧化物(1,2,3-三噁烷)。伯臭氧化物是不稳定的,与羰基化合物经历1,3-裂环,得到“正常的”臭氧化物,即1,2,4-三噁烷。
流程1
在副反应中,羰基氧化物能够参加二聚化,得到过氧化二聚物,即1,2,4,5-四噁烷。
流程2
羰基氧化物是强亲电剂,在亲核剂(例如醇或水)的存在下,它容易经历亲核加成,得到1-烷氧基过氧化氢。在某些条件下,1-烷氧基过氧化氢能够经历进一步的反应,得到羧酸衍生物。
流程3
仍然不希望受理论所限,据信在本发明中含醇烯烃的臭氧分解期间,合理的是预期将存在三种主要类型的过氧化产物:正常的臭氧化物、羰基四噁烷二聚物和1-烷氧基过氧化氢。在水的存在下,这些过氧化产物有些还可能导致在粗的产物混合物中存在有机过酸。
本发明涉及DMSO“稳定化”臭氧分解的最初产物的用途。类似地,不希望受任何理论所限,据信稳定化作用最有可能是简单的溶剂化现象。不过,已知二甲基亚砜本身是一种亲核试剂。它作为亲核配偶体参与稳定化反应属也是可能的(例如作为二甲基氧化锍盐)。
用于氧键合性不饱和烃的渗透溶剂可以是软化剂、液体、膜、胶束、等离子体或蒸汽。
可用的渗透溶剂是水、脂肪、固醇、卵磷脂、磷脂、pH缓冲盐水、乙醇、丙二醇、二甲基亚砜、甲磺酰基甲烷和聚乙烯吡咯烷。优选的渗透溶剂包括二甲基亚砜、聚乙烯吡咯烷和pH缓冲盐水。最优选的渗透溶剂包括二甲基亚砜。
基于药物制剂的总重量,渗透溶剂可以占约50%至约99%,优选约90%至约98%,更优选约95%至约98%。
“被稳定的”过氧化分子及其渗透溶剂已经从目前用于生产的组分制成,它们已获得食品与药品管理局(FDA)的许可。这些成分是DrugMaster Files,Drug Monographs的主体,见于USP/NF,或者是被公认为安全的(GRAS)。超氧化物生成性染剂和持恒剂也是生物学上可相容的,很可能适宜构成分子配合物。
药物制剂的其他组分可以包括金属卟啉和芳族醌。金属卟啉在光化学激发下使氧敏感的倾向有大量文献为证,这也是亚铁卟啉和铜卟啉键合含氧系统的倾向。
光动力学疗法的研究人员已经知道,超氧化物染剂和持恒剂选择性吸收被感染的和发育异常的细胞。这些病态细胞偶尔是过氧化氢酶缺陷的。染剂和持恒剂的电子活化仅需要毫伏AC脉冲。这种必需的脉冲适宜由心跳提供。而且,正常的细胞也不受伤害。
可用的染剂包括天然或合成的染剂。实例包括卟啉、玫瑰红、叶绿酸、氯化血红素、卟吩、咕啉、texaphrin、亚甲基蓝、苏木精、曙红、藻红、flavinoid、核黄素、蒽染剂、金丝桃素、甲基胆蒽、中性红和荧光素。
本发明所优选的染剂可以是任何天然或合成的卟啉、血卟啉、叶绿酸、玫瑰红、它们各自的同种物或其组合。最优选的染剂是天然存在的卟啉,例如血卟啉,和玫瑰红。
基于药物制剂或组合物的总重量,染剂可以占约0.1%至约30%,优选约0.5%至约5%,更优选约0.8%至约1.5%。
染剂可以敏感于光子;激光;电离辐射;声子;心电穿孔;磁或等离子脉冲;或连续的流动激发。
芳族氧化还原化合物包括任何取代的或未取代的苯醌、萘醌或蒽醌。优选的芳族氧化还原化合物包括苯醌、甲基苯醌、萘醌和甲基萘醌。最优选的芳族氧化还原化合物包括取代的或未取代的苯醌和萘醌。
基于药物制剂的总重量,芳族氧化还原化合物可以占约0.01%至约20.0%,优选约0.1%至约10%,更优选约0.1%至约0.5%。
可用于本发明的电子供体包括等离子体、电流、抗坏血酸盐和倍半氧化锗。优选的电子供体包括抗坏血酸盐和倍半氧化锗。最优选的电子供体是抗坏血酸的任意盐形式。
基于药物制剂的总重量,电子供体可以占约0.01%至约20%,优选约1%至约10%,更优选约1%至约5%。
为了获得体内生物学效果,有必要输注萜烯醇臭氧分解所得过氧化四噁烷产物,而不是臭氧化物,以及超氧化物生成性金属卟啉和芳族醌。尽管不希望受任何理论所限,不过假定优选的药物制剂是生化成分的组合,这些成分诱导被感染的或发育异常的巨噬细胞重新进行自动催化的氧化作用。重新进行自动催化的氧化作用通过畅通无阻的过氧化作用刺激所定向的编程性细胞死亡(细胞自杀)。
