发明领域field of invention
本发明涉及包含活性成分和外部润滑层的颗粒，其中所述外部润滑层抑制活性成分从颗粒中形成粉尘。The present invention relates to granules comprising an active ingredient and an outer lubricating layer, wherein the outer lubricious layer inhibits dust formation of the active ingredient from the granule.
发明背景Background of the invention
包含活性成分如酶的颗粒已经在许多工业领域中应用了几十年。已经开发了一些技术来提供这样的颗粒。以颗粒的形式提供活性的一个目的是为了防止或抑制活性生成，因为活性会对处理活性的人造成健康损害。通常这可以通过提供含有活性成分的颗粒来达到目的，其中所述含有活性成分的颗粒包含含有活性的核心和多层包被层。含有活性成分的颗粒一般由核心和包被层组成，其中包被层的重要特征是当处理颗粒时包被层可减少粉尘生成。Granules containing active ingredients such as enzymes have been used in many industrial fields for decades. Several techniques have been developed to provide such particles. One purpose of providing the active in the form of particles is to prevent or inhibit the production of the active which could cause health damage to persons handling the active. Typically this is achieved by providing an active ingredient-containing granule comprising an active-containing core and a multilayer coating. Granules containing active ingredients generally consist of a core and a coating, where an important feature of the coating is that the coating reduces dust generation when handling the granules.
WO96/16151涉及用非水成液或油性混合物和防结块剂包被的酶颗粒。WO96/16151 relates to enzyme granules coated with a non-aqueous liquid or oily mixture and an anti-caking agent.
WO01/04279和WO00/01793(未在优先权日公开)也公开了包含润滑剂的颗粒。WO01/04279 and WO00/01793 (not published at the priority date) also disclose particles comprising lubricants.
发明概述Summary of the invention
我们已研发了除包含包被层外在颗粒外表面上还包含有润滑层的颗粒。We have developed particles that contain a lubricating layer on the outer surface of the particle in addition to the coating layer.
因此，本发明涉及在颗粒外表面上包含润滑剂的含有活性成分的颗粒，其特征在于：Accordingly, the present invention relates to active ingredient-containing granules comprising a lubricant on the outer surface of the granules, characterized in that:
(a)润滑剂在25℃时为液态并且25℃时粘度低于5000厘泊，或(a) the lubricant is liquid at 25°C and has a viscosity at 25°C of less than 5000 centipoise, or
(b)当使用流速计，叶梢圆周速度为50转/分钟，螺旋角为3°(压缩模式)，使用46mm转子并且称量170克颗粒至50mm测试容器中测量时，润滑颗粒与未润滑的颗粒相比较，前者的相对摩擦系数低于80％，或(b) When using a flow meter, the peripheral speed of the blade tip is 50 rpm, the helix angle is 3° (compression mode), using a 46mm rotor and weighing 170 grams of particles into a 50mm test container, the difference between the lubricated particles and the unlubricated Compared with the particles, the relative coefficient of friction of the former is lower than 80%, or
(c)润滑剂为矿物油(c) The lubricant is mineral oil
或它们的组合。or a combination of them.
另一方面，本发明涉及产生本发明颗粒的方法、包含本发明颗粒的组合物和本发明颗粒的用途。发明详述In another aspect, the invention relates to methods of producing the particles of the invention, compositions comprising the particles of the invention and uses of the particles of the invention.Detailed description of the invention
包含活性成分如酶的颗粒为干燥颗粒，其在处理时，由于单个颗粒相互碰撞易发生磨损和撕裂(碰撞和摩擦)并使得颗粒表面“磨光”。据认为这会导致包被破损或甚至颗粒解体，当为干燥活性成分如酶蛋白时，则其可被释放并形成危害健康的粉尘。但是例如通过降低单个颗粒相对于其它颗粒的运动来限制这些处理损害是不合适的，因为颗粒也应该拥有良好的流动和混合能力以使颗粒的处理变得容易，其中所述的颗粒处理需要单个颗粒相对自由的运动。Granules comprising active ingredients such as enzymes are dry granules which, when handled, are subject to abrasion and tearing due to individual particles colliding with each other (bump and friction) and "polish" the surface of the granules. This is thought to lead to breakage of the coating or even disintegration of the particles which, in the case of dry active ingredients such as enzyme proteins, can then be released and form a health-hazardous dust. But it is inappropriate to limit these handling damages, e.g. by reducing the movement of individual particles relative to other particles, since the particles should also possess good flow and mixing capabilities to facilitate the handling of the particles, which requires individual Relatively free movement of particles.
不被这种理论所束缚，我们认为将润滑剂施用到颗粒外表面会使单个颗粒“润滑”，也就是减少颗粒间的摩擦，提供颗粒良好的流动和混合能力，同时降低导致颗粒破损和活性粉尘释放的摩擦力。进一步润滑剂也可减弱如在其上施加了润滑剂的包被层中粘合剂的粘附性，从而进一步防止颗粒凝结。因此，这里所定义的润滑剂可起防凝结剂的作用和润湿剂的作用并减少粉尘形成和颗粒破损。Without being bound by this theory, it is believed that the application of lubricants to the outer surface of the particles will "lubricate" the individual particles, that is, reduce friction between particles, provide good flow and mixing ability of particles, and reduce particle breakage and activity. Friction for dust release. Further lubricants may also reduce the adhesion of binders such as in coatings on which lubricants are applied, thereby further preventing particle agglomeration. Thus, lubricants as defined herein can function as anti-coagulation agents and wetting agents and reduce dust formation and particle breakage.
除了润滑剂外，本发明的含有活性成分的颗粒合适地包含含有活性成分的核心和一种或多种包被层，这在本领域内是公知的。In addition to the lubricant, the active ingredient-containing particles of the invention suitably comprise an active ingredient-containing core and one or more coating layers, as is well known in the art.
定义definition
术语润滑剂可理解为任何在25℃和大气压下形成液体的非含水化合物或化合物的混合物。优选地在此条件下它具有低于5000厘泊的粘度。The term lubricant is understood to mean any non-aqueous compound or mixture of compounds which forms a liquid at 25°C and atmospheric pressure. Preferably it has a viscosity under these conditions of less than 5000 centipoise.
核心core
核心包含活性成分，优选地为酶。核心除了活性成分外，可以通过任一方式或任何提供核心材料所需功能特性的材料构建，例如核心可由在导入含水介质后允许活性成分易于释放的材料组成。The core contains active ingredients, preferably enzymes. In addition to the active ingredient, the core may be constructed by any means or any material that provides the desired functional properties of the core material, for example the core may consist of a material that allows the active ingredient to be readily released after introduction into an aqueous medium.
优选的核心构建体包括：Preferred core constructs include:
-喷雾干燥的核心粒子，其通过喷雾干燥含有酶的液体溶液，由此含有活性物质的溶液小滴干燥直至形成含有活性的微粒物质而制备。可以以这种方法制备很小的粒子(Michael S.Showell(编辑)；强力去污剂(Powdered detergents)；表面活性剂科学系列(Surfactant ScienceSeries)；1998；71卷；140-142页；Marcel Dekker)。- Spray-dried core particles prepared by spray-drying an enzyme-containing liquid solution whereby droplets of the solution containing the active substance are dried until an active-containing particulate substance is formed. Very small particles can be prepared in this way (Michael S. Showell (editor); Powdered detergents; Surfactant Science Series; 1998; Vol. 71; pp. 140-142; Marcel Dekker ).
-层叠式核心粒子，其中活性成分作为一层包被于预先形成的核心粒子上或吸附到核心粒子的表面。如果能找到具有所需大小的可用核心粒子，则具所需大小的粒子可以通过这种方法得到。这类产品在例如WO97/23606和WO97/39116(此处引用作为参考)中有描述。- Layered core particles, wherein the active ingredient is coated as a layer on a pre-formed core particle or adsorbed to the surface of the core particle. Particles of the desired size can be obtained by this method if available core particles of the desired size can be found. Such products are described, for example, in WO97/23606 and WO97/39116 (herein incorporated by reference).
