JP2004508040A - Lubricated granules - Google Patents

Abstract

There is provided an active-containing granule comprising a lubricant on an outer surface, wherein the lubricant is liquid at 25 ° C. and has a viscosity at 25 ° C. of less than 5000 centipoise.

Description

この実施例において証明されるように、０．２５％ｗ／ｗまたは０．５０％ｗ／ｗの量においてノニオン界面活性剤を使用する粒体の最終潤滑化はダストレベルを有意に減少させる。
【００６３】
実施例 ２ ．
実施例１におけるように、未被覆酵素粒体を製造した。
実施例１に記載されているように、５．０％のＰＥＧ ４０００および１２．５％の１：１ ＴｉＯ_２／カオリン混合物の溶液を適用することによって、粒体を被覆した。レヂゲ・ミキサー中で粒体を１．５％のＰＥＧ ４０００で被覆し、次いで粒体を１．５％のカオリンで粉末処理することによって、粒体をさらに被覆した。
冷却後、下記表に記載されているようにレヂゲ・ミキサーの中に鉱油を添加する （温室において５分間混合する） ことによって、粒体の一部分を潤滑化した。ヘウバッハ法を使用して、最終粒体をダストについて試験した。表に記載する値は３回の測定の平均である。
【００６４】
【表２】

この実施例において証明されるように、鉱油を使用する粒体の最終潤滑化はダストレベルを有意に減少させる。
【００６５】
実施例 ３ ．
実施例１におけるように、未被覆酵素粒体を製造した。
実施例１に記載されているように、４．５％のＰＥＧ ４０００および１２．５％の１：１ ＴｉＯ_２／カオリン混合物の溶液を適用することによって、粒体を被覆した。レヂゲ・ミキサー中で粒体をＰＥＧ ４０００と潤滑剤との予備配合混合物 （下記表参照） で被覆し、次いで粒体を１．５％のカオリンで粉末処理することによって、粒体をさらに被覆した。ＰＥＧ ４０００中に可溶性の潤滑剤 （Ｓｏｆｔａｎｏｌ ５０） およびＰＥＧ ４０００中に不溶性の潤滑剤 （Ｗｈｉｔｅｗａｙ Ｔ１５） の両方を使用した。ヘウバッハ法を使用して、最終粒体をダストについて試験した。表に記載する値は３回の測定の平均である。
【００６６】
【表３】

この実施例において証明されるように、潤滑剤を被覆物質 （ＰＥＧ ４０００） と混合する場合、被覆物質中に不溶性の潤滑剤から最良の効果が得られる。
【００６７】
実施例 ４ ．
マムニット・パウダー・レオメーター （Ｍａｎｕｍｉｔ Ｐｏｗｄｅｒ Ｒｈｅｏｍｅｔｅｒ） （Ｆｒｅｅｍａｎ Ｔｅｃｈｎｏｌｏｇｙ ＦＴ３ Ｐｏｗｄｅｒ Ｒｈｅｏｍｅｔｅｒ） からの粉末レオメーターを使用して、実施例１からの潤滑化粒体の相対摩擦係数を測定した。５０ ｒｐｍの先端速度、３°のねじれ角 （圧縮モード）、４６ ｍｍのローターを使用し、１７０ ｇの粒体を５０ ｍｍの試験容器に秤量して入れることによってレオメーターで測定したトルク（ＴＯＲＱＵＥ） で割った力（ＦＯＲＣＥ） に対して、摩擦係数は比例する。相対摩擦係数は、非潤滑化粒体からの摩擦係数で割ることによって計算される：
（ＦＯＲＣＥ／ＴＯＲＱＵＥ） _試料 ／ （ＦＯＲＣＥ／ＴＯＲＱＵＥ） _参照
【００６８】
結果：
【表４】

