CN102753142A - 含益生菌、抗生素和不饱和非酯化脂肪酸的直肠、阴道或尿道给药的栓剂 - Google Patents
含益生菌、抗生素和不饱和非酯化脂肪酸的直肠、阴道或尿道给药的栓剂 Download PDFInfo
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Abstract
本发明涉及一种直肠、阴道或尿道给药的栓剂。本发明还涉及在含益生菌和抗生素的组合物中的至少一种不饱和非酯化脂肪酸在制备用于直肠、阴道或尿道给药的栓剂中的用途。
Description
发明领域
本发明涉及药物制剂领域,尤其涉及直肠、阴道或尿道给药的栓剂和至少一种不饱和非酯化脂肪酸的用于制备栓剂的用途。
发明背景
人体内直肠包括最后12-19cm的大肠,直肠上皮由单层的柱状或立方细胞和杯状细胞形成。其表面积大约为200-400cm2且血管丰富。该重要的血液供给包括直接与体循环连接的下静脉和中静脉以及与与门脉系统连接的直肠上静脉。直肠的血管形成确保了所施用药物的吸收、分布和全身作用。以栓剂的形式施用到直肠下部的药物被下静脉和中静脉吸收并绕过肝的门静脉‘首过’消除,门静脉负责许多口服给药的药物的代谢和快速清除(Bergogne-Bérézin and Bryskier,1999)。
属于抗微生物化合物组的抗生素广泛用于治疗各种微生物包括细菌、真菌和原生动物导致的感染。益生菌因其微生物特性而众所周知并已经用于治疗胃肠的和阴道粘膜的感染。益生菌目前与抗生素一起用于几种适应证,或者试图改善治疗本身的抗菌效果,或者主要用于缓和常与抗生素的施用相关的胃肠副作用(D′Souza等人,2002)。
益生菌通常口服给药。抗生素主要通过口服或通过肠胃外途径给药-后者用于口服途径生物利用差或不能利用或者当临床情形需要在体内达到迅速或较高的抗生素浓度时。
直肠给药后被动转运是吸收的主要机制,即吸收主要依赖于分子量、脂溶性和分子的离子化程度。依赖于其化学结构,药物可或多或少通过跨过上皮细胞或经相互连接粘膜细胞的紧密连接部(tightjunctions)吸收穿过直肠壁。含药物的药物制剂在直肠吸收中起主要作用,因此在经栓剂施用的药物的全身分布中起主要作用。
因此,所要解决的技术问题是提供药物粘膜给药吸收性能改进的药物制剂。
解决该技术问题的技术方案通过提供权利要求书、以及以下进一步的描述表征的实施方案实现。
发明概述
本发明的第一方面涉及直肠、阴道或尿道给药的栓剂,其包含至少一种益生菌、至少一种抗生素、和至少一种不饱和非酯化脂肪酸。
本发明的第二方面涉及至少一种不饱和非酯化脂肪酸用于制备抗生素和/或益生菌直肠、阴道或尿道给药的栓剂的用途,其中抗生素的吸收增加。
本发明根据以下说明的公开将是显而易见的。
发明详述
一方面,本发明涉及直肠、阴道或尿道给药的栓剂,其包含至少一种益生菌、至少一种抗生素和至少一种不饱和非酯化脂肪酸。
本文中所用的术语“栓剂”指粘膜应用形式,如普通栓剂以及直肠用的胶囊和灌肠剂即溶液剂和混悬剂。本文中所用的术语“脂肪酸”指包含低于7个C原子的链的脂肪族单羧酸,亦称低链脂肪酸,包含8至12个C原子的链的脂肪族单羧酸,亦称中链脂肪酸,以及具有多于12个C原子的链的脂肪单羧酸,亦称高链脂肪酸。本文中所用的术语“不饱和脂肪酸”指单和多不饱和脂肪酸,术语“非酯化脂肪酸”指不含酯化残基的脂肪酸。本文中所用的术语“抗生素”指天然、合成及微生物来源的抗微生物的化合物。本文中所用的术语“益生菌”指还包括其减弱形式(attenuated form)的活微生物,其在给药之后给予宿主健康益处。
本发明的栓剂的给药形式提供抗生素的全身活性并直接对其靶向部位-即直肠、阴道或尿道粘膜上的菌群(flora)带来益生菌。栓剂避免了口服输送的缺点,如恶心、呕吐和由此产生的拒绝摄取,特别是在小儿科产生高依从性。尽管吞咽和意识困难但它可施用并避免肝门静脉的首过效应。
本发明的栓剂包含单一栓剂中的一种或多种抗生素和一种或多种益生菌的组合。抗生素通过杀死病原体有效地治疗感染,同时益生菌通过恢复受抗生素影响的粘膜生理细菌群落使抗生素的副作用(如胃肠症状)减到最小。通过减少胃肠症状,如腹泻或恶心,治疗期间患者依从性和生活质量提高。而且,益生菌不仅恢复生理菌群,而且用于抵抗粘膜表面的感染。益生菌通过补充机制如产生抑制因子、竞争性抑制营养素和适当的空间、和通过产生例如H2O2、有机或挥发性脂肪酸改变粘膜环境来抑制病原体的生长。通过本发明的栓剂益生菌和抗生素的有益作用得到扩大。例如,在抗生素治疗的末期真菌的定居(colonization)以及耐抗生素细菌发展的可能性下降。因此,抗生素治疗的效力通过益生菌协同提高。