-挤压或制成粒的核心粒子，其中含有活性成分的糊剂压制成粒或在压力下通过小孔挤压并切割成粒子，随后干燥。这样的粒子通常具有相当的大小，因为在其中可制造挤压孔的材料(通常为带有钻孔的板)限制了允许施加在挤压孔的压力。当使用小孔时非常高的挤压力也会增加含有活性成分的糊剂中的热产生并可损害活性成分(Michael S.Showell(编辑)；强力去污剂；表面活性剂科学系列；1998；71卷；140-142页；MarcelDekker)。- Extruded or granulated core particles, wherein the paste containing the active ingredient is compressed granulated or pressed through small holes under pressure and cut into granules, followed by drying. Such particles are usually of considerable size, since the material in which the extrusion holes can be made (usually a plate with drilled holes) limits the pressure allowed to be exerted on the extrusion holes. Very high extrusion forces when using small holes can also increase heat generation in active ingredient-containing pastes and can damage the active ingredient (Michael S. Showell (editor); Strong Detergents; Surfactant Science Series; 1998; 71; pp. 140-142; Marcel Dekker).
-含有活性成分的粉末固定在固化蜡基质中的成颗粒状核心粒子。成颗粒状粒子通常通过将活性粉末悬浮于熔化的蜡中，并将悬浮物例如通过旋转式圆盘喷雾器将其喷入冷却室使液滴快速固化而制备(MichaelS.Showell(编辑)；强力去污剂；表面活性剂科学系列；1998；71卷；140-142页；Marcel Dekker)。- A granulated core particle containing a powder containing the active ingredient immobilized in a solidified wax matrix. Granulated particles are usually prepared by suspending the active powder in molten wax and spraying the suspension into a cooling chamber, such as by a rotary disc sprayer, to rapidly solidify the droplets (Michael S. Detergents; Surfactant Science Series; 1998; Vol. 71; pp. 140-142; Marcel Dekker).
-通过加入颗粒成分中的活性物质、液体和干粉组合物制备的混合颗粒化粒子。以适当比例混合液体和粉末，并且随着干粉吸收液体的水分后干粉成分开始粘附和凝结，而粒子将会形成含有活性成分的颗粒。这样的方法在4,106,991(NOVO NORDISK)和相关文献EP 170360B1(NOVONORDISK)、EP304332B1(NOVO NORDISK)、EP304331(NOVONORDISK)、WO90/09440(NOVO NORDISK)和WO90/09428(NOVONORDISK)中有描述，它们均在此引用作为参考。- Mixed granulated particles prepared by adding active substance, liquid and dry powder composition to the granule ingredients. The liquid and powder are mixed in the proper proportions, and the dry powder ingredients begin to adhere and coagulate as the dry powder absorbs the moisture from the liquid, while the particles will form granules containing the active ingredient. Such a method is described in 4,106,991 (NOVO NORDISK) and related documents EP 170360B1 (NOVONORDISK), EP304332B1 (NOVO NORDISK), EP304331 (NOVONORDISK), WO90/09440 (NOVO NORDISK) and WO90/09428 (NOVONORDISK), which are all in This quote is for reference.
核心成分可以是本领域公知的那些成分，其包括但不限于：Core ingredients may be those known in the art, including but not limited to:
活性成分active ingredient
活性成分可以是任一其用途受益于成型为颗粒的活性成分。这样的活性成分可以是药物。The active ingredient may be any active ingredient whose use benefits from being shaped into granules. Such an active ingredient may be a drug.
术语“活性成分”包括所有这样的成分，其为当在加工中施用颗粒时，从颗粒中释放可起到改良该加工的目的的成分。适当的活性成分为失活作用物质/或为在含有颗粒的组合物中引起其它成分失活的物质。The term "active ingredient" includes all ingredients which, when applied to a granule in a process, are released from the granule for the purpose of improving that process. Suitable active ingredients are inactivating substances and/or are substances which cause the inactivation of other ingredients in the composition containing the particles.
活性成分可以是天然无机物如漂白成分或为有机物。优选的活性成分是生物活性材料如催化活性材料(诸如酶)、人体或动物体的药用活性材料、或农用化学品如除草剂、杀虫剂、杀菌剂和/或杀真菌剂。这样的化合物一般对周围环境很敏感并适于通过化学方法或微生物发酵得到。最优选的活性成分是肽或多肽，如酶。The active ingredient may be naturally occurring inorganic such as a bleaching ingredient or be organic. Preferred active ingredients are biologically active materials such as catalytically active materials such as enzymes, pharmaceutically active materials of the human or animal body, or agrochemicals such as herbicides, insecticides, bactericides and/or fungicides. Such compounds are generally sensitive to the surrounding environment and are suitable for obtaining by chemical methods or microbial fermentation. Most preferred active ingredients are peptides or polypeptides, such as enzymes.
本发明上下文中的酶可以是任何受益于粒化从而可用于特定用途的酶或不同酶的组合。因此当谈到“酶”时，通常理解为包括一种或多种酶的组合。An enzyme in the context of the present invention may be any enzyme or combination of different enzymes that would benefit from granulation for a particular application. Thus when reference is made to "enzyme", it is generally understood to include one or a combination of more enzymes.
应当理解酶变体(例如通过重组技术生产)也包括在术语“酶”的范围内。此类酶变体的例子例如在EP251,446(Genencor)、WO91/00345(NovoNordisk)、EP525,610(Solvay)和WO94/02618(Gist-Brocades NV)中公开。It should be understood that enzyme variants (eg produced by recombinant techniques) are also included within the scope of the term "enzyme". Examples of such enzyme variants are eg disclosed in EP251,446 (Genencor), WO91/00345 (NovoNordisk), EP525,610 (Solvay) and WO94/02618 (Gist-Brocades NV).
本说明书和权利要求书中使用的酶分类与国际生物化学和分子生物学协会命名法委员会的建议(1992)(Recommendations(1992)of theNomenclature Committee of the International Union of Biochemistry andMolecular Biology)，Academic Press，Inc.，1992中的酶分类一致。Classification of enzymes used in this specification and claims and Recommendations (1992) of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology, Academic Press, Inc ., the classification of enzymes in 1992 is consistent.
因此本发明的颗粒中可适当掺入的酶类型包括氧化还原酶(EC1.-.-.-)、转移酶(EC 2.-.-.-)、水解酶(EC 3.-.-.-)、裂解酶(EC 4.-.-.-)、异构酶(EC 5.-.-.-)和连接酶(EC 6.-.-.-)。Enzyme types that may be suitably incorporated in the granules of the invention thus include oxidoreductases (EC 1.-.-.-), transferases (EC 2.-.-.-), hydrolases (EC 3.-.-. -), lyase (EC 4.-.-.-), isomerase (EC 5.-.-.-) and ligase (EC 6.-.-.-).
本发明上下文中优选的氧化还原酶是过氧化物酶(EC 1.11.1)、漆酶(EC 1.10.3.2)和葡糖氧化酶(EC 1.1.3.4)，而优选的转移酶是在下列任一亚类中的转移酶：Preferred oxidoreductases in the context of the present invention are peroxidases (EC 1.11.1), laccases (EC 1.10.3.2) and glucose oxidases (EC 1.1.3.4), whereas preferred transferases are Transferases in a subclass:
a)转移一碳基团的转移酶(EC 2.1)；a) a transferase (EC 2.1) that transfers one carbon group;
b)转移醛或酮残基的转移酶(EC 2.2)；酰基转移酶(EC 2.3)；b) transferases (EC 2.2) that transfer aldehyde or ketone residues; acyltransferases (EC 2.3);
c)糖基转移酶(EC 2.4)；c) Glycosyltransferase (EC 2.4);
d)转移不为甲基的烷基或芳基的转移酶(EC 2.5)；以及d) transferases that transfer an alkyl or aryl group that is not a methyl group (EC 2.5); and
e)转移含氮基团的转移酶(EC 2.6)。e) Transferases that transfer nitrogen-containing groups (EC 2.6).
