CN88102851A - 药剂组合物的制备方法 - Google Patents
药剂组合物的制备方法 Download PDFInfo
- Publication number
- CN88102851A CN88102851A CN88102851.7A CN88102851A CN88102851A CN 88102851 A CN88102851 A CN 88102851A CN 88102851 A CN88102851 A CN 88102851A CN 88102851 A CN88102851 A CN 88102851A
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- Prior art keywords
- lipid
- cefuroxime axetil
- drug particles
- coated drug
- dispersion
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Classifications
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- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- A—HUMAN NECESSITIES
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
以脂质或脂质混合物整体包衣的头孢呋新axetil药粒,可以掩蔽头孢呋新axetil的苦味而当与胃肠液接触时即分散或溶解。这样的颗粒剂可以制成为口服药剂组合物,例如水悬浮液。
Description
本发明涉及含有头孢呋新的1-乙酰氧乙酯的药物组合物,该乙酰氧乙酯已定名为“头孢呋新axetil”。
如美国专利说明书No1453049所披露,头孢呋新具有广谱的抗菌活性,其对广泛系列的革兰氏阳性和革兰氏阴性微生物均有高的抗菌活性,由于该化合物对于革兰氏阴性微生物产生的β-内酰胺酶稳定性很高,其抗菌活性被提高。考虑到头孢呋新及其盐经胃肠道吸收性差,一般以注射抗生素使用。
如英国专利说明书N。1571683所披露,头孢呋新的羧基酯化为1-乙酰氧乙酯得到的头孢呋新axetil后,改进了口服给药的效果。1-乙酰氧乙基的存在导致该化合物显著地被胃肠道吸收,因而该酯基被例如血浆和机体组织中的酶水介,得到具有抗菌活性的酸。如英国专利说明书N。2127401所述,使有无定形的头孢呋新axetil是特别有益的。
由于得到了可以口服而不仅仅注射的抗菌形式,头孢呋新axetil大大扩展了头孢呋新的有价值的治疗潜力。
该抗生素口服给药的合宜剂型是颗粒剂,这种颗粒剂可以溶液或悬浮液或水剂给药。颗粒剂的溶液或悬浮液例如糖浆作为口服抗生素特别适宜于儿童。但是,头孢呋新axetil有长时间不消失的非常苦的味,这种苦味通过添加常规颗粒剂用增甜剂和矫味剂也不能充分地掩蔽。
头孢呋新axetil存在的另一问题是,当其结晶形或前述的无定形与水介质接触时都易形成胶状物。这种胶凝效应与温度有关,而且在约37℃下易发生,此温度恰好是口服颗粒剂崩解的生理温度。头孢呋新axetil较慢地分散到周围的水介质中并嚥下后,存在于该药物制剂中的头孢呋新就有形成凝胶的危险。形成的凝胶头孢呋新axetil溶解性降低,因而经胃肠道的吸收差,即生物利用度变低。为了避免凝胶的形成,在颗粒剂的情况下,要采用较小颗粒和较大表面积的颗粒。
对于作为颗粒剂的头孢呋新axetil制剂来说,避免药物进入任何所用的悬浮液或口中是问题的关键。通过把头孢呋新axetil制成脂质包衣颗粒可以把这样的问题减到最小程度,这种包衣限制了水的渗透。在包衣颗粒上任何孔隙都意味着苦味不能有效的掩蔽,所以,颗粒完整地包衣是很重要的。
