CN115137699A - 一种增效防腐的右美托咪定鼻喷剂 - Google Patents
一种增效防腐的右美托咪定鼻喷剂 Download PDFInfo
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- CUHVIMMYOGQXCV-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CNC=N1 CUHVIMMYOGQXCV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A—HUMAN NECESSITIES
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- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P25/20—Hypnotics; Sedatives
Abstract
本发明属于医药卫生技术领域,提供一种增效防腐的右美托咪定鼻喷剂,通过本发明的技术方案,较大的缩减苯扎氯铵浓度的同时,通过添加极少量的依地酸或其盐作为防腐增效剂,即可让本发明制剂处方满足抑菌标准要求。由此,兼顾了苯扎氯铵高浓度下的使用对呼吸道粘膜造成的影响、刺激感和不舒适性,以及苯扎氯铵低浓度下难以满足抑菌效力标准要求的两个矛盾问题。
Description
技术领域
本发明属于医药卫生技术领域,具体涉及一种增效防腐的右美托咪定鼻喷剂。
背景技术
右美托咪定,dexmedetomidine,(+)-4-[(S)-1-(2,3-二甲基苯基)乙基]-1H-咪唑,是由Orion Pharma和Abbott公司合作开发的具有抗交感、镇静和镇痛性质的非麻醉性α-2肾上腺素受体激动剂,其结构式如下:
右美托咪定暂仅被批准以注射液形式进行上市。中国药监局官网显示,江苏恒瑞医药、四川普锐特药业、无锡济煜山禾制药正着手进行改剂型的2类新药右美托咪定鼻喷剂的研发,江苏恒瑞医药、四川普锐特药业的相关产品均已进入临床阶段。
苯扎氯铵是较为常用的鼻用药物制剂的防腐剂,相对于其他种类的防腐剂,其对人鼻腔粘膜的刺激性和损害是较低的。在右美托咪定鼻喷剂处方中,含有较高的苯扎氯铵浓度才可满足抑菌标准,虽然苯扎氯铵本身的刺激性和损害较低,但是较高浓度的苯扎氯铵依然会给对鼻粘膜纤毛摆动的功能产生影响,Hofmann T等的研究试验显示人鼻粘膜纤毛上皮细胞暴露于苯扎氯铵(0.005%和0.01%)7分钟后,分别使纤毛摆动频率降低和不可逆静止(Hofmann T,Gugatschga M,Koidl B,Wolf G.Influence of Preservatives andTopical Steroids on Ciliary Beat Frequency In Vitro.Arch Otolaryngol HeadNeck Surg.2004;130(4):440–445.),较高浓度的苯扎氯铵同时给患者用药带来刺激感和不舒适的感受,降低患者易受性。进一步研究发现,如若将右美托咪定鼻喷剂处方中的苯扎氯铵浓度降低以提升患者使用体验和易受性,则右美托咪定鼻喷剂处方的抑菌效力将受到显著影响,不满足抑菌标准。因此,本发明要面临的问题是如何满足降低苯扎氯铵浓度,减少对呼吸道粘膜特别是鼻粘膜纤毛摆动影响、提升患者使用体验和易受性的需求,且在不引入其他常规刺激性更强的防腐剂的前提下,同时使处方满足抑菌标准要求。
本发明的申请人在先申请的公布号CN112107544A的中国发明专利申请中,公开了一种右美托咪定鼻喷剂,在其抑菌效力试验中披露了“0.02%BKC”的单方防腐剂浓度以及“0.1%丙二醇+0.01%BKC”的二方复配防腐剂浓度均能使处方满足中国药典抑菌标准。