本发明上下文中最优选的转移酶类型是转谷氨酰胺酶(蛋白质-谷氨酰胺γ-谷氨酰转移酶；EC 2.3.2.13)。The most preferred type of transferase in the context of the present invention is transglutaminase (protein-glutamine γ-glutamyltransferase; EC 2.3.2.13).
合适的转谷氨酰胺酶的进一步实施例在WO96/06931(Novo NordiskA/S)中有描述。Further examples of suitable transglutaminases are described in WO96/06931 (Novo Nordisk A/S).
本发明上下文中优选的水解酶是：羧酸酯水解酶(EC 3.1.1.-)，如脂肪酶(EC 3.1.1.3)；肌醇六磷酸酶(EC 3.1.3.-)，如3-肌醇六磷酸酶(EC3.1.3.8)和6-肌醇六磷酸酶(EC 3.1.3.26)；糖苷酶(EC 3.2，包括在这里称为“糖酶”的组中)，如α-淀粉酶(EC 3.2.1.1)；肽酶(EC 3.4，也称为蛋白酶)；以及其它羰基水解酶。Preferred hydrolases in the context of the present invention are: carboxylate hydrolases (EC 3.1.1.-), such as lipases (EC 3.1.1.3); phytases (EC 3.1.3.-), such as 3 - phytases (EC 3.1.3.8) and 6-phytases (EC 3.1.3.26); glycosidases (EC 3.2, included in the group here called "carbohydrases"), such as alpha - Amylases (EC 3.2.1.1); peptidases (EC 3.4, also known as proteases); and other carbonyl hydrolases.
在本文中，术语“糖酶”不仅用来表示可分解尤其是五元和六元环结构的糖链(例如淀粉)的酶(即糖苷酶，EC 3.2)，还用来表示可异构化糖类的酶，如将诸如D-葡萄糖的六元环结构异构化为诸如D-果糖的五元环结构的酶。In this context, the term "glycosidase" is used not only to denote enzymes that break down sugar chains, especially five- and six-membered ring structures (such as starch) (i.e. glycosidases, EC 3.2), but also to denote enzymes capable of isomerizing Enzymes for sugars, such as enzymes that isomerize a six-membered ring structure such as D-glucose to a five-membered ring structure such as D-fructose.
相关糖酶包括下列酶(EC号在括号中)：Related carbohydrases include the following enzymes (EC numbers in brackets):
α-淀粉酶(3.2.1.1)、β-淀粉酶(3.2.1.2)、葡聚糖1，4-α-葡糖苷酶(3.2.1.3)、纤维素酶(3.2.1.4)、内-1，3(4)-β-葡聚糖酶(3.2.1.6)、内-1，4-β-木聚糖酶(3.2.1.8)、葡聚糖酶(3.2.1.11)、几丁质酶(3.2.1.14)、聚半乳糖醛酸酶(3.2.1.15)、溶菌酶(3.2.1.17)、β-葡糖苷酶(3.2.1.21)、α-半乳糖苷酶(3.2.1.22)、β-半乳糖苷酶(3.2.1.23)、淀粉-1，6-葡糖苷酶(3.2.1.33)、木聚糖1，4-β-木糖苷酶(3.2.1.37)、葡聚糖内-1，3-β-D-葡糖苷酶(3.2.1.39)、α-糊精内1，6-α-葡糖苷酶(3.2.1.41)、蔗糖α-葡糖苷酶(3.2.1.48)、葡聚糖内1，3-α-葡糖苷酶(3.2.1.59)、葡聚糖1，4-β-葡糖苷酶(3.2.1.74)、葡聚糖内-1，6-β-葡糖苷酶(3.2.1.75)、阿拉伯糖内1，5-α-L-阿糖苷酶(3.2.1.99)、乳糖酶(3.2.1.108)、脱乙酰几丁质酶(3.2.1.132)和木糖异构酶(5.3.1.5)。α-amylase (3.2.1.1), β-amylase (3.2.1.2), dextran 1,4-α-glucosidase (3.2.1.3), cellulase (3.2.1.4), endo-1 , 3(4)-β-glucanase (3.2.1.6), endo-1,4-β-xylanase (3.2.1.8), glucanase (3.2.1.11), chitinase (3.2.1.14), polygalacturonase (3.2.1.15), lysozyme (3.2.1.17), beta-glucosidase (3.2.1.21), alpha-galactosidase (3.2.1.22), beta - Galactosidase (3.2.1.23), Amyl-1,6-glucosidase (3.2.1.33), Xylan-1,4-β-xylosidase (3.2.1.37), Endoglucan-1 , 3-β-D-glucosidase (3.2.1.39), α-dextrin 1,6-α-glucosidase (3.2.1.41), sucrose α-glucosidase (3.2.1.48), glucosidase Endoglucan 1,3-α-glucosidase (3.2.1.59), Glucan 1,4-β-glucosidase (3.2.1.74), Endoglucan-1,6-β-glucosidase ( 3.2.1.75), arabinose 1,5-alpha-L-alabinosidase (3.2.1.99), lactase (3.2.1.108), chitosanase (3.2.1.132) and xylose isomerase (5.3.1.5).
商业上可获得的氧化还原酶(EC 1.-.-.-)的实例包括GluzymeTM(可从Novo Nordisk A/S获得的酶)。Examples of commercially available oxidoreductases (EC 1.-.-.-) include Gluzyme™ (enzyme available from Novo Nordisk A/S).
商业上可获得的蛋白酶(肽酶)的实例包括KannaseTM、EverlaseTM、EsperaseTM、AlcalaseTM、NeutraseTM、DurazymTM、SavinaseTM、PyraseTM、胰蛋白酶NOVO(PTN)、Bio-FeedTM Pro和Clear-LensTM Pro(都可从丹麦的Novo Nordisk A/S，Bagsvaerd获得)。Examples of commercially available proteases (peptidases) include Kannase™ , Everlase™ , Esperase™ , Alcalase™ , Neutrase™ , Durazym™ , Savinase™ , Pyrase™ , Trypsin NOVO (PTN), Bio-Feed™ Pro and Clear-Lens™ Pro (both available from Novo Nordisk A/S, Bagsvaerd, Denmark).
其它商业上可获得的蛋白酶包括MaxataseTM、MaxacalTM、MaxapemTM、OpticleanTM和PurafectTM(可从Genencor International Inc.或Gist-Brocades获得)。Other commercially available proteases include Maxatase™ , Maxacal™ , Maxapem™ , Opticlean™ and Purafect™ (available from Genencor International Inc. or Gist-Brocades).
商业上可获得的脂肪酶的实例包括LipoprimeTM LipolaseTM、LipolaseTM Ultra、LipozymeTM、PalataseTM、NovozymTM 435和LecitaseTM(都可从Novo Nordisk A/S获得)。Examples of commercially available lipases include Lipoprime™ Lipolase™ , Lipolase™ Ultra, Lipozyme™ , Palatase™ , Novozym™ 435 and Lecitase™ (all available from Novo Nordisk A/S).
其它商业上可获得的脂肪酶包括LumafastTM(来自GenencorInternational Inc.的门多萨假单胞菌(Pseudomonas mendocina)脂肪酶)；LipomaxTM(来自Gist-Brocades或Genencor InternationalInc.的类产碱假单胞菌(Ps.Pseudoalcaligenes)脂肪酶)；以及来自Solvay酶的芽孢杆菌种脂肪酶。Other commercially available lipases include Lumafast™ (Pseudomonas mendocina lipase from Genencor International Inc.); Lipomax™ (Pseudomonas mendocina from Gist-Brocades or Genencor International Inc. Pseudoalcaligenes lipase); and Bacillus species lipase from Solvay Enzymes.
