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CN1011571B - 可用于治疗肿瘤的一种药物的制备方法 - Google Patents

可用于治疗肿瘤的一种药物的制备方法

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CN1011571B
CN1011571B CN85103992A CN85103992A CN1011571B CN 1011571 B CN1011571 B CN 1011571B CN 85103992 A CN85103992 A CN 85103992A CN 85103992 A CN85103992 A CN 85103992A CN 1011571 B CN1011571 B CN 1011571B
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肯尼思·R·韦斯豪普特
威廉·R·波特
托马斯·J·多尔蒂
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Abstract

本发明涉及通过合成带有吡咯或类吡咯结构分子的化合物，制造一种光致荧光物质的方法和应用这种物质的特定光照设备，用该物质与设备配合，可用于诊断和治疗诸如恶性肿瘤的不正常组织。这些光敏性物质：(1)它们的叁级态能级必须高于3.5千卡/克分子；(2)不易被氧化，和(3)不会光物理猝灭所规定的能级。这种光敏物质最好是亲脂的。所用激光设备包括光传导器、传输探头和传光接合系统，以及与剂量有头的辐射光反馈光路。

Description

本发明涉及一种用于诊断和治疗诸如恶性肿瘤不正常组织的光敏物质的制造方法。
人们已经从下列的出版刊物中了解到血红蛋白衍生物这类光敏药物的制造方法：（1）“血卟啉的衍生物在肿瘤探查上的应用”（国家癌症研所杂志26期1-8页，1961年，利普森Lipson等著“光辐射方法治疗恶性肿瘤”（癌症研究Cancer.Rcs.38期：2628-2635页，1978年）（3）“光辐射治疗复发乳腺癌”（国家癌症研究所杂志，62期231-237面，1979年，多尔蒂Dougherty    et    al）
用于给含药组织光照的设备也已从“光辐射治疗恶性肿瘤”一文中为人所知。这篇文章揭示了包括用激光辐射含光敏物质的组织所用的几种光源。
用上述方法制造的物质虽然有用。它还不是我们所要求那样纯。它的应用导致了正常组织对光长期的敏感性。因此，本发明的任务是提供制造一种光敏物质的新方法以及对含这种光敏物质的组织光照的设备。
本发明的特征是（1）制成一种混合物。其中至少有一种化合物分子带吡咯或类吡咯结构;（2）从混合物的一些其余化合物中至少可以分离出一些量这类分子的化合物。
这类化合物最好由血卟啉制造，它们中间至少有一种有以下的分子式构成：
（a）DHE
Figure 85103992_IMG1
（b）或叶绿三酸
Figure 85103992_IMG2
或（c）根皮三酸
Figure 85103992_IMG3
在这个方法的一个实施例中，在分离出化合物是R1至少包含一个高于一价的原子。R1还可能含一个醚键或一个取代的乙醚基团或一个碳-碳键或取代的烷基。该化合物可以通过血卟啉脱水成醚制取。
分离该化合物或这类化合物的步骤包括按照它们聚集体的分子量进行分离的步骤。这是通过选择分子量大于10，000范围的聚集体，然后按照分子量这个范围加以分离。更准确地说，至少有一种化合物是通过把pH调至9.5，再把得到的不纯的溶液通过多孔的膜层，以排除低分子量影响纯度的副产品而分离出来的。
在一个实施例中，一种已知试剂是通过血卟啉和醋酸-硫酸反应混合物水解生成的，这种试剂通过微孔薄膜过滤除去低分子量化合物，精制成适用的药物。