我们业已发现,用脂质将整个头孢呋新axetil颗粒包衣,可以克服头孢呋新axetil的苦味,这种包衣药粒基本上不溶于水但易在胃肠液中分散或溶解。这种包衣颗粒在口腔的湿环境中不释放有苦味的头孢呋新axetil,一旦与胃肠液接触即崩解,于是在胃肠道中迅速分散并溶解。
英国专利说明书N。2081092讨论了为掩蔽药物苦味应用蜡(即脂质)包衣。然而如第1页第4行至第二页第5行的进一步解释,以英国专利说明书N。1323161所述组合物为例,蜡包衣的应用导致药物在消化道中的溶解性差,该药物组合物中含有用含氢化蓖麻油的脂质包衣的醋甲西林。在英国专利说明书N。2081092中建议通过混合所用的蜡与水可溶胀的物质克服这一问题。对于制成水悬浮液的头孢呋新axetil颗粒剂来说,贮存直到14天仍必须保持其掩蔽苦味的性质,这显然是不适宜的。如果要用含水可溶胀的物质体包衣剂,那么,在水介质中贮存期间,包衣的苦味掩蔽效应不可避免会失去。
迄今,脂质包衣也已用于流动粉剂(参见例如美国专利N。3247065)和可以制成片剂或胶囊剂的缓释药物的剂型中(参见例如美国专利N。3146167)。然而,这些产品一般比为口服而混入水悬浮液中的颗粒大得多。此外,考虑到:(ⅰ)以往应用脂质对缓释药物进行包衣,(ⅱ)如英国专利说明书N。2081092所述蜡包衣药物的低生物利用度的问题和(ⅲ)已知的头孢呋新axetil胶凝倾向引起的胃肠道吸收差等,用脂质对头孢呋新axetil颗粒整个包衣在胃肠道中可以迅速分散和溶解并达到合意的生物利用度水平,这尤其令人感到惊奇。
因此,本发明的一个方面是提供了一种在颗粒形式中含有头孢呋新axetil的组合物,这些颗粒用脂质或脂质混合物作整个包衣,这种脂质是水不溶的并用于掩蔽口服时头孢呋新axetil的苦味,并且在与胃肠液接触时即分散或溶解。
为了提供适宜口服的掩蔽苦味的头孢呋新axetil颗粒,所用脂质的熔点应足够高以防止在口腔中包衣颗粒熔化而致使释放出苦味活性组分,但不能高到包衣过程中头孢呋新axetil活性组分本身熔化和/或发生化学降解。本发明所用的脂质或脂质混合物一般具有30~80℃的熔点,最好是40~70℃。含有无定形头孢呋新axetil的本发明的药品,其中脂质或脂质混合物的熔点最好在45~60℃。
适合的脂质包括脂肪酸或其一元醇,固定油类,脂肪,蜡,甾醇,磷脂和糖脂。脂质例如可以是高分子量(C10-30)直链饱和或不饱和脂肪酸,如硬脂酸或棕榈酸;甘油三酯例如高分子量(C10-30)脂肪酸甘油酯,如三月桂酸甘油酯或三肉豆蔻酸甘油酯;部分氢化的植物油如棉籽油或豆油;蜡例如蜂蜡或巴西棕榈蜡,高分子量(C10-30)直链脂肪醇如十八烷醇或十六烷醇;或它们的混合物。高分子量脂肪酸的混合物如硬脂酸和棕榈酸的混合物,高分子量直链脂肪醇的混合物如鲸蜡醇与十八烷醇的混合物,部分氢化的棉籽油和豆油的混合物以及高分子量脂肪酸和甘油酯的混合物如硬脂酸和三月桂酸甘油酯的混合物。提供优良的生物利用度并具有与头孢呋新axetil配伍性质的特别好的脂质是硬脂酸与棕榈酸的混合物,两种酸的重量比为3∶7-7∶3,最好是大约1∶1。
本发明的组合物可以含结晶形头孢呋新最好是无定形的,如英国专利说明书N。2127401所述。
如果需要,头孢呋新axetil可以先内涂具有包衣性质的物质。这种内涂的目的在于保护对包衣脂质化学敏感的头孢呋新axetil。
用于内涂的具有包衣性质的物质最好是水溶性的和最好是成膜剂。有用的成膜剂包括多糖类如麦芽糖糊精,烷基纤维素,如甲基或乙基纤维素,羟烷基纤维素例如羟丙基纤维素或羟丙基甲基纤维素,聚乙烯吡咯烷酮和甲基丙烯酸的聚合物。这些成膜剂可以水溶液或非水溶液系应用。麦芽糖糊精尤其为好。在内涂颗粒中头孢呋新axetil的浓度为10~30%(重量),例如在20%(重量)情况下可以方便地用脂质包衣。
