CN1236764C - 制备组合物的方法 - Google Patents
制备组合物的方法 Download PDFInfo
- Publication number
- CN1236764C CN1236764C CNB018119026A CN01811902A CN1236764C CN 1236764 C CN1236764 C CN 1236764C CN B018119026 A CNB018119026 A CN B018119026A CN 01811902 A CN01811902 A CN 01811902A CN 1236764 C CN1236764 C CN 1236764C
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- Prior art keywords
- compositions
- dispersion
- solution
- water
- gum
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- 239000006185 dispersion Substances 0.000 claims abstract description 38
- 239000007788 liquid Substances 0.000 claims abstract description 35
- 239000007970 homogeneous dispersion Substances 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
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Abstract
本发明涉及一种制备组合物,优选药物组合物的方法,所述组合物在溶液和分散体外以膨胀的,机械稳定的,薄片状,多孔的,海绵-样或泡沫结构存在。该方法包含如下步骤:a)制备一种液体和一种化合物的溶液或均匀分散体,所述化合物选自一种或多种药用活性化合物,一种或多种药用合适的赋形剂,和它们的混合物,接着b)不沸腾膨胀该溶液或均匀分散体。本发明还涉及用上述方法获得的组合物,它们的进一步加工和任何相应的剂型。
Description
本发明涉及一种制备组合物,优选药物组合物的方法,所述组合物呈在溶液和分散体外的膨胀的,机械稳定的,薄片状,多孔的,海绵-样(spongue-like)或泡沫结构。该方法包含如下步骤:a)制备一种液体和一种化合物的溶液或均匀分散体,所述化合物选自一种或多种药用活性化合物,一种或多种药用合适的赋形剂,和它们的混合物,接着b)不沸腾膨胀该溶液或均匀分散体。本发明还涉及用上述方法获得的组合物,它们的进一步加工和任何相应的剂型。
在制药工艺中,制剂制品主要由纯活性药物或其它重要的添加剂的物理-化学性能(颗粒大小和形状,流动性,压缩性,多晶,润湿性,熔点,稳定性,贮存期限等)所决定。很多剂型在药物市场上是众所周知的,其中最重要的是片剂和胶囊。为了稳定非常敏感的药品,其被建议口服或再水化后胃肠外使用或施用,速干剂(dry solutions)或分散体(如混悬剂,乳剂)也是主要感兴趣的剂型。
纯药物流入最终市场制剂的方法通常包括几项基本的操作,如研磨,筛选(seizing),润湿或干燥粒化,击块,包囊等。现今,将很多这些加工设计成制造大量的物质,如高速压片。从而将由碰撞产生的机械能,压力或剪切应力传导给物质。通常,这导致药物的熔化,分解或失效。如此引起的沉淀或结壳可能导致该加工程序的中断或甚至导致机器的破坏。
为了简化剂型的制造过程,通常将药物与不同的药物赋形剂如润滑剂,填料,粘合剂,流动或分散剂等混合,调和或粒化。这些添加剂将影响最终组合物的性能,但仅能部分地提供对机械能的保护或甚至导致由它们本身产生的稳定性问题。
也认为在施用前,期间或之后,最终组合物以及相应的剂型具有非常具体的性能。对于疏松材料(粉末,颗粒,丸剂,片剂等),在贮存期间需要高度的稳定性和相容性。干悬剂在液体中必须显示灵敏的分散性;片剂在被吞咽后,必须很快或很慢地崩解。药物颗粒在胃或肠液中的足够的润湿性是良好的溶解性和吸收的前提。由于大量给药,为了压片或包囊,药物粉末或颗粒需要足够的堆积密度。取决于剂量,由于含有具有不合适的物理-化学性能(如低熔点;低溶解性等)的药物或赋形剂,这些重要的盖伦制剂的性能可被极坏地影响。
总之,将药用活性化合物或药用合适的赋形剂加入盖伦制剂组合物或制剂的方法是最重要的因素,其必须被控制以便
-掩盖不理想的性能,
-稳定,惰性化并保护关键的、加入的化合物,
-获得适于下游工作的最佳的流动性和密度,
-在施用期间或之后,获得必需的分散性和释放特性等。
为了改进一些提及的性能,在本领域中有几种众所周知的技术,但常常它们不能克服所有的问题,但却甚至导致新的问题
-流化床包衣不适于具有低熔点的物质或具有非常高的表面面积和圆柱或针形的细并且轻的颗粒
-来自(共)沉淀方法(如喷雾干燥)的粉末仍具有位于颗粒表面的显著量的反应物质
-冷冻干燥是非常昂贵的,并且不适于对冻融循环(freeze-thewcycles)敏感的物质;
-喷雾冷凝,熔体包埋,熔体挤出仅仅对于耐温性物质是可行的。
国际专利申请WO96/40077(Quadrant Holdings Cambridge Limited)公开了一种制备薄的、泡沫玻璃基体的方法,其包含下述步骤:(a)制备初始混合物,其包含至少一种玻璃基体-形成物质和至少一种溶剂,该溶剂包括适于玻璃基体-形成物质的溶剂,(b)从混合物中蒸发大部分溶剂,以获得糖浆,(c)将糖浆曝露于足以使糖浆沸腾的压力和温度下,和(d)任选地,去除残留水分。
国际专利申请WO98/02240(通用保存工艺(Universal PreservationTechnologies))公开了一种通过从将被脱水的流体物质形成稳定泡沫来保存敏感生物分散体,混悬液,乳液和溶液的方法,作为对于在流体中干燥一种或多种生物活性底物的辅助方法,和作为在制备适于进一步商业应用的易于可分的干燥产品的过程中的辅助方法。稳定泡沫是如此形成的,即部分去除水以形成粘性液体并进一步对减少的液体抽真空,以使它在温度显著低于100℃的温度下进一步干燥期间沸腾。换句话说,对生物活性物质的粘性溶液或混悬液施以降低的压力,以使溶液或混悬液在沸腾期间起泡,并且利用起泡方法进一步去除溶剂,产生稳定的开-孔或闭-孔泡沫的最终产品。
然而,这些参考文献均建议把沸腾作为制备相应组合物必需的步骤。另外,通过蒸发大部分的溶剂,所述混合物,溶液,乳液或分散体最初必须被浓缩,以获得进一步使用的必需的糖浆(低真空;<30/<24托)。然后,在获得具有足够粘度的糖浆后,在引起糖浆沸腾的温度和压力条件下进行“起泡”(结构的膨胀)。
Sinnamon等(J.Dairy Sci.