公开号CN111481506A,申请人江苏恒瑞医药的中国发明专利申请公开了一种右美托咪定鼻喷雾剂,其主要技术构思是提出了不添加络合剂/螯合剂EDTA-2Na,也能使制剂产品获得相当的处方稳定性。其实施例3具体公开了不含络合剂EDTA-2Na的处方,由0.02(W/V)%的盐酸右美托咪定(以游离碱计)、0.015(W/V)%的苯扎氯铵、0.9(W/V)%的氯化钠、适量氢氧化钠和水组成。但未有处方抑菌效力方面的研究披露。
公开号CN104470516A,申请人瑞克欧的中国发明专利申请公开了一种右美托咪定鼻喷剂,其实施例具体处方中使用的防腐剂为“苯基乙醇”,其发明内容章节泛概念的罗列了涉及苯扎氯铵的多种防腐剂,其发明内容章节提出了其处方中可以添加EDTA或其盐作为螯合剂或络合剂,目的是络合过量钙离子防止储存过程中形成凝胶,防止右美托咪定或其他化合物的多价阳离子降解。
《药用辅料手册原著第四版》([英]R.C.罗等著,郑俊民主译)中披露了“(依地酸)与其他抗菌防腐剂合用时依地酸表现出显著的抗菌协同作用。因此,通常把依地酸和依地酸盐与苯扎氯铵、溴硝丙二醇、西曲溴、咪唑烷脲、羟苯甲酯和苯酚,特别是与氯二甲苯酚联合使用。一般依地酸的使用浓度是0.1%-0.15%(W/V)”。
发明内容
为了解决现有技术存在的上述问题,本发明目的在于提供一种新处方的右美托咪定鼻喷剂。
如《药用辅料手册原著第四版》记载,依地酸作为防腐增效剂与苯扎氯铵的通常配合使用浓度为0.1%-0.15%(W/V)。而本发明实践中意外发现,在右美托咪定鼻喷剂本品种中,依地酸盐仅以极少的0.005%-0.015%的添加量即可使原本不符合抑菌标准要求的低浓度苯扎氯铵处方重新满足抑菌效力标准要求。
基于以上意外发现和技术构思下,本发明提供一种新的右美托咪定鼻喷剂,包括水和右美托咪定或其盐,还包括防腐剂苯扎氯铵和防腐增效剂依地酸或其盐,苯扎氯铵的质量百分比浓度为0.005%-0.0095%,依地酸或其盐的质量百分比浓度为0.005%-0.015%。根据具体实施方式,防腐增效剂优选为依地酸二钠,其质量百分比浓度优选为0.005%-0.01%、0.005%、0.0075%、0.01%或0.015%。根据具体实施方式,防腐剂苯扎氯铵的质量百分比浓度优选为0.005%、0.0075%、0.0085%或0.0095%。
尤其是本发明所提供的新的右美托咪定鼻喷剂可不含比苯扎氯铵对人鼻粘膜刺激性更强的防腐剂、或者不含有除苯扎氯铵外的其他种类任何防腐剂。也可以进一步优化表示为所提供的右美托咪定鼻喷剂仅仅只含有苯扎氯铵作为防腐剂。应当声明的是,本发明中提及的“右美托咪定”、“氯化钠”、“甘油”、“EDTA-2Na”、“依地酸”和“依地酸盐”均排除出本发明中所定义的防腐剂范畴。
以上本发明所提供的新的右美托咪定鼻喷剂,优化了处方设计,较大的缩减了苯扎氯铵的浓度。与常规用量0.02%、以及CN112107544A或CN111481506A等现有技术相比较,现有技术的苯扎氯铵浓度是本发明的1.76倍~4倍。在较大的缩减苯扎氯铵浓度的同时,通过添加极少量的依地酸或其盐作为防腐增效剂,即可让本发明处方满足抑菌标准要求。由此,兼顾了苯扎氯铵高浓度下的使用对呼吸道粘膜造成的影响、刺激感和不舒适性,以及苯扎氯铵低浓度下难以满足抑菌效力标准要求的两个矛盾问题。不同于教科书披露的依地酸或其盐作为防腐增效剂功用下的高使用浓度0.1%-0.15%,本发明意外发现,在右美托咪定鼻喷剂处方中,依地酸或其盐仅以0.005%-0.015%该极为少量的浓度使用,即可协同低浓度的苯扎氯铵取得良好的抑菌效力。本发明方案中的依地酸或其盐的用量仅为教科书规定用量的1/30~1/7。