按照本发明的脂质包衣颗粒含头孢呋新axetil5~90%(重量)为好,5~50%(重量)较好,而5或10~30%(重量)最好。对于首先内涂而后包衣脂质的头孢呋新axetil颗粒最好含5~15%(重量)头孢呋新axetil;而未内涂的脂质包衣颗粒最好含10~30%(重量)头孢呋新axetil。
一般地,为了掩蔽头孢呋新axetil苦味,用脂质整个包衣的颗粒大小不小于250微米。大小为1~250微米的包衣颗粒最合适。对于头孢呋新axetil的生物利用度和该产品口服的可接受性来说,包衣颗粒的大小是一个重要因素,平均颗粒大小超过直径为250微米时,会有不希望的砂粒感。本发明的药剂产品一般地做成平均直径小于100微米的包衣颗粒,例如20~100微米,最好是30~60微米。应用先内涂,平均直径小于80微米如在5~50微米范围内的脂质整个包衣颗粒是合宜的。例如,无定形头孢呋新axetil可以通过英国专利说明书N。2127401所述喷雾干燥法制成平均直径为5~50微米的空心微球形。
本发明的包衣颗粒可以通过在熔融的脂质中喷雾分散粒状头孢呋新axetil,然后冷却所得包衣颗粒而方便地制备。这一方法构成本发明的另一特征。分散液可通过加粒状头孢呋新axetil于熔融的脂质或脂质混合物中或者是混合固态的分散液组分并熔融脂质或脂质混合物来制备。
应用常规技术可以把粒状的头孢呋新axetil分散于熔融的脂质中,例如用高剪切混合器。一般地,熔融温度要高于脂质熔点10~20℃。
制备脂质包衣的头孢呋新axetil颗粒的特别好的分散液是头孢呋新axetil在重量比为3∶7-7∶3,最好是1∶1的硬脂酸和棕榈酸的混合物中的分散液。在本发明的制备脂质包衣颗粒的分散液中头孢呋新axetil的量按照上面讨论的在包衣颗粒中头孢呋新axetil的要求量进行计算。熔融的分散液喷雾后一冷却即得到脂质包衣头孢呋新axetil的颗粒。可供采用的技术包括常规的喷雾器,例如旋转喷雾器,压力喷头,气压喷头和声波喷头。
采用装在标准喷雾干燥/急冷设备上的气压喷头,特别是双流内或外混合气压喷头是特别合宜的。适合的内混双流喷头叙述于英国专利说明书N。1412133中。
在采用内混双流喷头喷雾器喷雾方法中(喷雾方法构成本发明的一个优选特征),一般地,在60~80℃最好是65~75℃下,将熔融的头孢呋新axetil脂质分散液装入喷雾器顶部,准确的温度取决于所用的特定脂质材料。进入喷头的喷雾气体可以是空气或惰性气体如干燥氮气。气体温度一般是60~90℃,最好是70~85℃,准确的温度取决于所用的特定的脂质材料。业已发现,在此包衣方法中,熔融分散液最好维持于所用脂质或脂质混合物熔点以上10~20℃,以便分散液具有要求的粘度。合理地控制喷雾压力以便获得上面要求大小的包衣颗粒。
包衣颗粒可通过常规技术固化并收集。于例如0~30℃最好是5~20℃,向喷雾室中通冷空气流或最好是干燥氮气,就可完成包衣颗粒的冷却和固化。可以用旋流分离器,粉末过滤器,或利用重力收集产品。
分散于脂质中的头孢呋新axetil被内涂,可以采用常规涂层技术将内涂物质涂于头孢呋新axetil上,例如用流化床成粒机,离心流化床涂层器或喷雾干燥机喷涂或者用施转成粒机涂层。在用上述方法制备脂质包衣颗粒时,在熔融分散液中内涂头孢呋新axetil的浓度以20~80%(重量)为宜,最好是35~65%(重量)。由内涂头孢呋新axetil制得的本发明的包衣颗粒,包衣脂质为20~80%(重量)为好,最好是35~65%(重量)。