40,1957,1036-1045)描述了一种新的干燥全脂奶的特性,其在高度真空和低温下干燥成膨胀的海绵-样的结构。获得的产品易于在冷水中分散,并当还原成新鲜状态时具有天然的香味。然而,该方法被设计成改进食物产品例如奶粉的分散性和香味。作为一个不利的前提,最初的浓缩步骤(直至50%重量/重量固体)对于随后的起泡步骤也是必需的。仅当氮气起泡穿过所述浓缩乳时,才能获得了需要的“疏松”的泡沫结构。
Schroeder(博士,论文标题“Entwicklung von kompaktenDarreichungsformen aus sprühgetrockneten Milcherzeugnissen zur spontanenRekonstitution”,1999)主要描述了一项技术的发展,所述技术在还原成原状的过程中,不改变最初喷雾干燥粉末的速溶性能而提供奶制品或非乳食品产品的稠化。然而,所描述的真空干燥的湿粉末的方法在引起加入的水沸腾从而产生需要的泡沫结构的条件(50℃/37.5托)下实施。
因此针对上述问题,本发明提供了使上述提及的缺点最小化的一种新方法和一种新的组合物。
依照本发明,用一种制备药物组合物的方法解决了所述问题,该方法包含下述步骤:
a)制备一种液体和一种化合物的溶液或均匀分散体,所述化合物选自一种或多种药用活性化合物,一种或多种药用合适的赋形剂和它们的混合物,接着
b)在不沸腾下膨胀所述溶液或均匀分散体。
令人惊讶地发现,在膨胀步骤前制备均匀的、充分粘的溶液或分散体是非常切实可行的,并且与如现有技术中所描述的技术相比产生了几个优点,包括:
-无获得膨胀浓缩物的合适的条件所必需的预蒸发大部分的溶剂;
-能具有高的生产能力(throughput)的连续法;
-在需要的膨胀步骤期间,支撑结构立即组成(连续法)或在几分钟内组成(分批法);
-即使在次临界(less critical)压力条件下(室温下,>30托)也能进行膨胀,因而,浓缩物的沸腾不是最初的先决条件;
-由于它们低的填充体积,在它们的胶囊壳,泡罩包装等中,高度浓缩的药物组合物可被容易地膨胀并固化。
关于物理-化学和生物制药性能的获得的利益和可能性的实例是药用活性化合物或药用合适的赋形剂在处理和贮存期间的保护和稳定性;贮存期限的延长;不相容性的消除,独立于最初性能,依照用于包埋的材料可产生所需的物理-化学特性;获得的形态学或下游的方法(即改性的润湿性,流动性,溶解性等);味-掩蔽;副作用的减少;更高的生物利用度(尤其对于凝固成无定形玻璃的药用活性化合物)和/或释放特性的控制。
除非另外指出,下列定义是用来举例说明并限定用于描述此处本发明的各种术语的含义和范围。
此处使用的术语“溶液”表示由至少两种化合物组成的物理体系,其中所有的化合物是以分子形式分布并作为一个相出现。
术语“分散体”表示由至少两种相组成的物理体系。这些相的一种是分散介质,一种或多种化合物(第二或第三相)均匀地分散于其中。
此处使用的术语“适于药用”表示从毒性观点出发适于使用的物质。
术语“沸腾”指的是在由环境对液体施加的压力等于由液体蒸汽施加的压力的情况下,液体的汽化;在这个条件下,热量的增加或由环境施加的压力的减少导致不升高温度,而液体转换成它的蒸汽。
术语“形成玻璃-基体的材料”指的是药用活性化合物或药用合适的赋形剂,它们在凝固后显示无定形状态。
术语“包埋材料”指的是能涂布,包装,分离,保护或惰性化(inertize)其它物质的物质。
术语“膨胀”表示溶液或均匀分散体显示由压力改变引起的增加的体积和表面,并且因此特征在于粘附的,层状的,泡沫-,海绵-或饼样结构。
与本发明有关的术语“多羟基化合物”指的是出自碳水化合物的一种物质,如麦芽糖糊精。
术语“树胶”指的是一种由多糖的混合物组成的物质,如黄原胶。
术语“聚合物”指的是大分子的物质(天然或合成物质)。它可以是均聚物(如聚乙二醇)也可以是共聚物(如聚甲基丙烯酸酯)。
术语“脂肪酶抑制剂”指的是能抑制脂肪酶如胃或胰腺脂肪酶作用的化合物。例如在美国专利号4,598,089中描述的orlistat和lipstatin是脂肪酶的有效抑制剂。Lipstatin是微生物来源的天然产品,orilistat是lipstatin的氢化产物。其它脂肪酶抑制剂包括通常表示为panclicin的一类化合物。Panclicin是orlistat的类似物(Mutoh等,J.Antibiot.,47(12):1369-1375(1994))。术语“脂肪酶抑制剂”也指合成的脂肪酶抑制剂,例如在国际专利申请WO99/34786(Geltex Pharmaceuticals有限公司)中所描述的脂肪酶抑制剂。这些聚合物的特征在于它们已被抑制脂肪酶的一个或多个基团所取代。术语“脂肪酶抑制剂”也包含这些化合物的药用盐。术语“脂肪酶抑制剂”也指2-氧基-4H-3,1-苯并噁嗪-4-酮类化合物,它们已在国际专利申请WO00/40569(Alizyme Therapeutics有限公司)中被描述,例如2-癸氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮,6-甲基-2-四癸氧基-4H-3,1-苯并噁嗪-4-酮和2-六癸氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮。最优选地,术语“脂肪酶抑制剂”指orlistat。
获得的药物组合物是固体或凝胶-样组合物,优选固体组合物。
任选地,该方法接着干燥和/或冷却(cooling)组合物。该方法尤其适用于制备药物组合物。
优选地,减压膨胀溶液或均匀分散体。
在一个优选的实施方案中,该溶液或均匀分散体由一种液体和一种药用活性化合物或药用合适的赋形剂制得。优选地,通过向液体中加入药用活性物质和药用合适的赋形剂制备该溶液或均匀分散体。
在上述方法中使用的液体应易于蒸发或汽化,并且可选自水(即纯化的,去离子的,蒸馏的或灭菌水),含水缓冲溶液或等渗溶液(isotonics)(即碳酸氢盐缓冲液pH7.38),营养培养基或培养肉汤(即蛋白胨肉汤),醇(即乙醇或异丙醇),酮(即丙酮),醚(即二乙醚),液态烃(即辛烷),油类(即精油如春黄菊油)和合成品(即血浆增充剂如右旋糖苷(dextranes))但不局限于这些。另外,上述提及的液体的混合物可用于本发明的方法。优选地,该液体是含水缓冲液和/或等渗溶液。
所述均匀分散体可具有胶体,溶胶,凝胶,液晶,乳状液,浆糊,混悬液或软膏形式。
所述溶液或均匀分散体可如下制得:将液体或液体混合物倒入行星式(或类似)混合器中,接着在液体或液体混合物中溶解和/或分散药用活性化合物或药用合适的赋形剂,直至制得所述均匀分散体。当与液体或液体混合物混合时,物质可以是干燥状态,溶解的,分散的或熔融状态。从而或然后可加入另外的各种化合物,赋形剂或液体。
在备选方法中,所述溶液或均匀分散体可如下制得:通过将药用活性化合物,药用合适的赋形剂或它们的混合物加入到行星式(或类似)混合器中,接着用溶剂或溶剂混合物润湿,溶解和/或分散该物质,直至制得所述溶液或均匀分散体。从而或然后可加入其它的各种化合物,赋形剂或液体。
为了改善所述溶液或分散体的均匀性,尤其是当固体含量很高时,可通过使用即静止混合器,微流化器(microfluidizer),均质器,捏和装置,高剪切力,超声,软膏磨机(ointment mill)或本领域中已知的其他装置支持混合或分散方法。只要物质保持可供给或可铺展,所述均匀溶液或分散体的粘度可低可高。
通过将溶液或分散体曝露于压力的改变下如通过真空或晶胀现象(puffing),其被转变成膨胀的结构,并且因此而被干燥或通过接触,对流,辐射,超声处理,高频,干燥(热或冷)气体或借助于一些干燥剂如有机溶剂,硅胶等而干燥。更详细地,通常将所述均化的溶液或分散体抽吸,分布,铺展或放置在板,筛子(sieve),带,辊等上,或在胶囊体,泡罩包装,管瓶,大口瓶,注射器或其它合适的形式中。然后,几乎立即(连续方法)或短时间后(分批方法),控制地改变压力产生所述膨胀结构。因此,30-150托的低压力条件是适于提供获得的固化物质的杰出密度的。依照使用的液体或液体混合物和选择的温度,通过以所述均化的溶液或分散体将不会沸腾的方式来调整压力条件,从而进行膨胀。依据使用的组合物,同时地或在稳定所述膨胀结构后,可改变压力条件,可改变温度或可应用每种本领域中已知的干燥方法以达到理想的残留溶剂水平。干燥可以是内在的或外在的过程,并且可通过振动,流化或有助于去除流体,溶剂或饱和气相的任何其它种类的众所周知的技术来进行。上述描述的温度和/或压力条件的改变可以几个步骤(分批方法)或在不同的区域(连续方法)进行,其中可包括最终的冷却步骤。