本发明的药物制剂用于消除患有马原虫性Myeloencephalitis(EPM)的马的肉孢子虫属原虫(Sarcocystis neurona)感染,EPM是一种代价巨大的、衰弱性的、最终致命的神经病学疾病。实施例二和实施例三详细描述了回顾性非随机化研究。该试验连续评价了344匹被诊断为EPM并据此治疗的马。
EPM是目前北美和南美最普遍的马神经病学病症。EPM通常是由脊与颅神经束被寄生虫Sarcocystis Neurona感染所导致的。EPM据报道产生大量中枢神经系统功能障碍的症状。S.Neurona把野负鼠(Didelphis virginiana)作为它的主要宿主。北美和南美的马似乎是EPM的非正常宿主,因为裂殖子不断在中枢神经系统中分化,不形成包囊。患有EPM的马最普遍地具有步态异常,但是它们还可能存在其他脑疾病征兆,包括视神经失明。疾病的严重性从轻微跛行到突然斜倒,临床征兆是进行性的。
血清学检查提示,美国大约有80%的马借助有寄生虫。发现与疾病风险明显有关的因素是马的品种和年龄。quarterhorse和更老的马比其他品种和年龄的马面临更高的感染风险。马神经病学疾病的误诊在EPM传染病的流行中是常见的。用210匹马测定临床诊断马神经病学疾病的准确性参数,其中确认了决定性的病理诊断。临床诊断全部疾病的总体效率为0.95,不过关于个别的疾病种类,有效性从0.79至1.00不等,敏感性从0.73至0.95不等,特异性从0.88至1.00不等。EPM被过度诊断,而东方马脑脊髓炎、马变性性脑脊髓病和创伤性神经病学疾病被诊断不足。在临床实践中提高诊断参数的准确度将允许新的诊断技术得以客观评价,导致诊断和治疗的效率更大。EPM被视为一种可治疗的疾病,不过对抑制性抗微生物治疗的响应尚不完全。
为了从导致肢体感觉丧失的其他疾病中鉴别诊断EPM,进行了广泛的神经病学检查。这种检查被证实准确度为97%,它检验脑脊液(CSF)中抗体的存在与否。
目前可利用的EPM治疗是源于抗疟疾疗法的,一般是基于使用乙胺嘧啶与磺酰胺的组合疗法的。临床经验提示,这些治疗必须持续至少三至十二个月,并且大多数马在目前可利用的治疗停止之后复发。因此,这种疾病迫切需要新的治愈性治疗。
实施例1
烯烃的臭氧分解既可以在溶剂中进行,也可以按净态进行。在两者情况下,反应混合物的冷却是关键的,以避免反应过氧化产物的暴发性分解。
下列一般工艺是液体烯烃臭氧分解的典型代表。
向配有磁搅拌器的1升烧瓶装入烯烃(2摩尔),将仪器称重。用冷却浴(冰水或冰盐)包围烧瓶。一旦内容物冷却至低于5℃,即开始搅拌,使含臭氧的干燥氧流(通常含3%臭氧)穿过混合物。有利的是分散臭氧化的氧在玻璃原料中,但是对搅拌的溶液而言这不是必要的。定期中止气流,将反应烧瓶称重或者对反应混合物取样。然后恢复气流。
一旦反应烧瓶的质量显示明显增重,或者一旦反应混合物的质子磁共振(H1NMR)光谱显示烯属质子共振强度减少了所需程度(通常约50%),即终止气流。
如上可以进行臭氧分解,代之以烯烃在溶剂中的溶液,溶剂对臭氧无反应性,例如饱和烃或氯代烃。
如上可以进行臭氧分解,有无溶剂均可,用烯醇代替烯烃,但决不影响反应。
然后将反应混合物缓慢倒入冷却的渗透溶剂中。
实施例2
如下制备本发明优选的药物制剂:
(1)向链二烯醇3,7-二甲基-2,6-辛二烯-1-醇(香叶醇)喷射120mg/L臭氧/纯氧气体混合物,每小时1升气体;
(2)保持反应温度在5℃左右;
(3)每小时取少量反应产物,用H1NMR测量过氧化属或反应产物的生成;
(4)当超过约50%的可用不饱和键已被反应时,终止反应;
(5)将产物混合物用二甲基亚砜稀释(1∶10),得到溶液或分散系;
(6)在用于靶生物系统之前,向溶液或分散系加入足量血卟啉、玫瑰红与甲基萘醌干粉混合物,以便在通过盐水静脉内输注方式释放至靶生物系统时,分散其中的每种组分的浓度为20毫摩尔。可选地,在使用前可以向制剂加入抗坏血酸盐。
实施例13
两种优选的制剂如下:
A.