本发明的粒状产品可以口服药物组合物使用,并且在口服前以干产品与水或其它赋形剂制成悬浮液服用,或直接服用干产品然后用水或其它适宜的液体冲服。这样的制剂可以用常规方法与药用添加剂一起制成,所说的添加剂例如悬浮和/或结合剂,如烷基纤维素(如甲基纤维素),羟烷基纤维素(如羟丙基纤维素和羟丙基甲基纤维素),羧甲基纤维素钠或其混合物,予凝胶玉米淀粉或聚乙烯吡咯烷酮;填充剂例如蔗糖,淀粉,乳糖和微晶纤维素;吸附剂和流动剂如滑石粉,氧化铝和二氧化硅;乳化或增稠剂如卵磷脂或硬脂酸铝;表明活性剂如十二烷基硫酸钠或非离子型聚氧乙烯-聚氧丙烯共聚物;防腐剂如羟基苯甲酸甲酯或丙酯或山梨酸;着色剂如二氧化钛颜料,色淀染料和氧化铁颜料;香料例如薄荷香料如欧薄菏调味剂;和分子量较大的增甜剂如山梨醇和蔗糖或人工增甜剂如糖精和环己烷氨基磺酸钠。
当添加剂是固体时,本发明的颗粒可以与添加剂混合成干混合物形式,或者添加剂本身制成与本发明的活性颗粒混合的赋形剂颗粒,或者最好是用常规技术把本发明的颗粒与添加剂一起成粒。
这样的成粒技术包括常规成粒机的应用,例如喷雾成粒机,旋转成粒机,离心流化床成粒机,高速混合成粒机和挤压粉碎技术。可以通过常规技术进行干燥,例如在成粒机或在干燥箱或热空气干燥机中干燥。不言而喻,用便于提供所要大小颗粒的方法制成颗粒是所希望的。一般来说,通过常规的调节成粒条件是可以办得到的,如果需要,可以过筛。
当口服药物组合物是悬浮液时,倘若水液或非水赋形剂可与脂质包衣配伍则可以用水溶液或非水赋形剂。悬浮液用的合适的非水赋形剂包括例如杏仁油,分馏的椰子油或油酯。
本发明的另一方面是提供一种口服药物组合物,其中包括本发明的组合物和一种或多种药用载体或赋形剂。
特别是本发明提供了一种口服颗粒剂,其中包括本发明的头孢呋新axetil包衣颗粒和一种或多种药用赋形剂。赋形剂物质最好包括增甜剂例如蔗糖。可以使用的其它药用赋形剂包括上面叙述的那些。颗粒剂可以用上述的常规方法制备。可以通过混合各组分并与水做成颗粒。通过过筛可以除去太大的颗粒。颗粒直往应小于1000微米,最好是小于800微米。
当本发明的颗粒在水介质中制成制剂时,其中含有较高浓度的口服可接受的溶质较好,这样有助于包衣的脂质掩蔽苦味性质。例如,该水介质中可含有糖如蔗糖,其浓度为50~85%(重量),最好是60~80%(重量)。这样的溶质可以方便于掺入含本发明微粒产品的颗粒中。对于蔗糖来说,同时也是一种增甜剂和防腐剂。
本发明的药剂产品,其口服悬浮液可含适量的水,以便服用头孢呋新axetil。典型的颗粒剂可以是含有相当于500mg-10g头孢呋新的多剂量悬浮液或含相当于100~1000mg头孢呋新的单剂量悬浮液。
用于治疗人的典型剂量为每日100~3000mg头孢呋新,例如成人每日250~2000mg头孢呋新和儿童每日125~1000mg头孢呋新,不过,准确的剂量还尤其取决于给药次数。
下面的实施例进一步说明本发明。
实施例中所用头孢呋新axetil是按英国专利说明书N。2127401所述方法制备的高纯度的喷雾干燥无定形物质,其干均颗粒直径为5~50微米。
Revel A是一种市售食品级硬脂酸,Hyfac是一种工业级硬脂酸,Dynasan 112是三月桂酸甘油酯和Dynasan 114是三肉豆蔻酸甘油酯。而Revel A,Hyfac,Dynasan 112和Dynasan 114都是商品名。
硬脂酸BPC在英国药典(1973)中规定为富硬脂酸和棕榈酸的脂肪酸混合物。在美国“国家准药典XV,1980”中,硬脂酸USNF被规定为至少含40%硬脂酸,至少40%棕榈酸,而硬脂酸和棕榈酸之和不少于90%。
下面例子1~3分别通过光学显微法,Coulter计数器和激光散射法测定颗粒大小:
1.光学显微法
将脂质包衣的少量样品悬浮于在硅氧烷液体中的显微镜计算板上,用一台Imanco FMS显微镜观察这些颗粒并于X100倍率下计数。
每批样品准备两个计算板,每个计算板计数9个视野。颗粒大小用英国标准分度镜(BS3406,1961)计算并按>60微米至<7.5微米的范围确定。记录每一大小范围的个数并用下式计算体积的平均直径(VMD):
m
∑ N(xi)xi4
i=1
m
∑ N(xi)xi3
i=1