商业上可获得的糖酶的实例包括α-GalTM、Bio-FeedTMα、Bio-FeedTMβ、Bio-FeedTM Plus、Bio-FeedTM Plus、NovozymeTM 188、CelluclastTM、CellusoftTM、CeremylTM、CitrozymTM、DenimaxTM、DezymeTM、DextrozymeTM、FinizymTM、FungamylTM、GamanaseTM、GlucanexTM、LactozymTM、MaltogenasTM、PentopanTM、PectinexTM、PromozymeTM、PulpzymeTM、NovamylTM、TermamylTM、AMGTM(淀粉葡糖苷酶Novo)、MaltogenaseTM、SweetzymeTM和AquazymTM(都可从Novo Nordisk A/S获得)。Examples of commercially available carbohydrases include α-Gal™ , Bio-Feed™ α, Bio-Feed™ β, Bio-Feed™ Plus, Bio-Feed™ Plus, Novozyme™ 188, Celluclast™ , Cellusoft™ , CeremylTM , CitrozymTM , DenimaxTM , DezymeTM , DextrozymeTM , FinizymTM , FungamylTM , GamanaseTM , GlucanexTM , LactozymTM , MaltogenasTM, Pentopan TM, PectinexTM , PromozymeTM , PulpzymeTM,Novamyl AMG™ (Amyloglucosidase Novo), Maltogenase™ , Sweetzyme™ and Aquazym™ (all available from Novo Nordisk A/S).
欲掺入本发明颗粒中的酶量取决于颗粒的预定用途。在很多应用中酶含量是尽可能高或为适用的量。The amount of enzyme to be incorporated into the granules of the invention depends on the intended use of the granules. In many applications the enzyme content is as high as possible or in a practical amount.
本发明颗粒中的酶含量(以在每颗粒重量中纯酶蛋白所占的百分比计算)一般占含酶颗粒重量的约0.5％至50％，但较高含量如50-90％w/w也是适合的。The enzyme content in the granules of the invention (calculated as a percentage of pure enzyme protein per granule weight) is generally about 0.5% to 50% by weight of the enzyme-containing granule, but higher levels such as 50-90% w/w are also acceptable. suitable.
当例如将蛋白酶(肽酶)掺入本发明的颗粒中时，最终颗粒的酶活性(蛋白水解活性)一般在1-20KNPU/g的范围内。这一蛋白酶活性单位是千诺和蛋白酶单位/克样品(Kilo Novo Protease Units per gram；KNPU/g)。活性是相对于酶标准的已知KNPU/g活性测定的。酶标准是通过测量溶液中定量酶消化二甲基酪蛋白(DMC)所释放的游离氨基的生成速率(μmol/分钟)而标准化的。生成速率是通过记录所生成的游离氨基与所加入的2，4，6-三硝基苯磺酸(TNBS)间的联立反应在420nm处的吸光度的线性延伸而监控的。DMC的消化和颜色反应在50℃pH8.3的硼酸缓冲液中进行，反应9分钟后测量3分钟。可通过向丹麦Novo Nordisk A/S索要而获得文件夹AF 220/1，该文件夹于此处引用作为参考。When for example proteases (peptidases) are incorporated into the granules of the invention, the enzymatic activity (proteolytic activity) of the final granules is generally in the range of 1-20 KNPU/g. This unit of protease activity is Kilo Novo Protease Units per gram (KNPU/g). Activity is determined relative to the known KNPU/g activity of an enzyme standard. Enzyme standards were standardized by measuring the rate of formation (μmol/min) of free amino groups released from quantitative enzymatic digestion of dimethylcasein (DMC) in solution. The rate of formation was monitored by recording the linear extension of the absorbance at 420 nm for the simultaneous reaction between the free amino group formed and the added 2,4,6-trinitrobenzenesulfonic acid (TNBS). Digestion and color reaction of DMC were carried out in boric acid buffer at pH 8.3 at 50°C, and measured for 3 minutes after 9 minutes of reaction. Folder AF 220/1 is available upon request from Novo Nordisk A/S, Denmark, which is incorporated herein by reference.
同样地，当例如为α-淀粉酶时，酶活性一般为10-500KNU/g。活性是相对于酶标准的已知KNU/g活性测定的。酶标准是通过测量溶液中在α-和β-葡糖苷酶的协助下定量的α-淀粉酶消化2-氯-4-硝基苯基-b-D-maltoheptaosid底物释放的2-氯-4-硝基苯酚的生成速率(μmol/分钟)而标准化的。进行α-淀粉酶检测的试剂盒可商业购买。α-淀粉酶检测的一个说明可从向丹麦Novo Nordisk A/S索要而得到的散页说明AF318/1-GB上找到。对于例如脂肪酶，范围在50-400 KLU/g的活性一般是适合的。Likewise, when eg alpha-amylase, the enzyme activity is generally 10-500 KNU/g. Activity is determined relative to the known KNU/g activity of an enzyme standard. The enzyme standard is quantified by measuring the release of 2-chloro-4-nitrophenyl-b-D-maltoheptaosid substrate in solution by α-amylase digestion with the assistance of α- and β-glucosidases. Normalized to the rate of formation of nitrophenol (μmol/min). Kits for alpha-amylase detection are commercially available. A description of the alpha-amylase assay can be found in the leaflet AF318/1-GB available on request from Novo Nordisk A/S, Denmark. For e.g. lipases, an activity in the range of 50-400 KLU/g is generally suitable.
在粒化过程中应用的酶通常为含酶液体。含酶液体可以酶浓缩物形式作为纯化产物应用，在该纯化产物中，酶作为结晶和/或无定形蛋白溶解或分散于水成液中，或含酶液体可为发酵肉汤形式。液体中的水可作为粒化过程(见上文)中的液体试剂。Enzymes used in the granulation process are usually enzyme-containing liquids. The enzyme-containing liquid may be applied as a purified product in the form of an enzyme concentrate in which the enzyme is dissolved or dispersed in an aqueous liquid as crystalline and/or amorphous protein, or the enzyme-containing liquid may be in the form of a fermentation broth. Water in the liquid can be used as a liquid reagent in the granulation process (see above).
预先形成的核心粒子preformed core particles
当本发明的颗粒通过将活性成分层施加于预先形成的核心粒子上而制备时，预先形成的核心粒子优选地为基于碳水化合物的核心粒子或基于盐的核心粒子，前者如植物面粉或产品(木薯、树薯、谷类面粉、糖、糊精等)形成的粒子，后者如从硫酸盐、亚硫酸盐、磷酸盐、膦酸盐、硝酸盐、氯化物或碳酸盐的碱或碱土金属盐制备，或从如优选为柠檬酸盐、丙二酸盐或醋酸盐的简单有机酸盐制备。When the granules of the present invention are prepared by applying a layer of active ingredient to a pre-formed core particle, the pre-formed core particle is preferably a carbohydrate-based core particle or a salt-based core particle, the former such as vegetable flour or a product ( cassava, cassava, cereal flour, sugar, dextrin, etc.) of alkali or alkaline earth metals from sulfates, sulfites, phosphates, phosphonates, nitrates, chlorides or carbonates salts, or from simple organic acid salts such as preferably citrate, malonate or acetate.
填充物filler
合适的填充物为水溶的和/或水不溶的无机盐如磨细的碱性硫酸盐、碱性碳酸盐和/或碱性氯化物、粘土如高岭土(例如SpeswhiteTM，英国陶瓷土)、膨润土、滑石、沸石和/或硅酸盐。Suitable fillers are water-soluble and/or water-insoluble inorganic salts such as finely ground alkaline sulfates, alkaline carbonates and/or alkaline chlorides, clays such as kaolin (eg Speswhite™ , English ceramic clay), Bentonite, talc, zeolites and/or silicates.
粘合剂Adhesive
合适的粘合剂为具有高熔点或根本无熔点且为非蜡状特性的粘合剂，例如聚乙烯吡咯烷酮、糊精、聚乙烯醇、纤维素衍生物如羟丙基纤维素、甲基纤维素或CMC。合适的粘合剂是碳水化合物粘合剂，如可从法国Roquette Freres获得的Glucidex 21D。Suitable binders are those with a high melting point or no melting point at all and of non-waxy character, for example polyvinylpyrrolidone, dextrin, polyvinyl alcohol, cellulose derivatives such as hydroxypropylcellulose, methylcellulose prime or CMC. A suitable binder is a carbohydrate binder such as Glucidex 21D available from Roquette Freres, France.
