CN110731943A - 一种氢溴酸常山酮可溶性粉及其制备方法 - Google Patents
一种氢溴酸常山酮可溶性粉及其制备方法 Download PDFInfo
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- CN110731943A CN110731943A CN201910976261.XA CN201910976261A CN110731943A CN 110731943 A CN110731943 A CN 110731943A CN 201910976261 A CN201910976261 A CN 201910976261A CN 110731943 A CN110731943 A CN 110731943A
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- soluble powder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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Abstract
本发明属于药物制剂技术领域,公开一种氢溴酸常山酮可溶性粉及其制备方法。由以下重量百分比的原料制成:氢溴酸常山酮0.6~2 %、乳化剂2.0~30.0 %、助乳化剂1.0~20.0 %、可溶性固体吸附材料50.0~90.0 %。制备方法:将氢溴酸常山酮、乳化剂和助乳化剂在40~70 ℃条件下混合均匀,经过胶体磨处理,冷却至室温,得到氢溴酸常山酮自乳化浓缩液;将水溶性固体吸附材料粉碎后,与氢溴酸常山酮自乳化浓缩液混合均匀,得半固体物;将半固体物干燥后粉碎,即得氢溴酸常山酮可溶性粉。本发明制备的氢溴酸常山酮可溶性粉,具有水溶性,不仅解决临床饮水给药问题,而且在包装、携带、运输等方面比液态的氢溴酸常山酮溶液更具优势且更为方便,用于治疗球虫病具有良好的应用前景。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种氢溴酸常山酮可溶性粉及其制备方法。
背景技术
常山酮有顺式和反式两种同分异构体,反式是活性成分,反式常山酮的抗球虫活性比顺式的抗球虫活性高出25倍,这可能与顺式常山酮中哌啶基团上的羟基和喹唑啉酮换上的酮基形成了半缩酮有关。本品是用量较小的一种抗球虫药,且抗球虫谱较广,对鸡多种球虫有效;对火鸡的小艾美耳球虫和腺状艾美耳球虫也有较强作用;对球虫早期生殖性芽孢及第一代和第二代裂殖体均有抑制作用,并能控制卵囊排出,减少动物在感染的可能性。本品抗球虫活性甚至超过聚醚类抗生素,与其他抗球虫药无交叉耐药性,即对其他药物已耐药的球虫,使用本品多数仍有效。相较于磺胺类抗生素只具体内作用,常山酮还以抑制环境中的球虫,减少养殖场环境中球虫量,从而避免球虫病的爆发。常山酮对球虫生理周期的作用范围广,在抗球虫上有绝对优势。
常山酮的氢溴酸盐已作为商品广泛销售。氢溴酸常山酮对球虫的3个生理阶段都有影响,即子孢子虫、第一代裂殖体、第二代裂殖体都有作用。体内主要作用于球虫生活历史的早期,阻止其侵入宿主细胞,然后通过抑制裂殖体分裂殖子,使裂殖体空泡化,达到破坏其发育的作用效果,导致繁殖体和裂殖子发育被抑制,发育速度减慢,从而被机体的免疫系统清除。体外作用机理,氢溴酸常山酮可以抑制孢子生殖,使卵囊孢子化率降低,在体外经常山酮处理后卵囊脱孢子囊能力降低,卵囊表面形态及细胞质超微结构发生明显异常,子孢子感染能力也下降。
