CN101909605B - 制造用于药物递送的咀嚼剂型的方法及其产品 - Google Patents
制造用于药物递送的咀嚼剂型的方法及其产品 Download PDFInfo
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Abstract
用于递送药学上可接受的活性成分例如药物到动物或人对象的适口的可食用软咀嚼药物载体。可食用软咀嚼物仅包含食品级或更好的非活性成分,并且优选地不包含动物来源的成分。制造客食用软咀嚼物的方法不需要在活性和非活性成分混合期间使用热或加入水,提供活性成分的稳定浓度,以及生产均一重量和质地的咀嚼物。
Description
发明领域
本发明涉及可口服施用的的药物剂量单位的领域;具体地,涉及可食用块形式的单位,例如大块(chunk)。
发明背景
使药物配制成为食用药物,例如咀嚼片或糖果剂可以增加药物的患者接受性,特别是动物,动物倾向于抵制吞咽硬片剂或胶囊。遗憾的是,许多药物和其它活性成分(统称为“活性物”)具有强烈苦味或其它不适口的味道,这使得咀嚼它们变得不愉快。
调味剂通常加入到可咀嚼药物中以增加它们的适口性。例如,兽医药物药可以包括基于动物产品的调味剂,诸如生的干肉部分例如牛肉、猪肉、鸡肉、火鸡肉、鱼肉和羔羊肉;器官肉类例如肝、肉粉(meatmeals)、骨粉和骨基质(ground bone);和动物来源的食品例如酪蛋白、牛奶(其可以包括干的形式和低脂肪形式,例如脱脂奶粉)、酸奶、明胶、奶酪和鸡蛋(统称为“动物来源调味剂”),它们可以被使用。
然而,使用许多动物来源调味剂(特别是肉、家禽或海鲜类来源(seafood origin))冒暴露于传染原的风险——不仅暴露于药物的接受者,而且通过制造调味剂剂量单位的生产设备污染。因为这个原因,制备具有动物来源调味剂的药物产品的生产设施通常只被用于它们的制备,其成本相应地大于在能够同时加工多种产品的设备中进行生产的情况下所产生的成本。
质地也是咀嚼药物的问题。咀嚼剂量单位最常用的形式之一是压制片剂,其成分(包括活性成分和非活性成分例如粘合剂)可以使片剂成为类砂质或者在其它方面不吸引人——特别是对于动物。因此,对于特别是动物使用的优选替代剂型是“可食用软咀嚼物(edible softchew)”,一般而言,肉样块或大块在可消费的宠物治疗中也被广泛地发现,其具有类似于熟的肉基质肉饼的软度。
可食用软咀嚼物一般通过掺合和挤压成形生产。预先混合的成分被引入到其中具有螺杆(screw)的挤出机料筒,然后混合、凝结、膨胀和剪切成为掺合的混合物,然后施加额外的热——如果期望较硬的质地的话,或者水被引入混合物中。引入混合物中的水一般必须是医药级,因为它将保留在该混合物中。然后,掺合的混合物在拉模板上形成为期望的形状,然后切割成为单独的单位。
在挤出成形过程期间生成的热可以引起混合物中活性物的稳定性(效力或完整性)降低,使得由每个形成的单位提供的有效剂量不同。具体地,来自挤出——特别是螺旋挤出(auger extrusion)期间施加的压缩的热,可能超过多种化合物的熔点。来自批次与批次间的挤出材料的咀嚼物的质地、形状和重量的一致性也可能受损失。
因此,对于生产可食用软咀嚼药物的方法存在需求,其中实现活性物掺合到咀嚼混合物中而不生成将引起活性物完全或部分地降解的水平的热。优选地,该方法将在不施加高于室温的任何热到混合物或形成的产品下进行。也期望的是,咀嚼物易于生产而不使用昂贵的医药级水作为成分。在本领域对可食用软咀嚼药物也存在需求,该药物的口味对动物有吸引力,其没有使用可能包括传染原或污染物的成分。此外,高度期望用于生产可咀嚼药物的制造方法,该方法以确保一致的咀嚼物重量、质地和活性剂量的方式进行生产。
发明概述
