CN1252003A - 增强药物化合物渗透作用的溶剂系统 - Google Patents
增强药物化合物渗透作用的溶剂系统 Download PDFInfo
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- CN1252003A CN1252003A CN98803908A CN98803908A CN1252003A CN 1252003 A CN1252003 A CN 1252003A CN 98803908 A CN98803908 A CN 98803908A CN 98803908 A CN98803908 A CN 98803908A CN 1252003 A CN1252003 A CN 1252003A
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Abstract
本发明揭示了一种组合物,由局部外用活性药物化合物或药物和能增加所述药物渗透性的缓冲的溶剂系统构成。缓冲溶剂系统能减少药物化合物在组合物中的用量而不明显改变所述化合物的效力。
Description
发明领域
本发明涉及其渗透性能被增强的药物组合物。这包括,但不限于,用于治疗皮肤疾病的局部外用组合物,其中局部外用活性药物化合物或药物通常是相对不溶的(或“溶解不良的”)弱酸或弱碱,但是,药物也可为可溶的化合物,其释药特征可以改变。更具体的是,本发明涉及缓冲的溶剂系统的加溶能力,这使它能明显地改变药物化合物或药物的皮肤渗透性。
发明背景
皮脂溢性皮炎是特征在于上皮细胞异常增生的皮肤疾病。皮肤细胞增生导致了在皮肤表面形成损伤。虽然治疗方法有多种,但本发明对使用咪唑类抗真菌剂尤感兴趣。
虽然其真正的原因仍处于讨论阶段,但现已提示,皮脂溢性皮炎可由真菌感染产生,这就是咪唑类抗真菌剂能如此有效地用于其治疗的原因。Ford等在英国皮肤学杂志(British Journal of Dermatology)第107卷,691-695(1982)一文中揭示了酮康唑可作为杀Pityrosporum ovale(Pityrosporum orbiculare或Malasseziafurfur)(在皮脂溢性皮炎中一种重要的病因)的杀真菌剂。美国专利4,942,162讨论了咪唑类抗真菌剂,特别是酮康唑和克霉唑在治疗牛皮癣和皮脂溢性皮炎中的应用。
该治疗可用口服或局部用药二种方式之一进行。USPat.No.4,491,588揭示了酮康唑和甲硝哒唑在口服组合物里治疗皮脂溢性皮炎的用途。但是,欧洲专利申请396,184揭示,通过局部外用酮康唑来治疗皮肤病,其效力和安全性增高。此外,根据美国专利4,446,145,只要局部外用是可行的,对于治疗皮肤病最好是避免口服疗法。
咪唑类虽然在组合物中作为单独的活性组分是有效的,但也可与其它药物活性剂组合使用。国际专利申请87/04617揭示了脲和咪唑衍生物在组合物里组合用于治疗各种皮肤病,但是,脲会在使用者的皮肤表面导致暂时性的敏感刺激。美国专利4,446,145揭示了咪唑与苯甲酰过氧化物组合的组合物特别用于治疗痤疮。相似的是,美国专利5,002,938揭示了供局部外用给药的咪唑类的稳定凝胶制剂,其中咪唑与甾族化合物组合,但皮脂溢性皮炎是慢性复发性疾病,因此,长期使用局部外用甾族化合物制剂的安全性是成问题的。
另外使用咪唑类的另一问题是释药系统。美国专利5,219,877揭示了用于局部外用给予咪唑类的增强渗透性的凝胶,它使用了月桂醇作为渗透增强剂。但是,该文揭示的组合物特别涉及被忽视的丙二醇,其加溶能力在本技术领域是公知的。
事实上,二元醇与其它溶剂的组合是增加活性剂皮肤渗透的极为有效的手段。英国专利申请2,202,743使用了丙二醇和乙醇的混合物作为溶解媒介,供局部外用给予硝酸双氯苯咪唑和硝酸益康唑,但该文所述的组合物需要有脲存在以增溶活性组分。相似的是,日本专利60-61518使用了低级醇-多元醇系统供局部给予克霉唑,但该文献揭示的组合物也需要中和剂和稳定剂。
低级醇和多元醇的组合是本技术领域公知的,作为可靠的液体载体系统。美国专利4,994,491使用了该类型的系统用反式视黄酸类治疗癌症。美国专利4,244,948也揭示了该组合局部给予乙酰水杨酸的释药能力,其中所述的系统被称为“方便的载体剂”。