氢溴酸常山酮难溶于水,目前市场上的产品多为氢溴酸常山酮预混剂,不能用于家禽饮用,只能用于拌料,大大限制了临床应用。CN201611053242.2公开了一种氢溴酸常山酮溶液及其制备方法,它是通过有机溶剂将氢溴酸常山酮溶解制成液体剂型,但是该发明中包含了大量的有机溶剂,对动物机体存在潜在的危害,另外液体剂型还存在包装和运输成本高的问题。
发明内容
本发明的目的在于提供一种氢溴酸常山酮可溶性粉及其制备方法。
为实现上述目的,本发明采取的技术方案如下:
一种氢溴酸常山酮可溶性粉,由以下重量百分比的原料制成:氢溴酸常山酮0.6~2 %、乳化剂2.0~30.0 %、助乳化剂1.0~20.0 %、可溶性固体吸附材料50.0~90.0 %。
较好地,所述乳化剂为自乳化单甘酯A165、月桂酸聚乙二醇甘油酯、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和聚乙二醇十六十八醇醚12中的一种或多种的组合。
较好地,所述助乳化剂为α-苯乙醇、三乙二醇、甘油缩甲醛、苯甲酸苄酯和二乙二醇单乙基醚中的一种或多种的组合。
较好地,所述可溶性固体吸附材料为β-环糊精、水溶性淀粉、聚乙烯吡咯烷酮K30、乳糖和甘露醇中的一种或多种的组合。
一种所述的氢溴酸常山酮可溶性粉的制备方法,步骤如下:
(1)、将氢溴酸常山酮、乳化剂和助乳化剂在40~70 ℃条件下混合均匀,经过胶体磨处理,冷却至室温,得到氢溴酸常山酮自乳化浓缩液;
(2)、将水溶性固体吸附材料粉碎后,与步骤(1)制备的氢溴酸常山酮自乳化浓缩液混合均匀,得半固体物;
(3)、将步骤(2)制备的半固体物干燥后粉碎,即得氢溴酸常山酮可溶性粉。
较好地,步骤(1)中,胶体磨处理时,定子和转子之间的缝隙大小为10~25 μm,研磨次数为3~5次。
较好地,步骤(3)中,干燥的温度为50~70 ℃。
本发明的有益效果:
(1)、氢溴酸常山酮的疏水性较强,其乳化过程相对比较困难,为了增加氢溴酸常山酮的亲水性,以便溶水时能在水中形成均匀的乳液,本发明以自乳化单甘酯A165、月桂酸聚乙二醇甘油酯、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和聚乙二醇十六十八醇醚12中的一种或多种的组合为乳化剂,其均为亲水性较大的表面活性剂,可以有效改善氢溴酸常山酮的亲水性;
(2)、本发明氢溴酸常山酮可溶性粉由乳化剂、助乳化剂及可溶性固体吸附材料制成,所选用的乳化剂、助乳化剂、可溶性固体吸附材料等均来自于药学上可接受的药用辅料,具有无毒、无刺激性等特征;
(3)、本发明提供的氢溴酸常山酮可溶性粉的制备方法,操作简便,成本低廉,适用于工业化生产,制备所得固体制剂具有分布均匀、水溶性好、质量稳定等优点,水中迅速溶解,形成乳剂,临床给药方便;
(4)、本发明制备的氢溴酸常山酮可溶性粉,具有水溶性,不仅解决临床饮水给药问题,而且在包装、携带、运输等方面比液态的氢溴酸常山酮溶液更具优势且更为方便,用于治疗球虫病具有良好的应用前景。
具体实施方式
为使本发明更加清楚、明确,以下对本发明的技术方案作进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1
氢溴酸常山酮可溶性粉的处方:
氢溴酸常山酮 0.6 g;
自乳化单甘酯A165 2.0 g;
三乙二醇 20.0 g;
β-环糊精 77.4 g。
氢溴酸常山酮可溶性粉的制备方法:
(1)、按照上述处方量取氢溴酸常山酮、自乳化单甘酯A165、三乙二醇、β-环糊精;将氢溴酸常山酮、自乳化单甘酯A165和三乙二醇加入到反应罐中,保温温度70 ℃,搅拌乳化30min,混合均匀后过胶体磨,定子和转子之间的缝隙大小为25 μm,研磨3次,得到氢溴酸常山酮自乳化浓缩液;
(2)、将上述β-环糊精粉碎,过100目筛,然后与步骤(1)中得到的自乳化浓缩液混合均匀,得半固体物;