本发明提供独特的可食用软咀嚼物剂型药物和其制造方法。本发明的可食用软咀嚼物对于宠物动物是特别适口的。它们包含至少食品级质量的非活性成分,并且最优选不包含动物来源的非活性成分。同样地,可以制造可食用软咀嚼物,而不担心传染原或污染物的传染,并且没有交叉污染相同生产设备中生产的其它产品的风险。
本发明的制造方法允许可食用软咀嚼物生产,其中在没有生成使活性物全部或部分降解的水平的热的情况下实现活性物掺入咀嚼混合物。进行该方法,因此咀嚼混合物和形成的咀嚼物没有暴露于在由在挤出成形中施加的压缩和/或剪切应力典型生成的温度或温度之上,所述温度可以通过制造领域普通技术人员已知的方法测量(参见,例如,Vermeulen等,Chemical Engineering Science(1971)26:1445-1455;Chung等,Polymer Engineering and Science(1977)17:9-20;Mount等,Polymer Engineering and Science(1982)22(12):729-737;Lindt,J.T.,Conference Proceedings,ANTEC’84,Society of Plastics Engineers(1984)73-76;Rauwendaal,C.,Conference Proceedings,ANTEC’93,Society ofPlastics Engineers(1993)2232-2237;Miller等,Conference Proceedings,ANTEC’74,Society of Plastics Engineers(1974)243-246;Derezinski,S.J.,Conference Proceedings,ANTEC’88,Society of Plastics Engineers(1988)105-108;Derezinski,S.J.,Journal of Materials Processing &Manufacturing Science(1997)6(1):71-77;Derezinski,S.J.,ConferenceProceedings,ANTEC’96,Society of Plastics Engineers(1996)417-421)。
优选地,咀嚼混合物和形成的咀嚼物没有暴露于高于室温(20℃)约10°的温度,可以暴露于低于室温0°至约10°的温度,和最优选地在整个掺合和形成步骤中维持在室温。如此,咀嚼混合物和形成的咀嚼物中的活性物没有暴露于高于或低于在进行掺合和形成步骤期间所说明的温度,无论通过与活性成分在说明的范围之外的温度混合,通过施加由热源或压缩生成的热,或通过其它方法。因此,活性物的稳定性在混合和形成可食用软咀嚼物期间被保持,并且被很好地掺合,提供软的质地。
没有使用水作为咀嚼物的成分,由此避免了使用昂贵的医药级水的需求,同时减少微生物生长或活性物的效力损失的机会。
也发现,活性物与油混合形成悬浮液,该悬浮液随后与咀嚼物干燥成分的混合有利于成品中活性物的均匀分布。优选地,活性物也将被包衣以在与油混合之前保存活性物的效力。
为了将包衣的活性悬浮液与可食用软咀嚼物(例如,调味剂)的其他成分掺合,优选地使用卧式混合机。这种混合机独特地适合于将咀嚼混合物旋转成为微粒形式。混合的动作使混合物中的成分被抛离混合的容器壁,使容器交叉以提供在没有施加热的情况下形成均匀混合的混合物。因为不需要冷却步骤,生产咀嚼物的时间与挤压蒸煮方法(cooking extrusion method)相比被缩短。
产生的高度混合的混合物被放入不挤压的模具中,并形成单独的剂量单位,该剂量单位被允许固定(set)而不需要施加热。可食用软咀嚼物可以以任何期望形状生产。在本发明中使用的优选混合和模制设备可以提供具有一致混合成分、稳定提供的活性物和一致重量的单独的独立可食用软咀嚼物。