这种药物至少含有50%的卟啉化合物，最好含90%以上，并且有下列近似的经验分子式：
C68H70N8O11或C68H66O11Na4
其它的衍生物可以由这个化合物制取。人们相信其它的化合物既可以由别的自然界存在的卟啉制 取，也可以由诸如单体吡咯通过二吡咯中间体聚合，由亚甲基吡咯、吡咯甲烷、吡咯酮、开链四吡咯中间体、胆色素、氧代胆色素和后胆色素作为材料人工合成卟啉得到的。它们也可能从像叶绿素、血红素等天然色素制造出来。这些适用的化合物在“卟啉和金属卟啉一书叙述的很详细。（福尔克J.E.Falk和凯文M.史密斯KcvinM.Smith著，1975年，埃尔塞维尔科学出版公司Elscvicr，阿姆斯特丹、纽约和牛津）。这些内容归纳如下：
根皮三酸（Phlorin）可以是（1）直接产生;（2）如果需要，可从其它化合物中分离出来，（3）与一种能进入瘤组织中的以下化合物材料相结合：
Figure 85103992_IMG4
根皮三酸也可以包藏在脂质体中。
另一方面，可以分离出叶绿三酸（chlorin），并使它与能进入瘤组织的材料相结合，叶绿三酸可与具下式的化合物结合：
Figure 85103992_IMG5
或可以包藏在脂质体或DHE中。
把光从作用光源传导到含光敏物质的组织其装置包括一个传光导体;一个可以使光从激光器进入上述传光导体的光结合系统。它的特征用传导头来加以说明：（1）这种传导头对液体是密封的;（2）它与传光导体相偶联;（3）它有一个控制辐射和传导光的控制部分;（4）包括一个称之为联收部件的接收光路;（5）用它来接收反射光，并作为反馈信号通过接收光路传导。
在一些实施例中，制造传导头的材料可以向外部透过辐射和回散辐射;传光导体在所述的传导头内有一个末端。传导头大体上是圆柱形的，其直径小于一英寸;传导头的壁厚度小于传导头直径的四分之一，所以与血液的接触面不会使血液受热而引起凝固。
传导头另一个实施例是做成环状的。杯状物周围有散射面，内部起反射作用。杯子的直径小于半英寸，传光导体进入杯中。管式柄杆至少围绕着传光导体的一部分，并与传光头以一定角度相联，以便于使用时眼睛贴近设备。
接收的光路一端有一个光传感器，以把辐射光转换为电信号，而且至少有一个激光器，传感器用检测来自激光器的光辐射。它对光电转换和涉及辐射剂量的信号放大是敏感的。
上面所述内容和本发明的其它特点从下面的详细描述，并参考附图，将更容易理解，其中：
图1是用一种甲醚形式存在的药物作的质谱图。
图2是该药物的水溶液的可见光谱。
图3和图3A一起，是分散在溴化钾中的药物的红外光谱。
图4是以二甲基亚砜作参比的该药物的碳13核磁共振谱图。
图5和5A一起，是用Water公司出品的可变波长检测器，匹配V形BondpakC-18柱子作出的，它表明了包括该药物的特征峰在内的HPD不同组分。
图6和图6A一起，是用Water公司出品的可变波长检测器，匹配V形BondpakC-18柱子做出的谱，它表明了药物DHE中的不同组分。
图7是在氘化和氯仿溶剂中四甲基硅烷作参比，测定的该药物碳13核磁共振谱。放大了的图谱范围在20-30ppm任55-75ppm。
每种药都可以分成两类（1）每个药物分子在水中凝聚成具有10.000以上结合分子量的聚集体;（2）药物的成份包藏在脂质体中，药物分子中至少包含一个那种光敏化学基团。
前一类的聚集体相当大，使它们具有能被淋巴系统排除，从而可以被大多数正常组织排除的特性，从而能经常进入并滞留在像肿瘤这样不正常的组织中，由于它们缺乏淋巴系统，实际上药物就不会从肿瘤中排除。本发明的药物在细胞内与血浆膜、细胞核膜、线粒体的溶酶体结合。虽然它也可能进入一些正常组织内，但正常组织和不正常组织在积累与排除药物速度上一般有很大差别，这就提供了选择条件，从而允许在不太多危害正常组织的情况下治疗不正常组织。
