CN1250669A - 离子复合体形式的水溶性药物组合物及其应用 - Google Patents
离子复合体形式的水溶性药物组合物及其应用 Download PDFInfo
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Abstract
一种水溶性组合物,它含有一种选自刺猬蛋白质,骨形态发生蛋白质,生长因子,红细胞生成素,血小板生成素,粒细胞集落刺激因子,白细胞介素和干扰素的离子药学效应多肽的复合体,其特征在于,所说的组合物还含有一种亲水亲油性化合物,所说的多肽和所说的亲水亲油性化合物形成一种离子复合体,其中该复合体的形成不提高所说的多肽的溶解性。
Description
本发明涉及一种多肽的组合物,它通过与细胞膜上的胞外受体相互作用而具有生物学效应,所说的多肽是与一种亲水亲油化合物形成的离子复合体的形式存在于所说的组合物中。本发明还涉及所说的组合物的应用。
亲水亲油性化合物作为药物传送系统的应用是现有技术中已知的(美国专利US-P5650393,US-P5688761,US-P5665328,US-P5124081,US-P5109038)。在表面活性物质和药物制剂之间的胶粒形式的复合物的形成也是已知的,例如用于改善活性制剂跨皮肤和跨膜的渗透(Tomlinson和Davis,J.Colloid.Interf.,Sci.74(1980)349)。药物制剂的非离子化的形式与其离子化的形式相比通常具有较好的通过生物膜的传送也是已知的(Cools和Jansen,J.Pharm.Pharmacol.35(1983)689-691)。也已知在生理pH值时以多重离子化的形式存在的肽对传送到作用位点(药物传送)不是最适的,这是因为带电分子,特别是多肽类,在脂肪中具有较低的溶解性(Hirai等,Int.J.Pharm.7(1991)317-325)。从Okada等,J.Pharm.Sci.72(1993)75-78可知,将亲脂性反粒子结合在药物制剂的离子部分可该善与生物膜的相互作用,从而便于蛋白质穿过小肠膜的传送。例如,Hazzenga和Berner在J.Controlled Release 16(1991)77-88中描述了一种用于两性离子活性制剂跨皮肤运输的改良的方法。
其它的用于改善药物制剂与生物膜相互作用的方法描述于例如,Lee等,Critical Rev.Therp.Drug Carrier Systems 8(1991)91-192,Morimoto等,Arch.Int.Pharmacodyn.302(1989)18-26和Aungst,Int.J.Pharm.33(1986)225-234。但在所有的这些方法中,其目的是提高活性制剂的疏水性,从而促进其通过生物膜例如皮肤,以及将所说制剂向细胞中的传送。为此使用了表面活性物质,其浓度高于临界胶粒浓度(CMC,Womack等,Biochim.Biophys.Acta 733(1983)210)。这些方法的一个缺点是所使用的高浓度的表面活性物质对细胞膜具有很大的影响,可能将其破坏。
从WO94/08599可知,通过加入适量的阴离子去垢剂形成沉淀,分离出沉淀并将其再溶解于有机溶剂中,可制备出活性制剂的均一溶液用于生产载体结合的活性制剂。然后就可以用这一含有阴离子去垢剂和活性制剂之间形成的复合体的均一溶液在一种固体基质中包埋或分散该活性制剂。此外,WO94/08599提到可形成蛋白质和阴离子去垢剂的复合体,可从中释放出活性制剂以控制蛋白质的释放。
已知蛋白质的活性可通过将其与疏水性化合物例如脂肪酸或胆固醇共价结合而得到改善。但是,这一方法非常复杂,并且由于偶联的化学反应而产生不均一的产物(例如,Ekrami,H.M.等,FEBS Letters371(1995)283-286,Peinski,R.B.等,J.Biol.Chem.273(1998)14037-14045)。
本发明的目的是提供具有药学效果的多肽的组合物,它可改善其中含有的多肽的活性。