本发明的可食用软咀嚼物生产为适口形式,不使用任何非食品级的非活性成分(或,优选地,任何动物来源的非活性成分)。因此,在不存在设备中的其它装置与源于源例如在动物的咀嚼药物中通常使用的动物来源肉调味剂的传染原或污染物的可能交叉污染的风险的情况下进行该制造方法。
发明详述
A.用于本发明的可食用软咀嚼物的材料
一般而言,可食用软咀嚼药物和治疗包括作为非活性成分的物质例如粘合剂、维生素和着色剂以增强产品的可制造性、质地和外观。本领域普通技术人员对于这些非活性成分是熟悉的,在本发明中使用的非活性成分不包括水。在软咀嚼物内不存在非食用成分。
为了在本发明中使用,可食用软咀嚼物的非活性成分不应该低于食品级质量,并且可以具有更高的质量(例如,USP或NF级)。在这种情况下,“食品级”指不包含或给予有害于健康的化学品或剂的物质。因此,如果食品调味剂为动物来源,则将是这样的物质,其被制备以显著降低或消除其中存在的传染原或污染物;例如,通过诸如巴氏灭菌法、增压或照射的方法。
后面的方法特别可以有效地消除来自各种广泛地食品和动物来源物质例如生肉产品、蔬菜、谷物和水果中的传染原诸如大肠杆菌O157:H7(E.coli O157:H7)、沙门氏菌(Salmonella)和弯曲菌(Campylobacter)。然而,优选地,本发明的可食用软咀嚼物将不包含任何动物来源的成分,并且最优选地,将不包含任何动物来源调味剂。所有的成分都应该是药学上可接受的(例如,视情况而定,食品级、USP或NF)。
在本发明的可食用软咀嚼物中优选地存在至少为食品级质量的调味剂,并且最优选地排除动物来源调味剂。优选的非动物来源调味剂是植物蛋白例如大豆蛋白,其中可食用人工食品样调味剂已经加入(例如,大豆来源的熏肉调味剂)。取决于目标动物,其它的非动物调味剂可以包括:茴香油,长豆角,花生,水果调味剂,甜味剂例如蜂蜜、蔗糖、枫糖浆和果糖,香草例如香菜、芹菜叶、薄荷、留兰香、大蒜,或它们的组合。
在本发明中使用的特别优选的调味剂是由Ohly,Inc.制造的ProvestaTM 356。它是淡褐色的水溶性粉末,其以酵母提取物和反应调味剂的性质为基础,从而提供令人愉快的烟熏味、熏制好的熏肉调味剂。Provesta 356不包含动物来源的成分。
为了施用给马和其它食草动物以及小的动物例如兔子、仓鼠、沙鼠和豚鼠,谷类和种子是特别吸引人的额外调味剂。谷物可以以与咀嚼物的生产相一致的任何形式存在,包括面粉、糠、谷类、纤维、全谷类和粗粉形式,包括麸粉(gluten meals),谷物可以是碾压的、卷曲的、磨碎的、脱水的或碾磨过的。无机物也可以加入作为调味剂,例如盐和其它种类。优选地,使用的谷物是脱水的、碾磨过的或压片的(flaked)。蔬菜例如脱水的胡萝卜和种子例如红花种子或蜀黍种子对于小动物是特别有吸引力的并且可以被包括。
此外,增强可食用软咀嚼物的可制造性和质地的剂可以包括软化剂(其可以是抗粘着剂)、抗粘结剂或润滑剂以及保湿剂或润湿剂。可以用于本发明的润滑剂或抗粘结剂的说明性实例包括硬脂酸镁、硬脂酸钙、固体聚乙二醇。如果熔化,剂在与活性物、十二烷基硫酸钠或它们的混合物混合之前返回到室温+/-10°。硬脂酸镁对于润滑和作为帮助模制后固化可食用软咀嚼物的成分是特别优选的。
保湿剂说明性地包括甘油和丙二醇,并且润湿剂包括十六烷醇和甘油单硬脂酸酯。甘油是用于保持可食用软咀嚼物在产品货架期期间的柔软性的优选保湿剂。甘油是清澈、无色、无味、粘性、吸湿的液体。
抗粘结剂,优选为聚乙二醇并且最优选为PEG 3350(DowChemical),将优选地在模制之前以约1.0%至3.0%w/w的体积被包括在可食用软咀嚼物混合物中。在模制后,将制备具有添加的抗粘结剂的可食用软咀嚼物,对于PEG 3350通常在8至24小时的时间期间。PEG3350快速凝结,软化咀嚼混合物并且防止可食用软咀嚼物单位在模制后粘结在一起。
使用的软化剂是限制可食用软咀嚼物产品的密度和硬度的那些。这样的剂可以包括多糖和纤维。多糖可以以复合食物诸如水果、植物淀粉例如马铃薯或木薯淀粉的形式被包括。多糖也可以分开提供,例如,以硫酸软骨素或葡糖胺盐酸的形式。
