CN104780908A - 半塑性药物剂量单位的制造 - Google Patents
半塑性药物剂量单位的制造 Download PDFInfo
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- CN104780908A CN104780908A CN201380060526.2A CN201380060526A CN104780908A CN 104780908 A CN104780908 A CN 104780908A CN 201380060526 A CN201380060526 A CN 201380060526A CN 104780908 A CN104780908 A CN 104780908A
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- Prior art keywords
- methyl
- dosage unit
- pharmaceutical dosage
- ethyl
- halogenated
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Classifications
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- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
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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
- A61K31/41—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
- A61K31/42—Oxazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
使用旋转模制机制造半塑性药物单位剂量的方法和通过该方法获得的半塑性药物剂量单位。
Description
发明领域
本发明涉及制造半塑性药物剂量单位如软咀嚼剂的领域。
发明背景
可咀嚼的药物剂量单位,如软咀嚼剂,是已知的并已经商业化用于宠物。将药物配制为可咀嚼剂型可以提高倾向于抗拒吞咽硬质片剂或胶囊的(动物)患者的药物接受度并甚至令动物自由选择服用该剂型。
质地对此类口服剂量单位的(动物)患者接受度是重要的。可咀嚼药物剂量单位最常用的形式之一是可咀嚼的压缩片剂,但其成分可使片剂呈砂砾质或不讨人喜欢,尤其是对非人类动物而言。因此,用于非人类动物的优选替代剂型是“软咀嚼剂”——通常是也广泛存在于可食用宠物零食中的肉状物。
现有技术中已经描述了软咀嚼药物剂量单位(软咀嚼剂)。美国专利号6,387,381公开了由具有淀粉、糖、脂肪、多元醇和水的基质构成的挤出物。
WO
2004/014143涉及以适合食用的形式,特别是以软咀嚼剂的形式向生物体递送添加剂的组合物和方法。
US
2009/0280159和US 2011/0223234涉及可口的可食用软咀嚼药物载体。其中描述的方法涉及挤出过程中生成的热造成该混合物中的活性成分的稳定性变差的问题。
用于生产模制食用肉饼的机器已被描述为可用于制造给药于非人类动物的软咀嚼剂。这样的机器是最初为用于制造模制食品而开发的模制机,例如Formax
Corporation制造的Formax F6™模制机或美国专利号3,486,186;3,887,964;3,952,478;4,054,967;4,097,961;4,182,003;4,334,339;4,338,702;4,343,068;4,356,595;4,372,008;4,535,505;4,597,135;4,608,731;4,622,717;4,697,308;4,768,941;4,780,931;4,818,446;4,821,376;4,872,241;4,975,039;4,996,743;5,021,025;5,022,888;5,655,436;和5,980,228中公开的模制机。
此类机器一开始用于由绞牛肉供给品通过将绞牛肉在压力下压入多腔模板而形成例如汉堡肉饼,该模板在装料位置与排料位置之间的线性滑轨上快速穿梭,其中可垂直往复运动的顶出器(knock-outs)从模腔中推出肉饼。此类机器的示意图显示在图1中。
但是已经观察到,采用此类成型机,在可以以所需品质大规模制造的软咀嚼药物剂量单位的尺寸和重量方面存在限制。
因此,以工业规模制造此类软咀嚼药物剂量单位和其它半塑性药物剂量单位的替代方法将是合意的。
旋转模制机已知用于制造糖果如杏仁糖、方旦糖、坚果组合物、水果组合物、乳脂软糖、焦糖、牛轧糖、椰子组合物等等。
现在已经发现,用旋转模制机成型的半塑性药物剂量单位,例如软咀嚼剂,具有合意的性质并解决了现有技术的问题。
发明概述
在一个方面,本发明涉及制造半塑性药物剂量单位的方法,其中用旋转模制机成型该半塑性药物剂量单位。
在一个实施方案中,该方法包括以下步骤:
a)将至少一种活性药物成分与至少一种干组分和/或液体组分混合以制备预混合料,
b)加热成型剂直到熔融,
c)将该预混合料与该成型剂混合在一起以形成团状物,
d)将该团状物进料到与旋转模制机连接的容器中;并
e)在旋转模制机中成型半塑性药物剂量单位。
在一个实施方案中,该旋转模制机包含具有凹边的成型模具。
在一个实施方案中,该成型剂是聚乙二醇。
在一个实施方案中,步骤d)中该团状物的温度为35℃至45℃。
在一个实施方案中,该半塑性药物剂量单位是用于口服的软咀嚼兽药产品。
在一个实施方案中,该活性药物成分是异噁唑啉化合物,优选具有如下定义的式(I)。
在一个实施方案中,该活性药物成分是4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基-N-[(2,2,2-三氟-乙基氨基甲酰基)-甲基]-苯甲酰胺。
本发明的另一方面是可以通过该方法获得的半塑性药物剂量单位。
在一个实施方案中,此类半塑性药物剂量单位是用于口服的软咀嚼兽药产品。
本发明的另一方面是一种半塑性药物剂量单位,其中在该三维体的至少一端处该药物剂量单位具有凹边。
在一个实施方案中,该半塑性药物剂量单位具有圆柱体形式。
在一个实施方案中,该剂量单位是用于口服的软咀嚼兽药产品。
在一个实施方案中,该活性药物成分是异噁唑啉化合物。
在一个实施方案中,该产品包含式(I)的异噁唑啉化合物作为活性药物成分
式(I),
其中
R1 = 卤素、CF3、OCF3、CN,
n = 0至3的整数,优选1、2或3,
R2 = C1-C3-卤代烷基,优选CF3或CF2Cl,
T = 5-或6-元环,其任选被一个或多个基团Y取代,
Y = 甲基、卤代甲基、卤素、CN、NO2、NH2-C=S,或两个相邻的基团Y一起构成链,尤其是三或四元链;
Q = X-NR3R4或5-元N-杂芳基环,其任选被一个或多个基团取代;
X = CH2、CH(CH3)、CH(CN)、CO、CS,
R3 = 氢、甲基、卤代乙基、卤代丙基、卤代丁基、甲氧基甲基、甲氧基乙基、卤代甲氧基甲基、乙氧基甲基、卤代乙氧基甲基、丙氧基甲基、乙基氨基羰基甲基、乙基氨基羰基乙基、二甲氧基乙基、丙炔基氨基羰基甲基、N-苯基-N-甲基-氨基、卤代乙基氨基羰基甲基、卤代乙基氨基羰基乙基、四氢呋喃基、甲基氨基羰基甲基、(N,N-二甲基氨基)-羰基甲基、丙基氨基羰基甲基、环丙基氨基羰基甲基、丙烯基氨基羰基甲基、卤代乙基氨基羰基环丙基,
其中ZA = 氢、卤素、氰基、卤代甲基(CF3);
R4 = 氢、乙基、甲氧基甲基、卤代甲氧基甲基、乙氧基甲基、卤代乙氧基甲基、丙氧基甲基、甲基羰基、乙基羰基、丙基羰基、环丙基羰基、甲氧基羰基、甲氧基甲基羰基、氨基羰基、乙基氨基羰基甲基、乙基氨基羰基乙基、二甲氧基乙基、丙炔基氨基羰基甲基、卤代乙基氨基羰基甲基、氰基甲基氨基羰基甲基或卤代乙基氨基羰基乙基;
或者R3和R4一起构成选自以下的取代基:
或其盐或溶剂合物。
在一个具体实施方案中,该活性药物成分是4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基-N-[(2,2,2-三氟-乙基氨基甲酰基)-甲基]-苯甲酰胺。
本发明的另一方面是该半塑性药物剂量单位在制造用于控制动物的寄生昆虫、螨或线虫感染的药物中的用途。
本发明的另一方面是用于控制动物的寄生昆虫、螨或线虫感染的半塑性药物剂量单位。
附图概述
图1显示了顶出式Formax机器的示意图。
图2显示了旋转模制机的实例的示意图。
图3显示了本发明的软咀嚼剂的侧视图。
发明详述
本发明人发现了旋转模制机尤其有益于制造软咀嚼剂和其它半塑性药物剂量单位(产品)。
对于以工业规模制造半塑性药物剂量单位而言,成型机是必要的,其能够以始终如一的高品质制造高容量的剂量单位以满足药物标准。在这方面的品质指的是该剂量单位具有在规定的狭窄范围内的重量与尺寸,具有均匀的外观(形状)与组成,即它们不会破裂或变形,并具有光滑无裂纹的表面。此外,有益的是该半塑性药物剂量单位如软咀嚼剂在成型过程后保持恒定的尺寸。现在已经发现采用旋转模制机成型获得此类合意的性质。
尽管将对制造软咀嚼药物剂量单位(软咀嚼剂)详细描述了该方法,该方法可以类似地用于制造向人类或动物给药的替代半塑性药物剂量单位。考虑的替代半塑性药物剂量单位的实例是膏药、用于直肠给药的栓剂或***片剂。
