CN108096408A - 一种鼻用喷雾剂及其制备和应用 - Google Patents
一种鼻用喷雾剂及其制备和应用 Download PDFInfo
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- CN108096408A CN108096408A CN201611011881.2A CN201611011881A CN108096408A CN 108096408 A CN108096408 A CN 108096408A CN 201611011881 A CN201611011881 A CN 201611011881A CN 108096408 A CN108096408 A CN 108096408A
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Abstract
本发明涉及一种喷雾剂，公开了一种含有植物精油亚微乳的鼻用喷雾剂的制备方法及其应用。其原料与质量组分为：植物精油0.6％～3％，油相4.4％～12％，tween‑80 0.8％～6.5％，短链醇0.5％～5％，乙醇0.5％～4.5％，维生素E0.05％～2％，防腐剂0.25％～1％，无菌水余量。该植物精油亚微乳喷雾剂，制备工艺简便，便于工业化生产，抑菌抗菌活性好，生物利用度高且无药物依赖性，可对污染条件及干燥环境中鼻腔起到保护及润湿作用，对鼻炎、鼻窦炎、过敏性鼻炎等疾病的发生有良好的预防及缓解效果。
Description
技术领域
本发明涉及医药保健品领域，具体地说是一种含有植物精油亚微乳的鼻用喷雾剂的制备方法及其应用。该植物精油亚微乳喷雾剂，制备工艺简便，便于工业化生产，对鼻腔内菌类的抑菌抗菌活性好，无药物依赖性，对污染条件及干燥环境中鼻腔起到保护及润湿作用，可预防及缓解鼻炎、鼻窦炎、过敏性鼻炎等疾病的发生和症状。
研究背景
随着我国工业化、城镇化等过程的快速发展，重点区域的大气污染尤其是细颗粒物PM2.5的污染呈现出常态化、超标状态。众多研究表明，大气细颗粒物PM2.5可诱发过敏性鼻炎、支气管哮喘等呼吸道疾病的发生并加重其症状(Abbery DE,Ostro BE,Petersen F,et al.Chronic respiratory symtoms associated with estimated long-term ambientconcentrations of fine particulates less than 2.5microns in aerodynamicdimmeter(PM2.5)and other air pollution,J Exposure Analy Envir Epide,5(2):137-159,1995.)。
鉴于目前日益严峻环境污染问题，呼吸系统疾病患者尤其是鼻炎、过敏性鼻炎、哮喘的患病人数会显著增加，呼吸系统治疗药物市场在未来将呈现持续增长的趋势，已成为医药研发的重点领域之一(Straif K,Cohen A,Samet J.Air pollution and Cancer,International Agency for Research on Cancer Scientific Publication,2013)。以过敏性鼻炎为例，亚洲的过敏性鼻炎发病率较高，约有30％的成人患有此病，我国北方更是高达36％。Kapsali等的调查研究发现，过敏性鼻炎与哮喘有着非常密切的关系，前者是诱发哮喘的重要因素之一，约有60％-80％的过敏性鼻炎患者可发展为哮喘(Kapsali,T etal.Rhinitis is ubiquitous in allergic asthmatics,Journal of allergy andclinical immunology,1997,99(1):556-556)。
过敏性鼻炎作为一种可控制的呼吸道常见病，目前的治疗手段主要有药物治疗和手术治疗两种，其中药物治疗是首选。目前针对过敏性鼻炎等呼吸道疾病的治疗多针对症状的缓解和控制。常用的药物治疗有抗组胺药(如扑尔敏)、减充血剂(如呋麻滴鼻剂)、糖皮质激素(如布地奈德)等，可有效控制并缓解症状。但药物治疗一般不超过7天，长期用药会引起药物性鼻炎或产生药物依赖性，副作用大。