为了获得所述膨胀结构的理想的外形,密度和稳定性,必须避免液体的沸腾。干燥的并且任选冷的结构具有长的贮存期并且可容易地被切割,捣碎,碾磨,分别研磨成自由流动的粉末,其一方面,提供容易的下游加工如润湿或干燥附聚,(熔化物-)成粒,击块,压片,压实,粒化,包囊或任何其它种的填充方法,和在另一方面,在冷的或回火的液体或体液具有杰出的重建(reconstitution)性能,从而保持了任何包埋的药用活性化合物或药用合适的赋形剂的性能和功效。此外,所描述的制备药物组合物的新方法还提供了直接在它的备用的最终制剂或包装中产生膨胀的,足够稠密的结构的可能性。
产生并干燥所述膨胀结构的最初方法可以是分批的(如在真空干燥炉中)或连续的(如在真空干燥带上)方法或借助于本领域中已知的其它技术。
在一个优选的实施方案中,步骤a)的化合物是药用活性化合物。在另一个优选的实施方案中,步骤a)的化合物是药用合适的赋形剂。
更具体地,本发明涉及一种制备药物组合物的方法,其包含下述步骤:
a)通过使药用活性化合物和/或药用合适的赋形剂与足够量的液体或液体的混合物混合以产生一种均匀分散体来制备均匀溶液或分散体,
b)将该分散体曝露于压力的改变下,而不使其沸腾,和
c)任选地,干燥和/或冷却该组合物。
上述方法还可以包含下述步骤:a)通过使药用活性化合物与足够量的液体或液体的混合物混合以产生溶液或均匀分散体来制备溶液或均匀分散体,b)将该溶液或分散体曝露于压力的改变下,而不使其沸腾,和c)任选地,干燥和/或冷却该组合物。
上述描述的方法尤其适用于制备药物组合物。适于该方法的合适的药用活性化合物可不局限于任何特殊的组。每当在开发药用相关产品(即药物,药剂(medicaments),维生素,医疗装置)期间或之后发生物理-化学、工艺、盖伦制剂(galenical)或生物制药问题时,根本上认为上述描述的制备药物组合物的方法是一个有效的工具。然而,脂肪酶抑制剂是在上述方法中使用的尤其优选的化合物,优选orlistat。
Orlistat(奥利司他),一种胃肠脂肪酶抑制剂,也已知作为orlistat,是一种用于控制或预防肥胖和高血脂的已知的化合物。参见美国专利号4,598,089,1986年七月1日授权,该项专利也公开了制备orlistat的方法和美国专利号6,004,996,该项专利公开了合适的药物组合物。更合适的药物组合物在例如国际专利申请WO00/09122和WO00/09123中进行了描述。
药用活性化合物的其它实例是神经氨酸酶抑制剂,如oseltamivir(奥塞米韦)和胰岛素敏化剂,如5-[7-[2-(5-甲基-2-苯基-噁唑-4基)-乙氧基]-苯并噻吩-4-甲基]-2,4-噻唑烷二酮或它的钠盐。这些化合物在本领域中是已知的,并且在例如欧洲专利申请号96912404.9和99117934.2和国际专利申请WO94/27995中分别进行了描述。
在本发明的一个优选实施方案中,上述溶液或分散体进一步包含一种包埋或形成玻璃基质物质。优选地,所述包埋或形成玻璃基质物质是多羟基化合物,树胶,聚合物或它们的药用盐。
所述包埋或形成玻璃基质物质可以是药用活性化合物,高度分散成晶体分别固化成非晶态,或药用合适的赋形剂,优选多羟基化合物如碳水化合物。所述包埋或形成玻璃基质的物质可以是非晶态,部分或完全结晶的。
作为药用合适的赋形剂的碳水化合物可选自如麦芽糖糊精,海藻糖,纤维素二糖,葡萄糖,果糖,maltulose(麦芽酮糖),异-maltulose(麦芽酮糖),乳果糖,麦芽糖,gentobiose(龙胆二糖),乳糖,异麦芽糖,麦芽糖醇,乳糖醇,赤藓醇,palatinitol,木糖醇,甘露糖醇,山梨醇,卫矛醇和核糖醇,蔗糖,棉子糖,龙胆三糖,planteose(车前糖),毛蕊花糖,水苏糖,松三糖,葡聚糖和还有肌醇,但不局限于这些。在一个优选的实施方案中,碳水化合物是麦芽糖糊精。在另一个优选的实施方案中,碳水化合物是海藻糖。在另一个优选的实施方案中,碳水化合物是麦芽糖醇。术语“麦芽糖糊精”优选指例如Glucidex Roquette,术语“海藻糖”优选指例如TrehaloseMerck,和术语麦芽糖醇优选指例如Maltisorb Roquette。
其它适于使用的药用合适的赋形剂选自聚合物,树胶和它们的盐例如聚乙二醇;改性的或取代的淀粉(如预胶凝的淀粉,羟乙基淀粉,淀粉辛烯基琥珀酸钠(sodium starchoctenylsuccinate),旋复花粉等);改性的或取代的纤维素(如甲基纤维素,乙基纤维素,羟乙基纤维素,羟丙基纤维素,羟丙基甲基纤维素,邻苯二甲酸羟丙基甲基纤维素,羧甲基纤维素钠,乙酸邻苯二甲酸纤维素等);聚乙烯吡咯烷酮(povidone);聚乙烯醇;阿拉伯树胶(acacia gum);carbomer(卡波姆);藻酸;环糊精;明胶;瓜尔胶(guar gum);welan gum;gellan gum;tara gum(他拉胶);刺槐豆胶;纤维(即果胶);鹿角菜胶;葡甘露聚糖;聚甲基丙烯酸酯;藻酸丙二酯;紫胶;藻酸钠;黄蓍胶,黄原胶和脱乙酰壳多糖,但不局限于这些。
一些提及的物质可以是完全非晶态的或也可以显示部分或完全处于结晶状态。
上述描述的方法也适用于制备药物组合物,其中依照上述描述的方法制备药用合适的赋形剂。适于这种方法的任何药用合适的赋形剂通常可选自所有可能的辅助剂,其有助于将药用活性化合物转换成它最终的制剂,改良或优化它的功效,改变它的性能,固定它的分子或保持它的稳定性。本发明适于改善惰性药用合适的赋形剂的理想的性能以及适于掩盖不理想的性能。一些优选的药用合适的赋形剂包含选自溶剂,加溶剂,溶解增强剂,成盐剂,(挥发)盐,缓冲剂,泡腾剂,稳定剂,凝胶形成剂(gel former),表面活性剂,类脂类,脂肪酸,抗氧化剂,增效剂,螯合剂,防腐剂,填料,增量剂,载体,吸附剂,粘合剂,崩解剂,助流剂,润滑剂,分离剂,流动性促进剂,涂层剂,阻滞剂,着色剂,颜料,气味和味调整/-掩盖剂,回吸增强剂,湿度调整剂,絮凝剂等的化合物。
具体地,本发明涉及上述方法,其中所述药用活性化合物选自例如分子,药物,维生素,无机物,痕量元素,酶,细胞,血清,疫苗,蛋白质,病毒,细菌,核酸,配合物,脂质体或纳米颗粒(nanoparticles),但不局限于这些。
特别地,本发明涉及方法,其中所述溶液或分散体包含表面活性剂。在本发明中表面活性剂指具有乳化、稳定、溶解、润湿、抗泡沫或铺展性能的药用合适的赋形剂。这些辅助剂具有两亲的特性并影响不同相之间的界面张力。术语“表面活性剂”包含阴离子表面活性剂或辅助-乳化剂(即洗涤剂,磺酸盐,十二烷基硫酸钠,docusate sodium(多库酯钠),酪蛋白酸钠,脂肪酸盐),阳离子表面活性剂(即季铵类,鲸蜡基氯化吡啶鎓),非离子表面活性剂(即聚氧乙烯脂肪酸酯,如硬脂酸40聚烃氧基酯,蔗糖脂肪酸酯,鲸蜡醇,脂肪酸酯,十六醇十八醇混合物,胆甾醇,脱水山梨醇脂肪酸酯,polysorbats,poloxamer,生育酚聚琥珀酸乙二酯(tocopherylpolyethylene glycol succinate))和两性表面活性剂(即磷脂,两性电解质,蛋白质)。在一个优选的实施方案中,所述表面活性剂是聚氧乙烯脂肪酯。在另一个优选的实施方案中,所述表面活性剂是磷脂。优选地,所述表面活性剂选自十二烷基硫酸钠,docusate sodium,酪蛋白酸钠,脂肪酸盐,季铵类,十六烷基氯化吡啶鎓,聚氧乙烯脂肪酸酯,蔗糖脂肪酸酯,鲸蜡醇,脂肪酸酯,十六醇十八醇混合物,胆甾醇,失水山梨糖醇脂肪酸酯,polysorbats,poloxamers,tocopheryl polyethylene glycol succinate和磷脂。
