CN102725393B - 包含生物活性材料的干燥玻璃质组合物 - Google Patents
包含生物活性材料的干燥玻璃质组合物 Download PDFInfo
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Abstract
本发明涉及用于在苛刻的储存和使用条件下稳定和保护生物材料的制剂和方法,其中所述制剂涉及包埋在保护性玻璃质基质中的生物活性材料和生物制品,包括活细菌。
Description
相关申请的互相参考
本申请要求2010年1月28日提交至美国专利与商标局(UnitedStatesPatentandTrademarkOffice)的美国临时申请No.61/299,315的优先权,其内容在此为所有目的通过参考结合于此。
技术领域
本发明涉及在苛刻的储存和使用条件下稳定和保护生物材料,更具体来说,本发明涉及将生物活性材料和生物制品包括活细菌包埋在无定形玻璃质基质的保护性制剂中。
背景技术
冷冻干燥在传统上是保存敏感性生物物质例如活或死细菌和病毒以及蛋白质的最常用方法,而其他方法例如喷雾干燥、流化喷雾干燥和干燥法一般不适合。在这些方法中使用的高干燥温度引起对生物活性材料本身的显著伤害。此外,它们不能将材料充分干燥至产物稳定性所需的特定的残余水分或水活度,因此可能需要通过其他手段进行的附加干燥步骤。常规的冷冻干燥方法典型地包括将含有生物活性材料的溶液冷冻,以及将冷冻的生物材料在完全真空下、在保持冷冻的同时冻干。冷冻干燥方法的低温减少了生物活性材料的降解反应,并使最终干燥形式中的活性损失降至最低。通常,由于在缓慢干燥过程期间形成冰晶,冷冻干燥方法往往引起生物活性材料的显著活性损失和损伤。此外,冷冻步骤本身如果不能正确执行,也能使生物活性材料变性或失活。通过向生物活性物质溶液加入低温保护剂可以在一定程度上避开由冰晶结构的形成所引起的损伤(Morgan等,2006)。这样的保护剂是高度可溶的化学物质,其被添加到制剂中以在冷冻期间保护细胞膜和蛋白质,并提高储存期间的稳定性。常用于活细菌和病毒的稳定剂包括相对于细胞物质或生物活性物质来说高浓度的高糖,例如蔗糖、甘油或山梨糖醇(Morgan等,2006;Capela等,2006)。然而,这样的保护剂可能不能足够地穿透到细胞内以保护细胞内体积中的活性组分,这可能引起冷冻干燥物质在储存后的不稳定性。因此,有膜生物材料例如病毒、细菌和细胞在冷冻干燥过程中不能良好存活。因此,对于开发能够使干燥损失最小化并同时获得干燥后材料足够的储存稳定性的最优干燥方法和制剂来说,仍存在显著的挑战。
通过使用某些制剂与在玻璃态、特别是糖玻璃中进行真空干燥的组合已解决了与冷冻干燥相关的一些问题(美国专利6,190,701)。干燥的稳定化生物活性材料在玻璃质基质中受到保护以对抗不利环境例如高的温度和湿度。一般来说,通过玻璃形成而进行的稳定化,从浓缩含有生物活性分子的糖溶液以形成超饱和糖浆开始。进一步去除水使糖浆逐渐固化,最终转变成残余水含量低的固体糖玻璃。在玻璃中的化学扩散是可以忽略不计的,因此化学反应事实上停止。由于变性或膜损坏是化学变化,它们不能在玻璃中发生,因此生物活性材料被稳定化并受到保护。许多玻璃由于在储存期间与生物活性材料反应,因此不能执行稳定化。使用还原糖时出现明显问题,所述还原糖可以形成良好的物理玻璃,然而它们的醛基在典型的美拉德(Maillard)反应中攻击生物活性物质上的氨基基团,而非反应性糖类提供稳定的完全不需要冷藏的产物。
由于糖类的固有吸湿性,超饱和糖浆的除水和最终干燥变得极为困难。(Annear1962)首先解决了这一缺点,其开发了在糖类和氨基酸的溶液中含有细菌的制剂以及涉及浓缩糖浆的沸腾和泡沫形成的真空干燥方法。Roser等(美国专利6,964,771)公开了通过泡沫形成进行干燥的类似概念,所述概念包括蒸发掉大部分溶剂的浓缩步骤,随后在真空下对浓缩的糖浆进行沸腾和发泡。为了减轻在沸腾步骤中可能发生的氧化和变性损伤,Bronshtein(美国专利5,766,520、7,153,472)介绍了含有糖类和表面活性剂的改进的保护性剂型。保护性溶液的干燥也包括在中度真空下浓缩,然后施加强真空以使剩余的水起泡沸腾,从而形成干燥的稳定泡沫的逐步过程。为了避开沸腾步骤,Busson和Schroeder(美国专利No.6,534,087)介绍了适用于敏感性生物活性材料的制剂的液态干燥方法,并在高于30Torr的非常温和的真空压力下使用真空烘箱。在不使材料沸腾的条件下获得一定干燥水平后,供热至高于20℃,并在仅仅几小时后就收获了干燥的材料。
生物活性物质溶液在整个干燥过程期间被维持在液态中的这种类型的干燥方法,具有由于液体在沸腾期间蒸发和发泡表面所表现出的表面积增加而造成的干燥更快的优点。然而,沸腾和发泡需要输入显著热量来提供必需的溶液喷发。这样的干燥方法不能良好适用于敏感性生物物质例如活病毒、细胞或细菌的干燥,这是由于施加的热加速了酶促降解(例如蛋白质水解)和化学氧化(例如氧化和自由基攻击),其可能破坏生物材料的活性或存活力。
上面描述的干燥方法在其被放大至大型工业过程的能力方面也是有限的。避免冷冻要求在比常规冷冻干燥或喷雾冷冻干燥过程循环中更低的真空度(>7TORR)下执行过程。上述方法的最显著的缺点是不能控制并限制容器、托盘或小瓶中泡沫的膨胀。这种无法控制的喷发和往往过度的泡沫形成使得在实践上不能开发出工业规模的方法。沸腾步骤的喷发和发泡性质导致一部分材料溅射到容器壁上并进入干燥室中。为了缓和沸腾期间的喷发,Bronshtein(美国专利6,884,866、6,306,345)提出了特殊的干燥室和受控的温度/压力施加方案,所述温度/压力施加方案将过度加热减低至可接受的程度。包含喷发和过度发泡的另一种方法被描述在美国专利公布No.2008/0229609中,在所述方法中将生物活性物质溶液封装在覆盖有透气膜的容器或袋子中。同样地,难以在工业规模上实现这些方案,它们需要特殊的设备并且难以使用不同制剂可靠地重复。
正如本技术领域中已知的,干燥泡沫方法不能特别良好地适用于保存有膜生物材料例如脂质体、病毒或活细胞和细菌。脂质膜通常阻止保护剂透入到所包围的体积中,或阻止从所包围的体积中除去足够的水。在保护剂没有足够透入的情况下,酶促过程例如蛋白质水解和化学过程例如氧化和自由基攻击,可以破坏有膜生物材料的活性或存活力。残留在膜包围的体积中的低渗流体可以助长生物材料的不稳定性。Truong-le,Vu(美国专利7,381,425)描述了适合于有膜生物活性物质的冷冻干燥方法。该发明的组合物包括多元醇和有膜生物活性材料。干燥方法从将制剂冷却至接近脂质膜的相转变温度的温度开始,降低制剂上的压力以形成稳定泡沫,将泡沫冷冻,然后使水从冷冻的泡沫升华以提供冻干的干燥泡沫组合物。可以采用二级干燥条件来进一步干燥泡沫。
对于能够在玻璃态中干燥而不沸腾和过度发泡的适合的保护性制剂,仍存在需求。特别是对于也适合于制药工业之外的应用例如食品和农业工业的成本效益高的制剂和可放大的干燥方法,存在着需求。为了提供足够的干燥而不暴露于高温,需要保护性制剂和温和的干燥过程。需要能够在高的温度和湿度条件下的储存中保护这些生物物质的组合物。如下所述,本发明为所有这些挑战提供了解决方案。本发明的脱水方法非常温和,并且不将活性试剂暴露于沸腾或发泡中,因此与使样品经受这些胁迫中的一种或两种的常规冷冻干燥和泡沫干燥技术相比,具有优势。
发明内容