针对过敏性鼻炎等疾病的给药方式大致分为吸入给药、口服给药、黏膜给药等，其中吸入给药是目前公认的预防、治疗哮喘、鼻炎等呼吸道疾病的首选给药方式，也是最有效和最安全的疗法。与其他给药方式相比，吸入给药具有吸收迅速、生物利用度高、副作用小、起效快、使用方便等优点。自Riker实验室(现3M pharmaceuticals公司)在1956年开发出全球首个产品以来，吸入剂已有60余年的发展历史。
鼻腔喷雾剂是指不含抛射剂，借助手动泵压力将内容物以雾状形态释到鼻腔，药物经鼻粘膜吸收而发挥局部或全身作用的制剂。与滴鼻剂相比，喷雾给药可使药物在鼻粘膜的弥散度和分布面积更广泛；与气雾剂相比，克服了氟利昂等抛射剂对鼻粘膜的刺激及副作用。
天然精油是萃取自植物的花、根茎、叶、果实、种子等部位的特有芳香物质，其挥发性高、分子量小，容易透过细胞膜，并且具有天然的抗菌、抗病毒、抗氧化等生物活性，长期使用无副作用，在医药、美容保健品及食品加工等领域广泛应用。鼻腔黏膜的吸收被认为是一种被动吸收过程，分子量小于1000，脂溶性强的物质容易透过细胞膜被吸收。通过上调过氧化氢酶、谷胱甘肽还原酶、超氧化物歧化酶等的表达从而上调抗氧化、抗炎症的基因通路，并通过降低血清中IgE、NK-kappa B以及AP-1的水平抑制或减少促炎性反应的发生(XiChen，et al.Curcumol exhibits anti-inflammatory properties by interfering withthe JNK-mediated AP-1 pathway in lipopolysaccharide-activated RAW264.7 cells,European Journal of Pharmacology,2014,723(15):339-345)。因此，天然精油是理想的鼻腔喷雾活性成分。
本发明选取天然植物精油为活性物质，辅以赋形剂制成用于预防治疗过敏性鼻炎的亚微乳鼻腔喷雾剂。该喷雾剂具有药物分散均匀、局部起效迅速、直接作用于病变部位、剂量稳定、无药物依赖性、无毒副作用、携带方便可多次使用等诸多优点。
发明内容
本发明目的是提供一种含有植物精油亚微乳的鼻用喷雾剂的制备方法及其应用。
本发明特征在于包括下列原料及质量百分比：
植物精油 0.6％～3％
油相 4.4％～12％
tween-80 0.8％～6.5％
短链醇 0.5％～5％
乙醇 0.5％～4.5％
维生素 E0.05％～2％
防腐剂 0.25％～1％
水余量。
上述的喷雾剂，其特征在于：所述植物精油为甜橙油、丁香罗列油、松节油、薄荷脑、丁香油、香柠檬油、山苍子油、香茅油、迷迭香油、麝香草油、苦艾油、桂皮油或洋甘菊油等中的一种或二种以上混合。
上述的喷雾剂，其特征在于：所述油相为精制大豆油、紫苏籽油、玉米油、椰子油、橄榄油、荷荷巴油、蓖麻油、月见草油、紫苏籽油等药用油相中的一种或二种以上混合。
上述的喷雾剂，其特征在于：所述短链醇为甘油、1,2-丙二醇及1,3丙二醇的一种或二种以上。
上述的喷雾剂，其特征在于：所述防腐剂为羟苯酯类、苯甲酸类及山梨酸类中的一种或二种以上。
上述任一一种含有植物精油微乳的鼻用喷雾剂的制备方法，有如下步骤：
(1)选取药用级植物精油、油相、tween-80、短链醇、乙醇、维生素E、防腐剂、水为原料，各原料占总重的质量百分比分别为植物精油0.6％～3％，油相4.4％～12％，tween-800.8％～6.5％，短链醇0.5％～5％，乙醇0.5％～4.5％，维生素E0.05％～2％，防腐剂0.25％～1％，无菌水余量；
(2)室温条件下将植物精油、维生素E溶于油相中，制成油相混合液；
(3)室温条件下将tween-80、短链醇、乙醇、防腐剂溶于无菌水中，制成水相混合液；
(4)室温下条件，磁力搅拌下将油相混合液缓慢滴加入水相混合液，制成初乳；
(5)将初乳在高剪切乳匀机剪切2～5次，每次3～5min制得精油亚微乳；
(6)将步骤(5)所得的亚微乳分装，密封。
上述的制备方法，其特征在于：步骤(2)中油相混合液的制备在密闭的容器中，磁力搅拌条件下完成，搅拌速度800～1200rpm，搅拌时间10～40min。