更具体地,上述描述的方法涉及溶液和分散体,其包含3-99.99%重量/重量溶剂和0.01-97%重量/重量药用活性化合物或0.01-97%重量/重量药用合适的赋形剂。本发明还涉及一种如上描述的方法,其中所述溶液或分散体包含3-99.98%重量/重量溶剂,0.01-96.99%重量/重量药用活性化合物,和0.01-96.99%重量/重量药用合适的赋形剂。此外,上述描述的溶液或分散体可包含3-99.98%重量/重量溶剂,0.01-96.99%重量/重量药用活性化合物,和0.01-96.99%重量/重量的多羟基化合物。更优选地,上述描述的溶液或分散体可由3-99.97%重量/重量溶剂,0.01-96.98%重量/重量药用活性化合物,0.01-96.98%多羟基化合物和0.01-96.98%重量/重量的表面活性剂制得。此外,本发明涉及上述方法,其中所述分散体包含溶液或分散体,其包含3-99.98%重量/重量溶剂,0.01-96.99%重量/重量药用合适的赋形剂和0.01-96.99%重量/重量的多羟基化合物,和涉及方法,其中所述溶液或分散体包含3-99.98%重量/重量水或水/乙醇混合物,0.01-96.99%重量/重量磷脂和0.01-96.99%重量/重量麦芽糖糊精。本发明还涉及上述方法,其中所述溶液或分散体包含3-99.98%重量/重量溶剂,0.01-96.99%重量/重量药用活性化合物和0.01-96.99%重量/重量药用合适的赋形剂。另外,本发明涉及上述方法,其中所述溶液或分散体包含5-95%重量/重量水或水/乙醇混合物,1-91%orlistat,3.9-93.9%麦芽糖糊精和0.1-90.1%重量/重量的一种或多种如上描述的药用赋形剂。本发明的一个尤其优选的实施方案涉及一种方法,其中所述溶液或分散体由5-95%重量/重量溶剂,优选水或水/乙醇混合物,1-91%重量/重量orlistat,3.9-93.9%重量/重量麦芽糖糊精和0.1-90.1%重量/重量的聚氧乙烯脂肪酸酯制成。本发明更优选的实施方案涉及上述方法,其中所述溶液或分散体包含5-95%重量/重量水或水/乙醇混合物,1-91%重量/重量orlistat,1-91%重量/重量类脂类,优选三肉豆蔻精,2.9-92.9%重量/重量麦芽糖糊精和0.1-90.1%的聚氧乙烯脂肪酸酯。此外,本发明涉及上述方法,其中所述溶液或分散体包含3-99.98%重量/重量异丙醇,0.01-96.99%重量/重量oseltamivir,和0.01-96.99%重量/重量聚甲基丙烯酸酯。
特别地,上述方法涉及组合物的制备,所述溶液或分散体是通过将所述溶剂或溶剂混合物倒入一个混合器如行星式混合器或本领域中已知的另外的合适的混合装置中,任选地加入表面活性剂或其它合适的赋形剂,并将它们分配在溶剂或溶剂混合物中来制备。在流体内均匀分散所述药用活性化合物或药用合适的赋形剂后,通过任选逐步加入多羟基化合物或其它合适的赋形剂,并通过不断地搅拌、混合、刮削或捏和形成最终的溶液或分散体。取决于粘度,通过使用如均化器或软膏磨机可优化颗粒脱附聚。用激光衍射或用“细度计”(具有刻度槽和刮刀的金属嵌段)可控制内在颗粒大小。如果适当,加工步骤的顺序是可变的,并且可被改变。通过加入一种或多种药用合适的赋形剂可增加或降低所述溶液或分散体的粘度。
在本发明的一个优选的实施方案中,可在20-35℃的温度范围和30-150托,更优选30-45托的减少的压力内实施膨胀(expansion)。这可通过将所述溶液或均匀分散体铺展在板上或更优选在筛子、筛网(screens)或网上并将它们置于温度在20-35℃范围的真空干燥炉中(或本领域中已知的另一种合适的装置)。关于该选择的温度,在30-150或更优选30-45托范围内的压力的减少产生理想的稠密的,膨胀的结构而不沸腾。当然,取决于使用的溶剂或溶剂混合物,只要在膨胀步骤过程中蒸发的液体不沸腾,可改变温度和压力条件。依照本发明,平行于或在膨胀的结构凝固(solidification)之后,通过改变温度和/或压力条件可进行任选的干燥和/或冷却步骤。
干燥过程可以是内部或外部的过程,并且干燥温度可高于或低于膨胀温度。干燥压力可高于或低于膨胀压力。可通过真空,加热,升华,振动,流化,辐射,接触,对流,超声处理,高频,干燥(冷或热)气体或借助于一些干燥剂(即有机溶剂,硅胶等)或有助于去除流体、溶剂或饱和气相的任何其它种类的众所周知的技术进行干燥。依照本发明,在膨胀并任选干燥结构后,可实施附加的冷却步骤。冷却温度可高于或低于0℃并低于干燥温度。所述冷却过程可以是一种内部或外部过程。当然,结构的膨胀,任选干燥和/或冷却分几个步骤(分批方法)或在不同的区域(连续方法)进行。可用真空干燥带、真空干燥辊或本领域中已知的其它合适的装置实施连续方法。
本发明还涉及用上述方法获得的组合物。
依照本发明可获得的组合物可用测定,体积,密度(优选碎物质的堆积密度),颗粒大小分布,表面测量,相对湿度,残留溶剂水平,固体物质含量,润湿性,溶解性,稳定性,分解时间,释放特性,X-射线衍射,动力蒸汽吸着(dynamic vapor sorption),微量热法,热重量分析法,差示扫描量热计等来表征。优选地,依照本发明获得的所述膨胀的、容易干燥的并且碾碎的组合物特征在于0.1-99.9%,更优选1-10%,和最优选2-5%重量/重量的残留溶剂水平。堆积(浇铸(poured))密度为0.1-0.9,更优选0.2-0.8和最优选0.3-0.6g/cm3。这些组合物的颗粒大小分布,表示为“d’(63.2%)值”,可以为50-600,更优选200-400μm。
特别地,本发明涉及一种药物组合物,其包含0.2-10%重量/重量残留水或水/乙醇混合物,1-96%重量/重量orlistat,3.7-98.7%重量/重量麦芽糖糊精或麦芽糖醇和0.1-95.1%重量/重量的一种或多种如上描述的药用合适的赋形剂如聚氧乙烯脂肪酸酯。此外,本发明涉及一种药物组合物,其包含0.2-10%重量/重量残留异丙醇,1-98.8%重量/重量oseltamivir,和1-98.8%重量/重量聚甲基丙烯酸酯。
上述组合物特征在于0.1-99.9%重量/重量,更优选0.2-10%重量/重量和最优选1-5%重量/重量重量/重量的残留溶剂水平。堆积(浇铸)密度为0.1-0.9,更优选0.2-0.8和最优选0.3-0.6g/cm3。这些组合物的颗粒大小分布可表示为“d’(63.2%)值”,可以为50-600,更优选为200-400μm。
依照上述方法可获得的组合物可被吹、切割、压碎、筛分、磨碾、砍碎、细碎或粉碎成(自由流动的)粉末。所述粉末可与一种或多种药用活性化合物或药用合适的赋形剂混合,组合,调合,粒化,压片或加工。所述组合物可被加工成粉剂,气溶胶,粉末,颗粒,丸剂,片剂,dragée,胶囊,速干剂,干糖浆剂,干乳剂(dry emulsion),干混悬液(dry suspension)或木领域中已知的其它形式。
依照本发明获得的组合物可直接被分别制成它们的最终制剂和剂型,和更优选以它的包装形式直接被制备。剂型可选自干凝胶,片剂或胶囊,但不局限于这些。剂型也可以它的包装形式被直接制备。所述包装可选自泡罩包装,管瓶,大口瓶,香囊或注射器,但不局限于这些。符合本发明方法的最终产品可以是药品,药剂,维生素,即溶饮料(instantdrink)或医疗装置,但不局限于这些。
优选以分开剂量的形式,每天2-3次,每天60-720mg口服给药Orlistat。优选的是其中对患者给药脂肪酶抑制剂每天120-360mg,最优选120-180mg,优选以分开剂量的形式每天两次或尤其是三次给药。所述患者优选是肥胖或超重人,即具有25或更大体重指数的人。通常,优选在摄取含脂肪的膳食约一或两小时内给药脂肪酶抑制剂。通常,为了给药如上述限定的脂肪酶抑制剂,优选对具有严重机能性消化不良家族史并具有25或更大体重指数的人实施治疗。
此外,本发明涉及下述限定的组合物的应用,所述组合物用于制备药物,药剂,维生素,医疗装置等,用于治疗和预防上述提及的疾病。
现在,通过下述实施例将更详细地举例说明本发明。
实施例
实施例1
A)分散
本实施例描述了一种依照本发明的组合物,其包含作为药用活性化合物的orlistat。制备所述均匀分散体所必需的溶剂的量表示为干物质(drymass)的百分比(重量/重量)。不考虑原材料的最初溶剂含量。这个组合物用于改善药用活性化合物的流动性,润湿性,分散性,效率和稳定性。另外,能够使得容易地下游加工成粉末,分别制成胶囊或片剂(通过将麦芽糖糊精的量减至80%并将得到的粉末与3%的聚乙二醇混合):
Orlistat 10.0%重量/重量
三肉豆蔻精 5.0%重量/重量
硬脂酸40聚烃氧基酯 2.0%重量/重量
麦芽糖糊精
83.0%重量/重量
水 22.5%重量/重量
B)膨胀
借助于注射器,在筛(目大小为0.5mm)上当场(in tracks)铺展100g的均匀分散体。将筛置于调节(tempered)至25℃的真空干燥炉(HeraeusVT 5050 EK)中。将室压降至30托(Leybold Heraeus TRIVAC D8B;COMATAG DPI 70)。5分钟后,完成结构的膨胀。
C)干燥
通过测量质量和室温(AOiP PJN 5210),将这些条件固定大约30分钟。然后,通过保持相同的压力条件,将室温升至50℃。当物质温度达到35℃的理想界限时,总共90分钟后停止该过程。依照进一步加工所需要的量调整残留溶剂的含量。
实施例2
A)分散
本实施例描述了一种依照本发明的组合物,其包含作为药用活性化合物的oseltamivir。制备所述均匀分散体所必需的溶剂的量表示为干物质的百分比(重量/重量)。不考虑原材料的最初溶剂含量。这个组合物用于进行味道-掩蔽,改善稳定性和贮存期限,减少副作用和预防不相容性:
Oseltamivir 10.0%重量/重量