本发明的目的由一种组合物达到,该组合物最好为一种药物组合物,它含有一种选自下组的具有药学效果的多肽:刺猬蛋白质(hedgehogprotein),骨形态发生蛋白质,生长因子,红细胞生成素,血小板生成素,粒细胞集落刺激因子(G-CSF),白细胞介素,干扰素,其特征在于,所说的组合物还含有亲水亲油性化合物,所说的多肽和所说的亲水亲油性化合物形成一种离子复合体,其中该复合体的形成不提高所说的多肽的溶解性。该组合物不含有任何一种有机溶剂。为了便于贮存,该组合物可被冷冻干燥。
在本发明中,该多肽和该亲水亲油性化合物可分别以所使用的浓度溶解于水中,最好为缓冲液中,并且仅是这两种物质的组合通过离子的相互作用导致复合体的形成,使该多肽疏水化,从而降低或者至少不改善其水溶性。令人惊奇地发现,这种多肽的活性可通过这种方式得到显著地改善。
根据本发明,该亲水亲油性化合物和该多肽的用量和比率的选择最好使该含有离子复合体的水性组合物为透明溶液。如果多肽和亲水亲油性化合物之间复合体的形成导致混浊,并且该组合物被直接用作给患者施用的溶液时,则将该溶液进行过滤,得到没有混浊的溶液。如果该组合物在给患者使用前被固定在一种载体上,则不需要避免其混浊性。
该具有药学活性的多肽是一种可以离子的形式存在的多肽,并且它是通过细胞表面受体(胞外受体)的识别和结合来呈现其生物活性的。这些多肽为生长因子(例如,NGF,TGF-β,FGF,GDF,胰岛素类生长因子),红细胞生成素,血小板生成素,G-CSF,诸如干扰素-α2b的干扰素,诸如白细胞介素-2和白细胞介素-12的白细胞介素,诸如BMP-2的骨形态发生蛋白质,或刺猬蛋白质,例如,sonic,印度(indian),或沙漠(desert)刺猬蛋白质。特别优选的是刺猬蛋白质。最好使用在按照本发明的复合体中所具有的活性(治疗效果和/或体外蛋白质活性)与非复合体的形式相比最好被提高10倍或者以上的多肽。该多肽的离子形式可通过将其存在于一种与其pK值相比至少相差0.5pH单位的环境中来得到。
本发明的亲水亲油性化合物应被理解为一种阴离子,两性离子或阳离子型疏水表面活性剂,脂肪酸,烷基磺酸盐或脂类。优选的阴离子表面活性剂为阴离子型去垢剂,例如,类固醇表面活性剂如脱氧胆酸盐,胆酸盐,牛磺胆酸盐,牛磺脱氧胆酸盐,脱氢胆酸盐(可用于阳离子型多肽);优选的两离子型表面活性剂为CHAPS(3[(3-胆酸酰胺丙基)二甲基氨]-1-丙烷磺酸盐)和Zwittergent(R)(N-十二烷基-N,N-二甲基-3-氨-1-丙烷磺酸盐);优选的阳离子型去垢剂为十六烷基三甲基铵溴化物或者十二烷基铵氯化物(可用于阴离子型多肽);优选的脂肪酸为诸如棕榈酸的脂肪酸(可用于阳离子型多肽)。优选的烷基硫酸盐为烷基磺酸盐,例如癸基烷基磺酸盐(可用于阳离子型多肽);优选的脂类为诸如磷脂酰基丝氨酸(可用于阴离子型多肽)和磷脂酸(可用于阳离子型多肽)的脂类。
该两性化合物是在使多肽疏水化的条件下加入该组合物中的,从而降低,至少不改善该多肽的水溶性。根据本发明,在这一过程中多肽和两性化合物之间形成水溶性的离子复合体是很重要的。该复合体中多肽与两性化合物的比率依赖于所使用的pH值,两种物质的pK值,并且依赖于浓度比率。优选使用一种与多肽和附属物质的pK值相差至少半个pH单位的pH值。加入的亲水亲油性化合物越多,结合在多肽上的亲水亲油性化合物越多,该复合体就变得更为疏水。这可导致复合体的沉淀,从而产生一种可溶性和不容性复合体的混合物,而不再是完全水溶性的。但是,非离子型去垢剂,例如,polyoxamer类Tween(R)的加入可至少部分恢复该复合体的水溶性,或者如果需要可将组合物过滤。在这种情况下,非离子型去垢剂也可以以导致胶粒形成的浓度存在。必须说明的是,亲水亲油性化合物的类型和浓度的选用应使多肽的分子结构保持在其天然的活性形式,特别是在蛋白质作为多肽的情况下,从而不降低多肽的活性。通常10倍摩尔过量的亲水亲油性化合物足以达到这一目的。优选在蛋白质的量为每毫升5μg蛋白质的情况下,加入0.001至0.05%(体积中的重量)的亲水亲油性化合物。
如果在本发明中使用例如变性表面活性剂,例如十二烷基硫酸钠(SDS),则该化合物只能在低浓度下使用。已知SDS在高浓度时使蛋白质变性,这可改善这些蛋白质的水溶性,但是是以变性的非活性形式进行的。这些像SDS那样的亲水亲油性化合物除了形成所需的按照本发明的复合体外在高浓度时也可形成胶粒,这本身也可提高多肽的溶解性。亲水亲油性化合物是否造成不期望的多肽的变性可通过本领域普通技术人员公知的方法进行确定。这些方法有例如活性确定或用于检查结构的物理化学方法,例如IR,CD和荧光光谱法。