基于以上技术构思和具体实施方式中记载的本发明的技术方案,本发明所提供的右美托咪定鼻喷剂中,渗透压调节剂优选为甘油或氯化钠。优选为甘油时,其质量百分比浓度为0.1%-5.0%或2.5-2.8%,优选2.7%。优选为氯化钠时,其质量百分比浓度为0.7%-1.0%、0.7%、0.8%或0.9%。本发明所提供的右美托咪定鼻喷剂中,以右美托咪定计,活性成分的质量百分比浓度为0.005%-1.3%、0.0125%-0.7%或0.006%-0.108%,优选为0.01%、0.015%、0.02%、0.03%或0.05%。右美托咪定以盐酸盐的形式添加。
具体实施方式
本发明中,除非另有定义,所采用的科技术语均遵循行业通常理解。
本发明中,如无另有特别说明,所提及的试剂和仪器均通过普通市售采购获得。
本发明中,盐酸右美托咪定与右美托咪定的换算系数以1.182近似折算。
本发明中,如无特别额外说明,所使用的“%”均指代“质量百分比”。
本发明中,右美托咪定鼻喷剂处方中以水占比为绝大部分,因此,其密度以水的密度1g/mL进行近似计算。以右美托咪定鼻喷剂的水溶液10mL含有1mgBKC示例,BKC的质量(g)体积(mL)浓度表示为0.01%(W/V),BKC的质量百分比浓度表示为0.01%(W/W)。
本发明中,BKC为苯扎氯铵的英文简写。EDTA-2Na为依地酸二钠,也称乙二胺四乙酸二钠的简写。
下面结合具体对比例和实施例对本发明做进一步阐释。
对比例1:不同浓度BKC的抑菌效力试验
分别采用0.01%、0.018%、0.025%、0.05%、0.1%的BKC浓度制备处方,进行抑菌效力试验。
1.处方设计
表1
注:[1]以右美托咪定计;[2]苯扎氯铵以n-C12H25和n-C14H29同系物的总量之和并折干计算。
2.制备工艺
按表1中各处方称取原辅料,加入到处方量纯化水中,搅拌溶解,调pH至4.0~6.0后,装入玻璃瓶,组装上定量泵,加推钮,即得右美托咪定鼻喷剂。
3.抑菌效力试验方法及结果
参考中国药典抑菌效力检查法进行大肠埃希菌、铜绿假单胞菌、金黄色葡萄球菌、白色念珠菌和黑曲霉的抑菌效力实验,不同浓度BKC的抑菌试验结果如下表。
表2
注:[1]N/A:Not Applicable,指此处不适用;[2]NI:未增加,是指对前一个测定时间,试验菌增加的数量不超过0.5lg;[3]I:增加,是指对前一个测定时间,试验菌增加的数量超过0.5lg。
表3
结果表明,右美托咪定鼻喷雾剂处方中,BKC在浓度较高,特别是0.018%以上时,能够抑制大肠埃希菌、铜绿假单胞菌、金黄色葡萄球菌、白色念珠菌和黑曲霉生长,满足抑菌要求;但是当BKC浓度较低,特别是在0.01%以下时,对大肠埃希菌的抑制效力开始变得不稳定,部分试验例达不到大肠埃希菌抑制的lg值减少标准要求(例如对比例1),在重复试验中另有少部分试验例临近满足标准要求的lg值减少界限(例如其中一个实施例2、7、14、28天的细菌减少的lg值分别为3.02、2.96、3.02、未增加),但是即使是该部分试验例满足了要求,其lg减少值也在要求的数值边缘徘徊。也即当BKC浓度较低,特别是在0.01%以下时,对于大肠埃希菌的抑制效力是不稳定的,无法保证稳定的符合相关标准要求。
对比例2:更低浓度BKC的抑菌效力试验
分别采用0.005%的BKC浓度制备处方,进行抑菌效力试验。
1.处方设计
表4
注:[1]以右美托咪定计;[2]苯扎氯铵以n-C12H25和n-C14H29同系物的总量之和并折干计算。
2.制备工艺
按表4中各处方称取原辅料,加入到处方量纯化水中,搅拌溶解,调pH至4.0~6.0后,装入玻璃瓶,组装上定量泵,加推钮,即得右美托咪定鼻喷剂。