聚甲基丙烯酸酯
90.0%重量/重量
异丙醇 80.0%重量/重量
B)膨胀
在板上当场铺展100g的均匀分散体。将板置于真空干燥炉(Heraeus VT5050 EK)中。在环境温度下,将室压降至45托(Leybold Heraeus TRIVACD8B;COMAT AG DPI 70)。5分钟后,完成结构的膨胀。
C)干燥
通过保持相同的温度和压力条件,将膨胀的结构干燥总共180分钟。
实施例3
A)分散
本实施例描述了一种依照本发明的组合物,其包含作为药用合适的赋形剂的磷脂。制备所述均匀分散体所必需的溶剂的量表示为干物质的百分比(重量/重量)。不考虑原材料的最初溶剂含量。这个组合物用于预防稳定性问题和不相容性:
卵磷脂 30.0%重量/重量
麦芽糖糊精
70.0%重量/重量
水 40.0%重量/重量
B)膨胀
在筛子(目大小为0.5mm)上当场铺展100g的均匀分散体。将筛子置于真空干燥炉(Heraeus VT 5050 EK)中。在环境温度下,将室压降至30托(Leybold Heraeus TRIVAC D8B;COMAT AG DPI 70)。5分钟后,完成结构的膨胀。
C)干燥
通过测量质量和室温(AOiP PJN 5210),将这些条件固定大约30分钟。然后,通过保持相同的压力条件,将室温升至35℃。在总共120分钟后停止该过程。
实施例4:直接制备的剂型
A)分散
本实施例分别描述了一种依照本发明的安慰剂组合物(placebocomposition),直接制备它的最终剂型,其包含作为药用合适的赋形剂的麦芽糖糊精和羟基丙基甲基纤维素。制备所述均匀分散体所必需的溶剂的量表示为干物质的百分比(重量/重量)。不考虑原材料的最初溶剂含量。这个组合物用于证明以泡罩包装的形式直接制备的剂型的可制造性,稳定性和重量均匀性:
麦芽糖糊精 | 20.0%重量/重量 |
羟基丙基甲基纤维素 | 20.0%重量/重量 |
水 | 60.0%重量/重量 |
B)膨胀
将50g的均匀分散体倒入(剂量:325mg干物质)PVC片剂泡罩包装的孔中。在用筛子(目大小为0.5mm)覆盖后,将泡罩包装置于真空干燥炉(Heraeus VT 5050EK)。在环境温度下,将室压降至75托(Leybold HeraeusTRIVAC D8B;COMAT AG DPI 700)。15分钟后,完成结构的膨胀。
C)干燥
通过测量质量和室温(AoiP PJN 5210),随后将室温增至50℃大约120分钟。
该容易干燥的泡沫片剂易于从卷起的泡罩包装脱落,分别显示出光滑的表面,良好的物理稳定性,低脆性和满意的重量均匀性(n=10;mv=323.7mg;sd=±2.6%)。
Claims (31)
1.一种制备药物组合物的方法,其包含下述步骤:
a)制备一种液体和化合物的溶液或均匀分散体,所述化合物选自奥利司他和奥塞米韦,一种或多种药用合适的赋形剂,和它们的混合物,接着
b)在使所述溶液或均匀分散体不沸腾的条件下,通过将其暴露于30-150托的减压下膨胀所述溶液或均匀分散体;以及
c)任选地干燥和/或冷却组合物。
2.依照权利要求1的方法,其中所述溶液或分散体包含一种包埋或玻璃基体-形成物质。
3.依照权利要求2的方法,其中所述包埋或玻璃基体-形成物质是药用合适的赋形剂。
4.依照权利要求3的方法,其中所述包埋或玻璃基体-形成物质是多羟基化合物,树胶,聚合物,或其药用盐。
5.依照权利要求4的方法,其中所述多羟基化合物是碳水化合物。
6.依照权利要求5的方法,其中所述碳水化合物选自麦芽糖糊精,海藻糖,纤维素二糖,葡萄糖,果糖,麦芽酮糖,异-麦芽酮糖,乳果糖,麦芽糖,龙胆二糖,乳糖,异麦芽糖,麦芽糖醇,乳糖醇,赤藓醇,palatinitol,木糖醇,甘露糖醇,山梨醇,卫矛醇和核糖醇,海藻糖,蔗糖,棉子糖,龙胆三糖,车前糖,毛蕊花糖,水苏糖,松三糖,葡聚糖和肌醇。
7.依照权利要求5的方法,其中所述碳水化合物是麦芽糖糊精。
8.依照权利要求5的方法,其中所述碳水化合物是麦芽糖醇。
9.依照权利要求5的方法,其中所述碳水化合物是海藻糖。
10.依照权利要求4的方法,其中所述树胶,聚合物或其药用盐选自聚乙二醇;改性的或取代的淀粉;改性的或取代的纤维素;聚乙烯吡咯烷酮;聚乙烯醇;阿拉伯树胶;卡波姆;藻酸;环糊精;明胶;瓜尔胶;welan gum;gellan gum;他拉胶;刺槐豆胶;纤维;鹿角菜胶;葡甘露聚糖;聚甲基丙烯酸酯;藻酸丙二酯;紫胶;藻酸钠;黄蓍胶,脱乙酰壳多糖,和黄原胶。
11.依照权利要求10的方法,其中所述改性的或取代的淀粉是预胶凝的淀粉,羟乙基淀粉,淀粉辛烯基琥珀酸钠。
12.依照权利要求10的方法,其中所述改性的或取代的纤维素是甲基纤维素,乙基纤维素,羟乙基纤维素,羟丙基纤维素,羟丙基甲基纤维素,邻苯二甲酸羟丙基甲基纤维素,羧甲基纤维素钠,乙酸邻苯二甲酸纤维素。
13.依照权利要求1的方法,其中所述溶液或分散体包含一种表面活性剂。
14.权利要求13的方法,其中所述表面活性剂选自阴离子表面活性剂,辅助-乳化剂,阳离子表面活性剂,非离子表面活性剂和两性表面活性剂。
15.权利要求13或14的方法,其中所述表面活性剂选自十二烷基硫酸钠,多库酯钠,酪蛋白酸钠,脂肪酸盐,季铵类,十六烷基氯化吡啶鎓,聚氧乙烯脂肪酸酯,蔗糖脂肪酸酯,鲸蜡醇,脂肪酸酯,十六醇十八醇混合物,胆甾醇,失水山梨糖醇脂肪酸酯,聚山梨酯,泊洛沙姆,生育酚聚琥珀酸乙二酯和磷脂。
16.依照权利要求1的方法,其中所述溶液或分散体由5-95%重量/重量水或水/乙醇混合物,1-91%奥利司他,3.9-93.9%重量/重量麦芽糖糊精和0.1-90.1%重量/重量的一种或多种药用赋形剂制成。
17.依照权利要求1的方法,其中所述溶液或分散体由5-95%重量/重量水或水/乙醇混合物,1-91%奥利司他,3.9-93.9%重量/重量麦芽糖糊精和0.1-90.1%重量/重量的聚氧乙烯脂肪酸酯制成。
18.依照权利要求1的方法,其中所述溶液或分散体由5-95%重量/重量水或水/乙醇混合物,1-91%重量/重量奥利司他,1-91%重量/重量三肉豆蔻精,2.9-92.9%重量/重量麦芽糖糊精和0.1-90.1%重量/重量聚氧乙烯脂肪酸酯制成。
19.依照权利要求1的方法,其中所述溶液或分散体由3-99.98%重量/重量异丙醇,0.01-96.99%重量/重量奥塞米韦,和0.01-96.99%重量/重量聚甲基丙烯酸酯制成。
20.依照权利要求1的方法,其中所述药物组合物具有0.1-10%重量/重量的残留溶剂水平。
21.依照权利要求1的方法,其中所述药物组合物具有0.1-0.9g/cm3的堆积密度。
22.依照权利要求1的方法,其中所述药物组合物具有50-600μm的颗粒大小分布。
23.依照权利要求1的方法,其中所述组合物以最终剂型的形式被直接制备。
24.依照权利要求1的方法,其中所述组合物以它的包装形式被直接制备。
25.通过权利要求1-24任一项的方法获得的一种粘附的、层状的、泡沫-、海绵-或饼样结构形式的组合物。
26.权利要求25的组合物,其包含0.2-10%重量/重量水或水/乙醇混合物,1-96%重量/重量奥利司他,3.7-98.7%重量/重量麦芽糖糊精和0.1-95.1%重量/重量的一种或多种药用赋形剂。
27.权利要求26的组合物,其包含聚氧乙烯脂肪酸酯。
28.权利要求25的组合物,其包含0.2-10%重量/重量异丙醇,1-98.8%重量/重量奥塞米韦,和1-98.8%重量/重量聚甲基丙烯酸酯。
29.依照权利要求25-28任一项的组合物,其具有0.1-0.9g/cm3的堆积密度。
30.依照权利要求25-28任一项的组合物,其具有50-600μm的颗粒大小分布。
31.依照权利要求25-28任一项的组合物,其具有0.1-10%的残留溶剂水平。
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US20030027786A1 (en) * | 2001-06-06 | 2003-02-06 | Karsten Maeder | Lipase inhibiting composition |
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US9174176B2 (en) | 2003-01-09 | 2015-11-03 | Disperse Systems, Inc. | Ultrasonic dispersion apparatus, system, and method |
US20050089502A1 (en) * | 2003-08-21 | 2005-04-28 | Todd Schansberg | Effervescent delivery system |
