CN1198665A - 用于阴道干燥的局部激素疗法的单位盖仑制剂 - Google Patents
用于阴道干燥的局部激素疗法的单位盖仑制剂 Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
一种用于局部,基本上是非全身性的,治疗阴道干燥,特别是绝经期妇女的阴道干燥的盖仑制剂。它包括在亲脂剂的溶液或悬浮液中的选自17β-雌二醇及其盐的天然的,特别是微细化或载体化的雌激素,雌激素含量相当于最多15微克,优选地低于10微克的17β-雌二醇的等同单位剂量,亲水性的形成凝胶的生物粘合剂、适合于亲脂剂的凝胶剂和水可分散剂。软胶囊包括含明胶和甘油的硬或软的外壳,和含亲脂剂、雌激素在溶液或在悬浮液中的非水性液体或半液体,亲水性的凝胶形成生物粘合剂,适合于亲脂剂的凝胶剂的内相。缓释阴道栓剂含有非水性的硬固体或半—软固体均相,它含有具有在溶液或悬浮液中的雌激素的亲脂剂、亲水形成凝胶的生物粘合剂、适合于亲脂剂的凝胶剂和水可分散剂。
Description
本发明涉及局部(基本上是非全身)治疗阴道干燥的药物。
已知有阴道干燥,特别是绝经期妇女阴道干燥的问题:交媾困难,会导致泌尿器功能产生问题的泌尿生殖器的萎缩,以及由于菌丛形成不足产生的感染危险。
本发明的一个目的是提供适合非全身治疗的药物,从而区分于激素经口、经皮肤或阴道内给药的替代的激素疗法。
相对比的是,欧洲专利EP-A-0103995和美国专利US-A-5019395揭示了用于一般激素疗法的盖仑制剂,其中组合物含高剂量的活性物质,各自含4wt%-15wt%和0.1wt%-8wt%药物。
更具体的是,本发明的药物形式上不同于含高剂量雌激素的阴道给药的替代激素疗法药物,如阴道霜剂、片剂、或栓剂。这样的情况有这样的优点:阴道给药时的全身通道优于口服给药时的,主要是因为阴道给药时没有雌激素的代谢。
相对比的是,本发明旨在提供局部治疗方法,以使直接使用天然的雌激素,特别是17β-雌二醇的全身通道最小或为0,从而通过避免某些病人产生的继发性全身影响,特别是避免子宫内膜增生来减轻局部问题。
人们已提出了该类型的局部治疗,例如以阴道圆环的形式,所述的阴道圆环含有雌激素,它能通过环的多孔膜扩散,这样能在长时期里持续释放。
但是,通常所有的阴道内用器具,如这类环具有需要有非降解的异体存在于器官内,并需要插入和除去的操作的缺点。
人们也提出了将含有17β-雌二醇的盖仑制剂以阴道片的形式每天给药以用作这类的局部治疗。这类片剂含有包括诸如纤维素聚合物的赋形剂的基质,所述的纤维素聚合物会吸收阴道内残留的潮气以浸润含活性物质的基质,并随后逐渐释放。
但是,由于它们特定的盖仑形式,这类片剂的剂量必须相对较高才能得到所需的结果,典型的是每片中17β-雌二醇的剂量为25微克(一片相当于一个单位剂量)以得到所需的阴道粘膜在细胞学、组织学和临床方面的改善。由于剂量相对较高,在临床研究中某些病人子宫内膜增生,这表明有17β-雌二醇的全身通道:具体参见C.Fielding等“在为妇女子宫脱垂阴道手术用雌二醇进行术前治疗的随机双盲试验”Maturitas,1992,15,241-149。
本发明的一个目的是提供具有特定盖仑制剂的上述类型的药物,它能使17β-雌二醇的剂量减低,以避免全身通道,尽管阴道粘膜对雌激素极其敏感,同时该制剂也能确保令人满意的营养的效果。
根据本发明,该药物的特征在于是单位盖仑制剂,它含有在亲脂剂的溶液或悬浮液中的选自17β-雌二醇及其盐的天然雌激素,雌激素含量相当于最多15微克,优选地低于10微克的17β-雌二醇的等同单位剂量,一种亲水性的形成凝胶的生物粘合剂、一种适合于亲脂剂的凝胶剂和水可分散剂。
与阴道分泌物相反,亲水的生物粘合剂凝胶和水可分散剂的存在会导致盖仑制剂乳化,这使活性物质在乳化的赋形剂和所接触的阴道粘膜之间直接、主动地扩散。亲水性凝胶剂的生物粘合性质(或更精确的是粘膜粘合性质)使轻轻流动的乳剂能粘附在粘膜上,这样保证了长期停滞。
该长期停滞可使用药次数减少,从而可每天仅使用一次,或使用频率更少(特别是在维持时期)。
雌激素,优选的是微细化的雌激素可以游离形式或载体形式在盖仑制剂中存在,特别是在诸如超分子生物载体的毫微(十亿分之一)颗粒形式载体中胶囊化。