本发明包括用于在储存中保存敏感性生物活性材料的组合物和干燥方法,所述敏感性生物活性材料例如肽、蛋白质、酶、激素、维生素、类胡萝卜素、矿物质、药物、抗生素、杀微生物剂、杀真菌剂、除草剂、杀虫剂、杀精子剂、核酸、抗体、疫苗、细菌(益生菌或其他细菌)、病毒和/或细胞悬液。所述干燥方法提供了用于干燥包含生物活性材料、基质形成剂和玻璃形成剂的制剂的方法。通过将所有固体组分和生物活性材料分散在溶液中来制备所述制剂。利用本技术领域中已知的手段例如液氮或干冰将所述溶液快速冷冻,以形成小珠、串或小滴形式的无定形组合物。冷冻粒子可以储存在低温冰箱(在-30℃和-80℃之间)中直至干燥,或以冷冻的无定形状态立即置于托盘上用于在常规冷冻干燥器中液体干燥。干燥方法从在低于2000mTORR的真空压力下对冷冻粒子进行短时间驱气和结构稳定化步骤开始,然后在高于2000mTORR的真空压力和所需温度下进行初级干燥步骤。在玻璃质无定形材料的二级和最后干燥步骤期间,使用完全真空压力和升高的温度以获得所需的干燥材料的最终水活度。
在一个实施方案中,所述制剂包含足够量的基质形成剂,其中包埋了生物活性材料。适合的基质形成剂的实例包括但不限于乙酸邻苯二甲酸纤维素(CAP)、羧甲基纤维素、果胶、藻酸钠、藻酸的盐、羟丙基甲基纤维素(HPMC)、甲基纤维素、卡拉胶、瓜尔胶、阿拉伯胶、黄原胶、刺槐豆胶、壳聚糖和壳聚糖衍生物、胶原、聚乙醇酸、淀粉和改性淀粉、环糊精和寡糖(菊粉、麦芽糖糊精、葡聚糖等),及其组合。在一个特定实施方案中,优选的基质形成剂是藻酸钠。优选情况下,以干物质总重量的百分数计,所述制剂包含0.1-20%、更优选1-12%。
在其他实施方案中,基质形成剂包含藻酸钠与寡糖的混合物,其中藻酸钠/寡糖的重量比为1:1-10、更优选为1:1-5。
在本发明的另一个实施方案中,使用二价金属离子将基质形成剂交联,以形成坚固的水凝胶。通过将料浆雾化或挤出到含有二价金属离子溶液的槽中,或通过将二价金属离子直接添加到料浆中,以及让制剂硬化并形成水凝胶来形成交联的水凝胶制剂。然后将水凝胶制剂快速冷冻并按照本发明的干燥方法进行干燥。
在另一个实施方案中,制剂包含显著量的玻璃形成剂,其中包埋了微生物。适合的试剂的实例包括但不限于蛋白质,例如卵清蛋白、卵清、明胶、免疫球蛋白、分离的大豆蛋白、小麦蛋白、豌豆蛋白、棉籽蛋白、脱脂奶粉、酪蛋白酸盐、乳清蛋白和任何水解的蛋白质;糖类,包括单糖(例如半乳糖、D-甘露糖、山梨糖等)、二糖(例如乳糖、海藻糖、蔗糖等);氨基酸,例如赖氨酸、谷氨酸、甘氨酸、丙氨酸、精氨酸或组氨酸以及疏水性氨基酸(色氨酸、酪氨酸、亮氨酸、苯丙氨酸等);甲基胺类例如甜菜碱;赋形剂盐类例如硫酸镁;多元醇例如三元以上糖醇(例如甘油、赤藓糖醇、丙三醇、阿拉伯糖醇、木糖醇、山梨糖醇和甘露糖醇);丙二醇;聚乙二醇;普卢兰尼克(pluronics);表面活性剂;及其组合。
在一个优选实施方案中,玻璃形成剂包含二糖和水解蛋白质的混合物。在特定实施方案中,优选的玻璃形成剂是海藻糖与水解蛋白质的混合物。优选情况下,以干物质总重量的百分数计,制剂包含10-90%的海藻糖和0.1-30%的水解蛋白质,更优选20-80%的海藻糖和0.1-20%的水解蛋白质,最优选40-80%的海藻糖和0.1-20%的水解蛋白质。
本发明的方法典型地包括将生物活性材料(例如肽、蛋白质、酶、激素、维生素、类胡萝卜素、矿物质、药物、抗生素、杀微生物剂、杀真菌剂、除草剂、杀虫剂、杀精子剂、核酸、抗体、疫苗、细菌、病毒和/或细胞悬液)、至少一种基质形成剂和至少两种玻璃形成剂在溶液中混合成均匀料浆,通过雾化、滴入或挤出到液氮槽中将料浆快速冷冻。从液氮槽收集珠子、微珠、串或小滴,并在液体状态下在冷冻干燥器中干燥,或者可选地将它们储存在低温冰箱(在-30℃和-80℃之间)中直至干燥。
在本发明的变体中,对制剂中基质形成剂的量进行调整以获得所需的制剂粘度和密度,所需粘度和密度允许进行有效率的初级干燥,同时避免了在初级液体干燥步骤期间典型发生的沸腾和过度发泡。通过本技术领域中已知的任何手段例如搅打或注入气体例如空气、氮气、二氧化碳、氩气等可以获得液体制剂的所需密度。优选情况下,在快速冷冻步骤之前将氮气在混合下注入到粘性料浆制剂中,以形成稳定的多孔或乳脂状料浆。
根据本发明,干燥过程包括三个主要步骤:1.在低于2000mTORR的真空压力下对冷冻粒子进行短时间驱气和结构稳定化的步骤,2.在高于2000mTORR的真空压力和所需温度下进行初级液体干燥的步骤,3.在完全真空压力和升高的温度下对玻璃质材料进行二级和最后干燥的步骤,其时间足以将干燥后制剂的水活度降低至0.3Aw以下。
在干燥方法的优选实施方案中,将生物活性材料混合在包含基质形成剂和玻璃形成剂的溶液中。在一个特定实施方案中,生物活性材料包括活细菌(例如益生菌)。适合的微生物的实例包括但不限于酵母例如糖酵母属(Saccharomyces)、德巴利氏酵母属(Debaromyces)、假丝酵母属(Candida)、毕赤氏酵母属(Pichia)和球拟酵母属(Torulopsis),霉菌例如曲霉属(Aspergillus)、根霉属(Rhizopus)、毛霉属(Mucor)、青霉属(Penicillium)和球拟酵母属(Torulopsis),以及细菌例如双歧杆菌属(Bifidobacterium)、梭状芽胞杆菌属(Clostridium)、梭杆菌属(Fusobacterium)、蜜蜂球菌属(Melissococcus)、丙酸杆菌属(Propionibacterium)、链球菌属(Streptococcus)、肠球菌属(Enterococcus)、乳球菌属(Lactococcus)、库克菌属(Kocuriaw)、葡萄球菌属(Staphylococcus)、消化链球菌属(Peptostrepococcus)、芽孢杆菌属(Bacillus)、片球菌属(Pediococcus)、微球菌属(Micrococcus)、明串珠菌属(Leuconostoc)、魏斯氏菌属(Weissella)、气球菌属(Aerococcus)、酒球菌属(Oenococcus)和乳杆菌属(Lactobacillus)。适合的益生微生物的具体实例以下面的种为代表,并包括那些种中的所有培养生物型:黑色曲霉(Aspergillusniger)、米曲霉(A.oryzae)、凝结芽孢杆菌(Bacilluscoagulans)、缓慢芽孢杆菌(B.lentus)、地衣形芽孢杆菌(B.licheniformis)、肠膜芽孢杆菌(B.mesentericus)、短小芽孢杆菌(B.pumilus)、枯草芽孢杆菌(B.subtilis)、纳豆芽孢杆菌(B.natto)、嗜淀粉拟杆菌(Bacteroidesamylophilus)、多毛拟杆菌(Bac.capillosus)、瘤胃生拟杆菌(Bac.ruminocola)、猪拟杆菌(Bac.suis)、青春双歧杆菌(Bifidobacteriumadolescentis)、动物双歧杆菌(B.animalis)、短双歧杆菌(B.breve)、两歧双歧杆菌(B.bifidum)、婴儿双歧杆菌(B.infantis)、乳双歧杆菌(B.lactis)、长双歧杆菌(B.longum)、假长双歧杆菌(B.pseudolongum)、嗜热双歧杆菌(B.thermophilum)、Candidapintolepesii、丁酸梭状芽孢杆菌(Clostridiumbutyricum)、乳脂肠球菌(Enterococcuscremoris)、二丁酮肠球菌(E.diacetylactis)、屎肠球菌(E.faecium)、中间肠球菌(E.intermedius)、乳酸肠球菌(E.lactis)、E.muntdi、嗜热肠球菌(E.thermophilus)、大肠埃希氏杆菌(Escherichiacoli)、脆壁克鲁维氏酵母(Kluyveromycesfragilis)、嗜酸乳杆菌(Lactobacillusacidophilus)、消化乳杆菌(L.alimentarius)、食淀粉乳杆菌(L.amylovorus)、卷曲乳杆菌(L.crispatus)、短小乳杆菌(L.brevis)、干酪乳杆菌(L.case