US8940321B2 (en) | 2003-12-12 | 2015-01-27 | Otic Pharma Ltd. | Compositions for treatment of ear disorders and methods of use thereof |
EP1699431B1 (en) | 2003-12-12 | 2015-08-19 | Otic Pharma Ltd. | Compositions for treatment of ear disorders and methods of use thereof |
CA2562213A1 (en) * | 2004-04-06 | 2005-11-24 | Rpg Life Sciences Limited | Mouth dissolvable and meltable, and water dispersable delivery formulation |
EP1790966A1 (en) * | 2004-09-15 | 2007-05-30 | Banyu Pharmaceutical Co., Ltd. | SAMPLING METHOD AND SAMPLING DEVICE, AND logD MEASURING METHOD AND logD MEASURING SYSTEM |
EP2163196A3 (en) * | 2004-12-31 | 2010-11-03 | Mikhail Yurievich Gotovsky | Device for measuring the presence of foreign substances in a living organism and for individually selecting preparations for increasing an organism's life activity |
US20060198856A1 (en) * | 2005-03-01 | 2006-09-07 | Keith Whitehead | Ibuprofen suspension stabilized with docusate sodium |
US20060246141A1 (en) * | 2005-04-12 | 2006-11-02 | Elan Pharma International, Limited | Nanoparticulate lipase inhibitor formulations |
US7984717B2 (en) * | 2005-04-29 | 2011-07-26 | Medtronic, Inc. | Devices for augmentation of lumen walls |
US20070060610A1 (en) * | 2005-06-16 | 2007-03-15 | Wempe Michael F | Methods and pharmaceutical formulations for increasing bioavailability |
WO2006136197A1 (en) | 2005-06-21 | 2006-12-28 | V. Mane Fils | Smoking device incorporating a breakable capsule, breakable capsule and process for manufacturing said capsule |
US20070048364A1 (en) * | 2005-08-04 | 2007-03-01 | Yingxu Peng | Free flowing granules containing carbomer |
KR100669497B1 (ko) * | 2005-08-17 | 2007-01-16 | 보람제약주식회사 | 안정성과 용출률이 뛰어난 약리학적 조성물 및 그 제조방법 |
AR056499A1 (es) * | 2005-09-06 | 2007-10-10 | Serapis Farmaceuticals Ltd | Compuestos |
EP1951186A4 (en) | 2005-10-19 | 2009-11-04 | Menni Menashe Zinger | METHODS FOR TREATING HYPERHIDROSIS |
DK1973406T3 (da) | 2005-12-28 | 2014-06-23 | Advanced Bionutrition Corp | Fremføringsmiddel til probiotiske bakerier omfattende en tør blanding af polysaccharider, saccharider, polyoler i glasform |
US8968721B2 (en) | 2005-12-28 | 2015-03-03 | Advanced Bionutrition Corporation | Delivery vehicle for probiotic bacteria comprising a dry matrix of polysaccharides, saccharides and polyols in a glass form and methods of making same |
FR2895908B1 (fr) * | 2006-01-12 | 2008-03-28 | France Etat | Procede de fabrication d'une forme pharmaceutique de phosphate d'oseltamivir |
KR20080097468A (ko) | 2006-02-20 | 2008-11-05 | 추가이 세이야쿠 가부시키가이샤 | 인산 오셀타미비어 함유 의약 조성물 |
JP2009530614A (ja) | 2006-03-16 | 2009-08-27 | デューク ユニバーシティ | フーリエ領域光コヒーレンス・トモグラフィーに基づく実時間直角位相投影を実行するための方法、システム及びコンピュータプログラム製品 |
CN1820744B (zh) | 2006-04-04 | 2011-01-26 | 中国人民解放军军事医学科学院毒物药物研究所 | 磷酸奥司他韦颗粒剂及其制备方法 |
EP1872777A1 (en) * | 2006-06-27 | 2008-01-02 | LEK Pharmaceuticals D.D. | Pharmaceutical composition comprising tetrahydrolipstatin |
KR100812824B1 (ko) | 2006-09-27 | 2008-03-12 | 주식회사 제닉 | 키토산과 폴리에틸렌글리콜을 이용한 생체친화성 저독성필름 |
US8460726B2 (en) | 2006-12-18 | 2013-06-11 | Advanced Bionutrition Corporation | Dry food product containing live probiotic |
US20080286349A1 (en) * | 2007-05-18 | 2008-11-20 | Youhei Nomoto | Systems, devices, and methods for passive transdermal delivery of active agents to a biological interface |
KR101439470B1 (ko) * | 2007-05-22 | 2014-09-16 | 한미사이언스 주식회사 | 오를리스타트 및 대변 연화제를 포함하는 비만의 예방 또는치료용 조성물 |
EP2219614A1 (en) * | 2007-10-15 | 2010-08-25 | Inventis DDS Pvt Limited | Pharmaceutical composition of orlistat |
PL216542B1 (pl) | 2008-03-20 | 2014-04-30 | Zakłady Farmaceutyczne POLPHARMA Spółka Akcyjna | Sposób wytwarzania stabilnej kompozycji orlistatu w postaci kapsułkowanego proszku |