重量% | 成分 |
0.54* | 来自香叶醇臭氧化的乙缩醛过氧化物的四噁烷二聚物 |
98.00 | DMSO |
0.83 | 血卟啉 |
0.24 | 甲基萘醌 |
0.39 | 玫瑰红 |
*用质谱测定
B.
重量% | 成分 |
0.54* | 来自香叶醇臭氧化的乙缩醛过氧化物的四噁烷二聚物 |
98.00 | DMSO |
0.83 | 血卟啉 |
0.24 | 甲基萘醌 |
0.39 | 叶绿酸钠-铜盐 |
*用质谱测定
实施例4
向脑脊液(CSF)单次注射0.5ml实施例3A所述未稀释的优选药物制剂或组合物,治疗33匹马。在注射之前取CSF样本,以确诊。通过神经病学检查,认为全部马都是EPM阳性的。CSF的实验室蛋白质印迹分析结果为28例抗体阳性(85%)、三例无特异性(9%)和两例阴性(6%)。
本组中前六匹所治疗的马有两匹死于错误的脊注射技术(允许头下垂),从研究中排除。改变技术后,治疗27匹马没有任何不良反应。其余31匹马中,26匹(85%)变为无症状,可以骑乘,恢复正常活动,超过1年没有复发。使3匹最终斜倒下的马(9%)安乐死,因为神经病状态的持续没有或几乎没有改善。2匹具有长期EPM病史的马(6%)表现显著的改善,能够骑乘,但是仍然有一些轻微的神经病学缺陷。
鉴于整组呈现疾病的进展、其他制度的失败和严重的神经病学症状,这些马的85%恢复率是相当显著的。相比之下,采用可利用的传统治疗预计部分恢复率为10-20%,马也将不可用于骑乘。
实施例5
在本组中治疗了311匹马,历时超过12个月。治疗是这样的,单次颈静脉注射6ml优选药物制剂(如实施例3A所述),稀释在50ml无菌盐水中,每天给药,连续三天。本组中没有不良反应,极少数马在治疗完成后昏睡2-3天。
本组中有296匹马(95%)在一个疗程后7-14天内变得无症状,在一个月内恢复至完整训练或以前的用途,水平相当或更大。本组有四匹马(1%)复发,表现轻微的EPM症状,但是在第二次三日治疗系列之后全都恢复至完整的用途。
7匹马(4%)的神经病学状态有改善,使它们可以骑乘和工作。根据骑手的说法,它们没有表现出与EPM发作之前相同的水平。
2匹马(<1%)呈现神经病学症状有所进展,包括颅神经缺损。这两匹马都在呈现症状之前两天斜倒,它们没有响应于优选的药物组合物。出于人道原因,使这两匹马安乐死。
本发明表现若干不同于常规治疗的优点。本发明制剂的静脉内输注在治疗EPM中是显著有效的。
给药溶剂以及疗程持续时间短,为客户提供比任何其他疗法都更实用和经济的选择。传统的治疗系列采用乙胺嘧啶与磺酰胺或地克珠利,每疗程可能持续超过十二个月。与这些长期治疗系列有关的另一个缺点是高复发率。
事实上,所报道的恢复时间在本研究中是显著的和空前的,仅为七天至三周。而且,静脉内释放途径表明本发明的药物制剂跨越血脑屏障,目的是对付感染。
本发明的制剂没有导致严重的并发症、死亡、子代动物遗传缺陷或妊娠困难(8匹母马)。这种引示研究中的大量病例以及杰出结果提示,本发明的药物组合物远远优于任何目前可利用的EPM治疗。
本发明可以体现为其他具体方式,而不背离其精神或本质特征。这些实施方式因此在各方面都被视为说明性的而非限制性的,本发明的范围是由附后的权利要求书所指示的,而不是上面的说明,所有在权利要求书的等价含义与范围内的变化因此都被涵盖其中。
实施例6
在5℃下,向100ml 100%香叶烯液体喷射120mcg/ml臭氧,速率为1/8L/min,使蒸汽进入大气中。由化学人员静电抵消蒸汽中的暴燃的火焰。
通过相同的方法产生臭氧化的柠檬烯,小心避免生成火花。在室温下将臭氧化物产物贮存在箱子内密封的褐色瓶子中过夜。第二天早上,化学人员和药学人员见到溅在箱子内部的微细玻璃粉末和糖浆状化学品。
实施例7
在5℃下,向1L纯净香叶醇通入臭氧(120mg/ml)达48小时。将反应产物用DMSO稀释(1∶9),得到产物混合物。
每天向患有带状疱疹(水痘)的患者静脉内给以3%混合物,连续3天。关于患者的带状疱疹(水痘)没有可观察到的效果或改善。
Claims (71)
1、药物制剂,包含:
烯烃被含氧氧化剂氧化所得过氧化属或反应产物,其中该烯烃具有少于约35个碳;
渗透溶剂;
染剂,含有螯合的二价或三价金属;和
芳族氧化还原化合物。
2、权利要求1的药物制剂,其中该烯烃包含开链不饱和烃、单环不饱和烃或二环不饱和烃。
3、权利要求1的药物制剂,其中该烯烃包含开链不饱和醇、单环不饱和醇或二环不饱和醇。
4、权利要求1的药物制剂,其中该烯烃是含有羟基的烯烃。
5、权利要求1的药物制剂,其中该烯烃是液体形式、溶液或分散系。
6、权利要求1的药物制剂,其中该烯烃包含类异戊二烯。
7、权利要求6的药物制剂,其中该类异戊二烯包含-萜品醇、香茅醇、橙花醇、植醇、薄荷醇、香叶醇、香叶基香叶醇、芫荽醇或法尼醇。
8、权利要求6的药物制剂,其中该类异戊二烯包含香叶烯、citrillene、柠檬醛、蒎烯或柠檬烯。
9、权利要求1的药物制剂,其中该烯烃包含含有不挥发油、酯、脂肪酸或醚的烯烃。