半塑性药物剂量单位是与常规硬片剂相比具有较低硬度和较高水分含量的固体(在室温下)药物剂量单位。此类剂量单位表现出塑性流变行为,并可以通过模塑设备成型为许多不同的形状。不同于三维的塑性产品,半塑性意味着该单位剂量是三维体,其中该体的底部是平坦的。半塑性药物剂量单位在模塑后是尺寸稳定的。此类半塑性药物剂量单位的成分具有药物等级。半塑性药物剂量单位的说明性实例是如现有技术和下文中描述的软咀嚼剂。
“软咀嚼剂”或“软咀嚼药物产品”意在指一种药物单位剂量,其在室温下为固体并且在口服后对由患者/动物咀嚼而言是柔软的,并且其在功能上是难嚼的,因为该产品在口腔中咀嚼的过程中具有一定的塑性质地。此类软咀嚼剂具有类似于烹煮过的碎肉小块的柔软性。
现在已经发现,使用旋转模制机,可以以所需品质制造具有不同形状与尺寸的半塑性药物剂量单位,如软咀嚼剂,其在已经描述过并且目前用于大规模制造软咀嚼剂的常规顶出式压力模塑成型机(例如Formax机器)上极难或甚至不可能以工业规模加工。
尤其用顶出式成型机(例如Formax)工业加工重量为2克或更小的小型软咀嚼剂已被证明是困难的,并且不能恒定的获得形状均匀的软咀嚼剂。
旋转模制机的另一益处是该方法的更高产率,即可以由填充到该机器中的规定重量的团状物制得的剂量单位的重量,该剂量单位,如成型的软咀嚼剂的尺寸与形状更均匀,能够快速清洗该模制机,并且能够容易地改变模塑工具。
旋转模制机是已知的,并通常用于面包房与糖果工厂的食品加工。旋转模制机的一般概念是,将团状物压入旋转模塑辊(成型辊)中并随后从不具有冲撞(knockoff)或冲压机构的模具中取出。
旋转模制机的一种形式包括两个平行排列并彼此切向接触的辊——第一辊(A),也称为压力辊,优选具有沟槽表面,以及第二辊(B),也称为成型辊,具有多个成型模具(或空腔)在其上按照设定图案排列的表面,且所述成型模具具有可与所需成品相比较的尺寸。两个辊在顶部与料斗(H)连通,在该料斗中可装载预先制备的团状物。该成型辊在相反的角方向上移动,使得团状物经由压力辊的沟槽被推向辊之间的切向接触区域,仍在上述接触区域中的该压力辊还将团状物推入成型辊的模具中以便在各模具中形成剂量单位。
该旋转模制机还装有合适的设备以收集来自该模具的剂量单位,以便随后在干燥和硬化后将其转送至用于包装的托盘。此类旋转模制机的示意图显示在图2中。
在旋转成型机的替代形式中,该旋转模制机的料斗装有团状物,并借助料斗下方的压力室经喷嘴将团状物压入旋转模塑辊(成型辊)。吸入式传送带由该成型辊回收预成型的产品,并将它们向前输送。在吸入式传送带的前部具有刀口和松料轴。
适用于本发明的方法的旋转模制机例如可获自Krüger
& Salecker Maschinenbau GmbH & Co KG, Bad Schwartau, Germany(例如MFT400)、OKA-Spezialmaschinen
KG, Darmstadt, Germany或获自Sollich KG, Bad
Schwartau, Germany。
在第一步骤中通过将至少一种活性药物成分与干组分和/或液体组分混合以制备预混合料来制备用该旋转模制机加工的团状物团块。
用于本发明的方法或产品的活性药物成分(或活性成分,或药物活性成分,或可药用活性成分)是用在药物剂量单位中、旨在提供药理活性或以其它方式在疾病的诊断、治愈、减轻、治疗或预防中具有直接作用或在人类或动物的生理机能的恢复、矫正或修正中具有直接作用的物质。
在本发明的方法中和在本发明的产品中可以提供任何药物活性成分。药物领域普通技术人员完全熟悉此类活性成分是什么,其可以包括但不限于抗生素、镇痛剂、抗病毒剂、抗真菌剂、抗寄生虫药,如抗体内和体外寄生虫药、激素和/或其衍生物、抗炎药(包括非甾体抗炎药)、类固醇、行为修正剂、疫苗、抗酸药、缓泻药、抗惊厥药、镇静剂、安定药、镇咳药、抗组胺药、解充血药、祛痰药、食欲刺激剂和抑制剂、心血管药、矿物质和维生素。
有用的活性药物成分优选是抗寄生虫药,更优选选自异噁唑啉化合物、除虫菌素类(例如伊维菌素、司拉克丁、多拉克丁、阿维菌素和依立诺克丁);米尔倍霉素类(莫昔克丁和米尔贝肟);前-苯并咪唑类(例如非班太尔、萘托比胺和托布津);苯并咪唑衍生物,如噻唑苯并咪唑衍生物(例如噻苯咪唑和坎苯达唑)、氨基甲酸酯苯并咪唑衍生物(例如芬苯达唑、阿苯达唑(氧化物)、甲苯咪唑、奥芬达唑、帕苯达唑、奥苯达唑、氟苯达唑和三氯苯咪唑);咪唑并噻唑类(例如左旋咪唑和四咪唑);四氢嘧啶(莫仑太尔和噻嘧啶)、水杨酰苯胺类(例如氯氰碘柳胺、羟氯柳苯胺、雷复尼特和氯硝柳胺);硝基酚化合物(例如硝碘酚腈和硝硫氰酯);苯二磺酰胺类(例如氯舒隆);吡嗪并异喹啉类(例如吡喹酮和依西太尔);杂环化合物(例如哌嗪、二乙基乙胺嗪和吩噻嗪);二氯酚、砷剂(例如硫乙胂胺、melorsamine和砷酰胺);环八缩酚酸肽类(cyclooctadepsipeptides)(例如emodepside);paraherquamides(例如德奎太尔),氨基-乙腈化合物(例如莫奈太尔、AAD 1566);和脒化合物(例如阿米太尔和三苯双脒),包括其所有可药用形式,如盐、溶剂合物或N-氧化物。
在一个实施方案中,该药物活性成分是异噁唑啉化合物。异噁唑啉化合物是本领域中已知的,且这些化合物和它们作为抗寄生虫药的用途例如描述在美国专利申请US
2007/0066617和国际专利申请WO 2005/085216、WO 2007/079162、WO
2009/002809、WO 2009/024541、WO 2009/003075、WO
2010/070068和WO 2010/079077中,它们的公开内容以及其中引用的参考资料通过引用并入本文。这类化合物已知具有优异的抗体外寄生虫,即寄生昆虫和螨,如蜱和跳蚤以及体内寄生虫,如线虫的活性。
在一个实施方案中,本发明的软咀嚼药物产品包含式(I)的异噁唑啉化合物
式(I),其中
R1 = 卤素、CF3、OCF3、CN,
n = 0至3的整数,优选1、2或3,
R2 = C1-C3-卤代烷基,优选CF3或CF2Cl,
T = 5-或6-元环,其任选被一个或多个基团Y取代,
Y = 甲基、卤代甲基、卤素、CN、NO2、NH2-C=S,或者两个相邻的基团Y一起构成链CH-CH=CH-CH、N-CH=CH-CH、CH-N=CH-CH、CH-CH=N-CH或CH-CH=CH-N、HC=HC-CH、CH-CH=CH、CH=CH-N、N-CH=CH;
Q = X-NR3R4或5-元N-杂芳基环,其任选被一个或多个基团ZA、ZB ZD取代;
X = CH2、CH(CH3)、CH(CN)、CO、CS,
R3 = 氢、甲基、卤代乙基、卤代丙基、卤代丁基、甲氧基甲基、甲氧基乙基、卤代甲氧基甲基、乙氧基甲基、卤代乙氧基甲基、丙氧基甲基、乙基氨基羰基甲基、乙基氨基羰基乙基、二甲氧基乙基、丙炔基氨基羰基甲基、N-苯基-N-甲基-氨基、卤代乙基氨基羰基甲基、卤代乙基氨基羰基乙基、四氢呋喃基、甲基氨基羰基甲基、(N,N-二甲基氨基)-羰基甲基、丙基氨基羰基甲基、环丙基氨基羰基甲基、丙烯基氨基羰基甲基、卤代乙基氨基羰基环丙基,
R4 = 氢、乙基、甲氧基甲基、卤代甲氧基甲基、乙氧基甲基、卤代乙氧基甲基、丙氧基甲基、甲基羰基、乙基羰基、丙基羰基、环丙基羰基、甲氧基羰基、甲氧基甲基羰基、氨基羰基、乙基氨基羰基甲基、乙基氨基羰基乙基、二甲氧基乙基、丙炔基氨基羰基甲基、卤代乙基氨基羰基甲基、氰基甲基氨基羰基甲基或卤代乙基氨基羰基乙基;或
R3和R4一起构成选自以下的取代基:
其中ZA = 氢、卤素、氰基、卤代甲基(CF3)。
在一个优选实施方案中,在式(I)中,T选自
其中在T-1、T-3和T-4中,基团Y是氢、卤素、甲基、卤代甲基、乙基、卤代乙基。
在一个优选实施方案中,在式(I)中,Q选自
其中R3、R4、X和ZA如上文所定义。
优选的式(I)的化合物是:
尤其优选的式(I)的化合物是
更优选的化合物具有式(II)
式II
其中
R1a、R1b、R1c彼此独立地为氢、Cl或CF3,优选R1a和R1c是Cl或CF3,且R1b为氢,
T是
其中Y是甲基、溴、Cl、F、CN或C(S)NH2,和
Q如上所述。
在另一个优选实施方案中,R3是H且R4是-CH2-C(O)-NH-CH2-CF3、-CH2-C(O)-NH-CH2-CH3、-CH2-CH2-CF3或-CH2-CF3。
在一个实施方案中,式(I)的化合物是4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基-N-[(2,2,2-三氟-乙基氨基甲酰基)-甲基]-苯甲酰胺(CAS RN 864731-61-3 - USAN fluralaner)。
在另一实施方案中,式(I)的化合物是(Z)-4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-N-[(甲氧基亚氨基)甲基]-2-甲基苯甲酰胺(CAS RN 928789-76-8)。
在另一实施方案中,式(I)的化合物是WO2009/0080250中公开的4-[5-(3,5-二氯苯基)-5-(三氟甲基)-4H-异噁唑-3-基]-2-甲基-N-(噻丁环-3-基)苯甲酰胺(CAS RN 1164267-94-0)。