在第一技术方案中,药物为胶囊形式,包括含明胶的硬质或软质的固体外壳和含亲脂剂、雌激素在溶液或在悬浮液中的非水性液体或半液体,亲水性的凝胶形成生物粘合剂,适合于亲脂剂的凝胶剂以及水可分散剂的内相。
胶囊可为硬胶囊,或优选的是软胶囊,即外壳含甘油,
优选的是下列情况:
●亲脂剂选自液体甘油三酯;
●亲水性形成凝胶的生物粘合剂选自羧乙烯基酸、羟丙基纤维素、羧甲基纤维素、明胶、黄原胶、瓜耳胶、硅酸铝及其混合物;
●适合于亲脂剂的凝胶剂是疏水的胶体二氧化硅;
●水可分散剂选自聚乙二醇、聚乙二醇7-甘油基可可酸酯(cocoate)及其混合物;
●内相的组合物是:游离或载体化微细化的17β-雌二醇:2.5-15微克;羟丙基纤维素:120毫克;疏水胶体二氧化硅:50毫克-80毫克;聚乙二醇7-甘油基-可可酸酯:400毫克;液体甘油三酯:适量到1600毫克。
在另一个技术方案中,药物为缓释阴道栓剂,它包括非水性的硬固体或半-软固体均相,它含有含亲水形成凝胶的生物粘合剂、适合于亲脂剂的凝胶剂和水可分散剂。
在此情况下,优选的是:
●亲脂剂选自熔点为约35℃的固体甘油三酯、巴西蜡棕榈、可可白脱或它们的混合物;
●亲水性的形成凝胶的生物粘合剂选自羧乙烯基酸、羟丙基纤维素、羧甲基纤维素、明胶、黄原胶、瓜耳胶、硅酸铝和它们的混合物;
●适合亲脂剂的凝胶剂是疏水的胶体二氧化硅;
●水可分散剂选自聚乙二醇和它们的混合物;
●组合物是:游离或载体化微细化的17β-雌二醇:2.5微克到15微克;羟丙基纤维素:80毫克;疏水的胶体二氧化硅:5毫克-60毫克;聚乙二醇:50毫克-200毫克;羧乙烯基酸:8毫克;固体甘油三酯:适量到1600毫克。
上述的两种情况的制剂有许多优点:
●它们的耐受性很好,稳定并为盖仑制剂所接受;
●它们的生物吸附性可最大程度地防止流动;
●它们保证载体与活性物质之间相配伍;
●它们鼓励含活性物质的载体与阴道分泌物进行乳化,以提供一些亲水特征。
下面将用各种制剂的例子更详尽地揭示本发明的不同方面。
活性物质的选择
选自17β-雌二醇、它的盐和它的衍生物的雌激素被选择作为本发明的药物。
该组包括具有下列化学结构通式的化合物组:
其中R=H时,化合物是17β-雌二醇,它是由育龄妇女的卵巢产生的天然生理激素,缺乏该物质会产生绝经期病人所经历的问题。
17β-雌二醇是生理上的雌激素激动剂。它在外阴粘膜中的营养作用已被认同,并已被广泛地揭示,使用17β-雌二醇使组织学功能和临床问题有可逆性。雌二醇及其衍生物(盐)降低了阴道的pH,增加了经阴道的电位差、阴道的分泌物量和局部血流量。
对于妇女,在阴道的上皮已发现了具有雌二醇亲和力很高的受体。它们对放射标记的雌激素的亲和力接近于算得的子宫肌层中的受体的亲和力,但数目较少。这些受体的特征在于对于下列化合物具有递减的亲和力:
17β-雌二醇>雌三醇>雌酮。
但是,虽然已证明17β-雌二醇是单纯的激动剂,它的天然代谢物雌三醇的特征属于部分激动剂性质,甚至有些拮抗性质。对天然的雌激素会产生拮抗作用。
因此用17β-雌二醇治疗时在内源性雌激素存在下具有加成作用,但用雌三醇治疗具有对内源性雌二醇产生拮抗影响的缺点。此外,由于其固有活性比17β-雌二醇低,已证明雌三醇的活性较差(一些作者通过它的中心受体的分解速度较快来解释该现象)。由于部分激动剂的活性比完全激动剂的活性更依赖于受体的数目,这两种雌激素化合物的活性差异由于阴道组织中受体比子宫肌层中的受体少而更为明显。
总之,由于17β-雌二醇对阴道雌激素受体的亲和力高,特别是它们是完全的激动剂活性特征,故选择天然雌激素比选择雌三醇能得到更好的局部营养作用。
相同的评论也适用于雌三醇的前体-雌酮和雌二醇合成的衍生物,如雌二醇的二醚氧化物普罗雌烯(promestriene DCI)。
剂量选择
必须选择剂量以减轻局部问题并防止经阴道的最大程度地吸收。
通过相当于一个单位剂量(每天单次给药,或更少的频率给药)选择剂量为10微克的17β-雌二醇可达到这些目的。
当17β-雌二醇以该剂量、微细化游离形式存在时,只观察到轻微的全身通道,给药后约1小时有简单血药浓度峰值;最大的血药浓度峰值从未超过30pg/ml,但很清楚的是该峰值极为短暂。