本发明所指的水溶液中的水溶性药物组合物应被理解为一种基本上不含有不溶性颗粒的含有药学活性多肽的组合物。特别是,根据本发明的水溶性药物组合物应被理解为不具有可见混浊物的组合物。当按照本发明的离子复合体在所使用的多肽和表面活性剂的浓度为完全水溶性时,或者不溶性的复合体通过过滤被除去时,可得到可溶性的组合物。按照本发明,该水溶性组合物不另外含有有机溶剂。而且,在制备该组合物时可能需要将这种亲水亲油性化合物,例如脂肪酸,溶解在少量的有机溶剂中(达到组合物体积的5%,优选达到1%)。
本发明的另一个主题是用于制备本发明的水溶性药物组合物的方法,其特征在于,药学活性多肽和不降低或者至少不改善该药学活性多肽的水溶性的亲水亲油性化合物被组合在一起,其浓度比率和pH值使在多肽和附属物质之间通过离子相互作用形成离子复合体。
本发明的另外一个主题是本发明的药物组合物在人类或哺乳动物的全身或局部的施用中的应用。
在一个优选的实施方案中,刺猬蛋白质被用作该药物组合物中的药学活性多肽。已知刺猬蛋白质的活性可通过共价疏水修饰得到改善(欧洲专利申请No.99108032.6)。
我们惊奇地发现刺猬蛋白质的活性通过在刺猬蛋白质和一种亲水亲油性化合物之间形成一种离子复合体而被显著提高。在一个优选实施方案中,刺猬蛋白质的活性(与在大肠杆菌中产生的重组刺猬蛋白质相比)被提高10倍或更多。
因而,本发明的优选主题是一种药物组合物,它含有一种刺猬蛋白质和一种亲水亲油性化合物通过离子相互作用形成的复合体,其中,该化合物以降低或至少不改善所说的刺猬蛋白质的溶解性的浓度存在。
刺猬(hh)蛋白质被认为是一族分泌的信号蛋白质,它负责胚胎形成中多种结构的形成(J.C.Smith,Cell(细胞)76(1994)193-196,N.Perrimon,Cell 80(1995)517-520,C.Chiang等,Nature(自然)83(1996)407,M.J.Bitgood等,Curr.Biol.6(1996)296,A.Vortkamp等,Science(科学)273(1996)613,C.J.Lai等,Development(发育)121(1995)2349)。在其生物合成中,在信号序列切除和自催化切割之后得到一个20kD的N-末端区域和一个25kD的C-末端区域。在其天然形式中,N-末端被胆固醇和棕榈酰基修饰(J.A.Porter等,Science274(1996)255-259和Pepinski等,J.Biol.Chem.273(1998)14037-14045)。在较高的生命形式中,hh家族由至少三个成员组成,即sonic,印度和沙漠hh(Shh,Ihh,Dhh;M.Fietz等,Development(Suppl.)(1994)43-51)。通过重组产生的刺猬蛋白质在原核和真核细胞中产生之后观察到了其活性的差别(M.Hynes等,Neuron 15(1995)35-44和T.Nakamura等,Biochem.Biophys.Res.Comm.237(1997)465-469)。
特别优选使用sonic,印度(indian),沙漠(desert)hh(Fietz M等,Development(Suppl.)(1994)43-53)。优选使用一种具有EMBL数据库中No.L38518所述的序列的hh蛋白质。刺猬家族的蛋白质在其氨基酸序列上具有显著的同源性,这就是优选表达那些编码与上述的sonic刺猬蛋白质的序列具有80%或更多的同源性的蛋白质的核苷酸的原因。最好使用例如描述于国际申请No.WO99/28454和欧洲专利申请No.99108032.6的刺猬蛋白质。
人类sonic刺猬前提蛋白质是由描述于EMBL数据库中No.L38518的氨基酸1-462的序列组成的。氨基酸1-23代表信号肽,氨基酸24-197代表成熟的信号区域,氨基酸32-197代表短缺8个氨基酸的信号区域,氨基酸198-462代表自身蛋白酶切后的自加工的C末端。