在另一实施方案中,式(I)的化合物是WO2007/079162中公开的4-[5-[3-氯-5-(三氟甲基)苯基]-4,5-二氢-5-(三氟甲基)-3-异噁唑基]-N-[2-氧代-2-[(2,2,2-三氟乙基)氨基]乙基]-1-萘甲酰胺(CAS RN
1093861-60-9, USAN - afoxolaner)。
在另一实施方案中,式(I)的化合物是WO2010/070068中公开的5-[5-(3,5-二氯苯基)-4,5-二氢-5-(三氟甲基)-3-异噁唑基]-3-甲基-N-[2-氧代-2-[(2,2,2-三氟乙基)氨基]乙基]-2-噻吩甲酰胺(CAS RN 1231754-09-8)。
尤其优选的化合物是
(fluralaner)。
尤其优选的式(II)的化合物是:
异噁唑啉化合物是本领域中已知的,且这些化合物和它们作为抗寄生虫药的用途例如描述在美国专利申请2007/0066617和国际专利申请WO 2007/079162、WO
2009/002809、WO 2009/024541、WO 2009/003075、WO2009/080250、WO 2010/070068、WO
2010/079077、WO 2011/075591和WO 2011/124998中,它们的公开内容以及其中引用的参考资料通过引用并入本文。这类化合物已知具有优异的抗体外寄生虫,如蜱和跳蚤的活性。
该异噁唑啉化合物可以以各种异构体形式存在。提到异噁唑啉化合物始终包括此类化合物的所有可能的异构体形式。除非另行指明,没有指示特定构象的化合物结构旨在包括该化合物的所有可能的构象异构体的组合物以及包含少于全部可能的构象异构体的组合物。在一些实施方案中,该化合物是手性化合物。在一些实施方案中,该化合物是非手性化合物。
式(I)的异噁唑啉化合物可以根据例如专利申请US
2007/0066617、WO 2007/079162、WO 2009/002809、WO
2009/080250、WO 2010/070068、WO 2010/079077、2011/075591和WO 2011/124998中描述的一种或其它方法或在熟悉化学合成的本领域技术人员的能力范围内的任何其它方法制备。关于本发明的产品的化学制备,本领域技术人员被认为尤其可任意利用“Chemical
Abstracts”和其中引用的文献的整个内容。
在一个实施方案中,该异噁唑啉化合物是4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基-N-[(2,2,2-三氟-乙基氨基甲酰基)-甲基]-苯甲酰胺(CAS RN
[864731-61-3])– USAN furalaner -化合物A。
该活性药物成分还可以包含超过一种药物活性成分的组合。优选的组合包含选自异噁唑啉类与除虫菌素类或米尔贝霉素类的活性药物成分。在一个实施方案中,该软咀嚼剂包含异噁唑啉类,尤其是fluralaner-化合物A或afoxolaner与伊维菌素的组合。在另一实施方案中,该软咀嚼剂包含异噁唑啉类,尤其是fluralaner-化合物A或afoxolaner与米尔贝霉素或莫昔克丁的组合。
本发明的其它组合可以包括昆虫或螨生长调节剂(AGRs或IGRs),例如苯氧威、氯芬奴隆、除虫脲、双苯氟脲、杀铃脲、吡虫隆、环丙氨嗪、烯虫酯、吡丙醚等,由此提供动物对象上以及动物对象的环境内的寄生虫(在昆虫发育的所有阶段,包括卵)的初始和持续控制。
干组分是通常以粉末或颗粒形式提供的固体赋形剂。可以存在于该软咀嚼剂中的通常用于药物组合物的干组分是例如填料(一种或多种)、调味料(一种或多种)和/或糖组分。
本文中所用的术语“填料”或“填料组分”是指并表示含有占优势的重量的淀粉和/或类似淀粉的材料的那些食物。填料的实例是谷粒和在研磨谷粒如玉米、燕麦、小麦、蜀黍、大麦、稻米后获得的粗粉或面粉,和这些谷粒的各种研磨副产物,如饲用小麦粉、小麦粉头(wheat
middlings)、混合饲料、次小麦粉(wheat shorts)、低等小麦粉(wheat red dog)、燕麦、玉米麸(hominy
feed)和其它这样的材料。可以使用替代性的非食物填料,如乳糖。在一个实施方案中,该填料是淀粉,优选玉米淀粉。
常将调味料添加到软咀嚼药物产品中以增强它们的适口性。例如,兽药可包括基于动物产品的调味料,如牛肉、猪肉、鸡肉、火鸡肉、鱼肉和羔羊,可以使用肝、乳、奶酪和蛋。非动物来源的调味料是植物蛋白,如大豆蛋白、酵母或乳糖,在其中已加入可食用的人造食品样调味料。取决于目标动物,其它非动物调味料可以包括茴香油、角豆胶、花生、水果调味料、草本如欧芹、芹菜叶、薄荷、留兰香、大蒜或其组合。
糖组分可充当甜味剂、填料或调味料或提供对动物有吸引力的质地,例如松脆质地。本文中所用的术语“糖组分”和它们的任何结合形式(conjugation)是指并表示至少部分可溶于水分、无毒并优选不提供任何不合意的味道效果的任何糖。此外,术语“糖”的使用应包括“代糖”或“人造甜味剂”。糖组分可包含白糖、玉米糖浆、山梨糖醇、甘露糖醇、寡糖、低聚异麦芽糖、果糖、乳糖、葡萄糖、来卡生(lycasin)、木糖醇、乳糖醇、赤藓糖醇、甘露糖醇、异麦芽糖、聚葡萄糖、棉子糖、糊精、半乳糖、蔗糖、转化糖、蜂蜜、糖蜜、多元醇和其它类似的糖类低聚物和聚合物和它们的混合物,或人造甜味剂,如糖精、阿斯巴甜和其它二肽甜味剂。在一个实施方案中,该甜味剂是阿斯巴甜。
各种实施方案进一步包含附加赋形剂,如表面活性剂、稳定剂、流动剂、崩解剂、防腐剂和/或润滑剂。
表面活性剂组分是本领域中公知的。合适的表面活性剂是例如十二烷基硫酸钠。
合适的稳定剂组分是柠檬酸、柠檬酸钠和/或类似物和抗氧化剂,如BHT、BHA、抗坏血酸、生育酚、EDTA。
流动剂通常可包括二氧化硅、改性二氧化硅、气相二氧化硅、滑石和任何其它合适的材料以助于活性成分和/或组合在递送和/或制造过程中的批量运动。
崩解剂通常可包括淀粉羟乙酸钠、预胶化玉米淀粉(Starch 1500)、交聚维酮(Polyplasdone XL™,
International Specialty Products)和交联羧甲基纤维素钠(Ac-Di-Sol™, FMC Corp.)及其衍生物和有助于使剂型崩解并有助于递送活性成分的任何其它合适的材料。
口服制剂的防腐剂是本领域中已知的并为延迟微生物如细菌和真菌的生长而加入。防腐剂的一个实施方案包括如山梨酸钾、苯甲酸钠或丙酸钙之类的产品。
润滑剂是例如硬脂酸镁、富马酸、硬脂酰富马酸钠和双羟萘酸钠。
药物组合物的液体组分是本领域技术人员已知的。该液体组分通常是水性和非水液体或此类液体的混合物。
在该方法的一个实施方案中,该液体组分包含油或油的混合物。在另一实施方案中,该液体组分包含一种或多种油和一种或多种非水溶剂。在一个实施方案中,该液体组分包含一种或多种油、一种或多种非水溶剂和润湿剂。
软咀嚼剂中所用的油可以是植物或动物来源的饱和或不饱和液体脂肪酸、其甘油酯衍生物或脂肪酸衍生物或其混合物。植物脂肪或油的合适来源可以是棕榈油、玉米油、蓖麻油、芥花油、红花油、棉籽油、大豆油、橄榄油、花生油及其混合物。另外,动物油或脂肪和动物或植物油或脂肪的混合物适用于本发明的剂量单位。植物油也可用于润滑软咀嚼剂混合物并保持其软度。在一个实施方案中,该油性组分是大豆油。
本文所用的术语“非水溶剂”意在指在其中可溶解或悬浮生物材料的任何非水液体,并包括无机溶剂,更优选有机溶剂。
合适的非水溶剂的示例性实例包括但不限于以下溶剂:丙酮、乙腈、苄醇、丁基二甘醇、二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、二甲基甲酰胺、N,N-二乙基-3-甲基苯甲酰胺、二丙二醇正丁基醚、乙基醇、异丙醇、甲醇、丁醇、苯基乙基醇、异丙醇、乙二醇单乙基醚、乙二醇单甲基醚、单甲基乙酰胺、二丙二醇单甲基醚、液体聚氧乙二醇、丙二醇、N-甲基吡咯烷酮、2-吡咯烷酮、二乙二醇单乙基醚、乙二醇、邻苯二甲酸二乙酯、聚乙氧基化蓖麻油、甲乙酮、乙基-L-乳酸酯、乳酸、苹果酯、甘油缩甲醛、乙酸乙酯、乙酸1-甲氧基-2-丙酯、乙酰乙酸乙酯、乙酸香叶酯、苯甲酸苄酯、碳酸丙烯酯、水杨酸甲酯、异亚丙基甘油、丙二醇甲基醚、二乙二醇单乙基醚。
本文中所用的术语“润湿剂”是指并表示吸湿物质。其可以是具有几个亲水基团,例如羟基的分子,但也可以遇到胺和羧基(有时酯化的);与水分子形成氢键的亲合力在此至关重要。
润湿剂具有使软咀嚼剂团状物保持湿润的作用。润湿剂的实例包括丙二醇、三乙酸甘油酯、乙烯醇和新琼脂二糖。另一些可以是糖多元醇,如甘油、山梨糖醇、木糖醇和麦芽糖醇,聚合多元醇,如聚葡萄糖,或天然提取物,如皂树皮、乳酸或脲。在一个实施方案中,该润湿剂是甘油。
在一个实施方案中,该液体组分占软咀嚼剂的大约5%至大约50%
w/w。在另一实施方案中,液体组分占软咀嚼剂的大约7.5%至大约40% w/w。在另一实施方案中,液体组分占软咀嚼剂的大约10%至大约30% w/w。在另一实施方案中,液体组分占软咀嚼剂的大约15%至大约25% w/w。
用于本发明的方法的干组分和液体组分按照惯例进一步包含本领域中已知的,例如如“Gennaro,
Remington: The Science and Practice of Pharmacy”(第20版,2000)(通过引用并入本文)中所述的生理学可接受的配制赋形剂。所有此类成分、载体和赋形剂必须基本药学或兽药学纯净并在所用量下无毒并且必须与药物活性成分相容。
该干成分与液体成分通过常规设备混合直到均匀共混以形成预混合料。本领域技术人员知道合适的共混设备,例如犁铧式混合搅拌机。在第二步骤中,加热该成型剂直到熔融。