N(Xi)=颗粒在给定大小区内的数目,Xi=颗粒大小区限的中点
2.Coulter计数器法
将脂质包衣的少量样品悬浮于显微镜计算板上的Coulter分散剂中。将定量的这种分散过的样品加到Coulter计数器的测定杯中(杯中有经0.45微米微孔滤纸过滤后的1%氯化钠的蒸馏水溶液)直至该计数器(TAII型)上浓度指数显示于5~10%之间。杯中的内容物被声波振动30秒钟后再放入该计数器并在读数前搅拌1分钟。在8.0微米至128.0微米范围内计数不同颗粒大小区限中的数目。在总计搅拌四分钟后重复计数。
得出每一尺寸区一分种和四分钟的平均值变按上述方法1的公式计算VMD。
重复测定每批五个样品的最小值。五个VMD平均值则为单一组合物的平均值。
用Coulter计数器法测定了文中所述全部样品的VMD值。
3.激光散射法
将5mg脂质包衣样品加到5ml 0.25%Tween80的蒸馏水溶液中并声波振荡60秒钟。该样品瓶被颠倒两次使内容物混合,然后将样品滴加到一台Malvern 3600E型粒度计的测定池中直到得到0.2暗光。在样品池中搅拌1分钟和四分钟后读数。
计算每一样品的VMD值。每批测定五个样品的最小值并得到组合物的平均值。
实施例1
制备无定形头孢呋新axetil(150g)在硬脂酸粉BPC(850g)中的分散体,是将脂质熔融并将温度升至其熔点以上约15℃并加入头孢呋新axetil使混合而成。
将熔融的脂质/头孢呋新axetil分散体用压缩泵填入喷雾干燥器/急冷设备中并用外混双流喷头喷雾(喷头外径为2.54mm(喷液口)和3.81-4.57mm(环形喷液口),所用空气温度为65~70℃,喷雾压力约为345KPa(50psi)。在室温下送空气流到喷雾空中使产品冷却,并用气旋分离器收集固化后的产品。
实施例2
制备无定形头孢呋新axetil(150g)在硬脂酸粉BPC(850g)中的分散体,是将各组分干混后,熔融脂质,并使温度控制在类脂熔点以上约15℃而制得。
以300~500毫升/分速度将熔融脂质/头孢呋新axetil泵入喷雾干燥器/冷却设备中并用内混双流喷头喷雾(由Delavan有限公司,Widnes,提供Cheshire目录号为32163-1,如英国专利说明书N。1412133所述),所用空气温度为65~70℃,喷雾压力范围为276~345KPa(40-50psi)。在室温下通空气流于喷雾室中使产品冷却并通过重力收集固化的产品。
实施例3
按照实施例2方法制备无定形头孢呋新axetil的硬脂酸粉BPC中的分散体。
用齿轮泵将熔融的脂质/头孢呋新axetil分散体泵入喷雾干燥器/冷却设备中并用外混双流喷头(210mm孔径)喷雾,空气温度为75℃,喷雾压力为310KPa(45psi)。在环境温度下通空气流于喷雾室中以冷却产品并在气旋分离器中收集固化的产品。
下面给出用实施例1~3的方法制备的数批产品的颗粒大小。
实施例号 MALVERN Coulter 光学显微镜法
3600E粒度计 计数器TAⅡ IMANCOFMS
1 44.91μm 48.73μm 42.07μm
n=10 n=5 n=2
2 43.93μm 38.80μm 40.10μm
A批 n=20 n=5 n=2
2 55.56μm 44.43μm 43.86μm
B批 n=10 n=5 n=2
3 29.46μm 37.21μm 35.18μm
n=10 n=10 n=2
所有颗粒大小以VMD值表示。
n=测定样品数
实施例4
在搅拌下加热头孢呋新(124g)和硬脂酸粉BPC(676g)的干混物到68℃,使脂质熔融并形成悬浮物。通过向熔融容器加压,以大约400毫升/分速度把熔融的脂质/头孢呋新axetil分散体转移到喷雾冷却室中。然后,用内混双流喷头喷雾(如实施例2所述),空气温度为78℃,压力为380kpa(55psi)。向喷雾室通空气流冷却产品并靠重力收集固化的产品。