この実施例において証明されるように、相対摩擦係数は潤滑化により有意に減少する。[0001]
Field of the invention
The present invention relates to a granule comprising an active ingredient and an outer lubricant layer that suppresses dusting of the active ingredient from the granule.
[0002]
Background of the Invention
Granules containing active ingredients, such as enzymes, have been used in various industries for decades. Several techniques have been developed to produce such granules. The purpose of providing the active ingredients in particulate form is to prevent or reduce the occurrence of dusting of the active ingredients, as the active ingredients may cause health hazards to the person handling them. Heretofore, this has been achieved by producing active ingredient-containing granules comprising an active ingredient-containing core and various coating layers. Typically, the active-ingredient-containing granules consist of a core and a coating, where an important feature of the coating is to reduce the formation of dust when handling the granules.
[0003]
WO 96/16151 relates to enzyme granules coated with an aqueous liquid or a fatty mixture and an anti-agglomerating agent.
Further, WO 01/04279 and WO 00/01793 (not disclosed on the priority date) disclose granules containing a lubricant.
[0004]
Summary of the Invention
We have developed granules comprising a lubricant layer on the outer surface of the active ingredient-containing granules in addition to the coating layer.
Accordingly, the present invention comprises a lubricant on the outer surface of the active ingredient-containing granules,
(A) the lubricant is liquid at 25 ° C and has a viscosity of less than 5000 centipoise at 25 ° C, or
(B) Tip speed of 測定 50 rpm, 3 ° helix angle (compression mode), using a 46 mm rotor, 170 g of granules were measured by rheometer by weighing into a 50 mm test vessel. Sometimes the lubricated granules have a relative coefficient of friction lower than 80% compared to the unlubricated granules, or
(C) the lubricant is mineral oil,
Or a combination of these
The present invention relates to an active ingredient-containing granule characterized by the following.
In a further aspect, the invention relates to a method for producing the granules of the invention, a composition comprising the granules of the invention, and the use of the granules of the invention.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
Granules containing active ingredients, such as enzymes, are dry particles, and when handling these, the granules wear and tear (collision) because the individual granules collide with each other and cause "grinding" of the granule surface. And friction). This is believed to cause disruption of the coating of the granules or even disintegration of the granules, in which case the dry active ingredients, eg, enzyme proteins, can be liberated and form health hazardous dusts. However, it is not desirable to limit these handling obstacles, for example, by reducing the movement of the individual particles with respect to each other. Because the granules should also have good flow and mixing capabilities to facilitate handling of the granules, this requires the free mobility of the individual granules.
[0006]
Without being bound by this theory, applying lubricant on the outer surface "smooths" the individual particles, i.e., reduces the friction between the particles, thus improving the flow and mixing capacity of the particles. At the same time, it is considered that the frictional force that destroys the granules and generates dust of the active ingredient decreases. In addition, the lubricant can also reduce, for example, the tackiness of the binder in the coating to which the lubricant is applied, further preventing agglomeration of the granules. Thus, the lubricants defined herein can serve as anti-agglomerating and wetting agents, and as substances that reduce dust formation and particulate destruction.
In addition to the lubricant, the active ingredient-containing granules of the present invention suitably comprise an active ingredient-containing core and one or more coating layers as known in the art.
[0007]
Definition
The term lubricant is to be understood as any non-aqueous compound or mixture of compounds which forms a liquid at 25 ° C. and atmospheric pressure. Preferably, the lubricant has a viscosity of less than 5000 centipoise under these conditions.
[0008]
core