纤维材料fiber material
纤维形式的纯的或不纯的纤维素可以是锯屑、纯的纤维状纤维素、棉花或其他形式的纯的或不纯的纤维状纤维素。也可使用基于纤维状纤维素的助滤剂。市场上有几种品牌的纤维状纤维素，如CEPO和ARBOCELL。在Svenska Trmjolsfabrikerna AB的出版物“Cepo纤维素粉末(CepoCellulose Powder)”中指出Cepo S/20纤维素的最大纤维长度约为500μm，平均纤维长度约为160μm，最大纤维宽度约为50μm，平均纤维宽度约为30μm。还指出CEPO SS/200纤维素的最大纤维长度约为150μm，平均纤维长度约为50μm，最大纤维宽度约为45μm，平均纤维宽度约为25μm。这种尺寸的纤维素非常适合本发明的目的。单词“Cepo”和“Arbocel”是商标。优选的纤维状纤维素是ArbocelTM BFC200。如EP 304331 B1中描述的合成纤维也可以使用，且一般由聚乙烯、聚丙烯、聚酯、尤其是尼龙、聚乙烯聚合物式(polyvinylformat)、聚(甲基)丙烯酸化合物制造。The pure or impure cellulose in fiber form may be sawdust, pure fibrous cellulose, cotton or other forms of pure or impure fibrous cellulose. Filter aids based on fibrous cellulose may also be used. There are several brands of fibrous cellulose on the market, such as CEPO and ARBOCELL. In the publication "Cepo Cellulose Powder (CepoCellulose Powder)" of Svenska Trmjolsfabrikerna AB, it is pointed out that the maximum fiber length of Cepo S/20 cellulose is about 500 μm, the average fiber length is about 160 μm, the maximum fiber width is about 50 μm, and the average fiber length is about 50 μm. The fiber width is about 30 μm. It is also indicated that CEPO SS/200 cellulose has a maximum fiber length of about 150 μm, an average fiber length of about 50 μm, a maximum fiber width of about 45 μm, and an average fiber width of about 25 μm. Cellulose of this size is well suited for the purposes of the present invention. The words "Cepo" and "Arbocel" are trademarks. A preferred fibrous cellulose is Arbocel™ BFC200. Synthetic fibers as described in EP 304331 B1 can also be used and are generally produced from polyethylene, polypropylene, polyester, especially nylon, polyvinylformat, poly(meth)acrylic compounds.
液体试剂liquid reagent
液体试剂用于常规的混合粒化过程，以使常规的粒化成分粒子形成或集结成颗粒。液体试剂为水和/或蜡状物质。液体试剂在粒化过程中总是以液相使用但随后可固化；如果存在蜡状物质，那么将该蜡状物质溶解或分散于水中或者熔化。这里使用的术语“蜡状物质”是指具有下列所有特性的物质：1)熔点在30至100℃之间，优选地在40至60℃之间，2)该物质有坚固且不易碎的特性，以及3)该物质在室温下具有一定可塑性。水和蜡状物质均为液体试剂，即它们在颗粒形成过程中都是有活性的；蜡状物质在最终的颗粒中作为组成部分保留，而大部分水在干燥步骤中被去除。蜡状物质的实例是聚乙二醇、脂肪醇、乙氧基化脂肪醇、高级脂肪酸的单、二和三甘油酯如甘油单硬脂酰酯、烷基芳基乙氧基化物和椰油单乙醇酰胺。Liquid reagents are used in conventional mixing and granulation processes to form or agglomerate conventional granulated ingredients into particles. Liquid reagents are water and/or waxy substances. Liquid reagents are always used in the liquid phase during the granulation process but may then solidify; if a waxy substance is present, this waxy substance is dissolved or dispersed in water or melted. The term "waxy substance" as used herein refers to a substance having all of the following properties: 1) a melting point between 30 and 100°C, preferably between 40 and 60°C, 2) the substance has a firm and non-brittle character , and 3) the substance has a certain plasticity at room temperature. Both the water and the waxy substance are liquid reagents, i.e. they are both active during particle formation; the waxy substance remains as a constituent in the final particle, while most of the water is removed during the drying step. Examples of waxy substances are polyethylene glycols, fatty alcohols, ethoxylated fatty alcohols, mono-, di- and triglycerides of higher fatty acids such as glyceryl monostearyl, alkylaryl ethoxylates and coconut oil Monoethanolamide.
如果用到大量的蜡状物质，则应加相对少量的水，反之亦然。因此，液体试剂可仅为水、仅为蜡状物质或为水和蜡状物的混合物。当用到水和蜡状物的混合物时，可以任何顺序加入水和蜡状物，例如先水后蜡状物，或先蜡状物后水，或蜡状物在水中的溶液或悬液。当用到水和蜡状物的混合物时，蜡状物也可以溶于或不溶(但可分散)于水。如果用水作为液体试剂，则水可能不为最终混合颗粒的一部分，因为大部分水通常在随后的混合颗粒干燥中除去了。If a large amount of waxy substance is used, a relatively small amount of water should be added, and vice versa. Thus, the liquid reagent can be water only, wax only or a mixture of water and wax. When a mixture of water and wax is used, the water and wax may be added in any order, such as water followed by wax, or wax followed by water, or a solution or suspension of wax in water. When a mixture of water and wax is used, the wax may also be soluble or insoluble (but dispersible) in water. If water is used as the liquid reagent, the water may not be part of the final mixed granule since most of the water is usually removed during subsequent drying of the mixed granule.
活性稳定剂或活性保护剂active stabilizer or active protectant
酶稳定剂或保护剂可分为几类：碱性或中性材料、还原剂、抗氧化剂和/或开始的过渡金属离子的盐。每种都可与其它同类或不同类的保护剂联合使用。碱性保护剂的实例是能有效中和例如氧化剂从而提供化学清除作用的碱金属硅酸盐、碳酸盐或碳酸氢盐。还原性保护剂的实例为亚硫酸盐、硫代亚硫酸盐或硫代硫酸盐，抗氧化剂的实例为甲硫氨酸、丁化羟基甲苯(BHT)或丁化羟基苯甲醚(BHA)。最优选的试剂是硫代硫酸盐，如硫代硫酸钠。酶稳定剂也可以是硼酸盐、硼砂、甲酸盐、二羧酸和三羧酸以及可逆性酶抑制剂如带巯基的有机化合物或烷基化或芳基化的硼酸。Enzyme stabilizers or protectants can be divided into several categories: basic or neutral materials, reducing agents, antioxidants and/or salts of starting transition metal ions. Each can be used in combination with other protectants of the same or different classes. Examples of alkaline protectants are alkali metal silicates, carbonates or bicarbonates which are effective in neutralizing, eg, oxidizing agents, thereby providing chemical scavenging. Examples of reducing protective agents are sulfites, thiosulfites or thiosulfates, examples of antioxidants are methionine, butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA). The most preferred agent is a thiosulfate, such as sodium thiosulfate. Enzyme stabilizers may also be borates, borax, formates, dicarboxylic and tricarboxylic acids and reversible enzyme inhibitors such as sulfhydryl-bearing organic compounds or alkylated or arylated boronic acids.
交联剂crosslinking agent
交联剂可为活性相容的表面活性剂，如乙氧基化醇，尤其是具有10至80个乙氧基的醇。The crosslinking agent may be a reactively compatible surfactant, such as an ethoxylated alcohol, especially an alcohol having from 10 to 80 ethoxy groups.
进一步地，可将悬浮剂、介质(用于如在洗涤应用中于颗粒分解后增加漂白作用)和/或溶剂掺入颗粒核心。Further, suspending agents, media (for increased bleaching after particle breakdown eg in laundry applications) and/or solvents may be incorporated into the particle core.
包被层Coating layer
可将一种或多种包被层应用于本发明的颗粒，以提供颗粒的所需特性，例如保护核心中的活性成分。包被层的成分合适地可为上述核心中用到的成分，优选地除了酶之外。One or more coating layers may be applied to the particles of the invention to provide desired properties of the particle, such as protection of the active ingredient in the core. The ingredients of the coating layer may suitably be the ingredients used in the above-mentioned core, preferably except for the enzyme.