该系统被用于许多抗真菌产品,如由Westwood-Squibb Pharmaceuticals,Inc.制备的Exelderm(1%硝酸硫康唑),Ortho Pharmaceutical Corporation制造的Monistat-Derm(2%硝酸双氯苯咪唑)和Glaxo Wellcome,Inc.生产的Oxistat(1%硝酸醋苯苄肟唑)。相似的是,美国专利5,476,852揭示了一种2%酮康唑局部外用凝胶制剂,它包括丙二醇和乙醇。但是,这些产品需要高浓度的咪唑类(约1-2%)以产生作用。另一个例子是Nizoral,由Janssen Pharmaceutica生产的2%酮康唑抗真菌霜剂,它含稍微不同的溶剂系统。该产品虽然相当有效,但也需要大比例的酮康唑。
因此本发明的一个目的是制造能以明显较低浓度的抗真菌活性剂释放出如目前抗真菌产品那样相同的治疗效果的组合物。
本发明的再一个目的是提供一种溶剂系统,它可用来增加相对不溶的弱酸或弱碱性药物化合物的释药。
本发明的再一个目的是提供一种溶剂系统,它能改变易溶的酸性或碱性药物化合物的渗透特性。
发明综述
本发明包括一种缓冲液溶剂系统,它能改变可溶解和溶解不良的局部外用活性药物化合物或药物的释药参数。令人惊奇的是,向适当平衡的溶剂系统里加入该缓冲组分,在局部外用组合物里可不需要过量的药物化合物。事实上,含有该系统的组合物仅需要不含该系统的产品的几分之一量的药物化合物。这很重要,因为它解决了缠绕了这些局部外用组合物多年的缺乏临床效力的问题。
该系统除了局部外用活性药物化合物或药物外,还包括挥发性的溶剂组分、非挥发性的溶剂组分和缓冲剂。该局部外用组合物通常含这样的任选组分,如螯合剂、抗氧化剂、防腐剂、胶凝剂和防晒剂以及其它本技术领域常用的物质。
附图简述
本发明由下列附图可更为明显,这些附图揭示了优选技术方案的一些特征。
图1是在酮康唑、丙二醇、乙醇和磷酸盐-柠檬酸盐缓冲剂的制剂里的实验1-4中得到的皮肤渗透性结果综述图。
图2是在酮康唑的闭合制剂里的实验6的皮肤渗透性结果综述图。
图3是酮康唑凝胶制剂在闭合和非闭合条件下由实验7得到的皮肤渗透性结果综述图。
发明详述
本发明涉及一种局部外用组合物,包括:
a)局部外用活性药物化合物或药物,和
b)缓冲的溶剂系统,包括:
I)挥发溶剂组分,
ii)非挥发溶剂组分,和
iii)缓冲剂。
本发明组合物里使用的局部外用活性药物化合物或药物可从两类里选择:溶解好的和溶解不良的。溶解不良的化合物可进一步分类为弱酸性和弱碱性。
弱碱性包括这类化合物,如咪唑类、三唑类、甾族抗炎药、其它抗真菌药物等。
优选的咪唑类和三唑类包括,但不限于,酮康唑、双氯苯咪唑、益康唑、衣屈康唑、特康唑、沙波康唑、氟康唑、甲硝唑、克霉唑、布康唑、奥昔康唑、硫康唑和它们的衍生物。该组中最优选的药物化合物是酮康唑。在下列示例性的实施例中,咪唑类和三唑类优选的用量是约0%(w/v)到约1%(w/v),更优选的是约0.1%(w/v)至约0.3%(w/v)。
合适的甾族抗炎剂包括,但不限于,皮质甾族化合物,如氢可的松、地塞米松、羟基曲安西龙、α-甲基地塞米松、地塞米松磷酸钠、倍他米松二丙酸盐、氯倍他松戊酸盐、地奈德、去氧地塞米松、去氧皮质酮乙酸盐、二氯松、二氯拉松二乙酸盐、二氟可龙戊酸盐、氟氢缩松、氟氢奈德、氟氢可的松、氟甲噻嗪新戊酸盐、氟轻松、氟轻松醋酸酯、氟可丁丁基酯、氟可龙、氟泼尼定(fluprednylidene)乙酸盐、哈西奈德、氢化可的松乙酸盐、氢化可的松丁酸盐、甲基泼尼松龙、曲安奈德、可的松、可托多松、flucetonide、氟氢可的松、difluorosone二乙酸盐、丙酮化氟氢缩松、甲羟松、安西法尔、安西非特、倍他米松和平衡的酯、氯泼尼松、氯泼尼松乙酸盐、氯可托龙、clescinolone、二氯松、二氟泼尼酯、氟氢奈德(flucloronide)、氟尼缩松、氟米龙、氟培龙、氟泼尼龙、氢化可的松戊酸盐、氢化可的松环戊基丙酸盐、氢可他酯、甲泼尼松、帕拉米松、泼尼松龙、泼尼松、倍氯米松二丙酸盐、倍他米松二丙酸盐、曲安西龙,也可使用它们的混合物。优选的甾族抗炎药是地塞米松和它的衍生物,而地塞米松磷酸钠是最好的。甾族抗炎药优选的存在量为约0%(w/v)到约5%(w/v)。
可从吗啉和它的衍生物以及特比萘芬和它的衍生物里选择其它抗真菌药物。优选的药物化合物是阿莫罗芬和它的衍生物,最好的是盐酸阿莫罗芬。这些抗真菌药物优选的存在量为约0%(w/v)-5%(w/v)。
用于本发明组合物的弱酸性化合物选自非甾族类抗炎剂(NSAID’s)。这些包括,但不限于,oxicams、水杨酸盐类、乙酸衍生物、灭酸酯类、丙酸衍生物、吡唑类和它们的混合物。虽然还有许多其它合适的弱酸存在,但优选的、适合用于本发明的弱酸是水杨酸、布洛芬和吲哚美辛。这些弱酸性化合物优选的存在量为约0.1%(w/v)-10%(w/v)。