4)、弯曲乳杆菌(L.curvatus)、纤维二糖乳杆菌(L.cellobiosus)、德氏乳杆菌保加利亚亚种(L.delbrueckiiss.bulgaricus)、香肠乳杆菌(L.farciminis)、发酵乳杆菌(L.fermentum)、加氏乳杆菌(L.gasseri)、瑞士乳杆菌(L.helveticus)、乳酸乳杆菌(L.lactis)、植物乳杆菌(L.plantarum)、约氏乳杆菌(L.johnsonii)、罗伊氏乳杆菌(L.reuteri)、鼠李糖乳杆菌(L.rhamnosus)、清酒乳杆菌(L.sakei)、唾液乳杆菌(L.salivarius)、肠系膜状明串珠菌(Leuconostocmesenteroides)、啤酒(有害)片球菌(P.cereviseae(damnosus))、乳酸片球菌(Pediococcusacidilactici)、戊糖片球菌(P.pentosaceus)、费罗伊登氏丙酸杆菌(Propionibacteriumfreudenreichii)、薛曼纳氏丙酸杆菌(Prop.shermanii)、啤酒糖酵母(Saccharomycescereviseae)、肉葡萄球菌(Staphylococcuscarnosus)、木糖葡萄球菌(Staph.xylosus)、婴儿链球菌(Streptococcusinfantarius)、唾液链球菌嗜热亚种(Strep.salivariusss.thermophilus)、嗜热链球菌(Strep.Thermophilus)和乳链球菌(Strep.lactis)。
在优选方法中,将制剂在室温下混合,或者略微加温以帮助将材料溶解在粘性溶液中(例如从20℃至40℃)。然后,在混合均匀后,将粘性料浆通过雾化、滴入或挤出到液氮中进行快速冷冻。从液氮槽收获冷冻粒子,并立即干燥或可选地储存在低温冰箱中以备随后干燥。典型情况下,将含有生物活性物质的料浆快速冷冻到-30℃至-180℃之间,更优选将制剂在液氮中快速冷冻。
在优选实施方案中,将快速冷冻的粒子立即干燥,或者将其储存在低温冰箱中、优选在-80℃下直至干燥。然后将冷冻粒子荷载在托盘上,并立即转移至真空干燥箱,在真空干燥箱中按照本发明对它们进行干燥。优选情况下,通过将冷冻粒子置于在0和2000mTORR之间的真空压力下开始干燥。将冷冻粒子脱气,并让它们的结构和体积发展和稳定化一段短的时间。典型情况下,使冷冻粒子经受高真空压力的理想时间长度不超过30分钟,更优选情况下,该时间长度在1和20分钟之间。在冷冻粒子的短时间初始脱气和结构稳定化之后,将真空调整到2000至10,000mTORR,并供热使粒子在高于其冷冻点的温度下融化。典型情况下,将真空调整到2000和4000mTORR之间,并将粒子温度升高到-5℃和+5℃之间。在这些优选的初级干燥条件下,冷冻粒子快速融化并松散地维持其原始形状,同时开始加速脱水。在除去约60-90%的游离水之后,安排进行随后的二级干燥,施加最大真空压力并供应热量,使制剂的温度升高到30℃至60℃。为了使最终产物的稳定性最大化,优选将制剂干燥一段足以使制剂的水活度降低至Aw=0.3以下的时间。在本发明的优选实施方案中,二级干燥包括在低于1000mTORR的压力下除去结合水。
干燥的制剂可以作为薄片直接使用,或者研磨成粉并筛分成约10μm至约1000μm的平均粒径。可以将制剂作为浓缩粉剂、作为复溶液体(例如饮料)直接施用于动物、包括人类,或者可以将其以薄片或粉末形式掺入到现有的食品和饲料产品中。
附图说明
图1.含有各种不同基质和玻璃形成剂、作为按照本发明的方法冷冻的固体珠子的不同干燥组合物的目测和显微镜观察结果。
图2.作为新鲜、冷冻珠子或干粉培养物的鼠李糖乳杆菌培养物形式对其在干燥组合物中的初始CFU计数的影响。
图3.作为在液氮或-80℃低温冰箱中冷冻的固体珠子和作为在+4℃下未冷冻的粘性料浆的含有鼠李糖乳杆菌的组合物的冷冻温度对干燥组合物中细菌的初始CFU计数的影响。结果只显示了在干燥之前没有附加的驱气步骤下料浆的冷冻固温度的影响。
图4.作为在液氮中冷冻的固体珠子和作为在+4℃下未冷冻的粘性料浆的含有动物双歧杆菌Bb12的组合物的冷冻温度对干燥组合物中细菌的初始CFU计数的影响。结果只显示了在干燥之前没有附加的驱气步骤下料浆的冷冻温度的影响。
图5.冷冻固体珠子在真空下的驱气时间长度对干燥组合物中鼠李糖乳杆菌的初始CFU计数的影响。
图6.本发明方法的组合物在冷冻干燥器中的干燥情况图。
图7.鼠李糖乳杆菌在本发明的组合物和干燥方法中的过程和干燥损失。
图8.干燥的益生菌鼠李糖乳杆菌组合物储存在40℃和33%相对湿度下的稳定性趋势。
发明详述
定义
应该理解,在本文中使用的术语的目的仅仅是为了描述具体实施方案,并不旨在限制。
当在本说明书和随附的权利要求书中使用时,不带具体数量的指称包括其复数形式,除非上下文明确指明不是如此。因此,例如指称“蛋白质”包括单个蛋白质或两种以上蛋白质的组合;指称“酶”、“维生素”、“细菌”等包括单数或几种的混合物,等等。
“生物活性材料”、“生物活性组合物”或“生物活性制剂”是指这样的制备物,所述制备物处于使生物活性成分的生物活性肯定有效的形式下。
“基质形成剂”是指添加到制剂中以增加湿制剂的粘度和/或密度或形成水凝胶的化合物或材料。适合的基质形成剂的实例包括但不限于水溶性纤维素衍生物,例如甲基纤维素、羟丙基纤维素、羟乙基纤维素和羟丙基甲基纤维素;藻酸盐,半乳甘露聚糖,结冷胶,黄蓍胶,包括它们的任何衍生物,乙酸邻苯二甲酸纤维素(CAP),羧甲基纤维素,果胶,藻酸钠,藻酸的盐,羟丙基甲基纤维素(HPMC),甲基纤维素,卡拉胶,瓜尔胶,阿拉伯胶,黄原胶,刺槐豆胶,壳聚糖和壳聚糖衍生物,胶原,聚乙醇酸,淀粉和改性淀粉,环糊精和寡糖(菊粉、麦芽糖糊精、葡聚糖等),及其组合。
“玻璃形成剂”或“糖玻璃形成剂”一般是指容易溶解在溶液中并且在与水接触后不变稠或聚合的化合物或材料。添加这些试剂是为了确保或增加生物活性材料在干燥过程期间和随后的稳定性,或干粉产物的长期储存稳定性。有用的玻璃形成剂可以是单体、低聚或聚合的。
根据一个优选实施方案,玻璃形成剂是糖类。糖类被定义为主要由碳、氢和氧构成的化合物。有用的糖类包括还原和非还原糖类和糖醇、寡糖、水溶性多糖及其衍生物。本发明的优选糖类包括葡萄糖、果糖、乳糖、蔗糖、海藻糖、麦芽糖、纤维二糖、半乳糖、麦芽三糖、棉子糖、糊精、葡聚糖、菊粉、甘露糖醇、山梨糖醇、木糖醇。特别优选的糖类是葡萄糖和海藻糖。
其他有用的玻璃形成剂可以选自其他化学类型,例如水溶性氨基酸、肽或蛋白质和水解蛋白质。例如,赖氨酸、甘氨酸、丙氨酸、精氨酸或组氨酸,以及疏水性氨基酸(色氨酸、酪氨酸、亮氨酸、苯丙氨酸等);甲基胺类例如甜菜碱。有用的蛋白质包括明胶、卵清蛋白、卵清、乳清蛋白、酪蛋白酸盐、免疫球蛋白、大豆蛋白、豌豆蛋白、棉籽蛋白或其他食品、乳制品或植物蛋白。
“水解蛋白质”一般是指来自于动物、乳制品或植物来源的,通过酶促水解或消化被分解成较短的肽片段和/或氨基酸的蛋白质。有用的水解蛋白质是那些经历过大量水解过程的蛋白质,所述大量水解过程使99%的天然蛋白质的分子量降低至低于50,000道尔顿、优选低于10,000道尔顿。
“环境”室温或条件是在给定环境中任何给定时间处的温度或条件。典型情况下,环境室温是22-25℃,环境大气压力和环境湿度是容易测量的,并且随着一年中的时节、天气和气候条件、海拔等而变。
在本发明的情形中,“驱气”或“脱气”是指从固体或液体制剂释放气体,在所述固体或液体制剂中气体的分压大于所施加的压力。这不是液体形式的溶液的沸腾,通常可以在比使溶液沸腾的压力更高的压力下发生。
“沸腾”是指当液体的温度高于其沸腾温度时发生的从液体到气体的快速相转变。沸腾温度是液体的蒸汽压等于所施加的压力时的温度。当向已经处于其沸点的液体加热时,沸腾会特别剧烈。