也可以提供纤维作为填充剂或作为膨胀剂,以提供或维持可食用软咀嚼物中的多孔性。用于此目的的纤维可以源自于水果、谷物、豆类、蔬菜或种子,或者以例如木质纤维、纸纤维或纤维素纤维例如成粉末的纤维素纤维的形式提供。用于本发明的特别优选的这种膨胀剂是糠,例如燕麦糠。
在可食用软咀嚼物中应用的粘合剂可以是粘性物质,但是粘合剂将优选地给予可食用软咀嚼物产品食物样质地。一般而言,粘合剂可以包括:糖蜜,玉米糖浆,花生酱,淀粉如马铃薯淀粉、木薯淀粉或玉米淀粉,蜂蜜,枫糖浆和糖。用于本发明的可食用软咀嚼物的优选粘合剂是淀粉。
特别优选的粘合剂是淀粉1500,其是由Colorcon公司制造的预凝胶化淀粉。预凝胶化淀粉是一种已经被化学和/或机械修饰以破裂所有或部分淀粉颗粒并且因此使淀粉可流动的淀粉。它包含5%的游离淀粉酶、15%的游离支链淀粉和80%未修饰的淀粉。来源是玉米。
粉末的糖(蔗糖)很适合作为甜味剂以及粘合剂。蔗糖从甘蔗或糖用甜菜获得。视情况而定,可以加入盐和/或其它种类,盐对于增强味道是特别优选的。
防腐剂例如山梨酸钾、苯甲酸钠或丙酸钙可以被包括,以阻止微生物和真菌的生长。Tenox 4是BHA和BHA抗氧化剂的组合物,由Eastman Chemicals制造。它是优选和方便的防腐体系。
根据目标动物的营养需求,可以提供维生素,并且维生素可以提供作为使用的油的成分。维生素也在可以被加入作为软化剂的各种油中存在;例如,油菜籽油、玉米油、豆油和植物油。
为了形成活性悬浮液以及风味增强剂和软化剂,使用油。植物油(例如玉米油、红花油、棉籽油、大豆油和橄榄油)是特别优选的,大豆油是最优选的。
可以使用的赋形剂包括淀粉、纤维素、或它们的衍生物或混合物,其量的范围为例如约1%至约60%(w/w)、优选地为约2%至约50%和更优选地为约15%至约50%。例如,赋形剂可以由羟乙酸淀粉钠、预凝胶化玉米淀粉(淀粉1500)、交联聚维酮(Polyplasdone XLTM,InternationalSpecialty Products)和交联羧甲基纤维素钠(Ac-Di-SolTM,FMC Corp.)以及它们的衍生物组成。
赋形剂可以用于生成活性物的研磨物。例如,为了生成10%研磨物,100克的活性物与900克的赋形剂例如优选的赋形剂淀粉1500结合。理想地,进行活性物的几何级数稀释,为此,它首先在合适的醇溶剂例如乙醇中溶解。溶解的活性物然后与赋形剂结合,并且使醇蒸发。这个步骤使小量的活性物在整个淀粉中被全面和均匀地混合。干燥的混合物通过筛网筛分、流化,然后优选地被包衣。
如果包衣被提供(以帮助保护活性物的稳定性和掩盖其味道),食品级包衣为优选的,例如Colorcon公司销售为OPADRYTM的水性膜包衣。OPADRY是基于甲基纤维素具有增塑剂和颜料的产品。由于包衣是水基的,在制造可食用软咀嚼物期间不需要特别地小心操作。然而,在给药后,当暴露于水或胃中的其它液体时,水性膜包衣开始受侵蚀和/或在数分钟内溶解。因此,在被给予受试者后,可食用软咀嚼物的崩解和分解不应该被延迟。
任何可口服给药的活性药物或者其它生物活性化合物可以提供为本发明的可食用软咀嚼物。然而,本发明独特地特别适合于与不耐热的活性物一起使用,特别是在超过30℃的温度。人类和/或兽医制药领域的普通技术人员对于这些活性物的特征完全熟悉,所述活性物可以包括但不限于抗生素、止痛剂、抗病毒药物、抗真菌药物、驱虫剂、杀体内寄生虫药和杀体外寄生虫药、激素和/或它们的衍生物、抗炎药(包括非甾族抗炎药)、类固醇、行为调节剂(behavior modifiers)、疫苗、抗酸剂、泻药、抗惊厥药、镇静剂、镇定剂、镇咳药、抗组胺药、解充血药、除痰剂、食欲刺激药和抑制剂、矿物质和维生素。