可溶性药物化合物或药物可为酸性或碱性,其中缓冲的溶剂系统改变了这些化合物的渗透参数以增加它们的释放特征和效力。可溶的药物化合物包括,如α-羟基酸。优选的是选自烷基羟基羧酸、芳烷基和芳基2-羟基羧酸、多羟基-羧酸和羟基-多羧酸的α-羟基酸。最好的是选自乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、它们的衍生物及其混合物的α-羟基酸。优选的是,溶解的药物化合物存在量为约4%(w/v)-15%(w/v)。
缓冲溶剂系统的挥发性溶剂组分优选地包括低级(C1-C6)烷基醇、低级烷基二元醇和低级二元醇聚合物。更好的是挥发性溶剂选自乙醇和异丙醇。最优选的是,挥发性溶剂是乙醇。挥发性溶剂组分被认为可作为渗透增强剂,也可随着其蒸发,对皮肤产生冷却作用。该系统里的挥发溶剂量根据所述局部外用活性药物化合物或药物的溶解度和皮肤渗透性,通过所使用的药物化合物来决定。不管所使用的是哪种药物化合物或药物,限制挥发性溶剂的范围标准是相同的。该系统里的挥发溶剂太少,则药物会不溶,而过量的挥发溶剂会导致刺激皮肤。
缓冲溶剂系统的非挥发溶剂部分选自低级亚烷基二元醇和低级二元醇聚合物。优选的是,可使用丙二醇、聚乙二醇和聚丙二醇。更优选的是,使用的是丙二醇。非挥发性溶剂可减慢挥发溶剂的蒸发,并降低缓冲溶剂系统的蒸压。该非挥发溶剂组分的用量,如挥发溶剂相同,由所用的药物化合物或药物来决定。当该系统里非挥发溶剂的用量太少,药物化合物可能会由于挥发溶剂的蒸发而结晶,而过量,由于药物从溶剂混合物里的不良释放会导致生物利用度缺乏。
缓冲溶剂系统的缓冲组分可选自本技术领域通常使用的缓冲剂。缓冲剂组分的目的是保证药物化合物或药物处于非电离状态。当药物化合物是弱酸时,缓冲剂的选择仅限于其将系统的pH调节到至少低于药物化合物的pKa约0.5单位的能力,当药物化合物是弱碱时,则调节到至少高于药物化合物的pKa约0.5单位的能力。再一次,所用的药物化合物或药物决定了使系统运行正常所需的缓冲剂种类和用量。一些优选的缓冲剂包括柠檬酸盐、磷酸盐和硼酸盐缓冲剂和它们的组合。
一些任选的组分可加入局部外用组合物。它们包括,但不限于,螯合剂、抗氧剂、防腐剂、胶凝剂、防晒剂、阳光阻断剂、视黄酸类(retinoids)、苯并呋喃衍生物、N-乙酰基-L-半胱氨酸和它们的衍生物、皮肤保护剂和维生素。优选的抗氧剂是丁基化的羟基甲苯(BHT)、但如Remington’s Pharmaceutical Sciences,Gennaro,A.R.(编辑者),第18版,1990,Mack Publishing Co.,美国宾夕法尼亚,1286-1288(在此并入供参考)里所讨论的那样,抗坏血酸和它的衍生物、维生素E和它的衍生物也是合适的试剂。相似的是,合适的胶凝剂可包括,但不限于,半合成的纤维素衍生物和合成的聚合物。优选的是胶凝剂是羟丙基纤维素。防腐剂可选自本技术领域公知的,如药物工业理论和实践(The Theory and Practice ofIndustrial Pharmacy),Lachman,L.,Lieberman,H.A.和Kanig,J.L.第3版,1986,Lea & Febiger,美国宾夕法尼亚费城,467,521和553页(在此并入供参考)所讨论的这些物质,但对羟基苯甲酸酯类,特别是对羟基苯甲酸甲酯和对羟基苯甲酸丙酯是优选的。优选的螯合剂包括EDTA和柠檬酸,但EDTA最好。
合适的防晒剂包括,如:对-氨基苯甲酸(PABA),它的盐和它的衍生物,氨茴香酸盐、水杨酸盐、肉桂酸衍生物、二羟基肉桂酸衍生物、三羟基肉桂酸衍生物、烃类、二亚苄基丙酮和亚苄基乙酰苯、萘酚-磺酸盐(2-萘酚-,6-二磺酸的钠盐和2-萘酚-6,8-二磺酸钠盐)、二羟基萘甲酸和它的盐、邻-和对-羟基联苯二磺酸盐、香豆素衍生物、奎宁盐、喹啉和它的衍生物、尿酸和vilouric酸、单宁酸和它的衍生物、氢醌、二苯甲酮和羟基-或甲氧基-取代的二苯甲酮、4-异丙基二苯甲酰甲烷、丁基甲氧基二苯甲酰甲烷和氰双苯丙烯酸乙酯。用于本发明组合物里最好的防晒剂是2-乙基己基-对-甲氧基肉桂酸酯、丁基甲氧基二苯甲酰基甲烷、2-羟基-4-甲氧基二苯甲酮、辛基二甲基-对-氨基苯甲酸和它们的混合物。
但是,本发明的关键是挥发性溶剂与非挥发性溶剂与缓冲剂在缓冲的溶剂系统里的比率。下列实施例提示,当该系统与酮康唑作为局部外用活性药物化合物组合使用时,组分优选的比例为约5%到约15%非挥发性溶剂,约40%到约45%挥发性溶剂和约45-50%缓冲剂。当使用该系统时,所需的酮康唑浓度仅为0.3%,缺少该系统的市售组合物里的活性组分是其7倍。
缓冲溶剂系统里组分的比率根据所用的药物化合物或药物的溶解度特性而定。组合物可为溶液、凝胶、洗剂、霜剂、软膏剂等形式。下列实施例仅供阐述本发明可能的技术方案。
实施例1
0.3%酮康唑溶液和凝胶局部外用制剂
酮康唑的化学名是(±)顺-1-乙酰基-4-[4-[[2-(2,4-二氯苯基)-2-(1H-咪唑-1-基甲基)-1,3-二氧戊环-4-基]甲氧基]苯基]哌嗪,具有下列结构式:
通过首先制备0.1μ pH 6.00磷酸盐-柠檬酸盐缓冲液来制备0.3%酮康唑凝胶。将EDTA二钠溶于该缓冲液中。将对-羟基苯甲酸甲酯、对-羟基苯甲酸丙酯、BHT和酮康唑溶于乙醇。然后将丙二醇加到乙醇溶液里,混合完全。然后加入含EDTA的缓冲剂。搅拌下向溶液里慢慢加入羟丙基纤维素(Klucel HF)。让凝胶水化24小时,用1MHCl将最终pH调节到7.00。
实施例2
0.3%酮康唑组合物
改变丙二醇、乙醇和缓冲溶液的比例来制备13种0.3%酮康唑的溶液。其组成列于下表1
表1:溶剂组成
组合物 丙二醇(ml) 乙醇(ml) 缓冲液(ml) pH
A 60 20 20-水 8.88
B 40 40 20-水 8.36
C 20 60 20-水 7.89
D 20 40 40
6.00
E 20 40 40 7.00
F 20 40 40 8.00
G 20 60 20 7.00
H 10 60 30 7.00
I 30 30 40 7.00
J 5 45 50 7.00
K 5 55 40 7.00
L 0.01M HCl溶液 4.00
M 15 40 45 7.00
在组合物A、B和C中,水相是水而没有缓冲剂,在其它所有的组合物(组合物L除外)里,缓冲剂是磷酸盐-柠檬酸盐缓冲剂系统。在组合物L里,盐酸被用作溶剂系统。
实施例3
对0.3%酮康唑组合物的渗透性研究
用Franz扩散池在人尸皮肤上对如实施例2所定义的来自溶液A-M的酮康唑渗透性进行研究。Franz扩散池由上部提供池和下部的接受池构成,其中皮肤放在它们之间。提供池是一个开口的杯形,允许接近表皮供给药或其它目的。将被试验物质/制剂放在提供池里的上皮表面上。提供池在非闭合条件下对大气开放,在闭合条件下紧紧密封。提供池和接受池用夹子夹在一起。接受池的容量是10毫升,池与皮肤接触的截面积是0.6362cm2(0.9cm直径)。在接受池的周围放置热护套,用外循环水浴加热。将Teflon涂覆的搅拌棒放在接受池内,等离子pH为5.00的磷酸盐-柠檬酸盐缓冲剂用作接受溶液充填于该池内。在实验期间,从池内取出小体积接受溶液供分析,并补充以保持溶液体积稳定。
用三个扩散室来评估每个溶剂组合物,并(除了另作陈述外)关闭所有的池。在实验进程的48小时末,分离出皮肤中的上皮和真皮,用10毫升甲醇萃取,分析其酮康唑含量。渗透性结果如表2所示。
表2:组合物A-M的渗透件结果(标准化到1%酮康唑强度)
溶剂组合物 pH 到36小时的渗 在上皮里的量 在真皮里的量(PG∶乙醇∶Aq相) 透量(微克) (微克) (微克)A(60∶20∶20H2O) 8.88 11.13 8.07±6.60 1.83±1.87B(40∶40∶20H2O) 8.36 2.03 6.13±1.23 3.17±1.40C(20∶60∶20H2O) 7.89 5.03 23.03±25.73 7.00±8.53D(20∶40∶40缓冲液) 6.00 22.63 15.07±1.33 8.67±3.60E(20∶40∶40缓冲液) 7.00 29.87 22.53±3.87 12.10±3.47F(20∶40∶40缓冲液) 8.00 21.53 16.53±8.13 8.83±4.27G(20∶60∶20缓冲液) 7.00 39.27 47.67±40.40 25.13±13.87H(10∶60∶30缓冲液) 7.00 136.60 89.90±31.37 48.27±20.97I(30∶30∶40缓冲液) 7.00 41.40 60.47±41.97 25.20±19.83J(5∶45∶50缓冲液) 7.00 133.47 219.27±90.67* 55.10±20.90K(5∶55∶40缓冲液) 7.00 143.60 353.93±121.13* 38.73±1.97L(0.01M HCl) 4.00 64.77 339.47±106.73* 27.30±18.33J凝胶-非闭合 7.00 5.23 32.63±10.37 11.37±1.30(5∶45∶50缓冲液)M凝胶-非闭合 7.00 2.83 24.73±2.00 8.30±1.27(15∶40∶45缓冲液)2%Nizoral霜 7.60- 0.47 15.41±4.85 1.98±1.02非闭合 7.75J凝胶-闭合 7.00 46.43 83.47±4.10 41.77±10.40J凝胶-非闭合 7.00 3.17 47.87±17.97 5.37±2.07M凝胶-闭合 7.00 9.80 53.37±13.60 18.90±9.00M凝胶-非闭合 7.00 2.03 29.70±4.13 2.83±1.10