10、权利要求1的药物制剂,其中该含氧氧化剂包含单线态氧、三线态的氧、超氧化物阴离子、高碘酸盐、羟基原子团、过氧化物或与过渡元素键合的氧。
11、权利要求1的药物制剂,其中该含氧氧化剂包含臭氧。
12、权利要求1的药物制剂,其中该渗透溶剂是液体、胶束膜、软化剂、等离子体或蒸汽。
13、权利要求1的药物制剂,其中该渗透溶剂是二甲基亚砜。
14、权利要求1的药物制剂,其中该渗透溶剂是聚乙烯吡咯烷或pH缓冲盐水。
15、权利要求1的药物制剂,其中该渗透溶剂是水溶液、脂肪、固醇、卵磷脂、磷脂、乙醇、丙二醇或甲磺酰基甲烷。
16、权利要求1的药物制剂,其中该染剂可以被一种能量活化。
17、权利要求1的药物制剂,其中该染剂包含卟啉或玫瑰红。
18、权利要求1的药物制剂,其中该染剂包含叶绿酸、氯化血红素、咕啉、texaphrin、亚甲基蓝、苏木精、曙红、藻红、核黄素、蒽染剂、金丝桃素、甲基胆蒽、中性红或荧光素。
19、权利要求16的药物制剂,其中该能量包含光子或电穿孔脉冲。
20、权利要求13的药物制剂,其中该能量包含激光、电离辐射、声子、电脉冲、磁场、等离子体脉冲、重力脉冲或连续流动激发。
21、权利要求1的药物制剂,其中该金属包含铁。
22、权利要求1的药物制剂,其中该金属包含铜、锰、锡、镁或锶。
23、权利要求1的药物制剂,其中该芳族氧化还原化合物包含苯醌或萘醌。
24、权利要求1的药物制剂,进一步包含电子供体。
25、权利要求24的药物制剂,其中该电子供体包含抗坏血酸或其药学盐。
26、权利要求24的药物制剂,其中该电子供体包含等离子体、电流或倍半氧化锗。
27、药物制剂,包含:
含羟基烯烃被臭氧与氧的混合物氧化所得过氧化属或反应产物,其中该含羟基烯烃具有少于约35个碳;
渗透溶剂;
染剂,含有螯合的二价或三价金属;和
芳族氧化还原化合物。
28、权利要求27的药物制剂,其中该含羟基烯烃包含开链不饱和醇、单环不饱和醇或二环不饱和醇。
29、权利要求27的药物制剂,其中该含羟基烯烃是液体形式、溶液或分散系。
30、权利要求27的药物制剂,其中该含羟基烯烃包含-萜品醇、香茅醇、橙花醇、芫荽醇、植醇、香叶醇、紫苏子醇、薄荷醇、香叶基香叶醇或法尼醇。
31、权利要求27的药物制剂,其中该渗透溶剂是液体、胶束膜、软化剂、等离子体或蒸汽。
32、权利要求27的药物制剂,其中该渗透溶剂是二甲基亚砜。
33、权利要求27的药物制剂,其中该渗透溶剂是聚乙烯吡咯烷或pH缓冲盐水。
34、权利要求27的药物制剂,其中该渗透溶剂是水溶液、脂肪、固醇、卵磷脂、磷脂、乙醇、丙二醇或甲磺酰基甲烷。
35、权利要求27的药物制剂,其中该染剂包含卟啉或玫瑰红。
36、权利要求27的药物制剂,其中该染剂包含叶绿酸、氯化血红素、咕啉、texaphrin、亚甲基蓝、苏木精、曙红、藻红、核黄素、蒽染剂、金丝桃素、甲基胆蒽、中性红或荧光素。
37、权利要求27的药物制剂,其中该金属包含铁。
38、权利要求27的药物制剂,其中该金属包含铜、锰、锡、镁或锶。
39、权利要求27的药物制剂,其中该芳族氧化还原化合物包含苯醌或萘醌。
40、权利要求27的药物制剂,进一步包含电子供体。
41、权利要求40的药物制剂,其中该电子供体包含抗坏血酸或其药学盐。
42、权利要求40的药物制剂,其中该电子供体包含等离子体、电流或倍半氧化锗。
43、药物制剂,包含:
含羟基烯烃被臭氧与氧的混合物氧化所得过氧化属或反应产物,其中该含羟基烯烃包含-萜品醇、香茅醇、橙花醇、芫荽醇、植醇、香叶醇、紫苏子醇、薄荷醇、香叶基香叶醇、或法尼醇;
渗透溶剂,其中该渗透溶剂包含二甲基亚砜、固醇、卵磷脂、丙二醇或甲磺酰基甲烷;
染剂,含有螯合的二价或三价金属,其中该染剂包含卟啉、玫瑰红、叶绿酸、氯化血红素、咕啉、texaphrin、亚甲基蓝、苏木精、曙红、藻红、核黄素、蒽染剂、金丝桃素、甲基胆蒽、中性红或荧光素;
芳族氧化还原化合物,其中该氧化还原化合物包含苯醌或萘醌。
44、权利要求43的药物制剂,其中该金属包含铁、铜、锰、锡或镁。
45、权利要求43的药物制剂,进一步包含电子供体。
46、权利要求45的药物制剂,其中该电子供体包含抗坏血酸或其药学盐。
47、权利要求45的药物制剂,其中该电子供体包含等离子体、电流或倍半氧化锗。
48、制备药物制剂的方法,包含:
使少于约35个碳的烯烃的液体形式或溶液或分散系与臭氧与氧的气体混合物在低于约30℃的温度下接触,得到过氧化属或反应产物;
将过氧化属或反应产物用渗透溶剂稀释,得到所得混合物;
向所得混合物加入含有螯合二价或三价金属的染剂,得到含有染剂的混合物;和
向含有染剂的混合物加入芳族氧化还原化合物。
49、治疗被原虫感染的动物的方法,包含:
向被原虫感染的动物给以有效量的药物制剂,该制剂包含:
烯烃被含氧氧化剂氧化所得过氧化属或反应产物,其中该烯烃具有少于约35个碳;
渗透溶剂;
染剂,含有螯合的二价或三价金属;和
芳族氧化还原化合物。
50、权利要求49的方法,其中该烯烃包含开链不饱和烃、单环不饱和烃或二环不饱和烃。