若要避免该极小的通道,第一个措施是减少活性物质的用量,典型的剂量为5微克/单位剂量,或甚至为2.5微克/单位剂量。
进一步的可能性是保留相同的赋形剂,并使活性物质被载体化,而不是在赋形剂中呈游离形式。
下面将解释这类载体化的重要性和载体化的方法。
17β-雌二醇的载体化
17β-雌二醇载体化的一个目的是通过更缓慢地释放17β-雌二醇来消除活性物质的全身通道,这通过降低其最大增幅来“分散”血药浓度峰值,持久地低于50pg/ml血药浓度。
载体化也可有利地延长活性物质局部作用的持续时间。
这两个目的可通过下面所述来达到:
为了防止任何全身通道,载体必须足以大到不能通过阴道的上皮。其大小为200nm可满足此标准。当然载体必须与17β-雌二醇配伍,让它逐渐扩散,它应当与阴道粘膜相容,且必须是有耐受性的。
为了增加作用时间,可选择静电交感的生物粘合剂系统。在正常条件下,阴道粘膜是酸性(pH为4),而在绝经期该pH逐步增加到6左右。因此有利地是提供具有正电荷的载体外围,它可与粘膜的负电荷相互作用。
应当注意,使粘膜和载体之间交感最大所需的酸性性质在绝经期(pH为6)会降低,但这些低酸性条件足以与载体进行有效的交互作用。
满足这些不同条件的载体的例子是由毫微颗粒构成(即,颗粒直径为数十或最多是数百毫微米级别),如国际专利申请WO-A-89/11271(Centre national de larecherche scientifique)所述的“超分子生物载体”(SMBV)和来自BiovectorTherapeutics S.A.的产品。
这些已知为载体的SMBV含有非液态亲水核,通过共价键与核心连接的内部脂质体壳以及通过疏水的交互作用与内部脂质体壳连接的外部两亲性的壳。
这些载体可负载活性物质,在本案中17β-雌二醇(它是亲脂的)被封在载体中,这样构成了生物拟态的活性物质运输器,它类似于诸如脂蛋白的内源性运输系统。
软胶囊制剂的例子
为了满足本发明盖仑制剂的生物粘合概念并最大程度地防止流动,在本例中软胶囊的内相包括生物相容的亲水性形成凝胶生物粘合聚合物,所述的聚合物可最大程度地掺入阴道分泌的水份以增加粘度,从而延长乳化的在原地的保留时间。
通过使用适合该亲脂剂的凝胶剂来防止胶囊内相的亲脂组份流动。在本例子中,内相中至少一个组份促进在脂肪相中的主要组份的亲脂衍生物与阴道分泌物乳化。
内相典型的组成如下:游离或载体化的17β-雌二醇 2.5-15微克
(即,1.5625ppm-9.375ppm)羟丙基纤维素(KlucelHXF) 120mg疏水胶体二氧化硅(AerosilR972) 70mg聚乙二醇7-甘油基可可酸酯(CeljolHE) 400mg液体甘油三酯(Miglyol812) 适量到1600mg
下面报道的临床试验中对于上述指出的单位剂量,使用了极低最终浓度的活性物质,1.5625×10-6到9.375×10-6,特别是6.25×10-6(0.000625%)。
制备时,该内相被引入含有明胶/甘油的相应于软胶囊结构的外壳体。
提出各种剂量的不同赋形剂。这样疏水性二氧化硅的剂量范围为50-80毫克。
也可以改进赋形剂组成。
这样亲水性的形成凝胶生物粘合剂聚合物(羟丙基纤维素)可被其它亲水性形成粘合的生物粘合剂组份取代,如:羧乙烯基酸、羟丙基纤维素、羧甲基纤维素、明胶、黄蓍胶、瓜耳胶、硅酸铝或上述组份的两种或多种混合物。
对于水可分散剂,聚乙二醇7-甘油基-可可酸酯可被聚乙二醇(PEG)所代替。
缓释阴道栓剂的处方例
在此情况中,药物包含硬或半软固体均相,其典型的组成如下:
游离或载体化的17β-雌二醇 2.5-15微克
羟丙基纤维素(KlucelHXF) 80mg
疏水胶体二氧化硅(AerosilR972) 40mg
聚乙二醇(PEG 400) 80mg
羧乙烯基酸(Carbopol974 P) 8mg
固体甘油三酯(WitespolS 551) 适量到1600mg
可以设想加入种种剂量的不同的赋形剂。这样疏水胶体二氧化硅的剂量范围为5毫克到60毫克,PEG的剂量范围为50毫克到200毫克。
也可以改进赋形剂的组份。
这样WitespolS51可被巴西棕榈蜡、可可白脱或其它熔点约为35℃的甘油三酯,如Ovucire型的所代替。