*上皮吸干技术与前面的操作不一致。真皮里的药物水平似乎是合理的。
在实验1(组合物A、B和C)里,在改变比例的丙二醇、乙醇和水里制备酮康唑溶液。在实验2(组合物D、E和F)里,用1MHCl将酮康唑缓冲溶液的最终pH调节到6.00、7.00或8.00。在实验3(组合物G、H和I)里,皮肤层(pH 7.00)里的最大渗透pH和残留的pH选自实验2,也改变丙二醇、乙醇和缓冲剂组成。在实验4里(组合物J、K和L),丙二醇组成被固定在5%,乙醇和pH7.00缓冲组成在组合物J和K里改变。将组合物J和K里酮康唑的渗透性与如美国专利4,569,935所述的酮康唑在盐酸(组合物L)里的渗透性相比。药物溶液L的pH为4.00。
基于实验1-4的结果,溶剂组合物J、H和K具有最大的渗透性和皮肤里的存留性。这如图1所示,图1是酮康唑在一段时间里渗透入皮肤的累计量的曲线。48小时后,组合物J、H和K的渗透量是其它组合物渗透量的两倍。
由于在制剂里的大量醇类会刺激患有皮脂溢性皮炎病人的敏感性皮肤,组合物J和M中醇量最小,故较为优选。也试图使用较少的乙醇的其它溶剂组合物,但0.3%酮康唑在这些组合物里形成了悬浮液。
表3:0.3%酮康唑在其中形成悬浮液的组合物
组合物 丙二醇(毫升) 乙醇(毫升) pH 7.00缓冲液(ml)
I 5 40 55
II 10 30 60
III* 10 40 50
IV 15 30 55
*部分溶解
如表3所述,0.3%酮康唑仅在特定比例的溶剂混合物里形成溶液。为了制备0.3%酮康唑溶液,乙醇含量需大于40%,或丙二醇含量应当大于10%,其中缓冲剂构成了组合物的其余部分。在此浓度范围里,组合物的刺激性最小,并具有可接受的生物利用度,同时保持物理上稳定。
实施例4
酮康唑凝胶组合物的制备
溶剂组合物J和M通过加入螯合剂、抗氧剂和防腐剂来改性,以制备凝胶。这样进行制备:首先将BHT、对-羟基苯甲酸甲酯和对-羟基苯甲酸丙酯溶于乙醇,然后加入丙二醇和含EDTA 二钠的磷酸盐-柠檬酸盐缓冲液。这些溶液然后用2%w/v羟丙基纤维素(高粘度级)来成凝胶,调节到pH7.00,该pH使皮肤的渗透性和存留性最大,也是使酮康唑的化学稳定性最大的pH。
表4:溶剂组合物J和M-改性以制备凝胶
组分 组合物J 组合物M丙二醇 5ml 15ml乙醇 45ml 40ml0.1μpH6.00磷酸盐-柠檬盐缓冲液 50ml 45ml(含0.05%w/vEDTA二钠)BHT 50mg 50mg对羟基苯甲酸甲酯 200mg 200mg对羟基苯甲酸丙酯 20mg 20mg
在实验6中,在非闭合条件下,将制剂J和M的酮康唑凝胶的渗透性与来自200毫克Nizoral霜剂的酮康唑渗透性进行比较。在实验7中,研究酮康唑凝胶J和M在闭合和非闭合条件下穿越人尸皮肤的渗透性。没有对来自实验5的数据作分析,因为用于试验渗透性的皮肤样品被发现有缺陷。如图2所示,实验5比较了Nizoral、J、K和M的闭合组合物。
图3是实验7显示透过皮肤的酮康唑随时间的累计量的图。在闭合条件下,凝胶J的渗透性稍好于凝胶M。但是,在非闭合条件下,两个凝胶制剂行为相似。
实验1显示的未缓冲药物溶液(自然pH 7.89到8.88),水作为组分之一,的渗透性和皮肤里药物的含量比凝胶J和M组合物里的低。酮康唑在0.01M盐酸溶液(组合物L)里也是这样的情况,其渗透性和真皮里的存留性都比丙二醇、乙醇和pH7.00缓冲溶剂混合物里的低。
酮康唑在皮肤层里的渗透性和存留性随着溶剂里丙二醇百分数的降低而增加。这可能是由于酮康唑在高比例的丙二醇里释放不良的原因。有5-10%丙二醇的组合物H、J和K的渗透性和皮肤存留性最大,这提示,该缓冲的溶剂系统已达到了酮康唑最大的热力学活性。
来自实验6和7的渗透性结果表明,闭合室比非闭合室具有更高的渗透性,皮肤里有更高的药物水平。对于J和M凝胶,在非闭合室里,在接受室里的和皮肤层里的酮康唑水平可与Nizoral霜剂类比,虽然凝胶的酮康唑强度仅为Nizoral霜剂的1/7。这些水平在皮脂溢性皮炎的皮肤里会更高,因为这样的皮肤比正常皮肤的通透性大。
实施例5
对0.3%酮康唑组合物的热稳定性分析
在30℃(抽取样品时间16周)、40℃(抽取样品时间8和16周)和50℃(抽取样品时间4周、8周、13周和16周)下对凝胶制剂J和M进行加速的热稳定性分析。将样品放入玻璃小瓶,在合适的温度下放置。表5的数据表明两种制剂里的药物是高稳定性的。在50℃贮存16周的样品仅有低于5%的降解。在50℃下放置13和16周可观察到稍显粉红色。
表5:0.3%酮康唑凝胶制剂在pH 7.00下的稳定性结果(保留百分数)组合物 开始 4周 8周 13周 16周