呈聚集体的药物形式必须是充分的亲脂的，并在脂类化合物中解离，从而聚集体在肿瘤中解体成具下列特点的形式：（1）在350-1200毫微米波长范围容易吸收光;（2）发生光致荧光效应。药物溶在水中形成的聚集体水悬浮液，但是它也是充分 亲脂的，在瘤组织中能解离。
过去治疗时应用的利普森试剂（Lipsons）那时不知其中有卟啉存在，实际上，它成份中至少有一个卟啉具有所需的特性，但在先前的技术中它是以卟啉混合物被利用的，这种混合物呈有害的副作用。人们还不知道该物质在利普森试剂中呈一种有效的成份，也不清楚它由于难以用液相色谱分离，它那时就已经存在在试剂中了。
当卟啉混合物含有重量高于56%的该药物，特别是卟啉含量达90%或以上时，它便是这种药物或具有类似性质的药物。这样的卟啉混合物副作用会降低。用这种纯化后的药物，在积累该药物的新生畸变组织曝光之前，卟啉使正常组织充分净化。
这种药物（DHE）如果以小于10，000分子量的聚集体形式存在，看来是无效的。这种低分子量的聚集体似乎是稳定的。这里，聚集体的分子量意味着是组成一个分子聚集体分子量总和。一个分子聚集体里由一种分子以除共价键以外的分子力相互联接所组成的。其余的药物像某些根皮三酸或叶绿三酸，可以用两种分子相互联结，或单种分子包藏在脂体中使用。任何药物都必须结合在瘤组织内部或在瘤组织内部释放出已结合的药物。更明确地说含有的该化合物其每个分子有两种分子组成，每种分子或者含有根皮三酸或者含吡咯环，或者是氢化的吡咯或者是取代的吡咯，它们以两个环的平面外露于别的药物分子的方式相连结。
用这种结构，分子间引力大于分子对水的引力，这样该药物的分子就能在水悬液中聚集。一种从利普森试剂纯化得到的二血卟啉醚（DHE）可以用分子式Ⅰ表示，而另一个这种化合物叶绿三酸可以用分子式2表示，式2叶绿三酸是由叶绿素合成的或制成式1化合物的衍生物。这类药物对脂类的亲合力大得足以导致聚集在脂类环境中解离。如果它们不干扰分子的光敏性质，那么也可以使用这类活性化合物的金属衍生物，例如镁的衍生物继续起作用但铜的衍生物就不行。
在一个实施例中，先制成血卟啉的衍生物。这里采用的是先有技术或同先有技术类似的新方法。得到的混合物含有适用的药物。当制成血卟啉衍生物时，这种适用的药物正常情况下处于其它不是我们要求的卟啉的混合物之中。
为了把有效药物同我们不需要的卟啉分开，将pH提高到6.5-12之间，最好是9.5，从而形成一种聚集体，然后再把它分离出来。分离方法可以通过过滤、沉淀、凝胶电泳，离心或任何合适的其它方式。在用过滤或其它基于聚集体大小的像离心等方法时，为得到最佳结果，pH要提高到9.5，在高pH下过滤可以迅速而彻底除去其它卟啉。过滤器应当能保留住分子量大于10，000的聚集体。
在过滤过程中必须调整pH，因为随着杂质的减少，pH也要降低。这里通过检测pH和加入诸如碱之类适当的调节剂来完成。为了在提纯期间节约时间和水，浓度提高到尽可能少的体积。在一个理想的体系中，这种做法受到溶解度限制以防止药物沉淀或不需要物质的聚集。
根据亲和性分离的方法，采用一种对DHE比对血卟啉衍生物中其它卟啉亲和力强的疏水填料，在其它卟啉除去后DHE给有选择性地分离出来分离用了一种在反相层析洗脱序比醇高的溶剂。更明确地说，是用装有5微米大小球状填料的反相色层柱。溶剂可用四氢呋喃。
当然从血卟啉衍生物得到的药物也可以用其它方法得到。最好实施例的药物是DHE，它是从血卟啉衍生物中分离出来。然而，DHE也可以用其它方法得到，而其它化合物又可以通过从吡定或取代吡咯结合等别的方法得到。例如：一种与DHE相似的药物能够以除氧键外其它形式键生成或者从别的血卟啉衍生物制取。这种药物不是醚。另外这类药物可以代之以从其它原料合成，这些仍具有我们需要性质的化合物可以从诸如叶绿素一类的其它化合物生成。