(3)、将步骤(2)得到的半固体物70 ℃干燥至水分合格后粉碎,过80目筛得到氢溴酸常山酮可溶性粉。
实施例2
氢溴酸常山酮可溶性粉的处方:
氢溴酸常山酮 2.0 g;
聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物 20.0 g;
二乙二醇单乙基醚 1.0 g;
甘露醇 77.0 g。
氢溴酸常山酮可溶性粉的制备方法:
(1)、按照上述处方量取氢溴酸常山酮、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、二乙二醇单乙基醚、甘露醇;将氢溴酸常山酮、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和二乙二醇单乙基醚加入到反应罐中,保温温度50 ℃,搅拌乳化30min,混合均匀后过胶体磨,定子和转子之间的缝隙大小为25 μm,研磨3次,得到氢溴酸常山酮自乳化浓缩液;
(2)、将上述甘露醇粉碎,过100目筛,然后与步骤(1)中得到的自乳化浓缩液混合均匀,得半固体物;
(3)、将步骤(2)得到的半固体物60 ℃干燥至水分合格后粉碎,过80目筛得到氢溴酸常山酮可溶性粉。
实施例3
氢溴酸常山酮可溶性粉的处方:
氢溴酸常山酮 1.5 g;
月桂酸聚乙二醇甘油酯 6.5 g;
甘油缩甲醛 2.0 g;
水溶性淀粉 90.0 g。
氢溴酸常山酮可溶性粉的制备方法:
(1)、按照上述处方量取氢溴酸常山酮、月桂酸聚乙二醇甘油酯、甘油缩甲醛、水溶性淀粉;将氢溴酸常山酮、月桂酸聚乙二醇甘油酯和甘油缩甲醛加入到反应罐中,保温温度40℃,搅拌乳化30 min,混合均匀后过胶体磨,定子和转子之间的缝隙大小为25 μm,研磨3次,得到氢溴酸常山酮自乳化浓缩液;
(2)、将上述水溶性淀粉粉碎,过100目筛,然后与步骤(1)中得到的自乳化浓缩液混合均匀,得半固体物;
(3)、将步骤(2)得到的半固体物50 ℃干燥至水分合格后粉碎,过80目筛得到氢溴酸常山酮可溶性粉。
实施例4
氢溴酸常山酮可溶性粉的处方:
氢溴酸常山酮 1.0 g;
自乳化单甘酯A165 30.0 g;
三乙二醇 19.0 g;
甘露醇 30.0 g;
β-环糊精 20.0 g。
制备方法:
(1)、按照上述处方量取氢溴酸常山酮、自乳化单甘酯A165、三乙二醇、甘露醇和β-环糊精;将氢溴酸常山酮、自乳化单甘酯A165和三乙二醇加入到反应罐中,保温温度70 ℃,搅拌乳化30 min,混合均匀后过胶体磨,定子和转子之间的缝隙大小为25 μm,研磨3次,得到氢溴酸常山酮自乳化浓缩液;
(2)、将上述甘露醇和β-环糊精粉碎,过100目筛,然后与步骤(1)中得到的自乳化浓缩液混合均匀,得半固体物;
(3)、将步骤(2)得到的半固体物70 ℃干燥至水分合格后粉碎,过80目筛得到氢溴酸常山酮可溶性粉。
对比例1
将实施例1处方中的乳化剂“自乳化单甘酯A165”替换为“吐温80”,其他原料和制备方法同实施例1,制备得到氢溴酸常山酮可溶性粉。
对比例2
将实施例1处方中的助乳化剂“三乙二醇”替换为“丙二醇”,其他原料和制备方法同实施例1,制备得到氢溴酸常山酮可溶性粉。
对比例3
将实施例1制备方法中“混合均匀后过胶体磨,定子和转子之间的缝隙大小为25μm,研磨3次”这一步骤去掉,处方和其它制备方法同实施例1,制备得到氢溴酸常山酮可溶性粉。
乳化剂、助乳化剂的种类和乳化后的制备方法对氢溴酸常山酮可溶性粉的质量有很大的影响,各方案各取1 g至100 mL温度为25 ℃的水中,考察本发明实施例1和对比例1-对比例3制备的氢溴酸常山酮可溶性粉的溶解时间、溶液粒径和多分散系数,试验结果如表1。