本领域中公知的常规包被适用于用作包被，如WO89/08694、WO89/08695、270608 B1和/或PA 1998 00876(在本发明的优先权日未公开的丹麦优先权申请)中所描述的包被层。常规包被材料的其它实例可在US4,106,991、EP170360、EP304332、EP304331、EP458849、EP458845、WO97/39116、WO92/12645A、WO89/08695、WO89/08694、WO87/07292、WO91/06638、WO92/13030、WO93/07260、WO93/07263、WO96/38527、WO96/16151、WO97/23606、US5,324,649、US4,689,297、EP206417、EP193829、DE4344215、DE4322229A、DD263790、JP61162185A和/或JP58179492中找到。Conventional coatings known in the art are suitable for use as coatings, as described in WO89/08694, WO89/08695, 270608 B1 and/or PA 1998 00876 (Danish priority application unpublished at the priority date of the present invention) Describe the coating layer. Other examples of conventional coating materials can be found in US4,106,991, EP170360, EP304332, EP304331, EP458849, EP458845, WO97/39116, WO92/12645A, WO89/08695, WO89/08694, WO87/07292, WO91/06633, WO92/1 , WO93/07260, WO93/07263, WO96/38527, WO96/16151, WO97/23606, US5,324,649, US4,689,297, EP206417, EP193829, DE4344215, DE4322229A, DD263790, JP9158/7185 or 9.4
在一个具体的实施方案中包被层可包含少量的能与使活性失活(对活性不利)的成分反应的保护剂，所述的成分为从环境基质中进入颗粒，即在该成分开始接触并使活性失活之前，保护剂可以如中和、还原或与成分反应从而使它不损害活性。可使活性失活的典型成分是氧化剂，如过硼酸盐、过碳酸盐、有机过酸等。In a specific embodiment the coating may contain a small amount of protective agent capable of reacting with an active inactivating (adverse to active) component that enters the particle from the environmental matrix, i.e. when the component comes into contact with And before inactivating the activity, the protecting agent may eg neutralize, reduce or react with the component so that it does not impair the activity. Typical ingredients that can inactivate activity are oxidizing agents such as perborates, percarbonates, organic peracids, etc.
保护剂可划分为几类：碱性或中性材料、还原剂、抗氧化剂和/或开始的过渡金属离子的盐。每种保护剂可与其它同类或不同类的保护剂联合使用。碱性保护剂的实例是通过有效中和例如氧化剂从而提供化学清除作用的碱金属硅酸盐、碳酸盐或碳酸氢盐。还原性保护剂的实例是亚硫酸盐、硫代亚硫酸盐或硫代硫酸盐，抗氧化剂的实例是甲硫氨酸、丁化羟基甲苯(BHT)或丁化羟基苯甲醚(BHA)。最优选的试剂是硫代硫酸盐，如硫代硫酸钠。包被中保护剂的量可为包被的5-40％w/w，优选地为5-30％，如10-20％。Protective agents can be divided into several classes: basic or neutral materials, reducing agents, antioxidants and/or salts of initial transition metal ions. Each protectant can be used in combination with other protectants of the same or different kind. Examples of alkaline protectants are alkali metal silicates, carbonates or bicarbonates which provide chemical scavenging by effectively neutralizing eg oxidizing agents. Examples of reducing protective agents are sulfites, thiosulfites or thiosulfates, examples of antioxidants are methionine, butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA). The most preferred agent is a thiosulfate, such as sodium thiosulfate. The amount of protective agent in the coating may be 5-40% w/w of the coating, preferably 5-30%, such as 10-20%.
包被通过形成基本上连续的均质层将含有活性成分的颗粒包封。Coating encapsulates the active ingredient-containing particle by forming a substantially continuous homogeneous layer.
包被可依据颗粒预期的用途行使颗粒的多种功能中的任一种功能。例如包被可起到下列一种或多种作用：The coating can perform any of a variety of functions of the particle depending on the intended use of the particle. For example, coating can play one or more of the following roles:
(i)含有活性成分的颗粒中活性粉尘形成的部分减少；(i) a reduction in the fraction of active dust formation in granules containing active ingredients;
(ii)保护含有活性成分的颗粒中的活性成分对抗漂白物质/体系(例如过硼酸盐、过碳酸盐、有机过酸等)的氧化；(ii) protection of the active ingredient in the active ingredient-containing granules against oxidation by bleaching substances/systems (e.g. perborates, percarbonates, organic peracids, etc.);
(iii)当颗粒导入液体介质(如含水介质)时，以所需速率溶解；(iii) dissolve at a desired rate when the particles are introduced into a liquid medium, such as an aqueous medium;
(iv)提供颗粒更好的物理强度。(iv) Provide better physical strength of the particles.
包被可进一步包含一种或多种下列试剂：抗氧化剂、氯清除剂、增塑剂、色素、附加的酶和芳香剂。The coating may further comprise one or more of the following agents: antioxidants, chlorine scavengers, plasticizers, pigments, additional enzymes and fragrances.
本发明上下文的包被层中有用的增塑剂包括如：多元醇如糖、糖醇，或分子量小于1000的聚乙二醇(PEGs)；尿素、邻苯二甲酸酯如邻苯二甲酸二丁酯或邻苯二甲酸二甲酯；以及水。Plasticizers useful in coatings in the context of the present invention include, for example: polyalcohols such as sugars, sugar alcohols, or polyethylene glycols (PEGs) with a molecular weight of less than 1000; urea, phthalates such as phthalic acid dibutyl or dimethyl phthalate; and water.
合适的色素包括但不限于磨碎的增白剂(如二氧化钛或高岭土)、有色色素、水溶性着色剂以及一种或多种色素和水溶性着色剂的组合。Suitable pigments include, but are not limited to, ground whitening agents such as titanium dioxide or kaolin, colored pigments, water soluble colorants, and combinations of one or more pigments and water soluble colorants.
在本发明的一个优选实施方案中本发明的颗粒以如丹麦专利申请WO00/01793第5-9页和实施例中描述的具有高的恒定湿度的保护性包被层包被，此外引用作为参考。In a preferred embodiment of the invention the particles according to the invention are coated with a protective coating with high constant humidity as described in Danish patent application WO 00/01793 pp. 5-9 and in the examples, hereby incorporated by reference .
待润滑的由核心和包被构成的含有活性成分的颗粒适合为球形或近球形，并且其最长尺寸适合具有的平均直径为50-2000μm，优选地为200-1200μm，更优选地为400-800μm或50-200μm。The active ingredient-containing particles to be lubricated, consisting of a core and a coating, are suitably spherical or nearly spherical, and suitably have an average diameter of 50-2000 μm, preferably 200-1200 μm, more preferably 400- 800μm or 50-200μm.