该成型剂是在室温下为固体并具有45至100℃的熔点的赋形剂。其包含在熔融形式的组合物中并对软咀嚼剂的质地和由团状物形成保持完整和独立的单个软咀嚼剂的可能性而言是重要的。在环境温度下,该成型剂固化并在硬化后获得尺寸稳定的剂量单位。合适的成型剂例如是蜡或聚合物,例如聚乙二醇(PEG)或聚乙烯基吡咯烷酮(PVP)。
在一个实施方案中,成型剂的选择是聚乙二醇(PEG)。此外,根据软咀嚼剂的所需稠度,可以使用不同分子量的PEG。在一个实施方案中,使用PEG 3350。但是,该分子量可能高于或低于3350,但优选高于600。或者,可以使用PEG 8000。
在一个实施方案中,该成型剂占软咀嚼剂的大约1%至大约40%
w/w。在另一实施方案中,成型剂占软咀嚼剂的大约5%至大约30% w/w%。在另一实施方案中,成型剂占软咀嚼剂的大约10%至大约20%w/w。如果该成型剂是聚乙烯基吡咯烷酮,在该咀嚼剂中存在例如2、4、5、6或9% w/w。
在第三步骤中,将如上所述通过混合该活性药物成分与干组分和液体组分形成的预混合料与熔融的成型剂混合以形成用于在旋转模制机中加工的团状物。常规设备可用于这一步骤。在成型剂与预混合料均匀混合以形成可模塑团状物(包含该活性药物成分、干组分与液体组分和成型剂的柔软的柔性团块)后,将该团状物进料到与旋转模制机相连的容器(例如料斗)中。或者该容器可以是将团状物输送至该旋转模制机的成型辊的替代装置,例如螺旋输送机。
团状物的温度对于在旋转模制机中加工而言是重要的。在该团状物装填到旋转模制机的料斗中时,其优选具有大约35℃至大约45℃的温度。在另一实施方案中,该团状物的温度为大约37℃至大约43℃。在另一实施方案中,该团状物的温度为大约42℃至大约45℃。
优选可以在预混合料与成型剂的混合步骤过程中、在输送到旋转模制机的成型辊的过程中和/或在旋转模制机中的成型工艺过程中控制该团状物的温度。
在一个实施方案中,在本发明的方法中,在该旋转模制机中控制料斗的温度,例如通过包含通常将温度控制在大约35℃至大约45℃的液体的夹套。
在另一实施方案中,此外或独立地,例如通过具有温控液体的夹套来控制旋转模制机的成型辊的温度,优选将其冷却。控制此类设备的温度的替代装置是本领域技术人员已知的。
该团状物随后在旋转模制机中加工以形成半塑性药物单位剂量。
本发明的方法可以基于连续或批量进行。
在本发明的方法中使用的旋转模制机的辊(一个或多个)可以由塑料或金属制成。在一个实施方案中,该成型辊为整块形式,并且成型模具刻在整块中。在一个实施方案中,该成型辊由不锈钢制成,并且该成型模具可以配备带有或不带有涂层的塑料镶嵌物。在一个实施方案中,该成型辊包含具有凹边的成型模具。
为了确保团状物样的团块能够离开成型模具,有几种不同的技术选项可供选择。该团块可以用粗传送带或用具有真空抽吸的传送带从成型模具中吸出。
在一个实施方案中,该传送带由对团状物的粘着系数高于对成型辊的材料的粘着系数的材料制成。由于这种粘附性差异,该输送带可以从跨越传送带与成型辊接触的部分的模具中提取该剂量单位并收集在其传送表面上。在使用此类抽吸传送带的情况下,该成型辊可以是其中该成型模具是在整块中并且不使用支持软咀嚼剂脱模的附加装置的辊。
另一选项可以是使用加压空气,该加压空气将该团块从成型模具中推出。通过压缩气体从成型模具中取出模塑剂量单位的一种技术方案描述在通过引用并入本文的US
8,029,841中。
各批剂量单位(例如软咀嚼剂)可以散装包装,或优选各软咀嚼剂随后独立包装以便储存和分配。合适的包装材料的实例包括HDPE瓶、泡罩或箔/箔包装。
泡罩可用于剂量单位如软咀嚼剂的独立包装。对于此类泡罩包装,重要的是该剂量单位如软咀嚼剂具有一致的尺寸且它们的尺寸在成型工艺后不会变化,并具有一致的形状以避免高百分比的离层(out-layers)。此外有益的是在该包装在运输、储存或处理过程中经受物理应力的情况下,该剂量单位如软咀嚼剂保持完好并且不会破裂。
本发明的另一方面是可以通过上述方法获得的半塑性药物剂量单位。可以通过这样的方法获得的剂量单位,尤其是软咀嚼药物产品(例如软咀嚼剂)具有一致的微稠度(micro
consistence)并且在成型后不显示膨胀(即不扩张)。此类剂量单位在单个软咀嚼剂中具有均匀的结构,并且活性药物成分和干组分与液体组分均匀分布在整个剂量单位中。
此类剂量单位可以具有不同的重量与尺寸,所述不同的重量与尺寸可以适应于待治疗的目标动物或患者的体重以及要给药的活性药物成分以便允许精确的剂量给药。
在一个实施方案中,该剂量单位(例如软咀嚼剂)具有0.5至50克的重量。在一个实施方案中,该剂量单位具有0.7至12克的重量。在一个实施方案中,该剂量单位具有大约2克和更少的重量。在另一个实施方案中,该剂量单位的重量为大约1.5克或更少,在另一个实施方案中,该剂量单位的重量为大约1克或更少。在另一个实施方案中,该剂量单位的重量为大约0.5克、大约0.6克、大约0.8克、大约0.9克、大约1.1克、大约1.2克、大约1.3克、大约1.4克、大约1.6克、或大约1.7克、大约1.8克。
在另一实施方案中,该剂量单位(例如软咀嚼剂)具有超过大约4克的重量。在一个实施方案中,该剂量单位具有超过大约7克的重量。在另一实施方案中,该剂量单位的重量为大于大约10克。在另一实施方案中,该剂量单位的重量为大约4克、大约5克、大约6克、大约7克、大约8克、大约9克、大约10克、大约11克、大约12克、大约13克、大约14克或大约15克。
该半塑性药物剂量单位(例如软咀嚼剂)具有三维的体,该体在底部具有平面(平坦)表面(半塑性药物剂量单位)。侧面与底面之间的边缘具有45°至110°的锐角。在一个实施方案中,侧面与底面的锐角为大约90°。侧面边缘的角度在底面的所有点处不一定相同。
在该体的另一端(顶面),该半塑性药物剂量单位(例如软咀嚼剂)具有至少一个凹陷的圆形边缘。该剂量单位的圆形边缘降低了剂量单位变形的风险,并限制了如果该单位剂量在包装或处理过程中暴露于物理应力的话剂量单位的碎片脱落的风险。在剂量单位碎片脱离的情况下,患者或动物在服用该剂量单位后将不能接受全部剂量的活性药物成分。
该半塑性药物剂量单位(例如软咀嚼剂)的顶面具有平面(平坦)、凹陷或凸出的规则或不规则表面,任选具有印痕。在一个实施方案中,该剂量单位具有凹陷的顶面。
该剂量单位的顶和/或底面通常可以具有任何形状。该剂量单位的形状可以适于促进向患者/目标动物的给药,或尤其在动物患者的情况下支持软咀嚼剂的自愿摄入。在一个实施方案中,该剂量单位(尤其是软咀嚼剂)的顶和/或底面为通常用于动物治疗的形状,例如为星星、十字、三角或骨头的形态。或者剂量单位的顶和/或底面是柱形面,例如椭圆形或圆形或矩形。在一个实施方案中,该顶面和底面的形状相同。
在一个实施方案中,该剂量单位是具有平坦底部的圆柱体形式的三维体。在该体的一端(底面),该圆柱体具有平面(平坦)表面,并且侧面与底面之间的边缘具有45°至110°的角度。在该圆柱体的另一端(顶面),该剂量单位(软咀嚼剂)具有至少一个凹陷的圆形边缘。
在一个实施方案中,该软咀嚼剂为圆柱体形式,在其一端具有平坦的底部,并在该圆柱体的另一端具有圆形的凹边。
在一个实施方案中,该剂量单位是锥体形式的三维体,具有平坦的底部,并在该锥体的顶端具有圆形的凹边。
在一个实施方案中,圆柱体或锥体形式的剂量单位的顶部和底部圆形表面的直径为5至50毫米。在一个实施方案中,该顶面的直径为5至10毫米,底面的直径为5至15毫米。在一个实施方案中,顶部圆形表面的直径小于底部圆形表面的直径。
在另一实施方案中,圆柱体或锥体形式的剂量单位的顶部和底部圆形表面的直径为5至50毫米。在一个实施方案中,该顶面的直径为15至30毫米,并且底面的直径为15至35毫米。在一个实施方案中,顶部圆形表面的直径小于底部圆形表面的直径。
在一个实施方案中,该剂量单位(例如软咀嚼剂)在该剂量单位的至少一个表面上具有印痕。在一个具体实施方案中,该印痕在该剂量单位的侧面区域上。在另一个实施方案中,该印痕在该剂量单位的顶面上。此类印痕可以是例如字母、数字、标志或符号等等。在一个实施方案中,在底面上存在印痕。
在另一个实施方案中,该剂量单位在一个表面上具有(交叉)刻痕或凹槽。该交叉刻痕具有便于切分该剂量单位的作用,并由此能够根据患者或动物的体重更准确地定量施用该活性药物成分。
此类剂量单位的实例,例如软咀嚼剂描述在图3a-g中。
该半塑性药物剂量单位包含如前所述的相同活性成分、干组分和液体组分以及成型剂。尤其优选的是包含异噁唑啉类,尤其是4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基-N-[(2,2,2-三氟-乙基氨基甲酰基)-甲基]-苯甲酰胺(CAS RN [864731-61-3])-化合物A的半塑性药物剂量单位,例如软咀嚼药物剂量单位。此类半塑性药物组合物可用于控制寄生虫,尤其是体外寄生虫,尤其是蜱和跳蚤,并因此可用于制造用于控制动物的寄生昆虫、螨或线虫感染的药物。
该剂量单位中各组分的量可以根据药物活性成分的性质、治疗的对象的体重和状况发生相当大的变化。本领域普通技术人员将能够根据本公开的教导针对特定药物活性成分调节剂量。
但是,通常,药物活性成分可以以组合物总重量的大约0.001%至75%(w/w)、更优选0.1%至40%的重量提供。