叶绿三酸的结构还不完全为人所知，它与DHE结合，表明在用它吸收光谱的光时有活体效应。用艾丽克博士（Dr.Eric    Mayhen）所述的方法制备的脂质体中包藏同样的叶绿三酸可得到较好的结果。（“脂质体技术手册”第二卷，CRC出版社，“Handbook    Of    Liposome.Technology’，Vol  Ⅱ.CRC    Pre，ed，G.Gregouodis，主编），该公开的技术参插在本文里，所用的分子比例是卵磷脂酰甘油∶卵磷脂∶胆固醇＝1∶4∶5。
为治疗起见，把光敏性药物注射入目的物所用药物包含有复杂的分子（1）它们在水悬浊液中聚集成分子量超过10，000的集团或被包藏在进入细 胞的其它材料上;（2）它们在瘤组织里解离并附着在里边。然后药物可以从正常组织中清除出来，当新生畸变组织暴露在功率0.005-0.75瓦/每平方厘米电磁辐射下，在350-1200毫微米光波范围没有热效应，光辐射可以摧毁积累了药物不正常组织中的血管组织和其它组织。
在用该药物给人类或哺乳动物治疗时，光照射在组织上特定位置使其辐射均一地照到癌组织。在辐射光把组织加热到超过39.5℃期间以及在这以前或以后另行加热都可以起协同增效作用，最好的温度范围是40.5℃-45℃。
当需要提高温度时可以采用以下方法：（1）传导光的方法;其中波长在近红外或红外区的传导光，如来自钕-钇铝石榴石激光器的1060毫微米波长的光，可用来加热组织，而630毫微米的传导光，则用来作用于光敏性药物。（2）采用诸如在2450兆赫（MH2）的微波加热的方法。（3）或采用任何其它合适的方法，在运用光敏药物的吸收光谱范围内的光进行辐射时，提高组织温度效果最好，但在辐射前或辐射后例如两小时内加热组织也会有温度协同增效作用。
此外在药物吸收光谱范围内的较高功率激光将使它与该药物的光致荧光效应相互影响组织发生热伤害，这就可以除掉大的肿瘤或汽化引起的阻塞以及由诸如凝血引起的血管堵塞。
最好的实例：药物DHE是水溶性，高分子量材料它是通过用醋酸和硫酸处理盐酸血卟啉，然后经过适当的水解，再基于其大小经过过滤分离得到该药物。这种药物不能通过诸如Milliporc    Pcllicon    10，000分子量的过滤器填料，说明其分子量超过了10，000是聚集了的DHE。
该新药的质谱分析见图1，特别是在质量数为149，219，591，609处出现很强的特征峰，而在12000，1218，1290，1809，处有小峰。这种新的桔红色药物的水溶液，其分光光度测定见图2。在大约505，537，565和615毫微米处有明显的吸收峰。分散在溴化钾中该新药的红外光谱示在图3，有一个与氢的张力有关的宽峰，峰中心在大约波长3微米位置，峰肩在大约3.4微米位置。在大约6.4、7.1、8.1、9.4、12和15微米处可以观察到一些小峰。
该新药的二钠盐衍生物的元素分析表明，它具有一个C34H35-36N4O5-6Na2的经验分子式，由于药物不能完成除掉水，因而氢原子和氧原子数目不能完全确定。该药在完全氘化了的二甲基亚砜中的碳-13核磁共振研究结果表示在图4，在大约9.0ppm处有一个-CH3的峰;18.9ppm处有一个-CH2的峰;24.7ppm处有一个CH3CHOH的峰;34.5ppm处有一个-CH2的峰;62ppm处有一个CH3CHOH的峰;在94.5ppm处有一个-C（甲川）的峰;130-145ppm有一个碳环的峰;171.7ppm处有一个C＝0的峰;参比物二甲基亚砜的共振在37.5ppm左右。另外在大约118ppm和127ppm处的乙烯峰可能表征有该新药，也可能是一种杂质。
没经过过滤的反应产物用Walcrs公司出品的U形Bandpak    C-18柱子淋洗，先用甲醇∶水∶醋酸＝20∶5∶1的混合液淋洗，然后再用四氢呋喃∶水＝4∶1的混合液洗，可以发现有四种成份，通过在薄层色谱上与标准样品比较可以鉴定出其中有血卟啉，羟乙基乙烯次卟啉和原卟啉三种副产物，它们的pH值分别大约为0.19，0.23和0.39（见图5）。薄层色谱用Brinkman    SIL二氧硅片为载体，苯∶甲醇∶水＝60∶40∶15的混合液作为淋洗剂。