51、权利要求49的方法,其中该烯烃包含开链不饱和醇、单环不饱和醇或二环不饱和醇。
52、权利要求49的方法,其中该烯烃是含有羟基的烯烃。
53、权利要求49的方法,其中该烯烃是液体形式、溶液或分散系。
54、权利要求49的方法,其中该烯烃包含类异戊二烯。
55、权利要求54的药物制剂,其中该类异戊二烯包含-萜品醇、香茅醇、橙花醇、植醇、紫苏子醇、薄荷醇或法尼醇。
56、权利要求54的药物制剂,其中该类异戊二烯包含香叶醇、香叶基香叶醇、香叶烯、citrillene、柠檬醛、蒎烯、柠檬烯或芫荽醇。
57、权利要求49的方法,其中该烯烃包含含有不挥发油、酯、脂肪酸或醚的烯烃。
58、权利要求49的方法,其中该含氧氧化剂包含单线态氧、三线态的氧、超氧化物阴离子、高碘酸盐、羟基原子团、过氧化物或与过渡元素键合的氧。
59、权利要求49的方法,其中该含氧氧化剂包含臭氧。
60、权利要求49的方法,其中该渗透溶剂是液体、胶束膜、软化剂、等离子体或蒸汽。
61、权利要求49的方法,其中该渗透溶剂是二甲基亚砜。
62、权利要求49的方法,其中该渗透溶剂是聚乙烯吡咯烷或pH缓冲盐水。
63、权利要求49的方法,其中该渗透溶剂是水溶液、脂肪、固醇、卵磷脂、磷脂、乙醇、丙二醇或甲磺酰基甲烷。
64、权利要求49的方法,其中该染剂包含卟啉或玫瑰红。
65、权利要求49的方法,其中该染剂包含叶绿酸、氯化血红素、咕啉、texaphrin、亚甲基蓝、苏木精、曙红、藻红、核黄素、蒽染剂、金丝桃素、甲基胆蒽、中性红或荧光素。
66、权利要求49的方法,其中该金属包含铁。
67、权利要求49的方法,其中该金属包含铜、锰、锡、镁或锶。
68、权利要求49的方法,其中该芳族氧化还原化合物包含苯醌或萘醌。
69、权利要求49的方法,进一步包含电子供体。
70、权利要求69的方法,其中该电子供体包含抗坏血酸或其药学盐。
71、权利要求69的方法,其中该电子供体包含等离子体、电流或倍半氧化锗。
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US09/823,252 US6884797B2 (en) | 2001-03-30 | 2001-03-30 | Targeted oxidative therapeutic formulation |
US09/823,252 | 2001-03-30 |
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CN1671393A true CN1671393A (zh) | 2005-09-21 |
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CNA028087038A Pending CN1671393A (zh) | 2001-03-30 | 2002-03-22 | 靶向氧化性治疗制剂 |
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US (3) | US6884797B2 (zh) |
EP (1) | EP1385525B1 (zh) |
CN (1) | CN1671393A (zh) |
AT (1) | ATE431151T1 (zh) |
AU (1) | AU2002338281A1 (zh) |
DE (1) | DE60232325D1 (zh) |
WO (1) | WO2002078622A2 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107998145A (zh) * | 2016-10-30 | 2018-05-08 | 西北农林科技大学 | 臭氧化含烯烃双键化合物 |
CN107998144A (zh) * | 2016-10-30 | 2018-05-08 | 西北农林科技大学 | 臭氧化维生素 |
CN108014123A (zh) * | 2016-10-29 | 2018-05-11 | 西北农林科技大学 | 臭氧化中草药、中药制剂提取物 |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6884797B2 (en) * | 2001-03-30 | 2005-04-26 | Robert F. Hofmann | Targeted oxidative therapeutic formulation |
US6790463B2 (en) * | 2001-03-30 | 2004-09-14 | Robert F. Hofmann | Uses of targeted oxidative therapeutic formulation in arteriosclerosis |
