CN117396188A - 6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮的水包油乳液 - Google Patents
6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮的水包油乳液 Download PDFInfo
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Abstract
本发明提供了水包油乳液形式的6‑乙氧基‑7‑甲氧基‑2‑(2‑甲基硫基苯基)‑3,1‑苯并噁嗪‑4‑酮的局部制剂及其在预防、阻止和/或治疗炎性皮肤病,特别是内瑟顿综合征中的用途。
Description
发明领域
本发明涉及6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮的局部制剂及其在治疗炎性皮肤病,特别是内瑟顿综合征中的用途。
发明背景
KLK7(hK7,或角质层胰凝乳蛋白酶,SCCE)是激肽释放酶基因家族的丝氨酸蛋白酶,其显示类似胰凝乳蛋白酶的活性。KLK7主要在皮肤中表达,似乎在皮肤生理学中起重要作用(Egelrud.1993.Purification and preliminary characterization of stratumcorneum chymotryptic enzyme:a proteinase that may be involved in desquamation.J.Invest.Dermatol.101,200-204;Yousef等人2000.The KLK7(PRSS6)gene,encodingfor the stratum corneum chymotryptic enzyme is a new member of the humankallikrein gene family-genomic characterization,mapping,tissue expression andhormonal regulation.Gene 254,119-1281)。
KLK7参与脱屑过程中角质化鳞状上皮细胞的细胞间粘附结构的降解。脱屑过程受到良好的调节,并与角质细胞的新生保持微妙的平衡,以保持角质层的恒定厚度。在这方面,据报道KLK7能够切割角膜小体蛋白(corneodesmosomal protein)角膜锁链蛋白(corneodesmosin)和桥粒蛋白1(Simon等人2001.Refined characterization ofcomeodesmosin proteolysis during terminal differentiation of human epidermisand its relationship to desquamation.J.Biol.Chem.276,20292-20299;Caubet等人2004.Degradation of corneodesmosome proteins by two serine proteases of thekallikrein family,SCTE/KLK5/hK5 and SCCE/KLK7/hK7.J.Invest.Dermatol.122,1235-1244;Brattsand等人2005.A proteolytic cascade of kallikreins in the stratumcorneum.J.Invest.Dermatol.124,198-203)。此外,已表明两种脂质加工酶β-葡糖脑苷脂酶和酸性鞘磷脂酶可被KLK7降解(Hachem等人2005.Sustained serine proteasesactivity by prolonged increase in pH leads to degradation of lipid processingenzymes and profound alterations of barrier function and stratum corneumintegrity.J.Invest.Dermatol.125,510-520)。这两种脂质加工酶与其底物葡糖神经酰胺和鞘磷脂共分泌,并将这些极性脂质前体加工成其非极性更强的产物,例如神经酰胺,其随后被整合到细胞外板层膜中。层状膜结构对于功能性皮肤屏障至关重要。最后,KLK7已被证明能激活促炎细胞因子Pro-白介素-1β(IL-1β)(Nylander-Lundqvist&Egelrud.1997.Formation of active IL-1β from pro-IL-1βcatalyzed by stratumcorneum chymotryptic enzyme in vitro.Acta Derm.Venereol.77,203-206)。
几项研究将KLK7活性的增加与炎症性皮肤病如特应性皮炎、银屑病和内瑟顿综合征联系起来。KLK7活性增加可能导致角膜锁链蛋白降解失控,导致脱屑失调,脂质加工酶降解增强,导致板层膜结构紊乱,或促炎细胞因子IL-1β活化失控。以前已经证明这可能导致皮肤屏障功能受损和炎症(WO 2004/108139)。