50℃ 40℃ 50℃ 50℃ 30℃ 40℃ 50℃
J 100 97.08 98.51 97.08 97.09 99.65 98.44 95.77
M 100 97.70 98.67 96.86 97.79 99.77 98.61 97.09
实施例6
非甾族抗炎药物(NSAID’s)的稳定性
水杨酸、布洛芬和吲哚美辛在水中的溶解度都很差。虽然它们在纯乙醇里的溶解度稍好[分别为37%(w/v),100%(w/v)和2.0%(w/v)],但上述的对皮肤刺激的问题成为关键。当放置在丙二醇、乙醇和pH6.00的0.1μ磷酸盐-柠檬酸盐缓冲液的两个极端缓冲溶剂系统里,其溶解度列于表6。
表6:NSAID’s的溶解度NASID 在10∶80∶10(PG∶乙醇∶缓冲液) 在80∶10∶10(PG∶乙醇∶缓冲液)
里的溶解度 里的溶解度水杨酸 35%w/v 20%w/v布洛芬 70%w/v 20%w/v吲哚美辛 1.5%w/v 1.0%w/v
布洛芬由Spectrum Chemical Mfg.Corp.,(美国加利福尼亚)提供。吲哚美辛由Sigma Chemical Co.(美国MO)提供,水杨酸由Sigma Chemical Co.(美国MO)提供。
实施例7
甾族抗炎药物的溶解度
氢可的松在丙二醇里的溶解度为1.27%(w/v),在乙醇里的溶解度为2.50%(w/v),在水里的溶解度为0.028%(w/v)。倍他米松二丙酸盐微溶于乙醇(1克溶于30-100毫升),实际上不溶于水(1克溶于多于10,000ml的水)。在丙二醇、乙醇和0.1μ磷酸盐-柠檬酸盐缓冲液(pH6.00)里的两个极端的缓冲溶剂系统里研究两种甾族抗炎药的溶解度,组合物列于表7。
表7:甾族抗炎药的溶解度
抗炎药 在10∶80∶10(PG∶乙醇∶缓冲液) 在80∶10∶10(PG∶乙醇∶缓冲液)
里的溶解度 里的溶解度
氢可的松 2.5%w/v 1.5%w/v倍他米松二丙酸盐 3.0%w/v 0.75%w/v
氢可的松和倍他米松二丙酸盐都由Spectrum Chemical Mfg.Corp.(美国加利福尼亚)提供。
实施例8
阿莫罗芬的溶解度
阿莫罗芬是吗啉衍生物,它以盐酸盐局部外用给药来治疗真菌感染的指甲和皮肤感染。对治疗的皮肤感染,包括各种形式的癣每天给予0.25%霜剂一次。为了治疗由于皮肤真菌、酵母和霉菌导致的指甲感染,将含相当于5%阿莫罗芬的指甲油被刷在感染的指甲上,每周一次,有时两次,直至指甲再生。阿莫罗芬碱溶解度差,但其盐酸盐,根据其结构,在水和乙醇中的溶解大于5%。
实施例9
α-羟基酸的溶解度
α-羟基酸(AHAs)在整个pH范围里的水性溶液里极溶。在两个极端溶剂组合物,丙二醇∶乙醇∶pH为6.00的0.1μ磷酸盐-柠檬酸盐缓冲液的比为10∶80∶10和80∶10∶10里研究它们的溶解度。表8给出了大致的溶解度。
表8:AHA的大致溶解度
α-羟基酸 10∶80∶10(PG∶乙醇∶缓冲液) 在80∶10∶10(PG∶乙醇∶缓冲液)
里的溶解度 里的溶解度
乙醇酸 >20%w/v 18%w/v
乳酸 >20%w/v >20%w/v
苹果酸 29%w/v 10%w/v
酒石酸 10%w/v 8%w/v
柠檬酸 16%w/v 10%w/v
虽然本发明通过一些可能的技术方案的实施例加以阐述,但应当明白它们不作为限定。
Claims (39)
1.一种局部外用组合物,包括:
a)局部外用活性药物化合物或药物,和
b)缓冲的溶剂系统,包括:
i)挥发溶剂组分,
ii)非挥发性溶剂组分,和
iii)缓冲剂组分,其功能是保持组合物的pH,使所述药物化合物大部分保持非电离状态。
2.根据权利要求1所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是在水中溶解度很差的弱碱。
3.根据权利要求1所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是在水中溶解度很差的弱酸。
4.根据权利要求2所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物选自咪唑类、三唑类、甾族抗炎剂和其它抗真菌药物。
5.根据权利要求4所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物量是0.01%(w/v)-5%(w/v)。
6.根据权利要求5所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是咪唑或三唑。