刺猬蛋白质的药学效应最好被理解为对神经细胞的神经效应,最好为骨发生和/或骨诱导,并且特别优选软骨发生和/或软骨诱导,如描述于Kindo等,FEBS Letters,404(1997)319-323的骨诱导效应,描述于Miao等,J.Neurosci.17(1997)5891-5899的对神经细胞的效应和描述于Stott等,J.Cell Sci.110(1997)2691-2701的软骨细胞诱导。
高浓度的刺猬蛋白质溶液对于制备用于涂布或包埋本发明的复合体的载体基质来说是必须的,从而使它们在局部施用时具有足够的药理活性。已经证明,可以用于药物的载体应最好含有0.1-10mg/ml载体或更高的刺猬蛋白质。刺猬蛋白质其本质上是难溶的。但是令人意外地发现,在含有精氨酸或精铵离子的溶液中在低浓度下(小于1mg/ml或更低)刺猬蛋白质的溶解度显著升高,并且hh蛋白质的稳定性被改善。因而最好在水溶液中或在载体结合的复合体中加入精氨酸或精铵离子。
本发明中所说的刺猬蛋白质的活性应被理解为该多肽在哺乳动物细胞中可以诱导的(碱性磷酸酶活性测试)碱性磷酸酶的活性(碱性磷酸酶的表达的刺激)。在这一方法中,将小鼠成纤维细胞系培养在含有小牛血清的培养基中。然后加入无菌过滤的样品,将细胞在大约5天后裂解,并通过裂解生色底物(pNP,对硝基苯酚)的方式确定细胞裂解物中的碱性磷酸酶(J.Asahina,Exp.Cell.Res.222(1996)38-47和T.Nakamura(1997))。
本发明的药物组合物含有药理学上有效剂量的hh蛋白质,并且可以全身施用或者最好是局部施用。优选将本发明的蛋白质与刺猬家族的其它蛋白质或骨生长因子例如骨形态发生蛋白质(BMP)(Wozney等,CellMol.Biol.of Bone,Bone Morphogenetic Proteins and their GeneExpression(骨形态发生蛋白质及其基因表达)(1993)Academic Press Inc.,131-167)或副甲状腺激素(Karablis等,Genes and Development 8(1994)277-289)或胰岛素类生长因子(IGF-I或II)或转化生长因子家族(TGF-β,GDF)组合施用。这些其它的蛋白质也可以但并不是必须地存在于本发明的复合体中。
因而本发明的再一个主题是一种用于生产最好是刺猬蛋白质的水溶性药物组合物的方法,这是通过将所说的刺猬蛋白质与一种亲水亲油性化合物在允许该刺猬蛋白质和该亲水亲油性化合物形成离子复合体的条件下组合来进行的。
本发明的又一个主题是本发明的这种刺猬蛋白质的复合体在生产一种药物组合物中的应用,其中该复合体被用作该组合物的必须组分,并且任选地与适当的另外的药物辅助物质组合使用,最好是在水溶液中。在另一个优选的实施方案中,本发明的刺猬蛋白质复合体存在于一种溶解的和沉淀的形式的混合物中,或者仅存在于一种沉淀形式中,从而可使刺猬蛋白质缓释或在体内作用位点局部施用。该蛋白质在作用位点从这种混合物中的释放低于从完全溶解的药物制剂形式中的释放。
而且,在生产这种药物组合物时优选加入辅助物质,例如,氯化纳,糖(甘露糖醇,蔗糖,乳糖,葡萄糖,蔗糖,海藻糖,最好为20-100mg/ml)或氨基酸例如甘氨酸或精氨酸,甲硫氨酸,半胱氨酸以及抗氧化剂例如EDTA,柠檬酸盐,硫甘油,乙酰基半胱氨酸,聚乙二醇(1-10%重量),消炎剂,局部麻醉剂,抗生素和/或稳定剂。
在另一个优选实施方案中,本发明的刺猬蛋白质的药物组合物最好含有苏拉明(suramin),其应用具有很多优点。
该药物组合物可含有另外的药物辅助物质,并且最好被冷冻干燥。
在一个优选实施方案中,该药物组合含有的刺猬蛋白质的浓度为0.1-10mg/ml,最好为0.1-5mg/ml。
在一个优选实施方案中,该药物组合物还含有一种药学上可接受的生物相容性的缓冲液,其pH值最好在4至10之间,特别优选在pH6至pH8之间。该缓冲液的浓度最好为10-500毫摩尔/升,优选10-100毫摩尔/升。可方便地对盐浓度进行选择以使其不因为离子强度的升高而影响复合体的形成。
在本发明的另一个实施方案中,该药物组合物含有包埋于一种生物相容性的载体中的本发明的复合体,并可例如被用作植入物。该载体最好是一种聚合物,该聚合物■ 当刺猬蛋白质被包埋于该载体中时不会使该刺猬蛋白质变性,■ 其平均分子量至少是10,000道尔顿。