除抗生素和益生菌外本发明的栓剂在单一药物制剂中还包含不饱和非酯化脂肪酸。本发明的栓剂中的脂肪酸改善抗生素通过粘膜的吸收并增加抗生素的细胞膜渗透性。这意味着1)抗生素更快进入体循环(tide)和在较短的时间内体循环中达到有效水平,和2)粘膜的吸收能力提高。因此,本发明的栓剂允许显著减少抗生素的应用剂量,因此副作用很大程度最小化且患者的机体受催化抗生素的应激影响较小。
不受任何理论的束缚,发明人相信本发明栓剂所改进的抗生素粘膜吸收是不饱和非酯化脂肪酸两亲性质的结果。由于这种两亲性质脂肪酸能穿过细胞膜被动扩散进入粘膜的细胞质和血管的内腔。在扩散过程中抗生素与不饱和非酯化脂肪酸缔合因而被输送到血液循环。可改变饱和度以增强脂肪酸和抗生素的缔合。通过计算脂肪酸的亲水-亲脂-平衡(HFB)改变脂肪酸链的长度以促进膜渗透(Brezesinsky and,1993)。
栓剂中的不饱和非酯化脂肪酸不仅改进抗生素的粘膜穿透概率,而且通过影响细菌粘附于粘膜表面来改进抗菌能力。当补充以游离的多不饱和脂肪酸时,大多数益生菌和病原菌的疏水性倾向于降低,由此附着力下降。因此,游离的多不饱和脂肪酸抑制宿主粘膜上大多数菌株的生长。一个例外是干酪乳杆菌Shirota(Lactobacillus caseiShirota),其生长被低浓度的γ-亚麻酸和花生四烯酸促进。
不同的原核生物和真核生物有机体可用作益生菌。在本发明优选的实施方案中益生菌包括乳杆菌属(Lactobacillus)、双歧杆菌属(Bifidobacterium)、糖酵母属(Saccharomyces)、链球菌属(Streptococcus)、和肠球菌属(Entereococcus),其以单价或者以组合不同益生菌的多价制剂的形式存在。长双歧杆菌(Bifidobacteriumlongum),加氏乳杆菌(Lactobacillus grasseri),干酪乳杆菌(Lactobacillus casei),保加利亚乳杆菌(Lactobacillus bulgaricus),屎肠球菌(Enterococcus faecium),布拉尔酵母菌(Saccharomycesboulardii)和嗜热链球菌(Streptococcus thermophilus)为优选的益生菌,因为对其预防或治疗与抗生素使用相关的和/或由艰难梭菌引起的腹泻而不产生任何副作用进行了评价(Czerucka等人,2007;Hickson等人,2007;Vahjen and ,2003)。优选短双歧杆菌(Bifidobacterium breve)菌株Yakult,因为其对硫酸链霉素天然有抵抗力并在致命的小鼠STEC感染模型中显示抗产Shiga毒素的大肠杆菌(Escherichia coli)的抗感染活性(Asahara等人,2004)。
在本发明的更优选实施方案中,抗生素包括氨基糖苷类、阿米卡星、氨苄西林、金链菌素(aureothidin)、杆菌肽、β-内酰胺(β-lactame)、头孢菌素(cephalosporine)、氯霉素、氯唑西林、环丝氨酸、地贝卡星、红霉素、氟喹诺酮、弗氏霉素(fradiomycin)、梭链孢酸、庆大霉素、短杆菌肽(gramacidin)、卡那霉素、卡那霉素B、利维霉素(lipidomycin)、大环内酯类抗生素、甲硝哒唑、萘啶酸、新霉素、新生霉素、巴龙霉素、青霉素、肽抗生素、多粘菌素B、喹诺酮、利福平、壮观霉素、链霉素、西索米星、四环素、妥布霉素、万古霉素或其组合。
在本发明的更优选实施方案中益生菌抵抗本发明的栓剂中使用的抗生素。抗生素和耐抗生素益生菌的优选的组合为:
-与短双歧杆菌菌株Yakult组合的链霉素;
-与嗜酸乳杆菌或乳糖双歧杆菌(Bifidobacterium lactis)组合的庆大霉素、卡那霉素、新霉素、或链霉素。
在本发明优选的实施方案中脂肪酸包括油酸和/或多不饱和脂肪酸。优选的多不饱和脂肪酸为γ-亚麻酸、亚油酸、Ω-3脂肪酸、Ω-6脂肪酸、花生四烯酸、或其组合。多不饱和脂肪酸和油酸发挥抗微生物效力并显示对抗生素最佳的膜渗透性能。