GB0900551D0 (en) * | 2009-01-14 | 2009-02-11 | Horton Richard | Ingestible compositions and processes of preparation |
CA2756883C (en) | 2009-03-27 | 2018-01-09 | Advanced Bionutrition Corp. | Microparticulated vaccines for the oral or nasal vaccination and boostering of animals including fish |
MY157343A (en) | 2009-05-26 | 2016-05-31 | Advanced Bionutrition Corp | Stable dry powder composition comprising biologically active microorganisms and/or bioactive materials and methods of making |
WO2011040956A1 (en) * | 2009-09-29 | 2011-04-07 | Michael Burnet | Novel pesticide formulations |
KR100940745B1 (ko) * | 2009-10-15 | 2010-02-04 | 광동제약 주식회사 | 오를리스타트 및 아타풀지트 함유 복합제의 코팅펠렛 및 이를 이용한 제제 |
US9504750B2 (en) | 2010-01-28 | 2016-11-29 | Advanced Bionutrition Corporation | Stabilizing composition for biological materials |
JP5886763B2 (ja) | 2010-01-28 | 2016-03-16 | アドバンスド バイオニュートリション コーポレーション | 生物活性物質を含む乾燥ガラス状組成物 |
KR101021030B1 (ko) * | 2010-03-25 | 2011-03-09 | 엘지이노텍 주식회사 | 형광체 코팅방법, 발광장치 제조방법 및 코팅된 형광체 |
EP2557151B1 (en) * | 2010-04-07 | 2017-10-04 | Mitsubishi Gas Chemical Company, Inc. | S-adenosyl-l-methionine-containing dry yeast composition with excellent storage stability and process for producing same |
AU2011289272B2 (en) | 2010-08-13 | 2015-02-05 | Advanced Bionutrition Corporation | Dry storage stabilizing composition for biological materials |
US9492387B2 (en) | 2010-10-29 | 2016-11-15 | Western University Of Health Sciences | Ternary mixture formulations |
PL2680815T3 (pl) | 2011-03-01 | 2017-02-28 | The Procter & Gamble Company | Porowate, ulegające rozpadowi stałe podłoże do zastosowań związanych z higieną osobistą |
AU2013234931B2 (en) | 2012-03-23 | 2017-12-07 | Intervet International Bv | Stabilizing composition for biological materials |
CN103222964B (zh) * | 2013-01-29 | 2014-10-08 | 青岛大学 | 一种奥利司他口服制剂及其制备方法 |
GB2524496A (en) * | 2014-03-24 | 2015-09-30 | British Airways Plc | Dynamic tracking and control of passenger travel progress |
US10851399B2 (en) | 2015-06-25 | 2020-12-01 | Native Microbials, Inc. | Methods, apparatuses, and systems for microorganism strain analysis of complex heterogeneous communities, predicting and identifying functional relationships and interactions thereof, and selecting and synthesizing microbial ensembles based thereon |
US9938558B2 (en) | 2015-06-25 | 2018-04-10 | Ascus Biosciences, Inc. | Methods, apparatuses, and systems for analyzing microorganism strains from complex heterogeneous communities, predicting and identifying functional relationships and interactions thereof, and selecting and synthesizing microbial ensembles based thereon |
EP3314007B1 (en) | 2015-06-25 | 2024-01-24 | Native Microbials, Inc. | Methods, apparatuses, and systems for analyzing microorganism strains from complex heterogeneous communities, predicting and identifying functional relationships and interactions thereof, and selecting and synthesizing microbial ensembles based thereon |
US10953050B2 (en) | 2015-07-29 | 2021-03-23 | Advanced Bionutrition Corp. | Stable dry probiotic compositions for special dietary uses |
JP6778051B2 (ja) * | 2016-08-18 | 2020-10-28 | 沢井製薬株式会社 | オセルタミビルリン酸塩含有医薬組成物 |
CN110366596A (zh) | 2016-12-28 | 2019-10-22 | 埃斯库斯生物科技股份公司 | 用于对复杂异质群落中的完整微生物株系进行分析、确定其功能关系及相互作用以及基于此来识别和合成生物活性改性剂的方法、设备和系统 |
WO2019069108A1 (en) * | 2017-10-04 | 2019-04-11 | Debreceni Egyetem | SOLID GALENIC FORM, MOLDED, GASTRIC RETENTION AND EXTENDED RELEASE AND METHOD OF PREPARING THE SAME |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS608117B2 (ja) * | 1977-02-08 | 1985-02-28 | 財団法人微生物化学研究会 | 新生理活性物質エステラスチンおよびその製造法 |