这种聚合物是,例如,透明质酸,胶原,藻酸盐或有机聚合物例如PLGA(聚乳酸和乙二醇酸的共聚物)或它们的衍生物。如果该复合体被包埋在一种载体中,则该复合体不是像它被用于上述的水溶性药物组合物中那样必须完全溶解在溶液中。当载体结合的复合体被施用在身体局部时,优选以骨或软骨中的刺猬多肽的复合体的形式,则它从该复合体中以溶解的形式被缓慢释放出来,从而产生所需的生物学效应。
本发明的再一个主题是固定在(可逆地结合在)一种生物相容性载体上的本发明的药物组合物的应用,用于局部施用于人体或动物。这种生物相容性载体是例如透明质酸,胶原,海藻酸盐,或有机聚合物例如PLGA或它们的衍生物。
本发明的复合体最好被固定在一种生物相容性载体上,其中,该载体可以活性的形式在体内局部释放该复合体。这种制剂形式特别适用于骨和软骨缺陷的修复,但也可用于修复神经缺陷或用于全身输送。
本发明的药物组合物最好含有一种聚合物,它基本上充当一种结构物质,并且最好也具有对细胞的粘合作用。这种结构物质是例如胶原。
在另一个优选实施方案中,本发明的药物组合物在局部施用时被用于降低期望的作用位点之外的全身性副作用。没有被完全固定化或者不具有非常短的局部半衰期的药物效应多肽的局部施用可导致该多肽的扩散,或者至少其一部分扩散至期望的作用位点之外,从而导致不期望的全身性作用。这些不期望的全身性作用可通过本发明被显著降低甚至完全避免。该方法适用于其离子复合体的形式与非复合体形式相比活性被提高10倍或更高的多肽,其中,该复合体在缓冲的水溶液中与非复合体的多肽相比具有较低的溶解性。这种多肽优选是刺猬蛋白质,细胞因子和生长因子例如NGF。
根据本发明,多肽的离子复合体和亲水亲油性化合物在这一方法中最好是局部施用,其施用量应使该多肽在复合体中显示出的活性相应于它在体内的治疗剂量(有效剂量)。对复合体的量的选择必须使当该复合体解离时,例如当在生理条件下例如在血液中被稀释10至20倍时所发生的情况,该多肽的活性仅是治疗剂量的20%或更少。因而,在本发明的复合体的这种局部施用中,药学效应多肽在期望的作用位点局部显示出其全部的治疗效应,例如当该多肽是一种骨生长因子时显示出骨生长,当该多肽是一种杀肿瘤制剂时显示出细胞静止或凋亡-诱导效应。当该复合体从作用位点扩散时,该复合体在作用位点之外的生理条件下被稀释,导致解离。这就使该复合化的多肽的浓度降低,使非复合化的多肽的浓度升高。由于非复合化的多肽的活性显著低于复合化的多肽,其在作用位点之外的治疗效应也被降低。
本发明的再一个主题是本发明的药物组合物在局部施用于人类中的应用,其特征在于,该复合体的施用量使该复合化的多肽显示出的活性相应于它的治疗剂量,从而使相同量的非复合体形式的多肽显示出治疗剂量的活性的20%或更少。
本发明的再一个主题是一种用于生产用于人类局部施用的药物组合物的方法,其特征在于,一种药学效应多肽和一种亲水亲油性化合物通过离子相互作用形成的复合体被用作必须组分,其中,该化合物存在的浓度使该药学效应多肽的水溶性降低,并且该复合体的施用量使该复合化的多肽显示出的活性相应于它的治疗剂量,而相同量的非复合体形式的多肽显示出治疗剂量活性的20%或更低。
下述实施例,公开的内容和附图进一步阐述本发明以及权利要求的保护范围。所述的方法应被理解为描述本发明主题的例子,虽然进行了一些变化。
图1显示在一个细胞测试中shh诱导的碱性磷酸酶对逐渐提高浓度的脱氧胆酸盐的依赖性。
图2显示凝聚体的形成对脱氧胆酸盐浓度的依赖性。
实施例1在细胞测试中对不同的刺猬蛋白质制剂的活性的分析:碱性磷酸酶的诱导
将5000个鼠间充质多能细胞系C3H10T1/2(ATCC CCL-226)的细胞播种在96-孔的微量滴定板的每一个孔中。这些细胞是在DMEM,2mM谷氨酰胺,100IU青霉素/ml,100μg链霉素/ml和10%小牛血清中。第二天,将培养基用根据不同的配方(0,0.00016,0.00052,0.0013,0.0019或0.01%脱氧胆酸钠)含有人shh(sonic hh)(0,5或50μg/ml)的培养基替换,或者直接加入各种刺猬蛋白质的配剂。5天后结束测试。将上清液弃去,并将细胞用PBS洗一次。将细胞在50μl 0.1%Triton(R)X-100下裂解并在-20℃冷冻。解冻后,将25μl的等份试样用于蛋白质测定并确定碱性磷酸酶的活性。按照制造商Pierce的说明进行蛋白质测定:
将75μl重蒸水加入该混合物中,然后加入100μl BCA蛋白质试剂(Pierce Micro BCA,No.23225)。60分钟后在550nm测定吸收值。按照制造商Sigma的说明进行碱性磷酸酶的测定:
将100μl的反应缓冲液(Sigma 221)加入混合物中。将一个底物胶囊(Sigma 104-40)溶解在10ml水中,然后将其100μl用吸管加入该测试混合物中。在405nm测定吸收值。在反应过程中,碱性磷酸酶将对硝基苯基磷酸盐转化成对硝基苯酚(pNP)。将测定的吸收值根据标准曲线换算成pNP的纳摩尔数。
各种刺猬蛋白质配方的以nmol pNP/min/mg蛋白质表示的活性示于图1。表明,在相同的蛋白质浓度下,所检测的刺猬蛋白质配方的活性随着脱氧胆酸盐浓度的升高而显著升高。实施例2hshh(二聚体)的疏水性离子对滴定
将重组人类sonic刺猬蛋白质(hshh)(二聚体,0.8mg/ml,溶于50mM Tris-Cl,pH7.4中或者0.1%Tween 80,50mM Tris-Cl,pH7.4)与逐渐提高浓度的脱氧胆酸钠混合。测定360nm的吸收值作为混浊度的指标(由离子蛋白质-去垢剂复合体组成的水不溶性凝聚体的形成)。从图2可以清楚看出,水不溶性凝聚体的转变发生在约0.04%脱氧胆酸钠以上浓度。水不溶性凝聚体的形成可在很大程度上由于0.1%Tween 80的存在而被防止。所述的吸收值没有用稀释度校正。实施例3在一个生物活性测试中对NGF配方的分析:背根神经节神经元发育测试
NGF生物活性是通过体外背根神经节(DRG)神经元发育的形态测量分析进行测定的。简而言之,将腰椎DRG从E7-E8鸡胚中切去,除去周围的连接组织,在用0.1%胰蛋白酶在37℃消化20分钟后通过用一个火抛光的巴氏滴管捣碎使其解离。污染细胞,例如成纤维细胞,通过将整个细胞制备物在塑料组织培养皿上预铺板2小时而被除去。在这些条件下,神经元不与基底相连,而成纤维细胞和其它的非神经元细胞粘附在组织培养塑料板上。将“清洁的”神经元通过收集上清液进行收集,并铺板在聚鸟氨酸/层粘连蛋白涂覆的塑料皿上(48孔),密度为10000细胞/孔,培养基为含有5%FBS的HAM’s F14培养基。从约1pg/ml至15ng/ml滴定出对于NGF的剂量响应曲线。在与不同的NGF配剂孵浴48小时后通过计数存活的并且发育出的神经突大于核周质的直径的两倍的分化的神经原来定量神经营养活性。将分化的神经元测定两次的平均值相对于NGF测试配方的浓度作图,并确定几个不同的配方中NGF的最大刺激活性的半值(EC50)(表1)。
表1
NGF配方的最大刺激活性的半值(EC50)
配方 | EC50(pg/ml) |
NGF(无添加剂) | 75 |
NGF(0.006%脱氧胆酸钠) | 17 |
NGF(0.02%脱氧胆酸钠) | 10 |
这些数据清楚表明,NGF的比活在含有亲水亲油性添加剂(这里为脱氧胆酸钠)的配方中被提高。实施例4与脱氧胆酸盐的药物组合物
为了制备药物组合物,将100ml的50mmol/l Tris缓冲液,pH7.4中的5mg/ml或1mg/ml Hshh(人类sonic刺猬蛋白质)的水溶液相对于没有脱氧胆酸盐的配方溶液在4℃透析24小时。在透析之后,从储备液中加入脱氧胆酸钠,同时搅拌得到一种配方溶液中的1mg/ml或5mg/ml Hshh的药物组合物水溶液。将该溶液进行无菌过滤,并在4℃贮存。0.05至2ml的这种溶液被用于注射人或动物。4.1离子疏水化的刺猬蛋白质在磷酸盐缓冲液中的配方(低脱氧胆酸钠)配方溶液:NaCl: 150mmol/l磷酸钠缓冲液: 10mmol/l脱氧胆酸钠: 0.05%(重量/体积)pH: 7.44.2离子疏水化的刺猬蛋白质在磷酸盐缓冲液中的配方(高脱氧胆酸钠)配方溶液:NaCl: 150mmol/l磷酸钠缓冲液: 10mmol/l脱氧胆酸钠: 0.1%(重量/体积)pH: 7.44.3离子疏水化的刺猬蛋白质在低离子强度磷酸盐缓冲液中的配方(低脱氧胆酸钠)配方溶液:NaCl: 30mmol/l磷酸钾缓冲液: 20mmol/l脱氧胆酸钠: 0.05%(重量/体积)pH: 6.54.4离子疏水化的刺猬蛋白质在低离子强度的磷酸盐缓冲液中的配方(高脱氧胆酸钠)配方溶液:NaCl: 30mmol/l磷酸钾缓冲液: 20mmol/l脱氧胆酸钠: 0.1%(重量/体积)pH: 6.5实施例5在磷酸盐缓冲液中的离子疏水化的刺猬蛋白质与脂类,脂肪酸或类固醇的药物组合物