CN1946385A (zh) * | 2004-02-20 | 2007-04-11 | 罗伯特·F·霍夫曼 | 靶向氧化治疗制剂在治疗病毒性疾病中的用途 |
US7414044B2 (en) * | 2004-05-06 | 2008-08-19 | Hofmann Robert F | Use of targeted oxidative therapeutic formulation in treatment of type 2 diabetes |
WO2005110388A1 (en) * | 2004-05-10 | 2005-11-24 | Hofmann Robert F | Use of targeted oxidative therapeutic formulation in treatment of cancer |
CN101027086A (zh) * | 2004-05-10 | 2007-08-29 | 罗伯特·F·霍夫曼 | 靶向氧化治疗剂在骨再生中的应用 |
US20050250756A1 (en) * | 2004-05-10 | 2005-11-10 | Hofmann Robert F | Use of targeted oxidative therapeutic formulation in treatment of age-related macular degeneration |
US8480797B2 (en) | 2005-09-12 | 2013-07-09 | Abela Pharmaceuticals, Inc. | Activated carbon systems for facilitating use of dimethyl sulfoxide (DMSO) by removal of same, related compounds, or associated odors |
JP5399072B2 (ja) | 2005-09-12 | 2014-01-29 | アベラ ファーマスーティカルズ インコーポレイテッド | ジメチルスルホキシド(dmso)若しくは関連化合物、又はそれに関連する臭気を除去するシステム |
EP1937286B1 (en) | 2005-09-12 | 2016-03-09 | Abela Pharmaceuticals, Inc. | Compositions comprising dimethyl sulfoxide (dmso) |
US8435224B2 (en) | 2005-09-12 | 2013-05-07 | Abela Pharmaceuticals, Inc. | Materials for facilitating administration of dimethyl sulfoxide (DMSO) and related compounds |
US20090312279A1 (en) * | 2005-12-23 | 2009-12-17 | Sterilex Technologies, Llc | Antimicrobial compositions |
US20070258996A1 (en) * | 2005-12-23 | 2007-11-08 | The Sterilex Corporation | Antimicrobial compositions |
US20080194518A1 (en) * | 2005-12-23 | 2008-08-14 | MOOKERJEE Pradip | Antimicrobial Compositions |
US8859760B2 (en) | 2008-07-29 | 2014-10-14 | Frontier Scientific, Inc. | Compositions for killing or preventing the growth of microbes |
US8633311B2 (en) | 2008-07-29 | 2014-01-21 | Frontier Scientific, Inc. | Topical application of porphyrins for killing or preventing the growth of bacteria or fungi on a mammal |
BRPI0921494A2 (pt) | 2008-11-03 | 2018-10-30 | Prad Reasearch And Development Ltd | método de planejamento de uma operação de amostragem para uma formação subterrãnea, método de contolar uma operação de amostragem de formação subterrânea, método de controlar uma operação de perfuração para uma formação subterrãnea, e método de realizar uma amostragem durante a operação de perfuração. |