颗粒的平均直径(Coulter计数法)为51微米。
头孢呋新axetil含量为15.4%。
实施例5
通过升温至脂质熔点以上15℃使脂质熔融,然后,用高剪切混合器加适量的头孢呋新axetil使混合,以制备脂质包衣分散体。
以大约300毫升/分的速度,将熔融的脂质/头孢呋新分散体泵入有1.82米高喷雾室的常规喷雾干燥器/冷却设备中,并用外混双流喷头喷雾(如实施例1所述),喷雾压力为275-414kpa(40-60psi)。向喷雾室通7~11℃的空气流使产品冷却。用气旋分离器收集固体产品。
下面的头孢呋新axetil和各种脂质的混合物经喷雾和冷却,得到掩蔽苦味的脂质包衣的头孢呋新axetil颗粒。采用“Quantimet 970”成象分析仪经光学显微镜法测定所得颗粒的直径。
%(重量/重量) 重量(g)
a)硬脂酸粉BPC 85 850
头孢呋新axetil 15 150
颗粒平均直径按数目计为7.18μm
(95%所得颗粒的粒径小于22微米)
颗粒平均直径按体积计为41.9μm
b)Hyfac 85 850
头孢呋新axetil 15 150
颗粒平均直径按数目计为7.93μm
(95%所得颗粒的粒径小于25微米)
颗粒平均直径按体积计为47.5μm
c)硬脂酸粉BPC 42.5 212.5
Dynasan 112 42.5 212.5
头孢呋新axetil 15 75.0
颗粒平均直径按数目计为8.38μm
(95%所得颗粒的粒径小于32微米)
颗粒平均直径按体积计为51.0μm
d)Dynasan 114 85 425
头孢呋新axetil 15 75
颗粒平均直径按数目计为7.32μm
(95%所得颗粒的粒径小于21微米)
颗粒平均直径按体积计为47.1μm
实施例6
通过高剪切混合将麦芽糖糊精(400g),果味香料(1g)和淀粉1500(25g)分散于蒸馏水中(最终为1升体积),再经用高剪切混合将头孢呋新axetil(100g)分散于此分散体中,然后,用常规喷雾干燥技术将此分散体喷雾干燥并用气旋分离器收集麦芽糖糊精包衣的头孢呋新axetil颗粒产品。
然后,按实施例5所述方法将此麦芽糖糊精包衣的头孢呋新axetil颗粒用硬脂酸粉BPC进行包衣。
%(重量/重量) 重量(g)
硬脂酸粉BPC 60 600
包衣麦芽糖的头孢呋新axetil 40 400
颗粒平均直径按数目计
为7.51微米(95%所得颗粒的粒
径小于23微米)
颗粒平均直径按体积计为46.0微米。
实施例7
按照实施例5和6的方法,将如下头孢呋新axetil和各种脂质的混合物喷雾,冷却,得到掩蔽苦味的脂质包衣的头孢呋新axetil颗粒剂。
%(重量/重量) 重量(g)
a)硬脂酸粉BPC 55 611
包衣麦芽糖糊精的头孢呋新axetil 45 500
b)硬脂酸粉BPC 80 800
头孢呋新axetil 20 200
c)Revel A 80 800
头孢呋新axetil 20 200
d)Cetostearyl alcohol 85 850
头孢呋新axetil 15 150
e)Cetostearyl alcohol 60 600
麦芽糖糊精包衣的头孢呋新axetil 40 400
f)Hyfac 60 600
麦芽糖糊精包衣的头孢呋新axetil 40 400
g)硬脂酸粉USNF 90 900
头孢呋新axetil 10 100
h)硬脂酸粉USNF 40 200
Dynasan 112 40 200
头孢呋新axetil 20 100
i)硬脂酸粉BPC 42.5 212.5
Dynasan 114 42.5 212.5
头孢呋新axetil 14 75
j)硬脂酸 42.5 212.5
棕榈酸 42.5 212.5
头孢呋新axetil 15 75
k)硬脂酸 40 200
棕榈酸 40 200
头孢呋新axetil 20 100