在成品中每种成分的量可以是相当地不同的,这取决于药物的性质、治疗的受试者的重量和状况和期望的单位剂量。本领域的普通技术人员将能够根据本公开的教导调节可食用软咀嚼物中的特定活性物的剂量。然而,一般而言,活性物可以通过下述基于组合物总重量的重量范围提供:约0.001%至75%(w/w)、更优选为0.095%至40%和最优选为不超过50%。例如,对于给予驱虫剂(anthelmetic)给狗,例如用于治疗犬恶丝虫、与淀粉研制在一起的伊维菌素(ivermectin)(参见实施例1)可以被加至占前述混合物的31.2%。
描述示例性产品的配方可以容易地被修改,用于递送活性物到其它物种。例如,马可食用软咀嚼物可以基于相同的基本配方,用糖蜜粉末、燕麦糠和苹果替代熏肉。对猫特别有吸引力的调味剂包括具有鱼样风味、基于人工大豆的化合物。对于人接受者可以优选更甜的风味,例如糖或糖蜜。
本发明的可食用软咀嚼物可以单独地包装,用于给药和稳定贮存。合适的包装材料的实例包括HDPE瓶或箔/箔包装。
B.制造本发明可食用软咀嚼物的方法
本发明可食用软咀嚼物的活性成分和非活性成分加至卧式混合机的混合容器中,该卧式混合机能够混合材料并将其沿着混合容器的边抛起。这个动作使得成分在不施加热或加入医药级水到混合物的情况下充分并一致地混合。
卧式混合机一般包括:混合室,转动的水平伸长混合轴,和多个混合工具,混合工具总体垂直于水平轴下垂以在室里面周围转动(参见,例如,美国专利5,735,603,其公开内容通过此引用并入本文)。根据混合方法的要求配置混合工具和形成需要的尺寸大小,以符合(follow)转动时用于适当混合所有存在的材料的室壁的形状。一些这样的混合室是圆柱形的,而其它的是槽形的,例如,在本领域通常称为双臂混合机或螺带式混合机的混合机。
一般而言,卧式混合机具有水平的混合轴,其在两端延伸出混合室。在电动混合机(motorized mixer)中,在轴的一端——称为驱动端,轴可操作地连接到用于转动轴的驱动马达。在驱动端,轴典型地通过位于驱动马达和室之间的支承结构连接。支承结构提供轴驱动端的支撑并也保证流畅的转动。分开地密封结构在沿着轴的长度通常被进一步提供,以密封它,防止材料泄露进入混合室和泄露出混合室。
使用的用于本发明的特别优选的混合机是具有任选的搅动刀片的犁型螺带式混合机(plough type ribbon mixer),由Littleford DayCorporation以FXM SeriesTM商标销售。200kg容量的混合器机可以用于商业规模生产,并且能够生产少至50kg的咀嚼混合物用于研究规模工作。在混合期间不施加热,产生的混合产品在批与批之间具有一致的重量、成分分布和质地。
优选地,咀嚼混合物的干燥成分首先被混合,然后活性物的油悬浮液在其中混合,接着与液体成分(例如,保湿剂和软化剂)混合以形成完全混合的混合物。在混合后,咀嚼混合物被放出,而没有从端口压缩通过混合机进入合适的容器,以利用成形机器加工成为单独的剂量单位。
各种成形设备可以在本发明中使用,但是特别优选使用的那些是用于生产模制食品产品例如预形成的汉堡肉饼和鸡块而开发的制模机。例如,在美国专利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(其公开内容并入本文)中公开的制模机是可以用于本发明的代表性成形设备。
在本发明中使用的优选成形设备是不施加压缩热至咀嚼混合物的制模机,例如由Formax公司制造的Formax F6TM模制机器。F6机器具有每分钟60个冲程(stoke)容积。6”乘以6”的正方形成形模具可以用于形成每个冲程大约16个大块样可食用软咀嚼物单位,每个单位重4克和为大约5/8”乘以5/8”大小。也可以使用生产其它形状(例如,骨形咀嚼物)的模具。
在这种机器中,旋转阀打开以使咀嚼混合物流过填充缝下面进入第一组模具腔。模板提升,推动咀嚼混合物进入第二组模具腔,然后模板缩回,如此循环可以再次开始。模制机构是水压的,并通过在模板上轻压工作,没有施加热。