通常,本发明的半塑性药物剂量单位(例如软咀嚼剂)包含有效量的活性药物成分,这意味着无毒但是足以提供所需治疗、预防或控制作用的量。本领域技术人员使用常规实验可以确定任何个例中适当的“有效”量。此类量将取决于患者或目标动物的年龄、状况、体重和类型。该剂量单位如软咀嚼剂可以配制成为含有为动物或患者而调整过的特定重量范围内的活性成分的量。该动物可以每2、3、4、5或6个月接受一剂量,或接受每月、每周或每日剂量。在一个实施方案中,该动物每2个月接受一剂量。在另一个实施方案中,该动物每3个月接受一剂量。在另一个实施方案中,该动物每6个月接受一剂量。该处理可以例如是连续的或季节性的。
通常,本发明的剂量单位可以给药于人类和所有动物物种。在一个实施方案中,该动物是哺乳动物。该剂量单位的接受者可以是畜牧动物,例如绵羊、牛、猪、山羊或家禽;实验室试验动物,例如豚鼠、大鼠或小鼠;或宠物,例如狗、猫、兔子、雪貂或马。本发明的剂量单位尤其适用于宠物,例如狗、猫或雪貂。
本文所用的术语“w/w”是指重量/重量,术语“w/v”是指重量/体积。本文所用的%w/w代表成分在剂量单位配方中的重量百分比。
实施例1
软咀嚼制剂
试验制剂13-009至13-014:
(异噁唑啉)化合物B(用于130-009和13-010)
(异噁唑啉)化合物C(用于13-011和13-012)
。
表3:测试制剂
实施例2
制备具有实施例1的组成的团状物
将表现为团聚体的实施例1的制剂的干燥粉末状成分过筛。将所有干燥粉末状成分称重并放置在水平犁铧式混合搅拌机的混合容器中,并混合直到该共混物目视几乎均匀。
缓慢添加规定量的甘油,接着短暂混合。缓慢添加大豆油并再次接着进行短暂混合。将混合机加热至抑制下一步骤中引入的PEG的过快沉淀的温度。
将PEG 3350熔融。将规定量的熔融PEG快速添加到水平犁铧式混合搅拌机中的咀嚼剂混合物中,其随后混合直到混合物均匀并可以与壁分离。所得团状物的温度为43℃。混合物类似于“曲奇面团样”外观。
实施例3
使用Formax F6模制机制造实施例1的软咀嚼剂的方法(现有技术)
如实施例2中所述制备团状物。将团状物转移到Formax
F6成型机的料斗中并加工。在成型后,检查软咀嚼剂的外观并计算产率。大量软咀嚼剂变形,并且软咀嚼剂的高度不一致。视检丢弃的小的(约0.8克)和大的(约10.3克)的软咀嚼剂超过15%。
实施例4
本发明的使用旋转模制机制造实施例1的软咀嚼剂的方法
如实施例2中所述制备团状物。将团状物转移到MFT-200成型机(Krüger &
Salecker, Bad Schwartau, Germany)的料斗中。
使用具有PTFE(Teflon)成型辊的Krüger &
Salecker, Bad Schwartau的旋转模制机MFT-200将该混合物成型为单独的块体,该成型辊含有圆柱形腔室,并在硬化后将该软咀嚼剂包装在保存容器中。检查该软咀嚼剂的重量、产率和外观。
如表1至4中所示,成型的软咀嚼剂在重量、尺寸和形状方面是一致的,并且没有显示任何形变,并且在旋转模制机中的加工进行顺利。视检丢弃的小的(约0.8克)软咀嚼剂为0%,大的(约10.3克)软咀嚼剂为2%。硬化后的产率为97%。
在成型后在该批量过程开始和结束时取10个软咀嚼剂的样品并称重。软咀嚼剂的重量在用旋转成型机成型后是均匀的。
表1:小的软咀嚼剂的个体重量(克)
表2:大的软咀嚼剂的个体重量(克)
测量包装前10个取样的软咀嚼剂的尺寸并评价外观。取样的小的和大的软咀嚼剂具有一致的尺寸,并具有均匀形状而不变形。因此它们适于个别包装在泡罩中。
表3:各小软咀嚼剂的尺寸(毫米)
表4:各大软咀嚼剂的尺寸(毫米)
Claims (17)
1. 制造半塑性药物剂量单位的方法,其中用旋转模制机成型所述半塑性药物剂量单位。
2. 如权利要求1所述的方法,包括以下步骤:
a)将至少一种活性药物成分与一种或多种干组分和/或液体组分混合以制备预混合料,
b)加热成型剂直到熔融,
c)将所述预混合料与所述成型剂混合在一起以形成团状物,
d)将所述团状物进料到与旋转模制机连接的容器中;并
e)在旋转模制机中成型半塑性药物剂量单位。
3. 如权利要求1或2所述的方法,其中所述旋转模制机包含具有凹边的成型模具。
4. 如权利要求1至3任一项所述的方法,其中所述成型剂是聚乙二醇。
5. 如权利要求1至4任一项所述的方法,其中在步骤d)中所述团状物的温度为35℃至45℃。
6. 如权利要求1至5任一项所述的方法,其中所述半塑性药物剂量单位是用于口服的软咀嚼兽药产品。
7. 如权利要求1至6任一项所述的方法,其中所述活性药物成分是异噁唑啉化合物。
8. 如权利要求7所述的方法,其中所述活性药物成分是4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基-N-[(2,2,2-三氟-乙基氨基甲酰基)-甲基]-苯甲酰胺。
9. 半塑性药物剂量单位,其可以通过如权利要求1至8任一项所述的方法获得。
10. 权利要求9的半塑性药物剂量单位,其中所述药物剂量单位是用于口服的软咀嚼兽药产品。
11. 半塑性药物剂量单位,其中在该三维体的一端处所述半塑性药物剂量单位具有至少一个凹边。
12. 如权利要求11所述的半塑性药物剂量单位,其中所述半塑性药物剂量单位具有圆柱体形式。
13. 如权利要求11或12所述的半塑性药物剂量单位,其中所述剂量单位是用于口服的软咀嚼兽药产品。
14. 如权利要求9至13任一项所述的半塑性药物剂量单位,其中所述活性药物成分是式(I)的异噁唑啉化合物
式(I),
其中
R1 = 卤素、CF3、OCF3、CN,
n = 0至3的整数,优选1、2或3,
R2 = C1-C3-卤代烷基,优选CF3或CF2Cl,
T = 5-或6-元环,其任选被一个或多个基团Y取代,
Y = 甲基、卤代甲基、卤素、CN、NO2、NH2-C=S,或两个相邻的基团Y一起构成链,尤其是三或四元链;
Q = X-NR3R4或5-元N-杂芳基环,其任选被一个或多个基团取代;
X = CH2、CH(CH3)、CH(CN)、CO、CS,
R3 = 氢、甲基、卤代乙基、卤代丙基、卤代丁基、甲氧基甲基、甲氧基乙基、卤代甲氧基甲基、乙氧基甲基、卤代乙氧基甲基、丙氧基甲基、乙基氨基羰基甲基、乙基氨基羰基乙基、二甲氧基乙基、丙炔基氨基羰基甲基、N-苯基-N-甲基-氨基、卤代乙基氨基羰基甲基、卤代乙基氨基羰基乙基、四氢呋喃基、甲基氨基羰基甲基、(N,N-二甲基氨基)-羰基甲基、丙基氨基羰基甲基、环丙基氨基羰基甲基、丙烯基氨基羰基甲基、卤代乙基氨基羰基环丙基,
其中ZA
= 氢、卤素、氰基、卤代甲基(CF3);
R4 = 氢、乙基、甲氧基甲基、卤代甲氧基甲基、乙氧基甲基、卤代乙氧基甲基、丙氧基甲基、甲基羰基、乙基羰基、丙基羰基、环丙基羰基、甲氧基羰基、甲氧基甲基羰基、氨基羰基、乙基氨基羰基甲基、乙基氨基羰基乙基、二甲氧基乙基、丙炔基氨基羰基甲基、卤代乙基氨基羰基甲基、氰基甲基氨基羰基甲基或卤代乙基氨基羰基乙基;
或者R3和R4一起构成选自以下的取代基:
或其盐或溶剂合物。
15. 如权利要求14所述的半塑性药物剂量单位,其中所述活性药物成分是4-[5-(3,5-二氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基]-2-甲基-N-[(2,2,2-三氟-乙基氨基甲酰基)-甲基]-苯甲酰胺。
16. 如权利要求9至15任一项所述的半塑性药物剂量单位在制造用于控制动物的寄生昆虫、螨或线虫感染的药物中的用途。
17. 用于控制动物的寄生昆虫、螨或线虫感染的方法中的包含如权利要求14中所规定的式(I)的异噁唑啉化合物的半塑性药物剂量单位。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108926540A (zh) * | 2017-05-25 | 2018-12-04 | 北京欧博方医药科技有限公司 | 一种用于制造药物递送的软咀嚼剂型的方法 |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9233100B2 (en) | 2012-02-06 | 2016-01-12 | Merial, Inc. | Parasiticidal oral veterinary compositions comprising systemically-acting active agents, methods and uses thereof |
AU2013245011B2 (en) | 2012-04-04 | 2017-11-23 | Intervet International B.V. | Solid oral pharmaceutical compositions for isoxazoline compounds |
WO2017106812A1 (en) * | 2015-12-19 | 2017-06-22 | First Time Us Generics Llc | Soft-chew tablet pharmaceutical formulations |
US20190022013A1 (en) * | 2015-12-19 | 2019-01-24 | First Time Us Generics Llc | Soft-chew tablet pharmaceutical formulations |