US4489438A (en) * | 1982-02-01 | 1984-12-18 | National Data Corporation | Audio response system |
CA1247547A (en) | 1983-06-22 | 1988-12-28 | Paul Hadvary | Leucine derivatives |
EP0553777B1 (en) | 1992-01-29 | 2002-04-24 | Takeda Chemical Industries, Ltd. | Fast dissolving tablet and its production |
US5560921A (en) | 1992-06-01 | 1996-10-01 | The Procter & Gamble Company | Chewable decongestant compositions |
US5343672A (en) | 1992-12-01 | 1994-09-06 | Scherer Ltd R P | Method for manufacturing freeze dried dosages in a multilaminate blister pack |
CA2151260A1 (en) * | 1993-02-23 | 1994-09-01 | Pankaj B. Gala | A process for the preparation of substantially alcohol free pharmaceutical compositions |
DE4317320A1 (de) | 1993-05-25 | 1994-12-01 | Boehringer Mannheim Gmbh | Neue Thiazolidindione und diese enthaltende Arzneimittel |
US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
US5536264A (en) * | 1993-10-22 | 1996-07-16 | The Procter & Gamble Company | Absorbent composites comprising a porous macrostructure of absorbent gelling particles and a substrate |
US5523106A (en) * | 1994-02-03 | 1996-06-04 | Nabisco, Inc. | Juice-based expanded snacks and process for preparing them |
BR9607098B8 (pt) | 1995-02-27 | 2014-11-18 | Gilead Sciences Inc | Composto e composição farmacêutica. |
CN102952033A (zh) | 1995-02-27 | 2013-03-06 | 吉里德科学公司 | 新颖化合物,其合成方法及治疗用途 |
NZ309841A (en) * | 1995-06-07 | 1999-10-28 | Quadrant Holdings Cambridge | Methods for producing foamed glass matrices (fgm) and compositions obtained thereby |
US5763483A (en) * | 1995-12-29 | 1998-06-09 | Gilead Sciences, Inc. | Carbocyclic compounds |
US6083531A (en) * | 1996-04-16 | 2000-07-04 | Novartis Consumer Health S.A. | Fast disintegrating oral dosage form |
US5766520A (en) * | 1996-07-15 | 1998-06-16 | Universal Preservation Technologies, Inc. | Preservation by foam formation |
EP0952820A1 (en) * | 1996-10-14 | 1999-11-03 | F. Hoffmann-La Roche Ag | Process for the manufacture of a pulverous preparation |
US6004996A (en) | 1997-02-05 | 1999-12-21 | Hoffman-La Roche Inc. | Tetrahydrolipstatin containing compositions |
US6565885B1 (en) * | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
JPH11137208A (ja) | 1997-11-14 | 1999-05-25 | Nikken Chem Co Ltd | 口腔内速溶性固形物及びその製造方法 |
US6267952B1 (en) | 1998-01-09 | 2001-07-31 | Geltex Pharmaceuticals, Inc. | Lipase inhibiting polymers |
CA2326349A1 (en) * | 1998-04-09 | 1999-10-21 | F. Hoffmann-La Roche Ag | Process for the manufacture of (sub)micron sized particles by dissolving in compressed gas and surfactants |
EP1105123B1 (en) * | 1998-08-14 | 2004-04-07 | F.Hoffmann-La Roche Ag | Pharmaceutical compositions containing lipase inhibitors and chitosan |
DK1105122T3 (da) | 1998-08-14 | 2005-08-08 | Hoffmann La Roche | Pharmaceutical compositions containing lipase inhibitors |
GB9827423D0 (en) * | 1998-12-11 | 1999-02-03 | Relax Limited | Method of drying a solution |
US6342249B1 (en) * | 1998-12-23 | 2002-01-29 | Alza Corporation | Controlled release liquid active agent formulation dosage forms |
GB9900416D0 (en) | 1999-01-08 | 1999-02-24 | Alizyme Therapeutics Ltd | Inhibitors |
ATE400252T1 (de) | 1999-02-10 | 2008-07-15 | Pfizer Prod Inc | Pharmazeutische feste dispersionen |
GB9904629D0 (en) * | 1999-03-02 | 1999-04-21 | Danbiosyst Uk | Oral drug delivery system |
FR2791569B1 (fr) * | 1999-03-31 | 2003-05-09 | Pf Medicament | Composition ou structure microporeuse expansee isotrope a dissolution rapide a usage pharmaceutique, veterinaire, dietetique, alimentaire ou cosmetique et son procede d'obtention |
SI1296656T1 (sl) * | 2000-06-27 | 2006-12-31 | Hoffmann La Roche | Postopek priprave sestavka |
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