KR20120093993A (ko) | 2009-10-30 | 2012-08-23 | 아벨라 파마슈티칼스, 인코포레이티드 | 퇴행성 관절염 치료를 위한 디메틸설폭사이드 및 메틸설포닐메탄 제제 |
US20160271096A1 (en) * | 2013-10-25 | 2016-09-22 | Ogenx Therapeutics Corporation | Therapeutic oxidative formulations and methods of use thereof |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1235306B (de) * | 1965-11-13 | 1967-03-02 | Gerberding & Co G M B H | Verfahren zur Herstellung von Terpinen-1-ol-(4) |
GB1553424A (en) * | 1976-02-10 | 1979-09-26 | Wellcome Found | Method of treating protozal diseases |
JPS53108934A (en) * | 1977-03-07 | 1978-09-22 | Eisai Co Ltd | 2-methyl-3-prenul-4,5,6-trimethoxy-phenol and its preparation |
US4229478A (en) * | 1978-06-05 | 1980-10-21 | Syntex (U.S.A.) Inc. | Naphthaquinone anti-psoriatic agents |
US4846789A (en) * | 1982-07-19 | 1989-07-11 | L. S. Van Landingham, Jr. | Combatting internal parasites in warm blooded animals |
US4820711A (en) * | 1987-05-15 | 1989-04-11 | Pearlman Dale L | Method for treating actinic keratosis with cytotoxic agents |
US4837399A (en) * | 1988-05-10 | 1989-06-06 | The United States Of America As Represented By The Secretary Of Agriculture | Napthoquinone antibiotics from fuserium solani |
US5260342A (en) * | 1988-06-24 | 1993-11-09 | Stephen Herman | Method for treating viral infection parenterally |
US4983637A (en) * | 1988-06-24 | 1991-01-08 | Stephen Herman | Method for treating viral infection of HIV |
US5270344A (en) * | 1988-06-24 | 1993-12-14 | Stephen Herman | Method of treating a systemic disorder using trioxolane and diperoxide compounds |
US5728898A (en) * | 1996-06-27 | 1998-03-17 | Bio-Technical Resources, L.P. | Process for making water-soluble derivatives of quinones |
BR9808114A (pt) * | 1997-03-31 | 2000-03-08 | David Granstrom | Formulação de ração para cavalos utilizável para tratar epm, processos para tratar pm em um cavalo que necessita deste tratamento, para prevenir infecção com s. neutrona em cavalos, e, para exterminar s. neurona em cavalos |