亲水的形成凝胶的生物粘合剂聚合物(Klucel和Carbopol)可被上述软胶囊制剂例子中指出的相同替代物所代替。
临床试验
对六个病人进行下列试验得到如下结果揭示了下列情况:
临床和生物耐受性:在试验条件下,2.5微克、5微克和10微克的本发明上述制剂的软胶囊的局部和总体临床耐受性很优良。未报道有不良作用。生物耐受性很优良。未报道有临床意义的不规则。
药动学分析:从药动学角度来看,以低剂量(2.5微克和5微克)给药组的对象、对象的一半以高剂量(10微克)给药后血浆的雌二醇浓度仍然是不可计量的。在三个其它对象中,在治疗不超过30pg/ml后的数个样品(2或3个)中可测量到高于定量限制的雌二醇量。
对于雌酮,治疗后测得的浓度级数一般与治疗前测得的相同。当治疗后的雌酮量较高时(每组2或3个对象),最高浓度不超过用2.5微克、5微克和10微克17β-雌二醇治疗前测量值的22%(对象号02)、34%(对象号06)和26%(对象号06)。在所有情况下,雌酮浓度不超过30pg/ml。检查雌酮血浆浓度曲线表明在C最大或SSC和给药剂量之间没有比例。
总的结论:阴道给予2.5微克、5微克和10微克剂量的17β-雌二醇软胶囊单剂后,试验中的6个对象的临床耐受力都很优良。其生物耐受力也很优良。未报道任何不规则的临床意义。
从药动学观点来看,给予2.5微克和5微克剂量17β-雌二醇胶囊后,阴道对雌二醇的吸收为0。给予10微克剂量17β-雌二醇的胶囊后,六个对象中的三个的雌二醇血药浓度仍然监测不出。在另外的对象中,一些雌酮的血药浓度显示:治疗后测得的量可与治疗前测得的量类比。因此可从该研究中推定阴道对2.5微克到10微克范围剂量的17β-雌二醇的软胶囊中的雌二醇吸收基本为0。
特别值得注意的是,大于50pg/ml的峰对某些对象(同上)没有上述限定的继发作用。微细化游离形式的17β-雌二醇是完全令人满意的,不需要以载体化的形式来避免超过50pg/ml的阈值。但是,若需要延长活性物质的作用时间,则可设想载体化的形式。
Claims (18)
1.一种局部,基本上是非全身性的,治疗阴道干燥,特别是绝经期妇女的阴道干燥的药物,其特征在于为单位盖仑制剂,它含有在亲脂剂的溶液或悬浮液中的选自17β-雌二醇及其盐的天然雌激素,雌激素含量相当于最多15微克,优选地低于10微克的17β-雌二醇的等同单位剂量,亲水性的形成凝胶的生物粘合剂、适合于亲脂剂的凝胶剂和水可分散剂。
2.根据权利要求1所述的药物,其中雌激素以其游离形式,较好的是微细化形式存在。
3.根据权利要求1所述的药物,其中雌激素以其载体化形式,较好的是微细化形式存在。
4.根据权利要求3所述的药物,其中雌激素通过在毫微颗粒类型的载体中胶囊化来载体化。
5.根据权利要求4所述的药物,其中雌激素通过在超分子生物载体类型的载体中胶囊化来载体化。
6.根据权利要求1所述的药物,它为胶囊形式,包括含明胶的硬质或软质的固体外壳和含亲脂剂、雌激素在溶液或在悬浮液中的非水性液体或半液体,亲水性的凝胶形成生物粘合剂,适合于亲脂剂的凝胶剂以及水可分散剂的内相。
7.根据权利要求6所述的药物,它为软胶囊,其中外壳含甘油,
8.根据权利要求6所述的药物,其中亲脂剂选自液体甘油三酯。
9.根据权利要求6所述的药物,其中亲水性形成凝胶的生物粘合剂选自羧乙烯基酸、羟丙基纤维素、羧甲基纤维素、明胶、黄原胶、瓜耳胶、硅酸铝及其混合物。
10.根据权利要求6所述的药物,其中适合于亲脂剂的凝胶剂是疏水的胶体二氧化硅。
11.根据权利要求6所述的药物,其中水可分散剂选自聚乙二醇、聚乙二醇7-甘油基可可酸酯(cocoate)及其混合物。
12.根据权利要求6所述的药物,其中内相的组成是:
游离或载体化微细化的17β-雌二醇 2.5-15微克
羟丙基纤维素 120毫克
疏水胶体二氧化硅 50-80毫克
聚乙二醇7-甘油基-可可酸酯 400毫克
液体甘油三酯 适量到1600毫克
13.根据权利要求1所述的药物,为缓释阴道栓剂,它包括非水性的硬固体或半-软固体均相,它含有具有在溶液或悬浮液中的雌激素的亲脂剂、亲水形成凝胶的生物粘合剂、适合于亲脂剂的凝胶剂和水可分散剂。
14.根据权利要求13所述的药物,其中亲脂剂选自熔点为约35℃的固体甘油三酯、巴西棕榈蜡、可可白脱和它们的混合物。