The core contains one or more active ingredients, preferably one or more enzymes. In addition to one or more active ingredients, the core can be composed of or in any manner that provides the desired functional properties of the core material, eg, the core is introduced into an aqueous medium. Sometimes it can consist of a substance that can easily release one or more active ingredients.
[0009]
Preferred configurations of the core include:
-Spray-dried core particles, which are spray-dried liquid enzyme-containing solutions, whereby small liquid particles of the active-ingredient-containing solution are dried to form active-ingredient-containing particulate matter. In this way, very small granules can be produced (Michael S. Showwell (editor); Powered detergents; Surfactant Science Series; 1998; vol. 71; pp. 140-142; Marcel Dek).
[0010]
-Layered core particles, wherein the active ingredient is coated as a layer around the preformed core particles or embedded in the surface of the core particles. Core particles of a desired size can be produced in such a way that useful core particles of a desired size can be found. Products of this type are described, for example, in WO 97/23606 and WO 97/39116, which are hereby incorporated by reference.
[0011]
-Extruded or pelletized core particles, where the active ingredient-containing paste is pre-pressed to form pellets or extruded through small openings, cut into particles and then dried. Such particles have a considerable size. This is because the material forming the extrusion opening (a plate with holes usually) limits the allowable pressure drop across the extrusion opening. The very high pressures required when using small openings generate heat in the active-ingredient-containing paste, which is detrimental to the active-ingredient (Michael S. Showwell (editor); Powered detergents; Surfactant Science Series 1998; vol. 71; pp. 140-142; Marcel Dekker).
[0012]
-Granulated core particles, wherein the active ingredient is immobilized in a solidified waxy substance. Typically, the active ingredient powder is suspended in molten wax and sprayed into a cooling chamber, for example, through a nebulizing device on a rotating disk, where the liquid particles are quenched to obtain a granular form. Particles are produced (Michael S. Showwell (editor); Powered detergents; Surfactant Science Series; 1998; vol. 71; pp. 140-142; Marcel Dekker).
[0013]
-Mixer granulated particles made by adding a dry powder composition of the active, liquid, and granulated components. When the appropriate liquid and powder are mixed and the moisture of the liquid is absorbed into the dry powder, the components of the dry powder begin to stick and agglomerate, the particles build up, and the granules containing the active ingredient are formed. Form. Such processes are described in the following documents: US Pat. No. 4,106,991 (NOVO NORDISK) and related documents EP 170360 B1 (NOVO NORDISK), EP 304332 B1 (NOVO NORDISK), EP 304331 ( NOVO NORDISK), WO90 / 09440 (NOVO NORDISK) and WO90 / 09428 (NOVO NORDISK), all of which are incorporated herein by reference.
The core component can be a component known in the art, including but not limited to:
[0014]
Active ingredient
The active ingredient can be any active ingredient that can benefit from being formulated into granules. Such an active ingredient can be a medicament.
The term "active ingredient" is meant to include all ingredients that are released from the granules when the granules are applied in a process and achieve the purpose of improving the process. Suitable active ingredients are those to be deactivated in the composition constituting the granules and / or those to be deactivated to other components.
[0015]
The active ingredient can be inorganic in nature, for example, a bleaching ingredient, or organic. Preferred active ingredients are biologically active substances, such as enzymes, pharmaceutically active substances that are active in the human or animal body, or agricultural chemicals, such as herbicides, pesticides, fungicides and / or It can be a fungicide. Such components are usually very sensitive to the surrounding environment and can suitably be obtained from chemical processes or from fermenting microorganisms. Most preferred active ingredients are peptides or polypeptides, for example enzymes.
[0016]
In the context of the present invention, an enzyme can be any enzyme or combination of different enzymes that can benefit when granulated to be applicable to a particular application. Thus, when referring to "enzymes", it will be understood that enzymes generally include a combination of one or more enzymes.