GB9710049D0 (en) * | 1997-05-19 | 1997-07-09 | Nycomed Imaging As | Method |
US6692694B1 (en) * | 1998-11-09 | 2004-02-17 | Clean Earth Technologies, Llc | Method and apparatus for photosensitized ultraviolet decontamination of surfaces and aerosol clouds |
US6790463B2 (en) * | 2001-03-30 | 2004-09-14 | Robert F. Hofmann | Uses of targeted oxidative therapeutic formulation in arteriosclerosis |
US6884797B2 (en) * | 2001-03-30 | 2005-04-26 | Robert F. Hofmann | Targeted oxidative therapeutic formulation |
-
2001
- 2001-03-30 US US09/823,252 patent/US6884797B2/en not_active Expired - Fee Related
-
2002
- 2002-03-22 AT AT02757804T patent/ATE431151T1/de not_active IP Right Cessation
- 2002-03-22 EP EP02757804A patent/EP1385525B1/en not_active Expired - Lifetime
- 2002-03-22 DE DE60232325T patent/DE60232325D1/de not_active Expired - Fee Related
- 2002-03-22 AU AU2002338281A patent/AU2002338281A1/en not_active Abandoned
- 2002-03-22 WO PCT/US2002/009088 patent/WO2002078622A2/en not_active Application Discontinuation
- 2002-03-22 CN CNA028087038A patent/CN1671393A/zh active Pending
-
2005
- 2005-03-07 US US11/074,192 patent/US7521440B2/en not_active Expired - Fee Related
- 2005-03-07 US US11/074,191 patent/US20050148568A1/en not_active Abandoned
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108014123A (zh) * | 2016-10-29 | 2018-05-11 | 西北农林科技大学 | 臭氧化中草药、中药制剂提取物 |
CN107998145A (zh) * | 2016-10-30 | 2018-05-08 | 西北农林科技大学 | 臭氧化含烯烃双键化合物 |
CN107998144A (zh) * | 2016-10-30 | 2018-05-08 | 西北农林科技大学 | 臭氧化维生素 |
Also Published As
Publication number | Publication date |
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US20050148569A1 (en) | 2005-07-07 |
EP1385525A4 (en) | 2006-06-14 |
US7521440B2 (en) | 2009-04-21 |
EP1385525B1 (en) | 2009-05-13 |
ATE431151T1 (de) | 2009-05-15 |
DE60232325D1 (de) | 2009-06-25 |
AU2002338281A1 (en) | 2002-10-15 |
US20050148568A1 (en) | 2005-07-07 |
US20030032677A1 (en) | 2003-02-13 |
WO2002078622A3 (en) | 2003-03-13 |
US6884797B2 (en) | 2005-04-26 |
WO2002078622A2 (en) | 2002-10-10 |
EP1385525A2 (en) | 2004-02-04 |
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