WO2017151571A1 (en) * | 2016-02-29 | 2017-09-08 | First Time Us Generics Llc | Abuse deterrent soft chewable drug formulations |
EP3668492A1 (en) | 2017-08-17 | 2020-06-24 | Ceva Sante Animale | Oral compositions and the preparation methods thereof |
CA3127621C (en) | 2019-02-20 | 2024-05-14 | Zoetis Services Llc | Palatable formulations |
USD941985S1 (en) * | 2020-04-07 | 2022-01-25 | Nutramax Laboratories, Inc. | Dietary supplement |
USD941457S1 (en) | 2020-04-07 | 2022-01-18 | Nutramax Laboratories, Inc. | Dietary supplement |
USD942609S1 (en) | 2020-08-11 | 2022-02-01 | Nutramax Laboratories, Inc. | Dietary supplement |
USD941458S1 (en) | 2020-08-11 | 2022-01-18 | Nutramax Laboratories, Inc. | Dietary supplement |
US20220160628A1 (en) * | 2020-11-24 | 2022-05-26 | Florida Research Group Llc | Process for manufacturing improved semi-soft solid dosage forms and soft chews produced thereby |
IT202100016310A1 (it) * | 2021-06-22 | 2022-12-22 | Alaia Idea S R L | Metodo per la produzione di compresse |
CN118368990A (zh) | 2021-12-23 | 2024-07-19 | 维克公司 | 基于大米淀粉的软咀嚼物 |
WO2023198476A1 (en) * | 2022-04-15 | 2023-10-19 | Krka, D.D., Novo Mesto | Soft chewable veterinary dosage form |
FR3138315A1 (fr) * | 2022-07-27 | 2024-02-02 | Virbac | Produit à usage vétérinaire et procédé pour sa fabrication |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4904495A (en) * | 1988-09-09 | 1990-02-27 | Nabisco Brands, Inc. | Chewy dog snacks |
WO2004014143A1 (en) * | 2002-08-13 | 2004-02-19 | Akzo Nobel | Compositions and process for delivering an additive |
CN101778566A (zh) * | 2007-08-17 | 2010-07-14 | 英特威国际有限公司 | 异噁唑啉组合物及其作为抗寄生虫药的用途 |
Family Cites Families (79)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB394489A (en) | 1931-07-03 | 1933-06-29 | Henri Le Cerf | Improvements in or relating to the moulding of plastic substances, such as confectionery |
US3006769A (en) * | 1954-08-26 | 1961-10-31 | Swift & Co | Manufacture of cheese slabs or the like |
US3486186A (en) | 1967-05-08 | 1969-12-30 | Hollymatic Corp | Molding apparatus |
US3887964A (en) | 1972-01-24 | 1975-06-10 | Formax Inc | Food patty molding machine |
CA1047714A (en) | 1973-12-26 | 1979-02-06 | Phillips Petroleum Company | Pressure-loaded punch and molding machine |
US3952478A (en) | 1974-10-10 | 1976-04-27 | Formax, Inc. | Vacuum sheet applicator |
DE2540613C2 (de) | 1975-09-12 | 1983-10-27 | Sollich Gmbh & Co Kg, 4902 Bad Salzuflen | Vorrichtung zum Ausformen von bei der Süßwarenfertigung verwendeten Massen zu Pralineneinlagen, Riegeln oder sonstigen Formstücken |
US4054967A (en) | 1975-10-20 | 1977-10-25 | Formax, Inc. | Food patty molding machine |
US4182003A (en) | 1978-02-28 | 1980-01-08 | Formax, Inc. | Food patty molding machine |
US4338702A (en) | 1979-03-29 | 1982-07-13 | Holly Harry H | Apparatus for making a ground food patty |
US4334339A (en) | 1980-05-12 | 1982-06-15 | Hollymatic Corporation | Mold device with movable compression insert |
US4356595A (en) | 1980-11-07 | 1982-11-02 | Formax, Inc. | Method and apparatus for molding food patties |
US4343068A (en) | 1981-01-19 | 1982-08-10 | Holly James A | Method and apparatus for unidirectional formation of a plug-formed patty with cleanout feature |
US4372008A (en) | 1981-04-23 | 1983-02-08 | Formax, Inc. | Food patty molding machine with multi-orifice fill passage and stripper plate |
CH657506A5 (de) | 1981-12-10 | 1986-09-15 | Hollymatic Ag | Portioniermaschine zum fuellen von hohlraeumen mit verformbarem material und verwendung derselben. |
CA1210631A (en) | 1982-09-10 | 1986-09-02 | Alison B. Warren | Nutritional cookies |
US4535505A (en) | 1982-11-23 | 1985-08-20 | Holly Systems, Inc. | Method and apparatus for forming a patty to accommodate tissue fiber flow |
US4608731A (en) | 1983-01-11 | 1986-09-02 | Holly Systems, Inc. | Food patty with improved void structure, shape, and strength and method and apparatus for forming said patty |
US4597135A (en) | 1984-02-21 | 1986-07-01 | Holly Systems, Inc. | Food patty forming method and apparatus employing two or more agitator bars |