3.抑菌效力试验方法及结果
参考中国药典抑菌效力检查法进行大肠埃希菌和铜绿假单胞菌的抑菌效力实验,不同浓度BKC的抑菌试验结果如下表。
表5
注:[1]NI:未增加,是指对前一个测定时间,试验菌增加的数量不超过0.5lg;[2]I:增加,是指对前一个测定时间,试验菌增加的数量超过0.5lg。
更低浓度BKC的抑菌效力试验结果表明,右美托咪定鼻喷雾剂处方中,BKC浓度低至0.005%时,对大肠埃希菌的抑菌效力均较差,不满足抑菌要求,这与对比例1的实验结果相应。
实施例1:BKC和EDTA-2Na组合联用的抑菌效力试验
分别采用0.005%~0.0095%BKC和0.005~0.015%EDTA-2Na组合制备处方,进行抑菌效力试验。
1.处方设计
表6
注:[1]以右美托咪定计;[2]苯扎氯铵以n-C12H25和n-C14H29同系物的总量之和并折干计算。
2.制备工艺
按表6中各处方称取原辅料,加入到处方量纯化水中,搅拌溶解,调pH至4.0~6.0,装入玻璃瓶,组装上定量泵,加推钮,即得右美托咪定鼻喷剂。
3.抑菌效力试验方法及结果
参考中国药典抑菌效力检查法进行大肠埃希菌、铜绿假单胞菌、金黄色葡萄球菌、白色念珠菌和黑曲霉的抑菌效力实验,不同浓度BKC和EDTA-2Na的抑菌试验结果如下表。
表7
结果表明,右美托咪定鼻喷雾剂处方中,BKC浓度0.005%-0.0095%和EDTA-2Na浓度0.005%-0.015%组合使用时,能够满足抑菌效力要求,特别是对于该BKC低浓度下单独使用难以有效抑制大肠埃希菌的问题,新的组合处方能够有效予以解决。
本发明不局限于上述可选的实施方式,任何人在本发明的启示下都可得出其他各种形式的产品。上述具体实施方式不应理解成对本发明的保护范围的限制,本发明的保护范围应当以权利要求书中界定的为准,并且说明书可以用于解释权利要求书。
Claims (8)
1.一种增效防腐的右美托咪定鼻喷剂,包括水和右美托咪定或其盐,其特征在于:还包括防腐剂苯扎氯铵和防腐增效剂依地酸或其盐,苯扎氯铵的质量百分比浓度为0.005%-0.0095%,依地酸或其盐的质量百分比浓度为0.005%-0.015%,特别是不含有比苯扎氯铵对人鼻粘膜刺激性更强的防腐剂,尤其是不含有除苯扎氯铵之外的其他种类防腐剂。
2.根据权利要求1所述的右美托咪定鼻喷剂,其特征在于:防腐增效剂为依地酸二钠,其质量百分比浓度优选为0.005%-0.01%、0.005%、0.0075%、0.01%或0.015%。
3.根据权利要求1所述的右美托咪定鼻喷剂,其特征在于:防腐剂苯扎氯铵的质量百分比浓度为0.005%、0.0075%、0.0085%或0.0095%。
4.根据权利要求1~3任一所述的右美托咪定鼻喷剂,其特征在于:还包括渗透压调节剂,渗透压调节剂优选为甘油或氯化钠。
5.根据权利要求4所述的右美托咪定鼻喷剂,其特征在于:所述渗透压调节剂为甘油,其质量百分比浓度为0.1%-5.0%或2.5-2.8%,优选2.7%。
6.根据权利要求4所述的右美托咪定鼻喷剂,其特征在于:所述渗透压调节剂为氯化钠,其质量百分比浓度为0.7%-1.0%,优选0.7%、0.8%或0.9%。
7.根据权利要求1~3任一所述的右美托咪定鼻喷剂,其特征在于:以右美托咪定计,其质量百分比浓度为0.005%-1.3%、0.0125%-0.7%或0.006%-0.108%,优选为0.01%、0.015%、0.02%、0.03%或0.05%。
8.根据权利要求1~3任一所述的右美托咪定鼻喷剂,其特征在于:右美托咪定以盐酸盐的形式添加。
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