本发明的最优选实施方案为包含1)适合于治疗各个感染的抗生素、2)干酪乳杆菌Shirota的耐抗生素变体、3)和γ-亚麻酸和/或花生四烯酸的栓剂。如果多不饱和的非酯化脂肪酸与益生菌同时释放,此实施方案是有益的,因为干酪乳杆菌Shirota的生长被低浓度的γ-亚麻酸和/或花生四烯酸促进。
在本发明优选的实施方案中益生菌以缓释的形式提供。益生菌与抗生素和脂肪酸被时控型保护包衣分开,从而使得抗生素首先释放进入体循环用于抗感染,益生菌延迟释放以恢复细菌群落并在粘膜上局部起作用。在最优选的实施方案中益生菌在存在于同一栓剂中的抗生素药代动力学循环末端之前不久释放。如果在抗生素和益生菌之间使用保护层,在本发明栓剂中,不仅可以使用耐抗生素的益生菌,而且也可以使用不耐抗生素的变体菌种。
在本发明优选的实施方案中栓剂还包含抗氧化剂。抗氧化剂使栓剂的组分稳定并保护它们免受氧化和降解。
在更优选的实施方案中抗氧化剂包括咪唑,肌肽,鹅肌肽,类胡萝卜素,硫辛酸,硫醇,硫代丙酸酯,硫代丙酸,磺基肟(sulfoxmine)化合物,α-羟基-脂肪酸、α-羟酸、金属络合剂、叶酸、醌、维生素C、生育酚、维甲类、维生素A、芸香酸、α-糖基芦丁、尿酸、甘露糖、锌化合物、硒、1,2-二苯乙烯、其衍生物、或其组合。
在本发明最优选的实施方案中抗氧化剂为生育酚,其能保护粘膜并使上皮细胞的功能最佳化。因此,生育酚使直肠、阴道或尿道粘膜快速复原。
在另一优选的实施方案中本发明的栓剂还包含中性脂肪。除前面提到的成分之外,在本发明的栓剂中还可以根据需要包括下列成分:着色剂,湿润剂,表面活性剂,增稠剂,稳定剂和防腐剂。
在其它方面,本发明涉及至少一种不饱和非酯化脂肪酸在制备用于抗生素和/或益生菌直肠、阴道或尿道给药的栓剂中的用途,其中抗生素的吸收增加。
本发明的栓剂用于治疗和/或预防各种急性和慢性炎症以及细菌感染,尤其胃肠、阴道或尿道的上述病症。例如,栓剂用于恢复粘膜菌群以及治疗和/或预防炎性肠疾病,如溃疡性结肠炎或MorbusCrohn-尤其复发的预防-腹泻,便秘,膀胱炎,结肠炎,过敏症或神经性皮炎。在对口服施用依从性差或出现胃敏感的情况下,本发明的栓剂优选施用于小儿科和老年科(geriatrics)。
栓剂配方的实施例
用于小儿科和儿童的栓剂的配方为1g重量或者用于成人的栓剂为2g重量:
-25mg加氏乳杆菌和25mg长双歧杆菌,在栓剂的延释芯内被保护层包衣
-对于轻度/中度感染30mg头孢克洛/kg体重,每日3次,或者对于重度感染50mg头孢克洛/kg体重,每日3次。
-0.05g生育酚
-0.05g亚麻酸
-混合脂肪酸甘油酯(Adeps neutralis):适量
参考文献
Asahara T.,Infect.Immun.72(4):2240-2247,2004
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Czerucka D.等人,Aliment.Pharmacol.Ther.26(6):767-778,2007
D′Souza A.L.等人,BMJ 324(7350):1361,2002
Hickson M.等人,BMJ 335(7610):80,2007
Claims (11)
1.用于直肠、阴道或尿道给药的栓剂,包含至少一种益生菌、至少一种抗生素、和至少一种不饱和非酯化脂肪酸。
2.根据权利要求书1的栓剂,其中益生菌选自乳杆菌属、双歧杆菌属、糖酵母属、链球菌属、肠球菌属及其组合。
3.根据权利要求1或2的栓剂,其中抗生素选自氨基糖苷类、阿米卡星、氨苄西林、金链菌素、杆菌肽、β-内酰胺、头孢菌素、氯霉素、氯唑西林、环丝氨酸、地贝卡星、红霉素、氟喹诺酮、弗氏霉素、梭链孢酸、庆大霉素、短杆菌肽、卡那霉素、卡那霉素B、利维霉素、大环内酯类抗生素、甲硝哒唑、萘啶酸、新霉素、新生霉素、巴龙霉素、青霉素、肽抗生素、多粘菌素B、喹诺酮、利福平、壮观霉素、链霉素、西索米星、四环素、妥布霉素、万古霉素、及其组合。
4.根据前述权利要求之一的栓剂,其中脂肪酸为油酸和/或多不饱和脂肪酸。
5.根据前述权利要求之一的栓剂,其中多不饱和脂肪酸选自γ-亚麻酸、亚油酸、Ω-3脂肪酸、Ω-6脂肪酸、花生四烯酸、及其组合。
6.根据前述权利要求之一的栓剂,其中益生菌为干酪乳杆菌Shirota耐抗生素的变体、且脂肪酸为γ-亚麻酸和/或花生四烯酸。
7.根据前述权利要求之一的栓剂,其中益生菌以缓释的形式提供。
8.根据前述权利要求之一的栓剂,还包含抗氧化剂。