第四种成份表示在图5，它是本发明的生物活性药物。图6的色层分析说明了在制药过程中采用配有10，000分子量过滤器填料的Milliporc    Pcllicon盒式系统，已排除了上面鉴定出的杂质。
在分子式中，作为本发明一种生物活性药DHE可能是由分子式1所示的用羟乙基乙烯基连结的两个血卟啉分子所形成的醚分子的聚集体。这种联结是在分子式Ⅰ中编号为3或8的位置上通过羟乙基乙烯基发生的。也可能是两个半醚在3位置相连，两个半醚分子在8位置相连或通过一个半醚分子的位置与另一个半醚分子的8位置相连。
这些结构可以命名为乙醚的衍生物，也就是：二-1-[3-（1-羟乙基）次卟啉-8-基]乙醚，这已在分子式1中表示。其它的结构异构体可以命名为：1-[3-（1-羟乙基）次卟啉-8-基]-1′-[8-（1-羟乙基）次卟啉-3-基]乙醚或1-[8-（1-羟乙基）次卟啉-3-基]-1′[3-（1-羟乙基）次卟啉-8-基]乙醚和二-1-[8-（1-羟乙基）次卟啉-3基]乙醚。
在3-或8-位置上的一个或两个羟乙基没用在 形成醚可能会脱水形成乙烯基，虽然没进行实验，但经验表明分子式Ⅰ所示的醚可被氢、烷基、羧酸基、含醇基以各种组合，在结构中不同位置所取代，此外还存在很多这些结构的可能的光学异构体。
以四甲基硅烷作参比，在氘化的氯仿溶液中该药的碳-1、3核磁共振研究结果表示在图7，谱图出现了两个在先前的图4中未有的吸收峰。图4中在24.7ppm和62ppm的峰也分别位移到25.9ppm和65.3ppm，图7的两个在27.9ppm和68.4ppm的新峰分别代表了图7中位置3联结的CH3和H-C-OH的共振，这两个新出现的共振证实了式Ⅰ揭示的分子式。
Figure 85103992_IMG6
虽然DHE是最好的实施药物，但还制备了别的光敏化合物和输送系统，从而能将药物进入新生畸变组织与细胞结合。还有其它化合物也是可用的，如式2的叶绿三酸化合物和式3的根皮三酸化合物都有希望对光做出响应。
用叶绿三酸试验表明，虽然不如DHE那样满意，在动物中还是显示响应叶绿三酸的确切结构还不知道，但它的光谱说明它是叶绿三酸。这种叶绿三酸没有输送特性，其原因是由于它仅包含一个叶绿三酸基而不是两个。它能输送进入肿瘤是由于将叶绿三酸包藏在脂质体中而进入细胞的，也可能通过与DHE混合来输送。这种叶绿三酸连结在细胞上，光照时显示出可观测到的响应。为使其能输送进入肿瘤，化合物必须用脂质体包藏，或者具有两个以共价键结合的基团，每个基团包含四个环，它们又组成一个成为这个基团的大环，这些环是叶绿三酸、根皮三酸卟啉或诸如此类中的吡咯。
为从血卟啉制备某种形式药物，使卟啉反形成以共价键结合的两个卟啉组成的化合物这个反应是脱水成醚DHE反应或者是一种可能形成碳-碳联结的缩合反应。或者是以其它可能的原子间结合反应。另外也可以引入第三种键合分子，诸如能与两个卟啉上的羟基反应的二囟烷基化合物。
DHE是通过以下两步制取（1）在降低pH情况下，血卟啉化合物的两个卟啉之一上的一个羟基与另一个卟啉反应，形成一个含两个吡咯环的醚;（2）通过这个反应从其它部分中分离出反应生成的DHE。
在另一种成醚方法中，从盐酸血卟啉可得到含大约20%血卟啉，50%二醋酸血卟啉和30%单醋酸血卟啉的混合物。然后水解这些反应通常可以用方程式4，5来表示。为清楚起见，可用方程式6和7表示，其中P是基本的卟啉基。其周围的基团如上面表明已被乙酰化，这个混合物是通过以下步骤得到（1）把285毫升的醋酸加入1000毫升的锥形烧瓶，里边放置一个外包一层聚四氟乙烯的磁搅棒;（2）搅拌醋酸;（3）缓缓地加入15毫升浓硫酸;（4）称出15.0克的盐酸血卟啉（最好用法国巴黎Roussel公司的产品;Paris    France）;（6）把这盐酸血卟啉加入到酸溶液中;（7）搅拌一小时。