在干燥制剂组合物的情形中,“水活度”或“Aw”是指水的可利用率,并且表示系统中水的能量状态。它被定义为样品上水的蒸汽压除以纯水在相同温度下的蒸汽压。纯蒸馏水的水活度正好为1,或Aw=1.0。
在储存稳定性的情形中,“相对湿度”或“RH”是指在给定温度下空气中水蒸气的量。相对湿度通常低于使空气饱和所需的湿度,并用饱和湿度的百分数表示。
“干燥”及其变体是指被冻干、脱水或无水,即显著缺乏液体的物理状态。干燥包括例如喷雾干燥、流化床干燥、冻干和真空干燥。
“冻干”或“冷冻干燥”是指通过快速冷冻并在冷冻状态下脱水(有时被称为升华)来制备干燥形式的组合物。该过程可以在真空下在足以维持冷冻产物的压力、优选为低于约2000mTORR的压力下发生。
对于本文中描述的方法来说,“初级干燥”或“液体干燥”是指从融化冷冻粒子的时间到开始二级干燥的时间点之间所发生的脱水干燥。典型情况下,大部分的初级干燥通过大量蒸发来进行,同时将产物温度维持在显著低于热源的温度下。该过程可以在真空下在足以维持融化的产物的压力、优选为高于约2000mTORR的压力下发生。
对于本文中描述的方法来说,“二级干燥”是指在高于制剂的冷冻温度并接近热源温度的温度下发生的干燥步骤。该过程可以在真空下在足以降低制剂的水活度的压力、优选为低于约1000mTORR的压力下发生。在典型的制剂干燥过程中,二级干燥步骤将制剂的水活度降低至Aw为0.3以下。
“泡沫形成”是指在生物制品在环境和更高温度下长时间保持活性或生存力的条件下,通过在真空下沸腾来干燥敏感性生物制品的程序。用于形成机械上稳定的多孔结构的特定程序分两步进行:(1)初级泡沫干燥并通过在真空下沸腾;(2)稳定性干燥/玻璃化,并且被公开在Bronshtein的美国专利No.5,766,520中。
“稳定的”制剂或组合物是其中的生物活性材料在储存后基本上保留其物理稳定性、化学稳定性和/或生物活性的制剂或组合物。对于选定的时间长度来说,可以在选定的温度和湿度条件下测量稳定性。可以使用趋势分析来估算预期的储存期限,然后才将材料实际储存该时间长度。例如对于活细菌来说,稳定性被定义为在预定的温度、湿度和时间长度条件下失去1log的CFU/g干制剂所花费的时间。
对于细菌来说,“生存力”是指在适合于细菌生长的营养介质上形成菌落的能力(CFU或菌落形成单位)。对于病毒来说,生存力是指感染适合的宿主细胞并在适合的宿主细胞中繁殖,导致在宿主细胞的菌苔上形成噬斑的能力。
本发明的组合物和方法解决了为含有敏感性生物活性材料例如肽、蛋白质、酶、激素、维生素、类胡萝卜素、矿物质、药物、抗生素、杀微生物剂、杀真菌剂、除草剂、杀虫剂、杀精子剂、核酸、抗体、疫苗、细菌、病毒和/或细胞悬液的且在干燥状态下的寿命显著延长的制剂提供成本效益高并且在工业上可放大的干燥方法的问题。
本发明提供了在溶液混合物中包含生物活性材料与基质和玻璃形成剂的组合物,以及干燥方法,所述干燥方法包括将所述组合物在液氮中快速冷冻以形成小滴、串、珠子或微珠形式的无定形固体结构,以及将冷冻粒子在高真空下驱气,然后通过在降低压力并同时向组合物供应热量的方案下冻干或蒸发水分,将生物活性材料稳定在糖玻璃形成物中。
微生物在干燥过程期间的大部分生存力损失,可归因于与溶液在低干燥压力和高温下的“沸腾”和发泡相关的空泡气蚀期间的冰晶形成、高渗透和氧化胁迫、剪切力和能量释放这些因素的组合。本发明避免了这些负面效应,并提供了组合物和损失最小的干燥方法,其产生在随后的苛刻储存和操作条件下保护在糖玻璃基质中的生物活性材料。
本发明的组合物
本发明包括生物活性材料、基质形成剂和玻璃形成剂在粘性溶液中的组合物。发现本发明的制剂在其物理结构和功能方面与使用或不使用快速冷冻和驱气进行干燥的非粘性或浓缩制剂具有本质上的区别。例如,现有技术的制剂首先通过沸腾进行“发泡”以促进有效干燥。发泡步骤通常引起溶液的大量沸腾和喷发,这是在液态中干燥不可避免的结果,因此在小瓶或容器中只能获得非常低的材料荷载容量(参见例如美国专利No.6,534,087,其中最终发泡产物的厚度小于2mm)。
本发明的组合物和干燥方法避免了制剂的沸腾和大量发泡,从而使单位干燥面积的材料荷载量大大提高,因此能够容易地放大规模至生产大量材料,而无需使用特别设计的容器、托盘或设备。
已经显示,益生菌特别受益于本发明的制剂和干燥方法。按照本发明的组合物和方法来制备制剂,所述方法包括将益生菌的新鲜、冷冻或干燥培养物与至少一种基质形成剂和至少两种玻璃形成剂混合,将粘性制剂在液氮中快速冷冻以形成冷冻的固体小滴、串或珠子的无定形结构。对于初级干燥来说,施加足够的真空压力以驱气并稳定冷冻粒子的结构,然后将冷冻粒子在降低的真空压力和高于制剂冷冻温度的升高温度下冻干或蒸发。可以通过将热量从制剂传导出去,和/或通过由水蒸发造成的潜热损失来实现将制剂的温度维持在高于冷冻点。为了完成干燥过程并进一步降低制剂的水活度,可以在1000mTORR以下的较高真空压力和最高达70℃的升高的温度下执行二级干燥步骤,以提供具有Aw为0.3以下的水活度的最终组合物。如图8中所示,这样的组合物能够在40℃和33%RH的储存条件下保持稳定30天以上。
组合物的制备
为了制备本发明的干粉组合物而与优选的生物活性物质在溶液中混合的材料,包括至少一种基质形成剂和至少两种玻璃形成剂。这样的材料在与优选的生物活性材料混合时在液氮中形成珠子、微珠、串或小滴,并且能够按照本发明的方法有效率地冻干或脱水成无定形玻璃态,以提供大量稳定的干燥组合物用于所述生物活性材料的储存和施用(对于不同制剂在干燥后的目测和显微镜观察结果以及水活度(Aw),参见图1A和B)。基质形成剂提供了制剂的结构稳定性,改进的干燥曲线和/或对生物活性材料的物理和化学保护益处。基质形成剂还为制剂提供增稠的粘度,对制剂在真空压力下的性质提供更好的控制,并增加本发明的干燥制剂组合物的结构强度(对于特定制剂的玻璃质结构和干燥性,参见图1B-照片4、4b、4c)。基质形成剂包含多糖与寡糖的混合物。由于水溶性胶在温和的温度下形成粘性凝胶的独特性质,水溶性胶是优选的多糖,特别是对于活生物体来说。还发现,一定浓度的胶能够有效地稳定制剂,促进无定形玻璃质结构的形成,并改进真空下的干燥曲线(参见图1A-照片3a、3b、3c、4和图1B-4c和图6)。
尤其是通过观察图1A的照片并结合下面表1中显示的结果,可以明显看出样品3b、3c、4、5和6都被充分干燥,在无定形玻璃质结构中提供一定孔隙度。
表1
各种干燥组合物的目测检查
本发明的玻璃形成剂可以包括各种糖类、非还原糖、糖醇、氨基酸、蛋白质、水解蛋白质和肽。玻璃形成化合物优选为在冷冻温度(例如低于-20℃)下不使制剂中的生物活性材料结晶和/或去稳定化的化合物。例如,生物活性材料可以被物理包埋在无定形糖玻璃结构例如蔗糖或海藻糖中,以促进在整个干燥过程中保留分子结构,并赋予干燥状态下的无定形基质以结构刚性。玻璃形成剂代替在干燥期间失去的结合水,以防止细胞膜损伤和酶的变性(参见Crowe等,1998的综述)。玻璃形成剂的其他功能可以包括保护生物活性材料以免暴露于损伤性的光、氧气、氧化剂和水分。大多数玻璃形成剂必须易于以约0.1重量%至约80重量%范围内的量溶解在溶液中。包含两种以上不同的玻璃形成剂,对于抑制晶体形成和增加干燥的生物活性材料制剂在储存条件下的长期稳定性是有益的(参见图1A-照片4、5和6中糖类和蛋白质混合物的效果)。
预干燥的制剂包含显著量的总固体(组分减去溶剂例如水)。总固体的主要部分由生物活性材料、基质形成剂和玻璃形成剂构成。例如,生物活性材料以在约5-60重量%范围内的浓度存在于制剂中,基质形成剂在约1-20重量%范围内,玻璃形成剂在约5-80重量%范围内。在另一个实例中,基质形成剂可以以在约0.5-10重量%范围内的浓度存在于制剂中,玻璃形成剂在约10-50重量%范围内。优选情况下,湿制剂应该具有在约5%和80%之间、更优选在30%和60%之间的固体含量。本发明的制剂的粘度典型地高于1000厘泊(cP)、更优选高于5,000cP、最优选高于10,000cP。本发明的制剂的密度优选在0.9和1.2g/ml之间。