KLK7活性在几个水平上受到控制。炎症性皮肤病中KLK7活性增加的原因可能是由于多种因素。首先,蛋白酶的表达量可能受遗传因素的影响。已经描述了这种遗传连锁,即KLK7基因中3’-UTR的多态性(Vasilopoulos等人2004.Genetic association between anAACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme geneand atopic dermatitis.J.Invest.Dermatol.123,62-66.)。其次,由于KLK7作为酶原通过板层体分泌到角质层细胞外空间,并且它不能自动激活,所以它需要被另一种蛋白酶如KLK5激活(上述Caubet等人)。这种激活酶不受控制的活性可能导致KLK7的过度激活。第三,激活的KLK7可被天然抑制剂如LEKTI、ALP或elafin抑制(Schechter等人2005.Inhibitionof human kallikreins 5and 7by the serine protease inhibitor lympho-epithelialKazal-type inhibitor(LEKTI).Biol.Chem.386,1173-1184;Franzke等人1996.Antileukoprotease inhibits stratum corneum chymotryptic enzyme-Evidencefor a regulative function in desquamation.J.Biol.Chem.271,21886-21890)。这种抑制剂的表达减少或缺乏可能导致KLK7活性增强。
已经发现编码LEKTI的spink基因的突变是内瑟顿综合征的病因(Descargues等人2005.Spink5-deficient mice mimic Netherton syndrome through degradation ofdesmoglein 1by epidermal protease hyperactivity.Nat.Genet.37,56-65)并且该基因中的单点突变与特应性皮炎有关(Walley等人2001.Gene polymorphismin Netherton andcommon atopic disease.Nat.Genet.29,175-178;Nishio等人2003.Association betweenpolymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese.Genes Immun.4,515-517)。
KLK7活性增加与炎症性皮肤病相关的假设得到了以下研究的支持:首先,内瑟顿综合征患者表现出丝氨酸蛋白酶活性的表型依赖性增加、角膜小体的减少、脂质加工酶β-葡萄糖脑苷脂酶和酸性鞘磷脂酶的减少以及屏障功能受损(Descargues等人2006.Corneodesmosomal cadherins are preferential targets of stratum corneumtrypsin-and chymotrypsin-like hyperactivity in Nethertonsyndrome.J.Invest.Dermatol.126,1622-1632;Hachem等人2006.Serine proteaseactivity and residual LEKTI expression determine phenotype in Nethertonsyndrome.J.Invest.Dermatol.126,1609-1621.)。其次,过度表达KLK7的转基因小鼠表现出与特应性皮炎患者相似的皮肤表型(Hansson等人2002.Epidermal Overexpression ofStratum Corneum Chymotryptic Enzyme in Mice:A Model for Chronic Itchy Dermatitis.J.Invest.Dermatol.118,444-449;Ny&Egelrud.2003.Transgenic mice over-expressing a serine protease in the skin:evidence of interferon gamma-independent MHC II expression by epidermal keratinocytes.Acta Derm.Venereol.83,322-327;Ny&Egelrud.2004.Epidermal hyperproliferation anddecreased skin barrier function in mice overexpressing stratum corneumchymotryptic enzyme.Acta Derm.Venereol.84,18-22)。第三,描述了在特应性皮炎和银屑病患者的皮肤中KLK7水平的升高(Ekholm&Egelrud.1999.Stratum corneumchymotryptic enzyme in psoriasis.Arch.Dermatol.Res.291,195-200)。因此,KLK7被认为是治疗炎性皮肤病如特应性皮炎、银屑病或内瑟顿综合征的靶标,并且需要其特异性抑制剂。
WO 2004/108139描述了作为KLK7抑制剂的某些取代的苯并噁嗪酮和噻吩并噁嗪酮化合物。
WO 2015/112081确定了6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮作为KLK7的特异性抑制剂。
发明描述
6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮在水中溶解度低,但可溶于各种有机溶剂。然而,这种有机溶剂不适合用于治疗皮肤病的局部制剂。