润滑剂lubricant
本发明的润滑剂是25℃时形成非含水液体的化合物或其混合物，且其优选地为25℃时具有低于5000厘泊的粘度，如500-5000厘泊，优选地低于4000厘泊，如500-4000厘泊，更优选地低于3000厘泊，如500-3000厘泊，且最优选地低于2500厘泊，如500-2500厘泊。使用低粘度润滑剂的一个优点是它们相当容易以少量在颗粒上形成薄层，并且低粘度可以促进少量润滑剂在颗粒的整个表面均质分布。当使用较高粘度润滑剂时，润滑剂趋向于以粘性块的形式不均匀粘附到颗粒表面。低粘度润滑剂的另一个优点是当极低粘度的润滑剂施用到所述颗粒外表面时减少了颗粒的摩擦。颗粒摩擦的减少可通过流速计测定。因此，如上文所述，本发明的一个方面涉及在颗粒的外表面上包含润滑剂的含有活性成分的颗粒，其中当使用流速计，叶梢圆周速度为50转/分钟，螺旋角为3°(压缩模式)，使用46mm转子并且称量170克颗粒至50mm测试容器中测量时，与未润滑的颗粒相比较，润滑颗粒的相对摩擦系数低于80％，例如为5-80％。优选地，与未润滑的颗粒相比较，润滑颗粒的相对摩擦系数低于78％，例如为5-78％，更优选地，与未润滑的颗粒相比较，润滑颗粒的相对摩擦系数低于75％，例如为5-75％，最优选地，与未润滑的颗粒相比较，润滑颗粒的相对摩擦系数低于70％，例如为5-70％。Lubricants according to the invention are compounds or mixtures thereof which form a non-aqueous liquid at 25°C, and which preferably have a viscosity at 25°C of less than 5000 centipoise, such as 500-5000 centipoise, preferably less than 4000 centipoise , such as 500-4000 centipoise, more preferably below 3000 centipoise, such as 500-3000 centipoise, and most preferably below 2500 centipoise, such as 500-2500 centipoise. One advantage of using low viscosity lubricants is that they form a thin layer on the particle fairly easily in small quantities, and the low viscosity can promote a homogenous distribution of small amounts of lubricant across the surface of the particle. When higher viscosity lubricants are used, the lubricant tends to adhere unevenly to the particle surface in the form of sticky clumps. Another advantage of low viscosity lubricants is the reduced friction of the particles when a very low viscosity lubricant is applied to the outer surface of the particles. The reduction in particle friction can be measured by a flow meter. Thus, as stated above, one aspect of the invention relates to active ingredient-containing granules comprising a lubricant on the outer surface of the granules, wherein when using a flow meter, the blade tip peripheral speed is 50 revolutions per minute and the helix angle is 3° (compression mode), lubricated granules have a relative coefficient of friction lower than 80%, eg 5-80%, compared to unlubricated granules when measured using a 46mm rotor and weighing 170 grams of granules into a 50mm test container. Preferably, the lubricated particles have a relative coefficient of friction lower than 78%, such as 5-78%, compared to unlubricated particles, more preferably, the lubricated particles have a relative coefficient of friction lower than 75% compared to unlubricated particles %, such as 5-75%, most preferably the lubricated particles have a relative coefficient of friction lower than 70%, such as 5-70%, compared to unlubricated particles.
润滑剂优选地为满足低粘度需求的有机化合物或有机化合物的混合物。优选的润滑剂为非离子表面活性剂如Softanol(例如Softanol 50)和/或Dobanol、天然精制矿物油如Whiteway T15(一种烷烃油)、合成矿物油如硅氧烷油、动物油、植物油或任何适合的混合物。The lubricant is preferably an organic compound or a mixture of organic compounds meeting the low viscosity requirement. Preferred lubricants are nonionic surfactants such as Softanol (e.g. Softanol 50) and/or Dobanol, natural refined mineral oils such as Whiteway T15 (an alkane oil), synthetic mineral oils such as silicone oils, animal oils, vegetable oils or any suitable mixture.
当使用这样的润滑剂，即该润滑剂的另一个特征为基本上不溶于其上施用该润滑剂的颗粒材料时，可获得特别的好处。该实施方案的一个好处是该润滑剂不溶于和/或不与其上施用该润滑剂的颗粒表面混合，并且不从它发挥功能的颗粒表面通过吸收而消失，其中润滑剂施用在颗粒表面上。该实施方案的另一优点是在润滑剂和包被施用于颗粒前可混合润滑剂和包被材料。这种混合物或分散体因此可同时施用于颗粒，且由于润滑剂在包被材料中的不溶性，润滑剂可从包被材料分离，以形成润滑外层。本文中的术语“基本上不溶”是指低于1克的润滑剂可溶于1千克其上将被施加润滑剂的颗粒材料。颗粒材料如其上将被施加润滑剂的包被材料通常为亲水的水溶性材料。因此在这些实施方案中优选的润滑剂是疏水的。特别地，矿物油润滑剂是适合的，并且因此本发明的一个方面涉及在颗粒外表面上包含矿物油润滑剂的含有活性成分的颗粒。最优选的润滑剂是粘度低于5000厘泊的矿物油润滑剂，与非润滑颗粒相比较，该矿物油润滑剂将润滑颗粒的摩擦系数降低至低于80％。Particular benefits are obtained when using lubricants which are further characterized by being substantially insoluble in the particulate material on which the lubricant is applied. An advantage of this embodiment is that the lubricant is insoluble and/or immiscible with the particle surface on which it is applied, and does not disappear by absorption from the particle surface on which it functions, on which the lubricant is applied. Another advantage of this embodiment is that the lubricant and coating material can be mixed before the lubricant and coating are applied to the particles. This mixture or dispersion can thus be simultaneously applied to the particles and, due to the insolubility of the lubricant in the coating material, the lubricant can separate from the coating material to form a lubricating outer layer. The term "substantially insoluble" herein means that less than 1 gram of lubricant is soluble in 1 kilogram of particulate material to which the lubricant is applied. The particulate material, such as the coating material onto which the lubricant will be applied, is typically a hydrophilic, water-soluble material. Preferred lubricants in these embodiments are therefore hydrophobic. In particular, mineral oil lubricants are suitable, and thus one aspect of the present invention relates to active ingredient-containing particles comprising mineral oil lubricants on the outer surface of the particles. The most preferred lubricant is a mineral oil lubricant with a viscosity of less than 5000 centipoise which reduces the coefficient of friction of lubricated particles to less than 80% compared to non-lubricated particles.
含有活性成分的颗粒的润滑剂将会润滑并减少颗粒间的摩擦，使之产生较少的粉尘并且降低破损的风险，我们也发现在一些情况下如果使用过多的润滑剂，润滑剂的润滑特性也会导致干颗粒变粘并结块。可通过用如TiO2(如US4,106,991实施例22中描述)的干微粒材料向颗粒施粉抑制结块。但是，这会起相反作用或抵消润滑效力，并且我们发现降低润滑剂的量，优选地低于润滑颗粒的1％w/w将能明显防止结块，同时仍具有有益的润滑效果。为了防止结块和/或颗粒发粘成为处理含有活性成分的颗粒的问题，并且避免由于加入多种防结块剂引起的花费和问题，润滑剂的添加应优选地以其组成低于颗粒重量1％的非常薄的一层施用，如在颗粒的0.01％至1％w/w之间，优选地为低于0.75％w/w，如在0.1％至0.75％w/w之间，更优选地约为0.5％w/w，如在颗粒的0.1％至0.5％之间。使用低粘度的润滑剂和/或如上文所述的基本上不溶于其上将施加润滑剂的颗粒材料的润滑剂，会使施加非常薄的润滑层变得容易。A lubricant containing particles of the active ingredient will lubricate and reduce friction between the particles, making it less dusty and reducing the risk of breakage, we have also found that in some cases if too much lubricant is used, the lubrication of the lubricant properties can also cause dry granules to become sticky and clump together. Agglomeration can be inhibited by dusting the granules with a dry particulate material such asTiO2 (as described in Example 22 of US 4,106,991). However, this can be counterproductive or counteract the lubricating effect, and we have found that reducing the amount of lubricant, preferably below 1% w/w of the lubricating particles, will significantly prevent caking while still having a beneficial lubricating effect. To prevent caking and/or granule stickiness from being a problem in handling granules containing active ingredients, and to avoid the expense and problems associated with the addition of multiple anti-caking agents, the lubricant should preferably be added with a composition below the weight of the granules 1% is applied in a very thin layer, such as between 0.01% and 1% w/w of the granule, preferably below 0.75% w/w, such as between 0.1% and 0.75% w/w, more Preferably about 0.5% w/w, such as between 0.1% and 0.5% of the particle. Applying a very thin layer of lubricant is facilitated by the use of a low viscosity lubricant and/or a lubricant, as described above, which is substantially insoluble in the particulate material onto which the lubricant is applied.
正如所阐明的，因为本发明颗粒上润滑剂的特性以及少量的润滑剂，在颗粒制造和储存过程中为防止结块而需使用的防结块剂可成功省去。因此在本发明的一个优选实施方案中本发明的颗粒不使用施加于润滑层上的防结块剂。As stated, because of the nature of the lubricant on the granules of the present invention and the small amount of lubricant, the use of anti-caking agents to prevent caking during the manufacture and storage of the granules can be successfully dispensed with. In a preferred embodiment of the invention the granules according to the invention therefore do not use anti-blocking agents which are applied to the lubricating layer.