上述的制备方法，其特征在于：步骤(3)中水相混合液的制备在磁力搅拌条件下完成，搅拌速度500～1000rpm，搅拌时间10～30min。
上述的制备方法，其特征在于：步骤(4)中搅拌速度1000～1500rpm，油相加入水相溶液后，密闭搅拌20-60min。
上述的制备方法，其特征在于：步骤(5)中高剪切乳匀机转速为15000～30000rpm。
该植物精油亚微乳喷雾剂，制备工艺简便，便于放大生产，对鼻腔内菌类的抑菌抗菌活性好，生物利用度高且药物依赖性；可对污染条件或干燥环境中鼻腔起到保护及润湿作用，作为对鼻炎、鼻窦炎、或过敏性鼻炎的预防或缓解制剂。
本发明具有以下优点：
1.天然植物精油为活性小分子、易挥发物质，易通过鼻黏膜屏障从而发挥抗菌、抗炎作用。
2.与现有治疗过敏性鼻炎、哮喘等药物相比，本发明主要成分来源于天然植物，生物活性高、安全有效、无药物依赖性、不导致药源性鼻炎，可长期多次使用，兼具预防及治疗用途。
3.制备制备过程绿色环保，工艺简便且易于中试放大。
具体实施方式
下面结合具体实施例对本发明做详细的说明。以下实例将有助于本领域技术及研究人员进一步理解本发明，但不构成对本发明的任何限制。任何人在本发明权利要求范围内所做的任何形式的修改，仍在本发明权利要求保护范围之内。
实施例1
(1)按下列质量辈分比称取药用原料：
(2)制备方法：将称取的甜橙油、丁香罗勒油、柠檬油、迷迭香油，维生素E逐滴加入紫苏籽油与椰子油的混合油中，密闭条件下800rpm搅拌20min，混合均匀得油相溶液A。将tween-80、乙醇、甘油、尼泊金甲酯溶于水中制得水相混合液B。室温条件下，1200rpm将A逐滴加入B中，密封搅拌30min得出乳。使用高剪切乳匀机室温下高速搅拌初乳，转速15000rpm搅拌3min，重复循环3次，分装密封后即得分散均匀粒度均一的精油亚微乳鼻喷剂。
(3)体外抑菌实验结果
实施例2
(1)按下列质量辈分比称取药用原料：
(2)制备方法：将称取的甜橙油、丁香罗勒油、柠檬油、迷迭香油，维生素E逐滴加入紫苏籽油、玉米胚芽油的混合油相中，密闭条件下1000rpm搅拌30min，混合均匀得油相溶液A。将tween-80、乙醇、1,2-丙二醇、尼泊金乙酯溶于水中制得水相混合液B。室温条件下，1000rpm将A逐滴加入B中，密封搅拌30min得初乳。使用高剪切乳匀机室温下高速搅拌初乳，转速20000rpm搅拌5min，重复3次，分装密封后即得分散均匀粒度均一的精油亚微乳鼻喷剂。
实施例3
(1)按下列质量辈分比称取药用原料：
(2)制备方法：将称取的甜橙油、柠檬油、薄荷油，维生素E逐滴加入蓖麻油、橄榄油与精制大豆油的混合油相中，密闭条件下1000rpm搅拌20min，混合均匀得油相溶液A。将tween-80、乙醇、1,3-丙二醇、山梨醇溶于水中制得水相混合液B。室温条件下，1500rpm将A逐滴加入B中，密封搅拌30min得初乳。使用高剪切乳匀机室温下高速搅拌初乳，25000rpm搅拌5min，重复3次，分装密封后即得分散均匀粒度均一的精油亚微乳鼻喷剂。
实施例4
选用4只新西兰大耳白，备皮，采用自身左右侧对比法，将实例1制备所得鼻喷剂按国家实验药品监督管理局发布的皮肤刺激性实验要求，参比制剂为无菌生理盐水。
采用同一部位多次给药方式，连续给药1-2周，参照皮肤刺激反应评分标准，进行刺激强度评价。
结果显示，4只实验动物均无红斑、无水肿不出现。实验组与对照组平均值无显著性差异。本发明所得鼻喷剂无皮肤刺激性。
实施例5
选用体重200±2g SD大鼠10只，雌雄各半，随机分为实验组与对照组，每组各5只。实验组为实施例2制备所得鼻腔喷雾剂，对照组为无菌生理盐水。
实验条件为室温，每次给各组大鼠经移液器定量滴入40μL喷雾剂或生理盐水至右鼻，给药时固定大鼠为侧卧或仰卧位，并保持至给药后5min，每日给药3-5次。记录大鼠局部刺激性症状，如流涕、抓鼻等症状或动作。连续给药14天后采用脱臼法处死大鼠，立即剪开鼻腔，PBS冲洗后观察鼻黏膜充血及水肿现象。按局部黏膜刺激性反应分级标准进行分级及计分。实验数据采用单因素方差分析进行统计学分析。
结果显示，给药后，对照组及实验组动物均出现流涕、抓鼻、喷嚏等症状或动作。出现时间及频率两组无显著性差异。刺激反应评分结果：生理盐水组＝0.24±0.17，实验组＝0.37±0.15，两组无显著性差异。