US4586888A (en) * | 1985-02-14 | 1986-05-06 | Werner Lehara, Inc. | Apparatus for shaping "soft" baking dough and the like by rotary molding apparatus |
US4768941A (en) | 1986-06-16 | 1988-09-06 | Hollymatic Corporation | Food patty and machine and method for making thereof |
US4697308A (en) | 1986-10-29 | 1987-10-06 | Formax, Inc. | Patty molding mechanism for whole fiber food product |
DE3636882C1 (de) | 1986-10-30 | 1988-05-19 | Schreiber Berthold | Vorrichtung zur feinblasigen Einleitung eines Gases in eine Fluessigkeit |
US4780931A (en) | 1987-02-13 | 1988-11-01 | Marlen Research Corporation | Feeding device for patty forming machine |
US4821376A (en) | 1988-06-02 | 1989-04-18 | Formax, Inc. | Seal-off for food patty molding machine with multi-orifice fill passage and stripper plate |
US4872241A (en) | 1988-10-31 | 1989-10-10 | Formax, Inc. | Patty molding mechanism for fibrous food product |
ES2045748T3 (es) | 1989-03-16 | 1994-01-16 | Procter & Gamble | Galletas horneadas con alto contenido en fibra, que contienen psyllium. |
US5000973A (en) | 1989-05-30 | 1991-03-19 | Nabisco Brands, Inc. | Nutritionally-balanced canine biscuits containing an inorganic pyrophosphate |
US5021025A (en) | 1989-09-12 | 1991-06-04 | Wagner Richard C | Method and machine for making food patties |
US5064584A (en) | 1989-09-14 | 1991-11-12 | Weidenmiller Company | Rotary molding machine |
US4975039A (en) | 1989-09-18 | 1990-12-04 | Dare Gary L | Food molding and portioning apparatus |
US4996743A (en) | 1990-01-29 | 1991-03-05 | Formax, Inc. | Mold plate drive linkage |
US5022888A (en) | 1990-05-03 | 1991-06-11 | Formax, Inc. | Co-forming apparatus for food patty molding machine |
JPH07112940A (ja) * | 1993-08-26 | 1995-05-02 | Takeda Chem Ind Ltd | 徐放性非経口投与製剤およびその製造方法 |
IT1274385B (it) | 1995-04-26 | 1997-07-17 | Barilla Flli G & R | Prodotto da forno consumabile come biscotto o utilizzabile per preparare bevande dolci o dessert tipo budino |
US5731029A (en) * | 1995-07-26 | 1998-03-24 | Nabisco Technology Company | Method for making jerky products |
US5655436A (en) | 1996-08-29 | 1997-08-12 | Progressive Technology Of Manitowoc, Inc. | Food patty molding machine |
US5730650A (en) | 1996-08-29 | 1998-03-24 | Progressive Technology Of Wisconsin, Inc. | Food patty molding machine |
US6270790B1 (en) * | 1998-08-18 | 2001-08-07 | Mxneil-Ppc, Inc. | Soft, convex shaped chewable tablets having reduced friability |
US6387381B2 (en) | 1998-09-24 | 2002-05-14 | Ez-Med Company | Semi-moist oral delivery system |
NL1010630C2 (nl) | 1998-11-23 | 2000-05-24 | Stork Pmt | Vormen. |
US7763276B1 (en) | 1999-02-26 | 2010-07-27 | Shionogi & Co., Ltd. | Chewable soft capsules having improved administration properties and process for producing the same |
FR2792529B1 (fr) * | 1999-04-26 | 2001-09-28 | Sod Conseils Rech Applic | Nouvelles compositions pharmaceutiques comprenant des derives de 2-isoxazole-8-aminotetralines |
US6112703A (en) * | 1999-06-22 | 2000-09-05 | Jw Pet Company, Inc. | Shrouded chewable pet toys and method of making |
US6217927B1 (en) | 2000-05-12 | 2001-04-17 | Mars, Inc. | Methods for continuously molding chocolate and products made thereby |
US6635292B2 (en) | 2001-10-26 | 2003-10-21 | Mars, Incorporated | Ultrasonic rotary forming of food products |
CA2476496C (en) * | 2002-02-21 | 2009-12-15 | Biovail Laboratories Inc. | Controlled release dosage forms |
US7029714B2 (en) | 2002-03-05 | 2006-04-18 | Kraft Food Holdings, Inc | Cold formed food bars containing fragile baked inclusions |
AR045142A1 (es) | 2003-07-30 | 2005-10-19 | Novartis Ag | Composicion veterinaria masticable ductil de buen sabor |
CN1852708B (zh) * | 2003-09-19 | 2010-09-22 | 大塚制药株式会社 | 人β防御素分泌促进剂 |
CA2558848C (en) | 2004-03-05 | 2013-11-19 | Nissan Chemical Industries, Ltd. | Isoxazoline-substituted benzamide compound and pesticide |
JP2005326491A (ja) * | 2004-05-12 | 2005-11-24 | Tokyo Ohka Kogyo Co Ltd | ポジ型レジスト組成物及びレジストパターン形成方法 |