出坯机构(knockout mechanism)设有杯状物,其与模腔对齐以从全部模板穴同时喷射模制的混合物。为了模制本发明的可食用软咀嚼物,这种机器可以产生每小时大约57,600单位的输出量,假定使用每个小批生成50,000单位的搅拌器混合的话。每批的咀嚼物可以大批量包装,或者优选地,每个咀嚼物随后单独地包装用于贮存。
本发明已经被充分地描述,其实施通过以下提供的实施例说明。在整个实施例中使用标准的缩写和测量,除非给出相反地定义。实施例不限制本发明的范围,其通过所附权利要求完整地限定。
实施例1
可食用软咀嚼物配方
适合于递送活性物的可食用软咀嚼物的实例在以下配方1中说明。
实施例2
本发明的可食用软咀嚼物活性成分的包被方法
活如下制备性物(伊维菌素)10%研制品:将100克的伊维菌素溶解入乙醇中,然后在900克的淀粉1500中混合活性物3至5分钟。使生成的研制品静置直至干燥,然后研磨和通过20目筛进行筛选。筛选的研制品在流化床柱中进行流化。使用Wurster包衣机,将食品级包衣(OPADRYTM)施加到研制的活性物。顶部喷雾流化包衣机或其它合适的设备也可以用于这个步骤。包被的活性物然后在大豆油中混合以形成悬浮液。
实施例3
本发明的可食用软咀嚼物的示例性制造方法
在实施例1和2中列出的所有干燥成分通过20目筛进行筛分,然后放入卧式混合器的混合容器中并混合5分钟。慢慢加入甘油,然后缓慢加入植物油/活性物悬浮液和已被加入油中的Tenox 4。产品混合3分钟。将PEG 3350熔化,然后相对快地加入咀嚼混合物中,其随后混合另外一分钟。混合物类似“曲奇饼样(cookie dough-like)”外观。
使用具有用于生产曲奇饼样形状的模具的Formax F6TM制模机,将混合物形成为单独的大块,然后包装用于贮存。
已经充分描述了本发明,其范围通过在此所附权利要求限定。
Claims (5)
1.用于制造可食用软咀嚼药物的方法,所述方法包括:
(a)形成包括含有抗生素和油的包衣药物的活性物悬浮液,其中所述抗生素的稳定性或效力可以受在室温以上10℃或更高的温度不利影响;
(b)使步骤(a)中形成的所述活性物悬浮液与非动物来源的干燥非活性成分在混合机中混合,所述非动物来源的干燥非活性成分包括调味剂、粘合剂、膨胀剂、保湿剂、油和赋形剂中的至少一种,其中所述混合机的操作使活性成分在其中均匀混合,形成可食用软咀嚼混合物;
(c)加入水溶性聚乙二醇抗粘着剂至干燥混合物中,并且在所述混合机中将所述成分混合在一起以形成具有曲奇饼样质地的软咀嚼混合物;
(d)从所述混合机中移走所述可食用软咀嚼混合物而不使其暴露于压缩或剪切应力;和,
(e)使所述可食用软咀嚼混合物模制为单独的单位块而不需要所述咀嚼混合物的之前冷却,其中如此形成的所述单位块的单位与单位的重量一致,
其中所述方法的步骤没有在室温以上10℃或更高下进行,并且其中在进行所述方法期间,没有水被另外加至所述活性剂。
2.根据权利要求1所述的方法,还包括在所述抗生素被加至步骤(b)中的所述混合机之前,制备与赋形剂在一起的所述抗生素的研制品的步骤。
3.根据权利要求2所述的方法,其中所述抗生素的研制品通过包括以下的方法制备:使所述抗生素溶解在醇溶剂中,使所述抗生素与所述赋形剂混合,和使所述醇在加入研制的抗生素至所述混合室之前干燥。
4.根据权利要求1所述的方法,其中所述抗生素是其效力或稳定性在室温以上或以下10℃的温度下受到不利影响的抗生素。
5.可食用软咀嚼药物,其是根据权利要求1所述的方法生产的。
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AU2008320992A1 (en) | 2009-05-22 |
US8865240B2 (en) | 2014-10-21 |
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