为了制备药物组合物,将100ml的50mmol/l Tris缓冲液,pH7.4中的1mg/ml或2mg/ml Hshh的水溶液相对于没有脂类,脂肪酸或脱氧胆酸盐的配方溶液在4℃透析24小时。在透析之后,从储备液中加入0.01克的磷脂酸盐,0.01克的磷脂酰丝氨酸,0.01克的棕榈酸盐,0.05克的胆酸盐,0.05克的牛磺脱氧胆酸盐或0.05克的牛磺胆酸盐,同时搅拌得到一种配方溶液中的1mg/ml或2mg/ml Hshh的药物组合物水溶液。将该溶液进行无菌过滤,并在4℃贮存。0.05至2ml的这种溶液被用于注射人或动物。配方溶液:NaCl: 150mmol/l磷酸钠缓冲液: 10mmol/l磷脂酸盐: 0.01%(重量/体积)pH: 7.4配方溶液:NaCl: 100mmol/l磷酸钠缓冲液: 10mmol/l磷脂酰丝氨酸: 0.01%(重量/体积)pH: 7.4配方溶液:NaCl: 150mmol/l磷酸钾缓冲液: 20mmol/l棕榈酸钠: 0.01%(重量/体积)pH: 7.4配方溶液:NaCl: 150mmol/l磷酸钠缓冲液: 10mmol/l胆酸钠: 0.05%(重量/体积)pH: 7.4配方溶液:NaCl: 100mmol/l磷酸钠缓冲液: 10mmol/l牛磺脱氧胆酸钠: 0.05%(重量/体积)pH: 7.4配方溶液:NaCl: 150mmol/l磷酸钾缓冲液: 20mmol/l牛磺胆酸钠: 0.05%(重量/体积)pH: 7.4实施例6离子疏水化的骨形态发生蛋白质(BMP-2)在精氨酸缓冲液中的药物组合物
为了制备药物组合物,将100ml的0.4mg/mlBMP-2水溶液相对于10mmol/l磷酸钾缓冲液,pH6.0中的500mmol/l精氨酸在4℃透析24小时。在透析之后,从储备液中加入0.01克(棕榈酸盐)或0.05克(脱氧胆酸盐或牛磺脱氧胆酸盐),同时搅拌得到一种配方溶液中的0.4mg/ml BMP的药物组合物水溶液。将该溶液进行无菌过滤,并在4℃贮存。0.05至2ml的这种溶液被用于注射人或动物。配方溶液:精氨酸: 500mmol/l磷酸钾缓冲液: 10mmol/l脱氧胆酸钠: 0.05%(重量/体积)pH: 6.0配方溶液:精氨酸: 500mmol/l磷酸钾缓冲液: 10mmol/l棕榈酸钠: 0.01%(重量/体积)pH: 6.0配方溶液:精氨酸: 500mmol/l磷酸钾缓冲液: 10mmol/l牛磺脱氧胆酸钠: 0.05%(重量/体积)pH: 6.0实施例7离子疏水化的白细胞介素-2在磷酸盐缓冲液中的药物组合物
为了制备药物组合物,将100ml的在50mmol/l Tris缓冲液,pH7.4中的1或2百万IU白细胞介素-2相对于没有亲水亲油性化合物的配方溶液在4℃透析24小时。在透析之后,从储备液中加入0.05克的脱氧胆酸盐,0.01克的磷脂酰丝氨酸或0.01克的棕榈酸钠,同时搅拌得到一种配方溶液中的1或2百万IU白细胞介素-2的药物组合物水溶液。将该溶液进行无菌过滤,并在4℃贮存。0.05至2ml的这种溶液被用于注射人或动物。配方溶液:NaCl: 150mmol/l磷酸钠缓冲液: 10mmol/l脱氧胆酸盐: 0.05%(重量/体积)pH: 7.4配方溶液:NaCl: 150mmol/l磷酸钠缓冲液: 10mmol/l磷脂酰丝氨酸: 0.01%(重量/体积)pH: 7.4配方溶液:NaCl: 150mmol/l磷酸钾缓冲液: 20mmol/l棕榈酸钠: 0.01%(重量/体积)pH: 7.4实施例8离子疏水化的干扰素-α在磷酸盐缓冲液中的药物组合物