制备稳定干燥制剂的方法
制备含有生物活性材料的稳定干燥制剂的方法包括:(1)通过将生物活性材料与基质和玻璃形成剂在溶液中混合来制备制剂,(2)将制剂快速冷冻以形成固体冷冻粒子,(3)使冷冻粒子经受短时间的高真空压力,以对粒子进行驱气并使其结构稳定,(4)在向制剂供应热量使其温度高于制剂的冷冻温度、优选高于-10℃的温度的同时,通过在降低的压力下冻干和/或蒸发水分来除去水,(5)在完全真空和升高的温下进一步将制剂的水活度降低至低于0.3Aw。
例如,在一个实施方案中,本发明的制剂包含被配制在含有基质和玻璃形成剂的溶液和悬液中的生物活性材料。将基质形成剂和/或高浓度的玻璃形成剂在搅拌下溶解在热的水溶液中并消毒,然后冷却并与生物活性材料混合。通过离心或过滤将生物活性材料例如培养的病毒或细菌浓缩并与培养基分开,然后重新悬浮到制剂中。
在本发明的一个实施方案中,在浓缩的活生物体的液体中提供了制剂中的全部水,并且活生物体悬液被维持在略高于室温的温度下。将干燥的组分掺混在一起,然后缓慢加入到活生物体的温暖(25℃至40℃)悬液中。将制剂悬液在行星式混合器中轻柔搅拌,直到所有组分完全分散并获得均匀的料浆。
然后通过雾化、滴入或挤出到液氮槽中将粘性溶液快速冷冻,以形成小的固体小滴、串或珠子。可以将冷冻的固体粒子储存在-30℃和-80℃之间的低温冰箱中直至干燥,或立即置于托盘上并按照本发明的方法冻干或干燥。将固体冷冻粒子在足够的真空(例如低于2000mTORR)下进行短时间驱气,典型地在1和20分钟之间。一般来说,在驱气步骤期间,在低于-20℃的温度下粒子保持固体冷冻形式。在初始驱气步骤后,将真空压力增加到2000和10,000mTORR之间,并且可以提供热量使得制剂温度快速增加到-5℃和+5℃之间并使粒子开始融化。在制剂温度达到所需温度后,调整加热以维持该温度并执行初级干燥步骤。在该步骤时,制剂已经融化,并且在没有任何沸腾或发泡的情况下发生水的加速蒸发。
典型的现有技术方法涉及大量发泡和/或溅射以及剧烈沸腾,这可以损坏敏感性生物制品,并对以高的荷载容量进行工业规模放大造成困难(参见例如美国专利No.6,534,087,其中施加的真空压力引起剧烈沸腾和发泡),而本发明的组合物和方法避免了制剂的任何沸腾或过量发泡,同时获得了明显更快的干燥速率,并能实现制剂的高荷载容量。此外,完全且有效率地将粘性液体料浆脱气是困难的,并可能需要长时间。在本发明中通过使用适合的组合物解决了所有这些障碍,所述组合物允许有效的初级液体干燥,并形成无定形玻璃质构造而没有任何沸腾和过度发泡。令人吃惊和重要的是,这主要是通过适合组合物的快速冷冻并通过在初级液体干燥步骤开始之前引入短时间的驱气步骤来实现的。与料浆或粘性糖浆相反,固体冷冻粒子在托盘上的荷载使得托盘上单位干燥面积的荷载容量比按照现有技术所能提供的高得多。在初级液体干燥阶段完成后,将稳定化的无定形玻璃质制剂保持在升高的二级干燥温度(在20℃和70℃之间)和低于1000mTORR的真空压力下,以在非常短的时间内进一步降低制剂的水活度。
本发明的另一个实施方案提供了制备用于保存生物活性材料的水凝胶制剂组合物的方法。例如,将含有生物活性材料和基质与玻璃形成剂的制剂在溶液中混合,并通过雾化或挤出到含有二价金属离子的槽中或通过将二价金属离子直接添加到料浆中并将变硬的水凝胶化厚块粉碎成小串或碎片,来交联形成坚固的水凝胶粒子。然后按照如上所述的本发明的干燥方法来干燥水凝胶化的粒子。
例如,在本发明的一个特定实施方案中,制剂在1-4%藻酸钠和10-40%海藻糖的溶液中包含活益生菌。向制剂添加5-10%的蛋白质、特别是水解蛋白质例如酪蛋白、乳清、豌豆、大豆或棉子蛋白,以改进制剂的干燥过程和无定形玻璃质稳定结构的形成(参见图1A照片4、5和6)。益生菌培养物可以是新鲜、冷冻的或已经干燥成干粉形式(对于干燥制剂中益生菌的不同培养物形式的CFU计数,参见图2)。将溶液在略高于室温的温度(典型在25℃-37℃之间)下混合,直到所有组分完全溶解。将制剂料浆雾化、挤出或滴入到液氮中以形成小滴或珠子,然后将其从液氮中取出,装入袋中,并可以储存在-80℃的低温冰箱中直至干燥。
活益生菌的典型干燥方法包括:将固体冷冻珠子在托盘上铺展成均匀的层,荷载容量在100-1000g/sqft之间,并将托盘立即置于冷冻干燥器中。然后施加约1000mTORR的真空压力,并且取决于冷冻干燥器的尺寸和热源类型,将架子温度调整至+20℃或足以将粒子维持在约-20℃的温度。允许对固体冷冻珠子驱气约5-30分钟,将真空调整到2000和10,000mTORR之间,并增加传热以将制剂温度升高到-5℃和+5℃之间。在初级液体干燥步骤期间维持这些温度和真空压力条件,取决于托盘载量,所述初级液体干燥步骤可能持续几小时并最高达24小时,优选为约3至10小时。在初级干燥过程中的某个时间点,溶剂的蒸发速率变缓,并由于干燥箱中热供应过多,制剂温度开始升高。该时间点表明初级干燥步骤结束。由于溶剂从制剂中被驱除,溶液中的玻璃形成剂变得浓缩和更稠,直至不再像液体一样流动并形成无定形和/或稳定的玻璃质结构。
然后在完全真空和在30℃和50℃之间的制剂温度下进行二级干燥步骤。二级干燥步骤的目的是除去残余的被夹带或结合的水分,并提供在环境温度下长期储存中稳定的组合物。二级干燥步骤可以持续几小时,其终点是制剂完全干燥并且水活度低于0.3Aw时。
本发明的干燥方法产生包覆在无定形玻璃质基质内的生物活性材料,由于无定形玻璃质组合物中的化合物和其他分子的移动性极大降低,由此防止了蛋白质解折叠并显著减缓了分子相互作用或交叉反应性。只要无定形固体处于低于其玻璃化转变温度的温度下,并且残余的水分保持相对低(即低于0.3的Aw),生物活性材料就能保持相对稳定(参见图8)。应该指出,获得玻璃态不是长期稳定性的必要条件,因为某些生物活性成分在更加晶态下可能保存得更好。
干粉的制备
干燥制剂可以被整块使用、切成所需形状和尺寸、或压碎并碾磨成自由流动的粉剂,所述自由流动的粉剂提供了容易的下游处理例如湿法或干法团聚、成粒、制片、压实、制粒,或混合在食品或饲料产品或任何其他种类的递送方法中。用于压碎、碾磨、研磨或粉碎的方法在本技术领域中是公知的。例如,可以使用锤式碾磨机、风力碾磨机、冲击式碾磨机、喷射式碾磨机、销棒碾磨机、Wiley碾磨机或类似的碾磨装置。碾磨后粒子的优选粒径为小于约1000μm,优选小于500μm。
本文描述的组合物和方法保存所包覆的生物活性材料的生物活性。例如,通过将组合物置于升高的温度(例如40℃)和高湿度(例如33%RH)下并测量制剂的生物活性,来测试组合物的稳定性。例如,对于活益生菌来说,这些研究的结果证实了被配制在这些制剂中的细菌稳定至少20天(参见图8)。稳定性被定义为效价损失一个logCFU/g的时间。即使在使用高浓度生物活性材料时,这样的制剂也是稳定的。因此这些制剂的优点在于它们可以在室温或高于室温的温度下长时间运输和储存。
具体实施方式
提供以下实施例来说明而不是限制所要求保护的发明。
实施例1
制备干燥且稳定的益生菌物质
基础制剂
将75g海藻糖(CargillMinneapolis,MN)和22g广泛水解的酪蛋白(Marcor,Carlstadt,NJ)与3g藻酸钠(ISPCorp.,Wayne,NJ)在干燥形式下均匀混合。在掺混器中加入嗜酸乳杆菌的新鲜浓缩物(100ml,含有至少10%固体,直接来自于发酵收获),并维持在35℃。向益生菌培养物缓慢加入胶、糖和水解蛋白质的干混物,并在35℃下混合10分钟。然后将粘性料浆转移至底部穿孔的容器中,并让其滴入含有液氮的槽中。然后从液氮中取出珠子并立即转移至干燥。