进一步制备DHE通过下列步骤：（1）在4升的玻璃烧杯，用3升玻璃蒸馏器的蒸馏水加150克醋酸钠制成溶液;（2）一小时后，过滤醋酸混合液，最好用惠特曼1号滤纸（Whatman    NO.1），滤液滴入含5%醋酸钠的4升烧杯;（3）在5%的醋酸钠溶液中出现了暗红色的沉淀，最好在偶而搅拌情况下将其放置1个小时;（4）再过滤暗红色沉淀，最好仍用上面相同的过滤器装置;（5）滤饼再用玻璃蒸馏器的蒸馏水洗涤，直到滤 液pH达5.5-6.0（大约需1500-2500毫升水洗涤;（6）滤饼最好在室温下空气干燥。
为进一步纯化DHE，把空气干燥了的沉淀物用杵和臼捣碎成粉末，然后把粉末转入250毫升的圆底烧瓶，再把烧瓶同转动蒸发器相连接，室温条件在真空下转动24小时。
再把20克真空干燥后的粉末最好放置在4升带磁搅棒的抽吸瓶中，然后加入1000毫升0.1N的氢氧化钠，把这溶液搅拌1小时，再逐滴加入1.0N的盐酸直到pH为9.5。
为分离DHE，把内装溶液的抽吸瓶同Millilpore    Pellicon盒式系统用转换导管相连，这系统匹配分子量为10，000的过滤器填料（由Milliilpor    Corporation，Bedford，Mass，O1730.出售）。在过滤过程中溶液的pH要保持在9.5溶液温度最好是室温。通过切断进料的水并继续减压抽气的方法使其总体积缩小直到400毫升，使溶液浓度提高。
蠕动进料泵继续把用水进料的溶液打入Pellicon盒式系统，保持pH为9.5，压力为10-20磅/英寸2，最终保留体积为400毫升。压力可以根据通过系统的流速而变化。
过滤连续进行到保留的溶液只含高分子量的有生物活性的产物为止。这时候无用的单体一般不再存在，通过高分子量的生物活性产物的分析可以证实废料已通过过滤系统的微孔膜除掉。这种分析可采用Bio-Rad公司，（Richmond，Ca，）出品的Bio-Gel    P-10层析柱或者采用高效液相色谱;其中Micro    Bondpak    C-18柱匹配Waters    Associate，Milfod，Ma出品的固定可变波长检测器。
通过停止进水运转Pellicon盒式系统可以提高产品浓度。也可以通过加水降低产品浓度。最好的实例中，溶液中该新药的浓度大约为2.5毫克/毫升，将pH调节至7.4，使其等渗压以供装瓶。
光敏药物被注入治疗对象，允许光照之前药物先在体内呆大约三小时到两天。这个时间可以根据患者和疗法而异，但须充分允许药物清除出正常的组织。
[实验]
尽管这种新药物主要在动物身上进行过实验，但可以确信：通过相对于体重的同样或较少药量，在人的身上也可以获得等当的效果。已经就支气管内（endobronchiad）肿瘤患者进行过有限程度的实验如表Ⅱ、Ⅲ、Ⅳ和Ⅴ所示。结果支持了这一观点。用本发明的药物屡次治疗，只要不过于激烈，相信不会对正常组织造成积累性损害。这个观点同样得到表Ⅱ、Ⅲ、Ⅳ和Ⅴ所示结果的支持。另外近来采用DHE药物作患者实验，其剂量达到与以前技术的药物相同或更好的效果，这种新药物的有效剂量对肺癌患者健康组织产生的毒性很小。虽然上面提到的动物实验采用了大约4毫克/公斤体重剂量的新药物。但在人类肿瘤的治疗中，采用这种新药物时，低达1毫克/公斤体重的剂量仍可确认为是有效的。无论如何，在达到和杀死肿瘤方面，新药物同大约等于其二倍剂量的以往技术药物是同样有效的。
另外，虽然上面提到动物实验是在注射了新药一天之后进行照射，而人类实验是在二天至三天之后进行照射，但可以相信，在照射之前七天内注入这种药物仍可以达到杀死肿瘤的目的，为了取得病变组织中药物相对于正常组织中药物的最佳治疗率，一般认为在人类身上注射同照射之间的延迟时间推荐是3小时至三天。但是相信这段时间随组织类型的不同而不同。最佳治疗率可以凭借经验和荧光测量结果来决定这个数值。可以在尽少波及正常组织情况下，病变组织的破坏程度它是根据病变组织，和正常组织中的药物含量选定。