JP4636847B2 (ja) | 2004-10-13 | 2011-02-23 | 株式会社ロッテ | 全粒粉からなる小麦粉の加工方法及びその加工方法により得られた加工小麦粉並びにその加工小麦粉を使用した食品 |
US8012522B2 (en) | 2005-02-11 | 2011-09-06 | Mars, Incorporated | Method and apparatus for vacuum forming contoured edible pieces |
US7556493B2 (en) | 2005-02-24 | 2009-07-07 | Suttle James M | Methods and apparatus for molding chocolate |
PT1695632E (pt) | 2005-02-25 | 2014-02-21 | Barilla Flli G & R | Aparelho e método para a produção de produtos de pastelaria de massa de tarte, em particular biscoitos com partículas comestíveis |
US7534381B2 (en) | 2005-09-14 | 2009-05-19 | Isp Investments Inc. | Process and apparatus for forming agglomerates of a powder composition of an active and binder |
US7955632B2 (en) | 2005-12-07 | 2011-06-07 | Bayer B.V. | Process for manufacturing chewable dosage forms for drug delivery and products thereof |
US20070128251A1 (en) | 2005-12-07 | 2007-06-07 | Piedmont Pharmaceuticals, Inc. | Process for manufacturing chewable dosage forms for drug delivery and products thereof |
TWI412322B (zh) | 2005-12-30 | 2013-10-21 | Du Pont | 控制無脊椎害蟲之異唑啉 |
US20070178204A1 (en) | 2006-02-02 | 2007-08-02 | Savul Shahnaz B | Method for making a cold formed segmented food product |
EP2015732A2 (en) * | 2006-05-04 | 2009-01-21 | Novartis AG | Heated roller compaction process for making pharmaceutical compositions |
US20080138472A1 (en) | 2006-12-12 | 2008-06-12 | Delse Alexandre | High fiber rotary molded cookies containing inulin and resistant starch |
TWI430995B (zh) * | 2007-06-26 | 2014-03-21 | Du Pont | 萘異唑啉無脊椎有害動物控制劑 |
MX2009013748A (es) | 2007-06-27 | 2010-01-26 | Du Pont | Metodo de control de plagas en animales. |
JP4922137B2 (ja) * | 2007-11-16 | 2012-04-25 | 株式会社マルハニチロ食品 | ヒアルロン酸産生促進物質 |
TWI411395B (zh) | 2007-12-24 | 2013-10-11 | Syngenta Participations Ag | 殺蟲化合物 |
WO2010079077A1 (en) | 2008-12-18 | 2010-07-15 | Novartis Ag | Isoxazolines derivatives and their use as pesticide |
MX2011006568A (es) | 2008-12-19 | 2011-08-03 | Novartis Ag | Compuestos organicos. |
US20110027412A1 (en) | 2009-07-31 | 2011-02-03 | Kris Eugene Spence | Compositions and Methods for Promoting Gastrointestinal and/or Cardiovascular Health |
EA021522B9 (ru) | 2009-12-17 | 2016-08-31 | Мериал Лимитед | Противопаразитарные дигидроазоловые соединения и содержащие их композиции |
MX2012011549A (es) | 2010-04-08 | 2013-01-29 | Ah Usa 42 Llc | Derivados de 3,5-difenil-isoxazolina sustituida como insecticidas y acaricidas. |
UA108881C2 (xx) * | 2010-05-27 | 2015-06-25 | Кристалічна форма 4-$5-$3-хлор-5-(трифторметил)феніл]-4,5-дигідро-5-(трифторметил)-3-ізоксазоліл]-n-$2-оксо-2-$(2,2,2-трифторетил)аміно]етил]-1-нафталінкарбоксаміду | |
JP6349087B2 (ja) | 2010-07-19 | 2018-06-27 | プロキヤプス・エス・アー | 方法およびソフトジェルカプセル |
EP3072395A3 (en) | 2010-07-20 | 2016-10-19 | Formax, Inc. | Rotary mold system |
US20120237662A1 (en) | 2011-03-18 | 2012-09-20 | The Hershey Company | Method of making a reduced fat chocolate confectionery product |
AR087158A1 (es) | 2011-06-20 | 2014-02-26 | Gen Biscuit | Masita en capas saludable |
US9233100B2 (en) | 2012-02-06 | 2016-01-12 | Merial, Inc. | Parasiticidal oral veterinary compositions comprising systemically-acting active agents, methods and uses thereof |
AU2013245011B2 (en) | 2012-04-04 | 2017-11-23 | Intervet International B.V. | Solid oral pharmaceutical compositions for isoxazoline compounds |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4904495A (en) * | 1988-09-09 | 1990-02-27 | Nabisco Brands, Inc. | Chewy dog snacks |
WO2004014143A1 (en) * | 2002-08-13 | 2004-02-19 | Akzo Nobel | Compositions and process for delivering an additive |
CN101778566A (zh) * | 2007-08-17 | 2010-07-14 | 英特威国际有限公司 | 异噁唑啉组合物及其作为抗寄生虫药的用途 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106551804A (zh) * | 2015-09-30 | 2017-04-05 | 董玲 | 一种使用滚模制备冻干赋形制剂的方法及其产品 |
CN107260557A (zh) * | 2016-04-07 | 2017-10-20 | 董玲 | 一种滚模法制备冻干制剂的方法及其产品 |
CN108926540A (zh) * | 2017-05-25 | 2018-12-04 | 北京欧博方医药科技有限公司 | 一种用于制造药物递送的软咀嚼剂型的方法 |
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