干燥基础制剂的冷冻珠子
将冷冻珠子以100g/sqft的荷载容量均匀铺展在托盘上,并立即置于冷冻干燥器(25SRC型,Virtis,Gardiner,NY)的架子上。然后施加1000mTORR的真空压力,并让固体冷冻珠子驱气10分钟。然后将真空调整至2700mTORR,并将架子温度升高至+30℃。将这些温度和真空压力维持3小时。然后在完全真空(150-200mTORR)和升高至30℃的架子温度下继续进行2小时的二级干燥步骤。制剂被完全干燥,通过HygropalmAw1仪器(RotonicInstrumentCorp.,Huntington,NY.)测量其水活度为Aw=0.23。
实施例2
含有益生菌鼠李糖乳杆菌LGG的稳定干燥组合物
将鼠李糖乳杆菌LGG(来自商业来源的500g冷冻浓缩物)在带有夹套的双行星混合器(DPM,1qt,RossEngineering,Inc.Savannah,GA)中在37℃下融化。将两种玻璃形成剂海藻糖(387g,CargillMinneapolis,MN)和广泛水解的酪蛋白(83g,Marcor,Carlstadt,NJ)与两种基质形成剂藻酸钠(15g,ISPCorp.,Wayne,NJ)和速溶菊粉(25g,CargillMinneapolis,MN)在干燥形式下均匀混合。向融化的益生菌缓慢加入干混物,并在40RPM和37℃下混合10分钟。通过加入50-200ml水,将料浆的粘度调整至12,000Cp。然后将料浆转移至底部穿孔的容器中,并让其滴入含有液氮的容器中。然后从液氮中取出珠子,置于密封的包有铝箔的袋子中,在低温冰箱中在-80℃储存几周。
对于干燥来说,将冷冻珠子以100至最高500g/sqft范围内的荷载容量均匀铺展在托盘上,并将托盘置于冷冻干燥器(25SRC型,Virtis,Gardiner,NY)中的架子上。施加1000mTorr的真空压力,并将架子温度调节到+20℃。让固体冷冻珠子驱气1至30分钟范围内的一段时间。在驱气步骤后,在将真空压力调整至2700mTORR并将架子温度升高至+30℃后,进行初级干燥步骤。将这些温度和真空压力维持12小时。然后在完全真空(150-200mTORR)和维持在30℃的架子温度下继续进行4小时的二级干燥步骤。制剂被完全干燥,其水活度经测量为0.23Aw。图6显示了所述益生菌制剂的干燥曲线。
在图3、4和7中,显示了料浆在不同温度(+4℃、-80℃和-180℃)下冷冻之后和在干燥步骤、包括冷冻珠子的制备和在冷冻干燥器中干燥之后的生存力损失。取决于细菌培养物的类型(冷冻或干燥培养物)和粘性料浆的冷冻温度,整个过程的生存力损失一般低于一个log。结果显示,益生菌在液氮(-180℃)中的快速冷冻与在-80℃下冷冻相比,是损伤更低的方法。
图5和8显示了在0分钟(没有驱气)至30分钟范围内的各种驱气时间长度对干燥组合物中的益生菌初始计数,以及在40℃和33%RH的加速储存条件下的储存稳定性的影响。结果表明,总的来说,较长的驱气时间增加干燥制剂中的细菌初始计数,但是对益生菌制剂的储存稳定性没有影响。
实施例3
将海藻糖(752g,CargillMinneapolis,MN)、广泛水解的豌豆蛋白(167g,Marcor,Carlstadt,NJ)、藻酸钠(30g,ISPCorp.,Wayne,NJ)和速溶菊粉(50g,CargillMinneapolis,MN)以干燥形式均匀混合。将干混物缓慢添加到在带有夹套的双行星混合器(DPM,1qt,RossEngineering,Inc.Savannah,GA)中的80℃的1000ml热去离子水中,并在40RPM混合10分钟。将混合物的温度降低至37℃,缓慢加入从商业来源获得的100g鼠李糖乳杆菌LGG的干粉,并继续混合20分钟。然后将料浆通过2mm孔针挤出到含有液氮的槽中。然后从液氮中取出串/珠子,置于密封的包有铝箔的袋子中,在低温冰箱中在-80℃储存几周。对于干燥来说,将冷冻的串/珠子以100至500g/sqft范围内的荷载容量均匀铺展在托盘上,将托盘置于冷冻干燥器(25SRC型,Virtis,Gardiner,NY)中的架子上,并如实施例2中所述进行干燥。所有制剂均令人满意地被保留在托盘内,在所有荷载水平下菌没有观察到溅射或发泡。即使在较高荷载容量下,制剂也被完全干燥,对于所有样品来说,测量到的水活度为0.26Aw以下。
实施例4
制备含有益生菌乳双歧杆菌(Bb12)的水凝胶制剂
按照实施例1制备浓缩的乳双歧杆菌(Bb12)益生菌料浆。向基础制剂加入0.5g磷酸氢二钙,然后加入0.5g葡萄糖酸内酯。在接下来的2小时内让料浆在室温下硬化,以形成固体水凝胶。使用可商购的切片机/切碎机,将坚固的凝胶切成细且长的丝。将细丝在液氮中快速冷冻,以700g/sqft的荷载容量荷载在托盘上并置于冷冻干燥器中,如实施例2中所述进行干燥。制剂的水活度(Aw)为0.05(通过HygroPalmAw1,RotonicHuntington,NY测量)。使用标准的锤式碾磨设备将干燥制剂进一步研磨成细粉,并通过50-250微米筛网进行筛分。
实施例5
含有益生菌嗜酸乳杆菌的无过敏原组合物
将海藻糖(752g,CargillMinneapolis,MN)、广泛水解的豌豆蛋白(167g,Marcor,Carlstadt,NJ)、藻酸钠(30g,ISPCorp.,Wayne,NJ)和速溶菊粉(50g,CargillMinneapolis,MN)以干燥形式均匀掺混。通过将干混物缓慢添加到在带有夹套的双行星混合器(DPM,1qt,RossEngineering,Inc.Savannah,GA)中的80℃的1000ml热去离子水中对其进行灭菌,并在40RPM混合10分钟,直至形成顺滑清澈的料浆。将混合物的温度降低至37℃,缓慢加入从商业来源获得的1000g含有嗜酸乳杆菌的冷冻珠子,并继续混合10分钟。然后将料浆通过2mm孔针挤出到含有液氮的槽中。然后从液氮中取出串/珠子,置于密封的包有铝箔的袋子中,在低温冰箱中在-80℃储存几周。对于干燥来说,将冷冻的串/珠子以1000g/sqft的荷载容量均匀铺展在托盘上,将托盘置于冷冻干燥器(25SRC型,Virtis,Gardiner,NY)中的架子上,并如实施例2中所述进行干燥。干燥组合物中益生菌的初始CFU计数为10.53log/g,在40℃和33%RH的加速储存条件下储存42天后的生存力损失为0.69logCFU/g。
实施例6
含有本发明的干燥制剂的婴儿配方食品
按照实施例2制备含有乳杆菌属GG(ValioCorp,芬兰)的稳定干燥制剂,然后筛分成两个粒径组(大于50μm和小于150μm)。通过将99.9gNutramigen(MeadJohnson;Evansville,IL)与0.1g粒径范围在50μm和150μm之间的干燥制剂粒子混合,制备了婴儿配方食品。最终产品含有每100g婴儿配方食品约108cfu乳杆菌属GG。
实施例7
含有本发明的稳定干燥制剂的益生菌增补剂
将含有嗜酸乳杆菌的稳定干燥组合物配制成口服制剂例如片剂、囊片或胶囊。通过在旋转机械上使用1/2"圆形标准凹形工具进行直接压制,制备了含有99.9g压制剂(右旋糖)和0.1g粒径范围在50μm和150μm之间的干燥制剂粒子的橙味片剂。最终产品含有约108cfu/单位剂量。片剂的硬度在8-10kp范围内,崩解时间为约20秒。将压制的片剂以每瓶100片的量包装在180ccHDPE瓶中,并暴露于40℃/33%RH的受控温度/湿度下。对产品进行每月微生物稳定性测试,共进行12个月的时间或者直至在测定中观察到计数减少至低于1x106/单位剂量。
实施例8
含有本发明的稳定干燥制剂的功能性饮料