使用普通药学上可接受的溶剂和赋形剂制备6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮制剂的最初尝试表明,在制剂储存时,6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮明显倾向于形成针状晶体。因此,需要进一步开发以获得稳定的局部制剂,其中可以避免6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮的晶体形成。
本发明人已经确定了稳定的局部制剂,其中可以避免6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮的结晶,即使是在室温下长期储存后。
本发明的一个方面涉及水包油乳液形式的包含6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮的局部制剂。
该制剂可以包含约0.01%(w/w)至约0.2%(w/w),例如约0.025%(w/w)至约0.1%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮。
优选地,该制剂包含约0.075%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮,其等于0.75mg/g制剂。
该制剂可包含约60%(w/w)至约75%(w/w)的油相。优选地,该制剂包含70%(w/w)油相。
油相可以包含甘油三酯油。甘油三酯油优选是中链甘油三酯油(MCT)。
优选地,油相包含超过50%(w/w)的MCT,例如超过60%(w/w)的MCT,或超过70%(w/w)的MCT。
该制剂还可以含有其他药学上可接受的赋形剂,如润肤剂、乳液形成剂/乳化剂、乳液增稠剂和稳定剂、抗氧化剂、防腐剂和中和剂/pH调节剂。
可用于本发明制剂的润肤剂包括常规润肤剂,例如肉豆蔻酸异丙酯(IPM)、棕榈酸异丙酯和异硬脂酸异丙酯。优选地,润肤剂是肉豆蔻酸异丙酯(IPM)。
可用于本发明制剂的成乳剂/乳化剂包括常规的成乳剂/乳化剂,例如聚乙二醇1000(PEG 20鲸蜡硬脂醇醚)、PEG 20硬脂醇醚和PEG 2硬脂醇醚。
优选地,乳液形成剂/乳化剂是聚乙二醇1000(PEG 20鲸蜡硬脂醇醚)。
可用于根据本发明的制剂中的乳液增稠剂和稳定剂包括常规的乳液增稠剂和稳定剂,例如鲸蜡硬脂醇、鲸蜡醇和硬脂醇。优选地,乳液增稠剂是鲸蜡硬脂醇。
可用于本发明的制剂的抗氧化剂包括常规抗氧化剂,例如α-生育酚、丁基化羟基甲苯(BHT)、丁基化羟基茴香醚(BHA)、叔丁基对苯二酚和没食子酸丙酯。
优选地,抗氧化剂是丁基化羟基甲苯(BHT)。
可用于本发明制剂中的防腐剂包括常规防腐剂,例如山梨酸、山梨酸钾、苯甲酸、苯甲酸钠、苯甲醇、苯氧乙醇、苯扎氯铵、对羟基苯甲酸(对羟基苯甲酸酯(parabens)),例如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯或其混合物,例如Phenonip。优选地,防腐剂系统是山梨酸和山梨酸钾的混合物。
可用于本发明制剂的中和/pH调节剂包括常规的中和/pH调节剂,例如缓冲水溶液。优选地,缓冲水溶液是柠檬酸盐缓冲液,优选pH为4.2。
在一个实施方案中,本发明提供了一种水包油乳液形式的局部制剂,所述制剂包含,
a)约0.01%(w/w)至约0.2%(w/w),例如约0.025%(w/w)至约0.1%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮,
b)约60%(w/w)至约75%(w/w)的油相,
c)约25%(w/w)至约40%(w/w)的水相,其中油相包含超过50%(w/w)的MCT。
在一个实施方案中,本发明提供了一种水包油乳液形式的局部制剂,所述制剂包含,
a)约0.075%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮,
b)约50%(w/w)的MCT,
c)约10%(w/w)的IPM,
d)约5%(w/w)的鲸蜡硬脂醇,
e)约5%(w/w)的聚乙二醇十六烷基醚,和
f)约30%(w/w)的柠檬酸盐缓冲液。
在另一个实施方案中,本发明提供了一种水包油乳液形式的局部制剂,所述制剂包含,
a)约0.075%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮,
b)约50%(w/w)的MCT,
c)约5%(w/w)的IPM,
d)约7.5%(w/w)的鲸蜡硬脂醇,
e)约7.5%(w/w)的聚乙二醇十六烷基醚,和
f)约30%(w/w)的柠檬酸盐缓冲液。
上述两种制剂为水包油乳液,包含约70%(w/w)的油相和约30%(w/w)的水相。乳液总体上包含约50%(w/w)的MCT,这对应于包含约71%(w/w)MCT的油相。本文制剂中使用的润肤剂、乳液形成剂/乳化剂、乳液增稠剂和稳定剂的量可以是油相量的一部分。
本发明的另一方面提供了根据本发明的用于预防、阻止和/或治疗皮肤病的局部制剂。
本发明的另一方面提供了一种预防、阻止和/或治疗皮肤病的方法,该方法包括给需要这种治疗的受试者施用根据本发明的局部制剂。
所述皮肤病可以是炎性皮肤病。皮肤炎症疾病可选自内瑟顿综合征、特应性皮炎、接触性皮炎、湿疹、银屑病、痤疮、表皮角化过度、棘皮病、表皮炎症、皮肤炎症、瘙痒和酒渣鼻。优选地,炎性皮肤病是内瑟顿综合征。