7.根据权利要求6所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物选自酮康唑、双氯苯咪唑、益康唑、衣屈康唑、特康唑、沙波庚唑、氟康唑、甲硝唑、克霉唑、布康唑、奥昔康唑、硫康唑、特比萘芬和它们的衍生物。
8.根据权利要求7所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物量为0%(w/v)-1%(w/v)酮康唑。
9.根据权利要求5所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是甾族抗炎药。
10.根据权利要求9所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是地塞米松磷酸钠。
11.根据权利要求5所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物选自阿莫罗芬和它的衍生物。
12.根据权利要求11所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是盐酸阿莫罗芬。
13.根据权利要求3所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是非甾族抗炎药。
14.根据权利要13所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物量为0.1%(w/v)到10%(w/v)。
15.根据权利要求14所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物选自水杨酸、布洛芬和吲哚美辛。
16.根据权利要求1所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物易溶于水。
17.根据权利要求16所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物是α-羟基酸。
18.根据权利要求17所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物量是4%(w/v)到15%(w/v)。
19.根据权利要求18所述的局部外用组合物,其中所述的局部外用活性药物化合物或药物选自乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、它们的衍生物和它们的混合物。
20.根据权利要求1所述的局部外用组合物,其中所述的挥发性溶剂组份是低级(C1-C6)烷基醇。
21.根据权利要求20所述的局部外用组合物,其中所述的挥发性溶剂组份选自乙醇和异丙醇。
22.根据权利要求21所述的局部外用组合物,其中所述的挥发性溶剂组份是乙醇。
23.根据权利要求1所述的局部外用组合物,其中所述的非挥发性溶剂组份选自低级亚烷基二醇和它们的衍生物,和低级二元醇聚合物。
24.根据权利要求23所述的局部外用组合物,其中所述的非挥发性溶剂组份选自丙二醇、聚乙二醇和聚丙二醇。
25.根据权利要求24所述的局部外用组合物,其中所述的非挥发性溶剂组份是丙二醇。
26.根据权利要求1所述的局部外用组合物,其中所述的缓冲剂选自柠檬酸盐、磷酸盐和硼酸盐缓冲剂系统和它们的组合。
27.根据权利要求26所述的局部外用组合物,其中所述的缓冲剂是磷酸盐-柠檬酸盐缓冲剂系统。
28.根据权利要求2和16所述的局部外用组合物,其中,当所述局部外用活性药物化合物或药物是碱性时,所述的缓冲剂将系统的pH保持在比所述局部外用活性药物化合物或药物的pKa高至少0.5个单位。
29.根据权利要求3和16所述的局部外用组合物,其中,当所述局部外用活性药物化合物或药物是酸性时,所述的缓冲剂将系统的pH保持在比所述局部外用活性药物化合物或药物的pKa低至少0.5个单位。
30.根据权利要求1所述的局部外用组合物,它进一步包括螯合剂、抗氧剂、防腐剂、胶凝剂、防晒剂、阳光阻断剂、视黄酸类、苯并呋喃衍生物、N-乙酰基-L-半胱氨酸和它的衍生物、皮肤保护剂和维生素类的任选组分,它们是非限定性的,为任何匹配的组合。
31.根据权利要求1所述的局部外用组合物,其中所述组合物为溶液、洗剂、凝胶剂、霜剂或软膏剂形式。
32一种局部外用组合物,包括:
a)0.3%酮康唑,
b)由下列组分构成的缓冲溶剂系统:
i)40%-45%(重量)乙醇,
ii)5%-15%(重量)丙二醇,
iii)45%-50%(重量)磷酸盐-柠檬酸盐缓冲剂。
33.根据权利要求32所述的局部外用组合物,它进一步包括EDTA、BHT、对-羟基苯甲酸甲酯、对-羟基苯甲酸丙酯和羟丙基纤维素。
34.根据权利要求32所述的局部外用组合物,其中所述组合物为溶液、洗剂、凝胶剂、霜剂或软膏剂形式。