制备了含有(以重量计的%)71%蔗糖、14%麦芽糖糊精、10%菊粉、2%右旋糖、1%无水柠檬酸、0.3%阿拉伯胶、0.3%调味剂、0.3%磷酸三钙和0.1%粒径范围在50μm和250μm之间的干燥益生菌制剂粒子(嗜酸乳杆菌)的干燥混合物。最终产品含有约109cfu/单位剂量(30g干混物)。将产品包装在小铝箔袋中(30g单位剂量/袋),通过搅拌在340mil水中以供饮用。对在饮料干混物中的益生菌的稳定性进行每月微生物稳定性测试,共进行12个月的时间或者直至在测定中观察到计数减少至低于1x107/单位剂量。
实施例9
制备益生菌宠物食品
将可商购的狗用颗粒宠物食品在对流烘箱中干燥至水活度为0.1,然后涂覆上按实施例3所述制备的稳定的益生菌干燥制剂。将干燥颗粒喷涂上约5%的基于脂肪的防潮层(40%鸡脂、40%可可脂和20%蜂蜡的混合物),在转鼓中与干粉制剂(通常为宠物食品总量的0.1-0.5%,其提供了108CFU/g的剂量)混合,最后喷涂上另一层基于脂肪的防潮层。涂层的总量为(宠物食品的)约15%。涂覆时间为约30分钟。
实施例10
制备含有几种益生微生物的鱼饲料
用几种益生菌的混合物制备了本发明的鱼用颗粒饲料。如实施例1中所述制备含有鼠李糖乳杆菌、嗜酸乳杆菌和乳双歧杆菌的混合物的稳定的干燥益生菌制剂。首先将可商购的鲑鱼用开口饲料(ZeiglerBros.,Gardners,PA)在对流烘箱中干燥至水活度为0.1,然后在转鼓中涂覆上益生菌制剂。首先将颗粒(1000g)喷涂上以重量计约5%的基于脂肪的防潮层(40%鱼油、40%可可脂和20%蜂蜡的混合物),然后与1g稳定的干燥益生菌制剂混合(以获得107cfu/g饲料的剂量),最后喷涂上另一层基于脂肪的防潮层。涂层的总量为(鱼饲料的)约10%。
实施例11
含有酶的稳定干粉
通过将600g实施例4中描述的制剂与400gSavinase(Novozymes,Denmark)在1000g水溶液中混合,制备了含有40重量%Savinase的水凝胶制剂。将切碎的水凝胶制剂在液氮中快速冷冻,并在50℃的制剂干燥温度下在真空烘箱中干燥。为了确定干燥制剂的载量和储存稳定性,准确称取(<100mg)干燥样品至微量离心管中。加入200μl二甲亚砜(DMSO)。通过涡旋振荡将制剂溶解在DMSO缓冲液中。向该样品加入0.8ml含有0.05NNaOH、0.5%SDS和0.075M柠檬酸(三钠盐)的溶液。将管在45℃下超声10分钟,然后在5,000rpm短暂离心10分钟。取清澈的DMSO/NaOH/SDS/柠檬酸溶液的等份试样至微孔板的孔中,并使用Bradford测定方法分析蛋白质含量。稳定的酶制剂的储存稳定性明显高于不含本发明制剂的干燥的酶。
实施例12
含有维生素A的稳定干粉
通过将320g速溶菊粉、320g麦芽糖糊精DE-1(Tate&Lyle,London,UK)、50g羧甲基纤维素钠(AshlandAqualonFunctionalIngredients,Wilmington,DE)、10g抗坏血酸钠和300g维生素A晶体(BASFCorp.,FlorhamPark,N.J)混合在1000g水中,制备了含30重量%维生素A的制剂。将湿制剂在Mobile-Minor喷雾干燥器(GEAProcessEngineeringInc.,ColumbiaMD)中喷雾干燥,其中入口和出口温度分别为180℃和80℃,或者在液氮中快速冷冻,然后以1000g/sqft的荷载容量铺展在托盘上,并如实施例2中所述干燥。所述维生素A组合物在40℃和75%RH下稳定(>80%)3个月。
实施例13
制备在保护制剂中的生物利用度提高的胡萝卜素类
按照本发明的制剂和方法制备了保护并提高胡萝卜素类的生物利用度的制剂,否则所述胡萝卜素类在储存期间或喂给生物体后会遭受到饲料中其他成分的氧化。将含有6g水溶性壳聚糖的制剂(LSKBioPartners,Inc.SaltLakeCity,Utah)溶解在200g水中。向该溶液加入90g天然虾青素(NaturoseTM,CyanotechCorp.,Kailua-Kona,HI),并将料浆喷雾或挤出到含有5%三聚磷酸钠的槽中。让水凝胶化的微粒或串在室温经4小时硬化。将粒子从交联槽中取出,用水洗涤,并与90g蔗糖和10g广泛水解的酪蛋白的干掺混物混合。将荷载有糖/蛋白质的粒子快速冷冻,并立即以500g/sqft的荷载容量置于托盘上,在冷冻干燥器中冻干,直到水活度降低到低于0.3。将干燥制剂进一步碾磨成所需的粒度分布,并包装。
实施例14
制备攻击性物种的诱饵
按照本发明制备了用于特异性针对攻击性物种的颗粒诱饵。按实施例1所述制备200g含有杀虫剂的制剂,并加入到200gm水中。向该溶液加入90gm鱼藤酮和0.5gm磷酸氢二钙,然后加入0.5gm葡萄糖酸内酯。让料浆在室温下经2小时硬化。通过切片机/切碎机将坚固的凝胶切成细且长的丝。将细丝荷载在托盘上,并置于冷冻干燥器中。将架子温度设定在-30℃并让制剂冷冻,然后施加完全真空,并将架子温度升高至+60℃,过夜干燥。将干燥制剂碾磨成对于所靶向的特定物种的诱饵尺寸规格来说适合的粒度分布。
实施例15
制备在水不溶性制剂中受保护的杀虫剂
用本发明的制剂和方法制备了杀虫剂的受保护的颗粒制剂,否则所述杀虫剂在储存期间或应用到环境中后将受到制剂中其他成分的分解。向200g水中加入含有6g果胶和102g蔗糖的制剂。向该溶液加入90g含有敏感性杀虫剂的干燥制剂和含有1.5g磷酸氢二钙和0.5g氯化钙的混合物,然后加入0.85g葡萄糖酸内酯。让料浆在室温下经4小时硬化,然后通过切片机/切碎机切成细且长的丝。将细丝荷载在托盘上,在冷冻干燥器中干燥至水活度达到0.1。将干燥制剂进一步碾磨成所需的粒度分布并包装。
实施例16
制备受保护的植物益生菌制剂
按照实施例4将生物控制剂例如根际细菌(Rhizobacteria)制备在干燥组合物中。在限菌条件下评估干燥的根际细菌组合物对莴苣生长的有效性。将每株植物100mg根际细菌干燥组合物的剂量接种到含有沙土的罐中,并种植预先发芽(24h)的莴苣苗。向罐中的植物施加5ml无菌霍格兰(Hoagland)溶液营养剂。将罐随机排列在维持在28℃和12小时光照期的生长室中。在接种后每隔7天,将植物和附着的沙土小心地从罐中取出。将根在无菌磷酸盐缓冲液(pH7.0)中清洗,并记录根长度的测量值。
参考文献
下面的参考文献以及本文中引用的所有参考文献在此为所有目的通过参考结合于此。
美国专利文献:
6,190,701用于稳定的可注射液体的组合物和方法(Compositionandmethodforstableinjectableliquids),1999年3月,Roser等。
6,964,771用于在干燥、发泡的玻璃基质中稳定地掺入物质的方法(Methodforstablyincorporatingsubstanceswithindry,foamedglassmatrices),1997年9月,Roser等。
5,766,520通过形成制剂进行保存(Preservationbyformulationformation),1998年6月,Bronshtein。
6,534,087用于制备药物组合物的方法(Processforpreparingapharmaceuticalcomposition),2001年6月,Busson和Schroeder。
6,884,866大体积干燥和诱导气泡成核的效果(Bulkdryingandtheeffectsofinducingbubblenucleation),2005年4月,Bronshtein。
7,153,472用于在疏水性载体中储存和递送的生物活性材料的保存和制剂(Preservationandformulationofbioactivematerialsforstorageanddeliveryinhydrophobiccarriers),2006年12月,Bronshtein。