9.根据前述权利要求之一的栓剂,其中抗氧化剂选自咪唑、肌肽、鹅肌肽、类胡萝卜素、硫辛酸、硫醇、硫代丙酸酯、硫代二丙酸、磺基肟化合物、α-羟基-脂肪酸、α-羟酸、金属络合剂、叶酸、醌、维生素C、生育酚、维甲类、维生素A、芸香酸、α-糖基芦丁、尿酸、甘露糖、锌化合物、硒、1,2-二苯乙烯、其衍生物、及其组合。
10.根据前述权利要求之一的栓剂,还包含中性脂肪。
11.至少一种不饱和非酯化脂肪酸在制备栓剂中的用途,所述栓剂用于直肠、阴道或尿道给药抗生素和/或益生菌,其中抗生素的吸收增加。
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PCT/EP2010/007268 WO2011066949A1 (en) | 2009-12-02 | 2010-12-01 | Suppository for rectal, vaginal or urethral administration containing a probiotic, an antibiotic and an unsaturated non- esterified fatty acid |
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CN108653729A (zh) * | 2018-08-27 | 2018-10-16 | 广州汇高生物科技有限公司 | 一种阴道泡沫剂及其应用 |
CN108853475A (zh) * | 2018-09-29 | 2018-11-23 | 沈阳师范大学 | 一种酸化肠道抑菌栓剂及其制备方法 |
CN109010825A (zh) * | 2018-08-27 | 2018-12-18 | 广州汇高生物科技有限公司 | 一种阴道原位凝胶制剂及其制备方法和应用 |
CN109195615A (zh) * | 2016-04-27 | 2019-01-11 | 百科达公司 | 用于制备阴道栓剂的组合物 |
CN111315400A (zh) * | 2017-05-19 | 2020-06-19 | 卢内拉生物技术有限公司 | Antimitoscin:用于根除癌症干细胞的线粒体生物发生的靶向抑制剂 |
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CN109195615A (zh) * | 2016-04-27 | 2019-01-11 | 百科达公司 | 用于制备阴道栓剂的组合物 |
CN111315400A (zh) * | 2017-05-19 | 2020-06-19 | 卢内拉生物技术有限公司 | Antimitoscin:用于根除癌症干细胞的线粒体生物发生的靶向抑制剂 |
CN108653729A (zh) * | 2018-08-27 | 2018-10-16 | 广州汇高生物科技有限公司 | 一种阴道泡沫剂及其应用 |
CN109010825A (zh) * | 2018-08-27 | 2018-12-18 | 广州汇高生物科技有限公司 | 一种阴道原位凝胶制剂及其制备方法和应用 |
CN109010825B (zh) * | 2018-08-27 | 2021-11-19 | 广州汇高生物科技有限公司 | 一种阴道原位凝胶制剂及其制备方法和应用 |
CN108653729B (zh) * | 2018-08-27 | 2021-11-19 | 广州汇高生物科技有限公司 | 一种阴道泡沫剂及其应用 |
CN108853475A (zh) * | 2018-09-29 | 2018-11-23 | 沈阳师范大学 | 一种酸化肠道抑菌栓剂及其制备方法 |
CN108853475B (zh) * | 2018-09-29 | 2021-06-18 | 沈阳师范大学 | 一种酸化肠道抑菌栓剂及其制备方法 |
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DK2338476T3 (da) | 2012-09-17 |
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CA2782204A1 (en) | 2011-06-09 |
EP2505188A1 (en) | 2012-10-03 |
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