药物实施例
硬脂酸BPC包衣的头孢呋新axetil与蔗糖和下示比例的专用香料混合。混匀后以水作团粒液用常规方法成粒。干燥后,过筛,以除去颗粒中的任何结块,最后装瓶。口服悬浮液用水制成,每5ml悬浮液中含125mg头孢呋新。
组分 %(重量/重量)
硬脂酸BPC包衣的
头孢呋新axetil 24.92
蔗糖 74.75
香料(树果味) 0.33
Claims (27)
1、一种制备含头孢呋新axetil颗粒剂的方法,这些颗粒剂由脂质或脂质混合物整个包衣,是不溶于水的并掩蔽了口服时头孢呋新axetil的苦味,但当与胃肠液接触时就分散开或溶解,该方法包括分散粒状头孢呋新axetil于熔融的脂质或脂质混合物中,喷雾此分散体得到脂质或脂质混合物整个包衣的药粒,冷却并收集所得的气衣粒剂。
2、权利要求1的方法,其中脂质或脂质混合物的熔点在30~80℃范围内。
3、权利要求2的方法,其中脂质或脂质混合物的熔点在40~70℃范围内。
4、权利要求1的方法,其中脂质或脂质混合物包括1种或多种有10~30个碳原子的直链脂肪酸。
5、权利要求4的方法,其中脂质混合物包括重量比为3∶7~7∶3的硬脂酸和棕榈酸的混合物。
6、权利要求5的方法,其中硬脂酸和棕榈酸混合物的重量比约为1∶1。
7、权利要求1~6的任一方法,其中粒状头孢呋新axetil和所用脂质或脂质混合物的量应满足所得包衣药粒含5~90%(重量)的头孢呋新axetil。
8、权利要求7的方法,其中粒状头孢呋新axetil和脂质或脂质混合物的用量应满足所得包衣药粒含10~30%(重量)头孢呋新axetil。
9、权利要求1~8的任一方法,其中头孢呋新axetil是无定形的头孢呋新axetil。
10、权利要求9的方法,其中头孢呋新axetil是喷雾干燥的空心微球粒状的头孢呋新axetil。
11、权利要求1~10的任一方法,其中的分散体被喷雾成粒径为1~250微米的包衣药粒。
12、权利要求1~11的任一方法,其中的分散体被喷雾成平均体积粒径小于100微米的包衣药粒。
13、权利要求1~12的任一方法,其中分散体用气压喷头喷雾器喷雾。
14、权利要求13的方法,其中喷雾器是内混双流喷头喷雾器。
15、权利要求13或14的方法,其中熔融的分散体是在高于所用脂质或脂质混合物溶点10~20℃的温度下喷雾。
16、权利要求13,14或15的方法,其中粒状头孢呋新axetil在包衣前的平均体积粒径为5~50微米。
17、权利要求13~16的任一方法,其中所用粒状头孢呋新axetil和脂质或脂质混合物的用量应使所得包衣药粒含5~50%(重量)的头孢呋新axetil。
18、权利要求17的方法,其中所用粒状头孢呋新axetil和脂质或脂质混合物的用量应使所得包衣药粒含5~30%(重量)的头孢呋新axetil。
19、权利要求13~18的任一方法,其中的分散体被喷雾成粒径为1~250微米的包衣药粒。
20、权利要求13~19的任一方法,其中的分散体被喷雾成平均体积粒往小于100微米的包衣药粒。
21、权利要求20的方法,其中的分散体被喷雾成平均体积粒径为20~100微米的包衣药粒。
22、权利要求21的方法,其中的分散体被喷雾成平均体积粒径为30~60微米的包衣药粒。
23、权利要求1~22的任一方法,其中的包衣药粒接着与一种或多种药用载体或赋形剂组合或口服的药剂。
24、权利要求23的方法,其中的包衣药粒被作成颗粒剂。
25、权利要求23的方法,其中的包衣药粒被悬浮于水介质中。
26、权利要求23的方法,其中的包衣药粒与口服可接受的溶质一起配制以便口服悬浮液时保持脂质包衣掩蔽苦味的性质。
27、权利要求25的方法,其中的水介质含有浓度范围为50~85%(重量)的糖。
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