20080229609通过汽化进行保存(PreservationbyVaporization),2005年6月,Bronshtein。
6,306,345用于在环境温度下保存敏感性生物材料的工业规模屏障技术(Industrialscalebarriertechnologyforpreservationofsensitivebiologicalmaterialsatambienttemperatures),2001年10月,Bronshtein等。
7381425通过冷冻干燥的泡沫保存生物活性材料(Preservationofbioactivematerialsbyfreezedriedfoam),2006年9月,Truong-le,Vu。
其他参考文献:
Morgan,C.A.,Herman,N.,White,P.A.,Vesey,G.2006.“通过干燥保存微生物,综述”(Preservationofmicro-organismsbydrying;areview),J.Microbiol.Methods.66(2):183-93。
Capela,P.,Hay,T.K.C,&Shah,N.P.2006.“低温保护剂、益生元和微囊化对酸奶和冷冻干燥的酸奶中的益生有机体的存活力的影响”(Effectofcryoprotectants,prebioticsandmicroencapsulationonsurvivalofprobioticorganismsinyoghurtandfreeze-driedyoghurt),FoodResearchInternational,39(3)203-211。
Annear,1962.“通过从液体状态干燥来保存钩端螺旋体”(ThePreservationofLeptospiresbyDryingFromtheLiquidState),J.Gen.Microbiol,27:341-343。
Crowe,J.F.,Carpenter,J.F.和Crowe,L.M.1998.“玻璃化在低湿休眠中的作用”(THEROLEOFVITRIFICATIONINANHYDROBIOSIS),Annu.Rev.Physiol.60:73-103。
Claims (19)
1.用于制备包含生物活性材料、基质形成剂和玻璃形成剂的干燥组合物的方法,其中所述基质形成剂的量在1-20重量%的范围内,所述玻璃形成剂的量在5-80重量%的范围内,所述方法包括:
(a)将生物活性材料、基质形成剂和玻璃形成剂在水性溶剂中组合以形成粘性料浆;
(b)在-30℃和-80℃之间快速冷冻料浆以形成粒子;
(c)在小于2000mTORR的真空压力和低于粒子的冷冻点的温度下对来自于步骤(b)的快速冷冻粒子驱气小于30分钟;
(d)将来自于步骤(c)的粒子在高于2000mTORR的真空压力和高于粒子的冷冻点的温度下进行初级干燥;
(e)将来自于步骤(d)的初级干燥粒子在完全真空压力和在20℃到70℃的温度下进行二级干燥,由此制备组合物,其中组合物具有Aw为0.3以下的水活度。
2.权利要求1的方法,其中步骤(d)中的真空压力为2000至10,000mTORR。
3.权利要求1的方法,其还包括将组合物切碎、压碎、碾磨或粉碎成自由流动的粉剂。
4.权利要求3的方法,其中粉剂的粒径小于1000μm。
5.权利要求1的方法,其还包括将组合物作为复溶的液体或作为研磨的粉剂施用于动物和植物。
6.权利要求1的方法,其还包括
(a)将组合物与选自婴儿配方食品、功能性饮料和宠物食品的组分混合;以及
(b)将来自于步骤(a)的混合物施用于人类婴儿、成人、动物或植物。
7.权利要求1的方法,其中在步骤(b)中在液氮中快速冷冻料浆以形成粒子。
8.权利要求1的方法,其中来自于步骤(b)的快速冷冻粒子是珠子、小滴或串的形式。
9.权利要求1的方法,其中步骤(d)中粒子的温度为高于-10℃。
10.权利要求1的方法,其中步骤(d)中粒子的温度为-5℃和+5℃之间。
11.干燥组合物,其包含生物活性材料、基质形成剂和玻璃形成剂,其中所述组合物通过权利要求1的方法来制备。
12.权利要求11的干燥组合物,其中组合物是干燥玻璃质组合物。
13.权利要求11的干燥组合物,其中生物活性材料包括微生物、细胞培养物、蛋白质、肽、激素、疫苗、抗生素、维生素、类胡萝卜素、矿物质、杀微生物剂、杀真菌剂、除草剂、杀虫剂或杀精子剂。
14.权利要求11的干燥组合物,其中生物活性材料包括细菌。
15.权利要求11的干燥组合物,其中基质形成剂是选自下列的多糖:乙酸邻苯二甲酸纤维素(CAP)、羧甲基纤维素、果胶、藻酸的盐、羟丙基甲基纤维素(HPMC)、甲基纤维素、卡拉胶、瓜尔胶、阿拉伯胶、黄原胶、刺槐豆胶、壳聚糖和壳聚糖衍生物、淀粉和改性淀粉、环糊精、菊粉、麦芽糖糊精、葡聚糖、及其组合。
16.权利要求11的干燥组合物,其中基质形成剂以1重量%至12重量%范围内的量存在于组合物中。
17.权利要求11的干燥组合物,其中玻璃形成剂易于溶解在水性溶剂中,在与水接触后不变稠或聚合,并且在干燥期间不形成晶体。
18.权利要求11的干燥组合物,其中玻璃形成剂选自:蛋白质;糖类;氨基酸;甲基胺类;多元醇;表面活性剂;磷脂类;及其组合。
19.权利要求11的干燥组合物,其中玻璃形成剂以1重量%至80重量%范围内的量存在于组合物中。
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RU2012134269A (ru) | 2014-03-10 |
AR125029A2 (es) | 2023-05-31 |
RU2535869C2 (ru) | 2014-12-20 |
PL2529004T3 (pl) | 2017-12-29 |
JP2013517801A (ja) | 2013-05-20 |
DK2529004T3 (en) | 2017-09-25 |
BR112012018839A2 (pt) | 2015-09-15 |
US8834951B2 (en) | 2014-09-16 |
US20150031544A1 (en) | 2015-01-29 |
MX2012008795A (es) | 2012-08-17 |
US20120322663A1 (en) | 2012-12-20 |
EP2529004A2 (en) | 2012-12-05 |
ES2639397T3 (es) | 2017-10-26 |
SG182317A1 (en) | 2012-08-30 |
JP5886763B2 (ja) | 2016-03-16 |
CN102725393A (zh) | 2012-10-10 |
BR112012018839B1 (pt) | 2020-04-14 |
CA2785815C (en) | 2018-04-24 |
WO2011094469A2 (en) | 2011-08-04 |
MX336076B (es) | 2016-01-07 |
AR080073A1 (es) | 2012-03-14 |
CA2785815A1 (en) | 2011-08-04 |
WO2011094469A3 (en) | 2011-12-29 |
EP2529004B1 (en) | 2017-06-07 |
US9731020B2 (en) | 2017-08-15 |
EP2529004A4 (en) | 2013-10-23 |
NZ601017A (en) | 2014-07-25 |
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