实施例6
选用昆明系小鼠20只，雌雄各半，体重22±5g，随机分为4组，每组5只，分别为生理盐水对照组及实施例1,2,3制备所得鼻喷剂实验组。
给药剂量为2μL/10g体重，每只小鼠每日相同时间给药3次，间隔4h，联系给药7日。末次给药后每只小鼠左耳廓内外两侧涂抹20μL二甲苯致敏，同侧右耳作为对照。致敏30min后脱臼法处死小鼠，用打孔器在双耳相同部位打孔，称重。以左右耳质量差异表示肿胀度，计算各组肿胀度及抑制率，抑制率＝(对照组肿胀度-实验组肿胀度)/对照组肿胀度×100％。实验数据采用单因素方差分析进行统计学分析。
结果如下表1，与对照组相比，各实验组均有不同程度的抑制肿胀度效果且结果均有显著性差异(p<0.05)。
表1植物精油喷雾剂对小鼠耳肿胀的影响
注：*表示p<0.05
实施例7
选用昆明系小鼠20只，雌雄各半，体重22±5g，随机分为4组，每组5只，分别为生理盐水对照组及实施例1,2,3制备所得鼻喷剂实验组。
给药剂量为2μL/10g体重，每只小鼠每日相同时间给药3次，间隔4h，联系给药7日。末次给药后30min每只小鼠注射金葡菌液0.2mL(浓度3.5×1010/mL)，注射后8h给药1次，给药剂量不变。观察48h小鼠的死亡情况并计算死亡率。实验数据采用单因素方差分析。结果如下表2。
表2植物精油喷雾剂对金葡菌感染小鼠的保护影响
注：*表示p<0.05。
Claims (9)
1.一种鼻用喷雾剂，其特征在于，包括下列原料及质量百分比：
植物精油 0.6％～3％
油相 4.4％～12％
tween-80 0.8％～6.5％
短链醇 0.5％～5％
乙醇 0.5％～4.5％
维生素E 0.05％～2％
防腐剂 0.25％～1％
水余量。
2.根据权利要求1所述的喷雾剂，其特征在于，所述植物精油为甜橙油、丁香罗列油、松节油、薄荷脑、丁香油、香柠檬油、山苍子油、香茅油、迷迭香油、麝香草油、苦艾油、桂皮油或洋甘菊油等中的一种或二种以上混合。
3.根据权利要求1所述的喷雾剂，其特征在于，所述油相为精制大豆油、紫苏籽油、玉米油、椰子油、橄榄油、荷荷巴油、蓖麻油、月见草油、紫苏籽油等药用油相中的一种或二种以上混合。
4.根据权利要求1所述的喷雾剂，其特征在于，所述短链醇为甘油、1,2-丙二醇及1,3丙二醇的一种或二种以上。
5.根据权利要求1所述的喷雾剂，其特征在于，所述防腐剂为羟苯酯类、苯甲酸类及山梨酸类中的一种或二种以上。
6.一种权利要求1-5任一所述鼻用喷雾剂的制备方法，其特征在于：
(1)选取药用级植物精油、油相、tween-80、短链醇、乙醇、维生素E、防腐剂、水为原料，各原料占总重的质量百分比分别为植物精油0.6％～3％，油相4.4％～12％，tween-800.8％～6.5％，短链醇0.5％～5％，乙醇0.5％～4.5％，维生素E0.05％～2％，防腐剂0.25％～1％，无菌水余量；
(2)室温条件下将植物精油、维生素E溶于油相中，制成油相混合液；
(3)室温条件下将tween-80、短链醇、乙醇、防腐剂溶于无菌水中，制成水相混合液；
(4)室温，磁力搅拌下将油相混合液缓慢滴加入水相混合液，制成初乳；
(5)将初乳在高剪切乳匀机剪切2-5次，每次3～5min制得精油亚微乳；
(6)将步骤(5)所得的亚微乳分装，密封。
7.根据权利要求6所述的制备方法，其特征在于，所述步骤(2)中油相混合液在密闭的容器中，磁力搅拌条件下制备，搅拌速度800～1200rpm，搅拌时间10～40min；
所述步骤(3)中水相混合液的制备在磁力搅拌条件下完成，搅拌速度500～1000rpm，搅拌时间10～30min；
所述步骤(4)中搅拌速度1000～1500rpm，油相加入水相溶液后，密闭搅拌20～60min。
8.根据权利要求6所述的制备方法，其特征在于，所述步骤(5)中高剪切乳匀机转速为15000～30000rpm。
9.一种权利要求1-5任一所述鼻用喷雾剂的应用，其特征在于：所述鼻用喷雾剂可对污染条件或干燥环境中鼻腔起到保护及润湿作用，作为对鼻炎、鼻窦炎、或过敏性鼻炎的预防或缓解制剂。
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