由上述结果可以看出:不同乳化剂、助乳化剂和制备步骤形成的氢溴酸常山酮可溶性粉的溶解时间、粒径和体系的多分散系数存在较大差异,本发明实施例1制备的氢溴酸常山酮可溶性粉的溶解时间短,粒径和多分散系数小,体系稳定。
效果验证
为说明本发明氢溴酸常山酮可溶性粉的优越性,鸡球虫药效试验进行评价。
(一)试验共分4 组,试验分组情况见表2:I组、II组、III组和IV组,各组均为30只,雌雄各半,健康状况良好。除III组外,I组、II组、IV组各组经口感染柔嫩艾美耳球虫孢子化的卵囊液1 mL(含1×105个卵囊)。试验期间除受试药物外不再喂其它任何药物,试验期间饲料的质量百分比组成为:玉米55.5 %、豆粕20 %、DDGS 4 %、喷浆玉米皮4.9 %、发酵酒糟2.5 %、石粒7.3 %、石粉2.65 %、磷酸氢钙1.6 %、豆油1.4 %、赖氨酸0.09 %、蛋氨酸0.02 %和苏氨酸0.04 %。
(二)抗球虫效果评定
根据农业部《实验临床试验技术规范》(试行) 的标准计算抗球虫指数(ACI),以判定药效。判定标准为ACI > 180 为高效,160~180为中效,<160为低效,< 120为无效。
(三)试验结果
感染不用药组(IV组)于攻虫感染后第四天开始出现临床症状,在第六、七、八天症状最严重,排血便,精神萎糜,采食量减少,饮水增加,第3天死亡2 只,第4天死亡3 只。从整个试验过程比较看,以IV组最严重(死亡5 只),氢溴酸常山酮预混剂组(II组)第三天死亡1只,其它2个试验组(I组和III组)均无异常表现,成活率为100 %。抗球虫指数(ACI) 值分析可见表3,使用氢溴酸常山酮可溶性粉0.2 mg/ kg和氢溴酸常山酮预混剂0.2 mg/ kg的ACI值均在180 以上,均属于高效抗球虫药物。
本次试验中,从所测定抗球虫指数来看,氢溴酸常山酮可溶性粉抗球虫效果优于氢溴酸常山酮预混剂,而且由于本品使用剂量极小,混料均匀难度较大,而可溶性粉剂型使用则不存在此问题,较易混匀,因此氢溴酸常山酮可溶性粉较易普及推广。
Claims (7)
1.一种氢溴酸常山酮可溶性粉,其特征在于,由以下重量百分比的原料制成:氢溴酸常山酮0.6~2 %、乳化剂2.0~30.0 %、助乳化剂1.0~20.0 %、可溶性固体吸附材料50.0~90.0%。
2.如权利要求1所述的氢溴酸常山酮可溶性粉,其特征在于:所述乳化剂为自乳化单甘酯A165、月桂酸聚乙二醇甘油酯、聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和聚乙二醇十六十八醇醚12中的一种或多种的组合。
3.如权利要求1所述的氢溴酸常山酮可溶性粉,其特征在于:所述助乳化剂为α-苯乙醇、三乙二醇、甘油缩甲醛、苯甲酸苄酯和二乙二醇单乙基醚中的一种或多种的组合。
4.如权利要求1所述的氢溴酸常山酮可溶性粉,其特征在于:所述可溶性固体吸附材料为β-环糊精、水溶性淀粉、聚乙烯吡咯烷酮K30、乳糖和甘露醇中的一种或多种的组合。
5.一种如权利要求1~4任一所述的氢溴酸常山酮可溶性粉的制备方法,其特征在于,步骤如下:
(1)、将氢溴酸常山酮、乳化剂和助乳化剂在40~70 ℃条件下混合均匀,经过胶体磨处理,冷却至室温,得到氢溴酸常山酮自乳化浓缩液;
(2)、将水溶性固体吸附材料粉碎后,与步骤(1)制备的氢溴酸常山酮自乳化浓缩液混合均匀,得半固体物;
(3)、将步骤(2)制备的半固体物干燥后粉碎,即得氢溴酸常山酮可溶性粉。
6.如权利要求5所述的制备方法,其特征在于:步骤(1)中,胶体磨处理时,定子和转子之间的缝隙大小为10~25 μm,研磨次数为3~5次。
7.如权利要求5所述的制备方法,其特征在于:步骤(3)中,干燥的温度为50~70 ℃。
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