制备润滑颗粒的方法Method for preparing lubricating particles
润滑剂可通过向酶颗粒中加入适当量的润滑剂并且混合该组合物直至润滑剂沉积并分布到颗粒表面而施加到酶颗粒上。可通过高速搅拌器或流化床涂布机将润滑剂喷雾到酶颗粒上进行混合。如上所述，在一个优选的实施方案中，本发明制备润滑颗粒的方法中方便地不包括任一向润滑层上加入抗结块剂的步骤。Lubricants can be applied to the enzyme granules by adding the appropriate amount of lubricant to the enzyme granules and mixing the composition until the lubricant is deposited and distributed over the surface of the granules. Mixing can be done by spraying the lubricant onto the enzyme granules by means of a high speed mixer or a fluidized bed coater. As noted above, in a preferred embodiment, the method of the present invention for preparing lubricating particles conveniently does not include any step of adding an anti-caking agent to the lubricating layer.
润滑颗粒的应用Application of Lubricating Granules
本发明的润滑颗粒适用于掺入工业用或家用的组合物中。这样的组合物包括还包含表面活性剂的清洁和/或消毒组合物，如去污剂组合物。这样的组合物在例如WO00/01793的“去污剂公开”部分有描述。其他组合物为抗菌组合物，其中酶任选地为抗菌氧化还原酶，以及用于处理微生物生物膜的组合物，其中酶任选地为抗菌氧化还原酶且该组合物任选地还包含水解酶。其它组合物可为如饲料组合物或食品组合物如动物饲料或焙烤面粉。The lubricating particles of the present invention are suitable for incorporation into compositions for industrial or domestic use. Such compositions include cleaning and/or disinfecting compositions, such as detergent compositions, further comprising a surfactant. Such compositions are described, for example, in the "Sterilizer Disclosure" section of WO 00/01793. Other compositions are antibacterial compositions, wherein the enzyme is optionally an antibacterial oxidoreductase, and compositions for treating microbial biofilms, wherein the enzyme is optionally an antibacterial oxidoreductase and the composition optionally further comprises a hydrolytic enzyme. Other compositions may eg be feed compositions or food compositions such as animal feed or baking flour.
实施例Example
实施例1Example 1
含未包被的Savinase(一种蛋白酶)的颗粒除了下述例外外，均按照US4,106,991实施例1中所述制备：Granules containing uncoated Savinase (a protease) were prepared as described in Example 1 of US 4,106,991 with the following exceptions:
·用硫酸钠代替氯化钠作填充物Use sodium sulfate instead of sodium chloride as filler
·酶浓缩物为也含碳水化合物粘合剂(Glucidex)和甲硫氨酸作为抗氧化剂的晶体酶的含水悬液。- Enzyme concentrate is an aqueous suspension of crystalline enzymes also containing a carbohydrate binder (Glucidex) and methionine as antioxidant.
颗粒按照US4,106,991实施例22中描述的通过加入6.9％的PEG4000和12.5％的1∶1的TiO2/高岭土混合物的溶液包被。颗粒进一步在Ldige搅拌器中以2.0％的PEG4000包被后用1.5％的高岭土施粉。The particles were coated as described in Example 22 of US 4,106,991 by adding a solution of 6.9% PEG4000 and 12.5% of a 1:1 TiO2/kaolin mixture. The granules were further coated with 2.0% PEG4000 in a Ldige mixer and powdered with 1.5% kaolin.
一部分颗粒按照下面的表格通过在Ldige搅拌器中加入非离子表面活性剂润滑(室温混合5分钟)。最终颗粒通过本领域公知的常规Heubach摩擦法检测粉尘(见例如WO93/07263)，检测产生的总粉尘(以毫克粉尘/20克颗粒表示)和酶的粉尘(以毫微克蛋白质/克颗粒表示)。表格中给出的值是三次测量的平均值。
这个实施例表明具非离子表面活性剂量为0.25％w/w或0.50％w/w的颗粒的最终润滑作用显著降低了粉尘水平。This example shows that final lubrication of particles with a non-ionic surfactant dosage of 0.25% w/w or 0.50% w/w significantly reduces dust levels.
实施例2Example 2
未包被的酶颗粒按照实施例1产生。Uncoated enzyme granules were produced as in Example 1.
颗粒按照实施例1中描述的通过涂加5.0％的PEG4000和12.5％的1∶1TiO2/高岭土混合物的溶液包被。颗粒进一步在Ldige搅拌器中以1.5％的PEG4000包被，然后用1.5％的高岭土对颗粒施粉。The particles were coated as described in Example 1 by applying a solution of 5.0% PEG4000 and 12.5% of a 1:1 TiO2 /kaolin mixture. The granules were further coated with 1.5% PEG4000 in a Lödige mixer, and then the granules were dusted with 1.5% kaolin.
冷却后，将一部分颗粒按照下面的表格通过在Ldige搅拌器中加入矿物油润滑(室温混合5分钟)。最终颗粒通过Heubach法检测粉尘。表格中给出的值是三次测量的平均值。
这个实施例表明具矿物油的颗粒的最终润滑作用显著降低了粉尘水平。实施例3This example shows that the final lubrication of the particles with mineral oil significantly reduces dust levels. Example 3
未包被的酶颗粒按照实施例1产生。Uncoated enzyme granules were produced as in Example 1.
颗粒按照实施例1中描述的通过涂加4.5％的PEG4000和12.5％的1∶1的TiO2/高岭土混合物的溶液包被。颗粒进一步在Ldige搅拌器中以预混合的PEG4000和润滑剂的混合物(见下表)包被，然后用1.5％的高岭土对颗粒施粉。使用了可溶于PEG4000的润滑剂(Softanol 50)和不溶于PEG4000的润滑剂(Whiteway T15)。最终颗粒通过Heubach法检测粉尘。表格中给出的值是三次测量的平均值。
这个实施例表明如果将润滑剂与包被材料(PEG4000)混合，最佳效果来自不溶于包被材料的润滑剂。This example shows that if the lubricant is mixed with the coating material (PEG4000), the best effect comes from a lubricant that is not soluble in the coating material.
实施例4Example 4
实施例1的润滑颗粒的相对摩擦系数使用来自Manumit PowderRheometer(Freeman Technology FT3 Powder Rheometer)的粉末流速计测量。摩擦系数与用流速计(叶梢圆周速度为50转/分钟，螺旋角为3°(压缩模式)，使用46mm转子并且称量170克颗粒至50mm测试容器中测量流速计(圆周速度为50转/分，螺旋角为3°(压缩模式))，使用46mm转子并且称量170克颗粒至50mm测试容器中所测得的力(FORCE)除以转矩(TORQUE)成比例。相对摩擦系数通过除以非润滑颗粒的摩擦系数计算。The relative coefficient of friction of the lubricating particles of Example 1 was measured using a powder flow meter from Manumit Powder Rheometer (Freeman Technology FT3 Powder Rheometer). Friction coefficient and flow meter (peripheral speed of blade tip is 50 rpm, helix angle is 3° (compression mode), using 46mm rotor and weighing 170 grams of particles into a 50mm test container to measure flow meter (peripheral speed is 50 rpm /min, a helix angle of 3° (compression mode)), using a 46mm rotor and weighing 170 grams of particles into a 50mm test container, the measured force (FORCE) is proportional to the torque (TORQUE). The relative coefficient of friction is given by Calculated by dividing by the coefficient of friction of non-lubricating particles.
(力/转矩)样品/(力/转矩)参照结果：
这个实施例表明润滑作用显著减小了相对摩擦系数。This example shows that lubrication significantly reduces the relative coefficient of friction.
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| CN01815335APendingCN1452657A (en) | 2000-09-08 | 2001-09-07 | Lubricated granules |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication | Open date:20031029 |