35.一种治疗皮脂溢性皮炎、牛皮癣或其组合的方法,它包括对被所述皮肤疾病侵染的皮肤区域局部外用给予如权利要求32所述的组合物。
36.一种局部外用组合物,包括:
a)局部外用活性药物化合物或药物,它是弱碱性,在水中溶解度差;和
b)缓冲的溶剂系统,包括:
i)挥发性溶剂组分;
ii)非挥发性溶剂组分;和
iii)缓冲剂组分,其作用是将所述组合物的pH保持在比所述局部外用活性药物化合物或药物的pKa高至少0.5个单位。
37.一种局部外用组合物,包括:
a)局部外用活性药物化合物或药物,它是弱酸性,在水中溶解度差;和
b)缓冲的溶剂系统,包括:
i)挥发性溶剂组分;
ii)非挥发性溶剂组分;和
iii)缓冲剂组分,其作用是将所述组合物的pH保持在比所述局部外用活性药物化合物或药物的pKa低至少0.5个单位。
38.一种局部外用组合物,包括:
a)含有吡咯化合物的局部外用活性药物化合物或药物;和
b)缓冲的溶剂系统,包括:
i)挥发性溶剂组分;
ii)非挥发性溶剂组分;和
iii)缓冲剂组分,其作用是将所述组合物的pH保持在比所述局部外用活性药物化合物或药物的pKa高至少0.5个单位。
39.一种局部外用组合物,包括:
a)含有选自非甾族抗炎药物和视网膜酸的弱酸性化合物的局部外用活性药物化合物或药物;和
b)缓冲的溶剂系统,包括:
i)挥发性溶剂组分;
ii)非挥发性溶剂组分;和
iii)缓冲剂组分,其作用是将所述组合物的pH保持在比所述局部外用活性药物化合物或药物的pKa低至少0.5个单位。
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GB0103046D0 (en) | 2001-02-07 | 2001-03-21 | Novartis Ag | Organic Compounds |
IL142037A0 (en) * | 2001-03-15 | 2002-03-10 | Agis Ind 1983 Ltd | Pharmaceutical compositions containing a non-steroidal anti-inflammatory drug |
MY129350A (en) * | 2001-04-25 | 2007-03-30 | Bristol Myers Squibb Co | Aripiprazole oral solution |
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---|---|---|---|---|
CN101820877B (zh) * | 2007-08-27 | 2013-09-11 | 日本农药株式会社 | 用于真菌性皮炎的药剂 |
CN115745757A (zh) * | 2022-11-07 | 2023-03-07 | 中国人民解放军军事科学院军事医学研究院 | 一种液态多甘醇柱芳烃衍生物的合成及对经皮药效分子缓释的应用 |
CN115745757B (zh) * | 2022-11-07 | 2024-04-26 | 中国人民解放军军事科学院军事医学研究院 | 一种液态多甘醇柱芳烃衍生物的合成及对经皮药效分子缓释的应用 |
Also Published As
Publication number | Publication date |
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AR012217A1 (es) | 2000-09-27 |
CO5050328A1 (es) | 2001-06-27 |
EP0971746A1 (en) | 2000-01-19 |
BR9811458A (pt) | 2000-09-19 |
HUP0001739A3 (en) | 2001-04-28 |
PL335934A1 (en) | 2000-05-22 |
IL132096A0 (en) | 2001-03-19 |
KR19980081207A (ko) | 1998-11-25 |
AU6677698A (en) | 1998-10-22 |
ZA982662B (en) | 1999-09-30 |
HUP0001739A2 (hu) | 2000-12-28 |
WO1998043673A1 (en) | 1998-10-08 |
JP2001518879A (ja) | 2001-10-16 |
CA2285368A1 (en) | 1998-10-08 |
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