定义
如本文所用,术语“约”是指本文中的值或参数,其包括(并描述)针对该值或参数本身的实施方案。例如,涉及“约50”的描述包括“50”的描述。数值范围包括定义该范围的数值。一般而言,术语“约”指的是变量的指示值和在指示值的实验误差内(例如,在平均值的95%置信区间内)或在指示值的10%内的所有变量值,以较大者为准。
中链甘油三酯油或中链甘油三酯(MCT)是含有两个或三个脂肪酸的甘油三酯,具有6-12个碳原子的脂肪族尾部,即中链脂肪酸(MCFA)。MCFA是:C6己酸或己酸、C8辛酸或辛酸、C10癸酸或癸酸、C12月桂酸或十二烷酸。
鲸蜡硬脂醇(cetostearyl alcohol)、鲸蜡硬脂醇(cetearyl alcohol)或鲸蜡硬脂醇(cetylstearyl alcohol)是脂肪醇的混合物,主要由鲸蜡醇(16C)和硬脂醇(18C)组成。
聚乙二醇1000是聚乙二醇十六烷基醚。
肉豆蔻酸异丙酯(IPM)是异丙醇和肉豆蔻酸的酯。
丁基化羟基甲苯(BHT),也称为二丁基羟基甲苯,是化合物2,6-二叔丁基-4-甲基苯酚。
聚乙二醇(PEG)是一种聚醚化合物,结构式为H-(O-CH2-CH2)n-OH。
Phenonip是苯氧乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯和对羟基苯甲酸异丁酯的混合物。
实施例
实施例1.6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮(活性物
质)的溶解度测试
1)所有百分比都是重量百分比
2)表中出现的辅料的关键:
MCM=中链单酰基甘油
MCT=中链三酰甘油
Cremophor RH40=聚氧乙烯40氢化蓖麻油
Tego SMO 80V=聚山梨醇酯80
NMP=N-甲基-2-吡咯烷酮
IPM=肉豆蔻酸异丙酯
实施例2.基于MCT的配方
实施例3.乳膏的制备-批次量100g
油相:
MCT 50.0%(w/w) 增溶剂和润肤剂
IPM 10.0%(w/w) 润肤剂
鲸蜡硬脂醇 5.0%(w/w) 增稠剂
聚乙二醇1000 5.0%(w/w) 乳化剂
BHT 0.1%(w/w) 抗氧化剂
6-乙氧基-7-甲氧基-2- 0.075%(w/w) 活性药物成分
(2-甲基硫基苯基)-3,1-
苯并噁嗪-4-酮
水相:
山梨酸钾 0.20%(w/w) 防腐剂
山梨酸 0.15%(w/w) 防腐剂
柠檬酸盐缓冲液,25 调节至100%
mM,pH=4.20
将油性成分称重并在烧杯中混合。水相在另一个烧杯中混合。搅拌下将油相和水相都加热至约75℃。在高剪切混合(等)期间,将温热的水相加入温热的油相中。乳化(高剪切混合)间歇地继续,直到温度达到约30℃并形成均匀的白色粘稠乳膏。
实施例4.膏的制备-批次量40kg
油相:
水相:
山梨酸钾 0.20%(w/w) 防腐剂
山梨酸 0.15%(w/w) 防腐剂
柠檬酸盐缓冲液,25 调节至100%
mM,pH=4.20
将油性成分称重并在50升的罐中混合。水相在15升的烧杯中混合。搅拌下将油相和水相都加热至约70℃。在高剪切混合期间,将温热的水相加入温热的油相中。然后将设备置于真空状态。乳化(高剪切混合)在3,000rpm下持续30分钟。然后在缓慢混合的过程中进行冷却,直到温度达到约25℃并形成均匀的白色粘稠乳膏。最后,将所述乳膏装入10-ml铝管中。/>
Claims (8)
1.一种为水包油乳剂的局部制剂,所述制剂包含,
a)约0.01%(w/w)至约0.2%(w/w),例如约0.025%(w/w)至约0.1%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮,
b)约60%(w/w)至约75%(w/w)的油相,和
c)约25%(w/w)至约40%(w/w)的水相。
2.根据权利要求1所述的局部制剂,其中所述油相包含超过50%(w/w)的中链甘油三酯油(MCT)。
3.根据权利要求1所述的局部制剂,其包含
a)约0.075%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮,
b)约50%(w/w)的中链甘油三酯油(MCT),
c)约10%(w/w)的肉豆蔻酸异丙酯(IPM),
d)约5%(w/w)的鲸蜡硬脂醇,
e)约5%(w/w)的聚乙二醇十六烷基醚,和
f)约30%(w/w)的柠檬酸盐缓冲液。
4.根据权利要求1所述的局部制剂乳剂,所述制剂包含,
a)约0.075%(w/w)的6-乙氧基-7-甲氧基-2-(2-甲基硫基苯基)-3,1-苯并噁嗪-4-酮,
b)约50%(w/w)的中链甘油三酯油(MCT),
c)约5%(w/w)的肉豆蔻酸异丙酯(IPM),
d)约7.5%(w/w)的鲸蜡硬脂醇,
e)约7.5%(w/w)的聚乙二醇十六烷基醚,和
f)约30%(w/w)的柠檬酸盐缓冲液。
5.根据权利要求1至4中任一项所述的局部制剂,其用于预防、阻止和/或治疗皮肤病。
6.根据权利要求1至4中任一项所述的局部制剂,其用于预防、阻止和/或治疗炎性皮肤病。
7.根据权利要求1至4中任一项所述的局部制剂,其用于预防、阻止和/或治疗炎性皮肤病,所述炎性皮肤病选自内瑟顿综合征、特应性皮炎、接触性皮炎、湿疹、银屑病、痤疮、表皮角化过度、棘皮病、表皮炎症、真皮炎症以及瘙痒和酒渣鼻。
8.根据权利要求7所述的用途,其中所述炎性皮肤病为内瑟顿综合征。
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