另外，虽然采用了160毫瓦/厘米2
（mw/cm2）的光强照射30分钟，以使药物活化，但可以确信，用高到1瓦/厘米2
（Watt/cm2）的光强照射20分钟或者用低至5毫瓦/厘米2
（mw/cm2）的光强延长时间照射，都可以达到杀死病变组织的目的。小于5毫瓦/厘米2（mw/cm2），的照射强度无论照射时间多长都可能没有治疗效果。超过400毫瓦/厘米2（mw/cm2），的光强在某些情况下可能会产生不希望有的热效应。对于插入的管式圆柱状光导纤维来说，采用功率为50至500毫瓦/厘米2（mw/cm2）的发射范围照射不产生热效应，如果希望产生热效应的话，可采用大于500毫瓦/厘米2（mw/cm2）的照射。
将SMT-F肿瘤植入DBA2Ha/D老鼠体内。当植入的肿瘤长到5-6毫米直径时，给老鼠 注射剂量为7.5毫克/公斤体重的以往技术未精制Lipson衍生物以作对比。
在注射后约24小时，将老鼠肿瘤区域的毛刮去。用弧光灯发出的（600-700毫瓦）的红光，对老鼠用160毫瓦/厘米2强度的光照射30分钟。在治疗之后七天，二十只老鼠中的十只没有出现明显的肿瘤。注入的药物在肿瘤细胞中停留的时间长于正常组织。
用本发明所公布的新型药物进行上述程序治疗，在获得同样结果的情况下，新药的使用剂量大约只有以往技术Lipsin药物的一半（4毫克/公斤体重）。
在另外的实验中，将治疗剂量的未精制利普森衍生物（7.5毫克/公斤体重）注入ICR瑞士（Acbino）鼠中。在注射后约二十四小时，用与前面所说的肿瘤反应研究相同的光条件，对这种老鼠的后脚进行照射。在一个任意取定的标准中，以0.0表示没有损害，以5.0表示完全杀死，则对该老鼠的损害评定为2.0。潮湿脱皮很明显，在大约40天后足部区域才慢慢转为正常。用剂量为4毫克/公斤体重的本发明药物进行这个程序的治疗。在治疗之后只观察到轻微的红疹和（或）水肿，其程度按前面所提到的损害标准小于1在48-72小时之后这些病状就消失了，并且没有残留反应。这使我们确信：采用这种
表Ⅰ
3H-HPD和3H-DHE
在组织内的含量（微克/克湿组织）
DBA/Ha鼠
SMT-F肿瘤
每种组织动物的最小数是10，
最大数17，肿瘤体积加倍大约是
3天
新型药物时，皮肤的光过敏性不再是一个重要问题了。
表1中总结了别的动物实验的结果将未纯化的HPD同纯化的DHE新药作比较，表明在老鼠体内的药物含量。
从前面的说明和附图，可以看到本发明提供了一种新颖的药物，这种新药物能用于肿瘤的诊断和治疗，与以往技术的类似药物相比，这种新药物的用量可以减小，并且没有多大副作用。本发明还提供了制作这种新型药物的新颖方法，以及在肿瘤治疗中利用这种药物的新颖方法。
前面所采用的术语和公式是供说明用途而不是为制约，在这些术语和公式的运用中，无意排除有所述特征的任何同等物，或其某部分。另外，在所要求的发明的范围之内，能够对这个推荐方案进行各种修正。
注射剂量    肝    肾    脾
（mg/kg）
10-HPd24小时    14.2±2    9.7±2.1    7.1±1.2
5-DHE24小时    19.1±33    8.3±2.3    8.1±2.9
10-Hpd72小时    13.8±6    7.3±3    6.1±1
5-DHE72小时    15±4    6±2.5    8.1±1.4
注射剂量    肺    肌肉    大脑
（mg/hg）
10-Hpd24小时    1.9±0.4    0.76±0.25    0.33±0.15
5-DHE24小时    2.7±1.4    0.68±0.26    0.19±0.1
10-Hpd72小时    2.3±0.9    1.2±0.7    0.7±0.4
5-DHE72小时    2.3±0.8    1.9±0.6    0.9±0.6
注射剂量    皮肤    肿瘤
（mg/hg）