为了制备药物组合物,将100ml的在50mmol/l Tris缓冲液,pH7.4中的4或40百万IU干扰素-α2b相对于没有亲水亲油性化合物的配方溶液在4℃透析24小时。在透析之后,从储备液中加入0.05克的脱氧胆酸盐,0.01克的磷脂酰丝氨酸或0.05克的牛磺脱氧胆酸盐,同时搅拌得到一种配方溶液中的4或40百万IU干扰素-α2b的药物组合物水溶液。将该溶液进行无菌过滤,并在4℃贮存。0.05至2ml的这种溶液被用于注射人或动物。配方溶液:NaCl: 150mmol/l磷酸钠缓冲液: 10mmol/l脱氧胆酸盐: 0.05%(重量/体积)pH: 7.4配方溶液:NaCl: 100mmol/l磷酸钠缓冲液: 10mmol/l磷脂酰丝氨酸: 0.01%(重量/体积)pH: 7.4配方溶液:NaCl: 150mmol/l磷酸钾缓冲液: 20mmol/l牛磺脱氧胆酸钠: 0.05%(重量/体积)pH: 7.4实施例9离子疏水化的人类NGF在乙酸盐缓冲液中的药物组合物
为了制备药物组合物,在100ml的在100mmol/l乙酸钠缓冲液,pH6.0中的1或2mg/ml类NGF中,从储备液加入0.05克的脱氧胆酸盐,0.01克的磷脂酸盐或0.05克的牛磺脱氧胆酸盐,同时搅拌得到药物组合物水溶液。将该溶液进行无菌过滤,并在4℃贮存。0.05至2ml的这种溶液被用于注射人或动物。组成:人类NGF: 1mg/ml乙酸钠缓冲液: 100mmol/l脱氧胆酸盐: 0.05%(重量/体积)pH: 6.0人类NGF: 2mg/ml乙酸钠缓冲液: 100mmol/l磷脂酸盐: 0.01%(重量/体积)pH: 6.0人类NGF: 1mg/ml乙酸钠缓冲液: 100mmol/l牛磺脱氧胆酸钠: 0.05%(重量/体积)pH: 6.0实施例10含有刺猬蛋白质的藻酸盐胶的制备
将实施例4.1中的配方溶液的一个等份试样与1%(重量/体积)的海藻酸钠贮存溶液的水溶液(Pronova Biopolymer,Norway)搅拌,从而形成胶状的海藻酸盐蛋白质混合物。这一胶状物被直接用作可注射的基质,其用量为0.05至2ml。实施例11含有BMP-2的胶原混合物的制备
将100μl的实施例6中配方溶液之一逐滴加在大小为10×10×3mm的胶原海绵上(Helistat,Integra Life Science,USA)。然后将装载的载体冷冻(-70℃)并冷冻干燥。该海绵被用于局部治疗骨折。
Claims (11)
1.一种水溶性组合物,它含有一种选自下组的药学效应多肽:刺猬蛋白质,骨形态发生蛋白质,生长因子,红细胞生成素,血小板生成素,粒细胞集落刺激因子,白细胞介素和干扰素,其特征在于,所说的组合物还含有一种亲水亲油性化合物,所说的多肽和所说的亲水亲油性化合物形成一种离子复合体,其中该复合体的形成不提高所说的多肽的溶解性。
2.按照权利要求1所述的组合物,其特征在于它是冷冻干燥形式的。
3.按照权利要求2所述的组合物,其特征在于该复合体被固定在一个生物相容性载体上。
4.按照权利要求3所述的组合物,其特征在于该复合体是以溶解的和沉淀的形式的混合物存在的。
5.按照权利要求1至4中任意一项所述的组合物,其特征在于,所说的组合物在水溶液中的pH值与所说的多肽和所说的表面活性剂的pK值相差至少半个pH单位。
6.按照权利要求1至5中任意一项所述的组合物,其特征在于,所说的多肽是刺猬蛋白质。
7.按照权利要求1至6中任意一项所述的组合物,其特征在于,该亲水亲油性化合物是脱氧胆酸盐。
8.权利要求1至7中任意一项所述的组合物在人体中在刺猬蛋白质的缓释或局部施用中的应用。
9.用于生产在人体中局部施用的药物组合物的方法,其中,将选自刺猬蛋白质,骨形态发生蛋白质,生长因子,红细胞生成素,血小板生成素,粒细胞集落刺激因子,白细胞介素和干扰素的药学效应多肽与一种亲水亲油性化合物通过离子相互作用形成的复合体用作必须组分,其中,辅助化合物存在的浓度不提高所说的多肽的水溶性。
10.按照权利要求9所述的方法,其特征在于,该复合体被固定在一种生物相容性载体上。
11.一种提高由细胞表面受体识别和结合的多肽的活性的方法,其特征在于在所说的多肽和一种亲水亲油性化合物之间形成一种离子复合体。
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CN113660953A (zh) * | 2019-04-01 | 2021-11-16 | 豪夫迈·罗氏有限公司 | 用于稳定含蛋白质制剂的组合物和方法 |
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