15.根据权利要求13所述的药物,其中亲水性的形成粘合的生物粘合剂选自羧乙烯基酸、羟丙基纤维素、羧甲基纤维素、明胶、黄原胶、瓜耳胶、硅酸铝和它们的混合物。
16.根据权利要求3所述的药物,其中适合亲脂剂的凝聚剂是疏水的胶体二氧化硅。
17.根据权利要求13所述的药物,其中水可分散剂选自聚氧乙二醇和它们的混合物。
18.根据权利要求13所述的药物,其中组合物是:
游离或载体化微细化的17β-雌二醇 2.5微克到15微克
羟丙基纤维素 80毫克
疏水的胶体二氧化硅 5毫克-60毫克
聚乙二醇 50毫克-200毫克
羧乙烯基酸 8毫克
固体甘油三酯 适量到1600毫克
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-
1995
- 1995-10-05 FR FR9511732A patent/FR2739558B1/fr not_active Expired - Fee Related
-
1996
- 1996-10-04 CN CN96197405.2A patent/CN1198665A/zh active Pending
- 1996-10-04 US US09/051,242 patent/US6060077A/en not_active Expired - Fee Related
- 1996-10-04 DE DE69620625T patent/DE69620625D1/de not_active Expired - Lifetime
- 1996-10-04 EP EP96933492A patent/EP0861067B1/fr not_active Expired - Lifetime
- 1996-10-04 CA CA002233919A patent/CA2233919A1/fr not_active Abandoned
- 1996-10-04 JP JP9514039A patent/JPH11514994A/ja active Pending
- 1996-10-04 AT AT96933492T patent/ATE215814T1/de not_active IP Right Cessation
- 1996-10-04 AU AU72204/96A patent/AU7220496A/en not_active Abandoned
- 1996-10-04 WO PCT/FR1996/001555 patent/WO1997012600A1/fr active IP Right Grant
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105307634A (zh) * | 2013-03-15 | 2016-02-03 | 沃纳奇尔科特有限责任公司 | 含有改性瓜尔胶的药物软明胶胶囊剂型 |
CN105307634B (zh) * | 2013-03-15 | 2020-03-10 | 沃纳奇尔科特有限责任公司 | 含有改性瓜尔胶的药物软明胶胶囊剂型 |
Also Published As
Publication number | Publication date |
---|---|
DE69620625D1 (de) | 2002-05-16 |
CA2233919A1 (fr) | 1997-04-10 |
WO1997012600A1 (fr) | 1997-04-10 |
FR2739558A1 (fr) | 1997-04-11 |
US6060077A (en) | 2000-05-09 |
ATE215814T1 (de) | 2002-04-15 |
JPH11514994A (ja) | 1999-12-21 |
FR2739558B1 (fr) | 1997-11-28 |
EP0861067B1 (fr) | 2002-04-10 |
AU7220496A (en) | 1997-04-28 |
EP0861067A1 (fr) | 1998-09-02 |
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