10-Hpd24小时    3.5±1.2    3.6±1.1
5-DHE24小时    3.4±1.3    3.5±1.2
10-Hpd72小时    2.8±1.9    2.3±1.08
5-DHE22小时    1.9±0.6    1.6±0.5

Claims (8)

1、制备主要含分子量为10Kd的卟啉聚集体组合物的方法，该组合物为光敏荧光物质，在肿瘤细胞中比正常组织中能停留更长一些时间，该方法的特征在于将用醋酸和硫酸混合物处理盐酸血卟啉所得的产物在水溶介质中提高pH至6.5-12，得到10Kd或大于10Kd的聚集体，再将其与所得产物的其余部分分离出来。
2、根据权利要求1的方法，其中的pH为9.5。
3、根据权利要求1的方法，通过过滤完成分离步骤，所得聚集体分子量大于10Kd。
4、根据权利要求3的方法，过滤期间pH保持6.5-12。
5、根据权利要求4的方法，过滤期间pH保持9.5。
6、根据权利要求1的方法，用亲合层析法分离。
7、根据权利要求6的方法，亲合层析用的是5微米孔径的逆向柱，THF为溶剂。
8、根据权利要求1的方法，其中先将醋酸和硫酸第一混合物加入盐酸血卟啉，搅动1小时得到第2混合物，再加5%醋酸钠溶液，得到红色沉淀，再回收沉淀。
CN85103992A 1982-09-27 1985-05-24 可用于治疗肿瘤的一种药物的制备方法 Expired CN1011571B (zh)

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AU588806B2 (en) 1989-09-28
US4649151A (en) 1987-03-10
DK210185D0 (da) 1985-05-10
NO941548L (no) 1985-11-15
DE161606T1 (de) 1986-06-12
MX9203266A (es) 1992-07-01
CA1275452C (en) 1990-10-23
JPH06105921A (ja) 1994-04-19
CA1265450A (en) 1990-02-06
AU4246185A (en) 1985-11-21
DE3587296T2 (de) 1993-11-18
EP0161606A3 (en) 1990-01-10
JP2532368B2 (ja) 1996-09-11
US5145863A (en) 1992-09-08
JPH084631B2 (ja) 1996-01-24
US5225433A (en) 1993-07-06
US4932934A (en) 1990-06-12
US4889129A (en) 1989-12-26
JPS6113A (ja) 1986-01-06
US5015463A (en) 1991-05-14
EP0161606A2 (en) 1985-11-21
NO180742C (no) 1997-06-11
NO176786C (no) 1995-07-25
NO941548D0 (zh) 1994-04-27
NO851897L (no) 1985-11-15
EP0161606B1 (en) 1993-04-28
US4866168A (en) 1989-09-12
US5028621A (en) 1991-07-02
DE3587296D1 (de) 1993-06-03
CN85103992A (zh) 1986-11-19
DK175615B1 (da) 2004-12-27
NO180742B (no) 1997-03-03
NO176786B (no) 1995-02-20
DK210185A (da) 1985-11-15

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