It should be understood that enzyme variants (eg, produced by recombinant techniques) are encompassed within the meaning of the term “enzyme”. Such enzyme variants are described, for example, in the following documents: EP 251,446 (Genencor), WO 91/00345 (Novo Nordisk), EP 525,610 (Solvay) and WO 94/02618 (Gist). -Brocades NV).
[0017]
The classes of enzymes used herein are as follows: Recommendations (1992) of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology, Atomology, Molecular Biology, Political Science, Molecular Biology. , 1992.
Accordingly, the types of enzymes that can be suitably incorporated into the granules of the present invention include: oxidoreductases (EC 1 .-.-.-), transferases (EC 2 .-.-.-), Hydrolases (EC 3 .-.-.-), lyases (EC 4 .-.-.-), isomerases (EC 5 .-.-.-) and ligases (EC 6 .-.-.-).
[0018]
Preferred oxidoreductases in the context of the present invention are peroxidase (EC 1.11.1), laccase (EC 1.10.3.2)} and glucose oxidase (EC 1.1.3.4), but preferred transferases are Transferases in any of the following subclasses:
a) transferase transferring one carbon group (EC 2.1);
b) Transferases that transfer aldehyde or ketone residues (EC 2.2); acyltransferases (EC 2.3);
c) Δglycosyltransferase (EC 2.4);
d) a transferase that transfers an alkyl or aryl group other than 基 methyl (EC 2.5); and
e) Transferase (EC 2.6) that transfers a nitro generating group.
[0019]
The most preferred form of transferase in the context of the present invention is transglutaminase (protein-glutamine γ-glutamyltransferase; EC 2.3.2.13).
Further examples of suitable transglutaminases are described in WO 96/069321 (Novo Nordisk A / S).
[0020]
Preferred hydrolases in the context of the present invention are: carboxylate ester hydrolases (EC 3.1.1.1-), for example lipases (EC 3.1.1.3); phytases (EC 3.1.3). .-), for example, 3-phytase (EC 3.1.3.8) and 6-phytase (EC 3.1.3.26); glucosidase (EC 3.2, which is referred to herein as "carbohydrase"). Α-amylase (EC 3.2.1.1); peptidases (EC 3.4, also known as proteases); and other carbonyl hydrolases.
[0021]
In the context of the present invention, the term "carbohydrase" refers not only to enzymes (ie glucosidases, EC 3.2) which are capable of breaking carbohydrate chains, in particular 5- and 6-membered ring structures (eg starch). And also used to mean an enzyme capable of isomerizing a carbohydrate, eg, a six-membered ring structure, eg, D-glucose, to a five-membered ring structure, eg, D-fructose.
[0022]
Relevant carbohydrases include the following (EC numbers in parentheses): α-amylase (3.2.1.1), β-amylase (3.2.1.2), glucans 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), dextranase (3.2.1.11), cutinase (3.2.1.14), polygalacturonase (3.2.1.15) ), Lysozyme (3.2.1.17), β-glucosidase (3.2.1.21), α-galactosidase (3.2.1.22), β-galactosidase (3.2.1.23) ), Amylo-1,6-galactosidase (3.2.1.33), chi Orchid 1,4-β-xylosidase (3.2.1.37), glucan endo-1,3-β-D-glucosidase (3.2.1.39), α-dextrin endo-1,6-α -Glucosidase (3.2.1.41), sucrose α-galactosidase (3.2.1.48), glucan-end-1,3-α-glucosidase (3.2.1.59), glucans 1,4 -Β-glucosidase (3.2.1.74), glucan endo-1,6-β-glycosidase (3.2.1.75), arabinan endo-1,5-α-L-arabinosidase ( 3.2.1.19), lactase (3.2.1.108), chitosanase (3.2.1.132) and xylose isomerase (5.3.1.5).
[0023]
Examples of commercially available oxidoreductases (EC 1 .-.-.-) are Gluzyme^TM (Enzymes available from Novo Nordisk A / S).
Examples of commercially available proteases (peptidases) are as follows: Kannase^TM, Everlase^TM, Esperase^TM, Alcalase^TM, Neutraze^TM, Durazym^TM, Savinase^TM, Pyrase^TM, Pancreatic Trypsin NOVO (PTN), Bio-Feed^TM, Pro and Clear-Lens^TM Pro (all available from Novo Nordisk A / S, Bagsvaerd, Denmark).
[0024]
Other commercially available proteases include: Maxatase^TM, Maxacal^TM, Maxapem^TM, Opticlean^TMAnd Purafect^TM (Genencor International Inc. or Gist-Brocades).
Examples of commercially available lipases are as follows: Lipoprime^TM, Lipolase^TM, Lipolase^TM Ultra, Lipozyme^TM, Palatase^TM, Novozyme^TM 435 and Lectitase^TM (All are available from Novo Nordisk A / S).
Examples of other commercially available lipases are as follows: Lumafast^TM (Lipase of Pseudomonas mendocina from Genencor International Inc.); Lipomax^TM (Ps. Pseudoalcaligenes lipase from Gist-Brocades / Genencor International Inc .; and Bacillus species lipase from Solvay enzyme).
[0025]
Examples of commercially available carbohydrases are as follows: Alpha-Gal^TM, Bio-Feed^TM Alpha, Bio-Feed^TM Beta, Bio-Feed^TM Plus, Bio-Feed^TM Plus, Novozyme^TM 188, Celluclast^TM, Cellusof^TM, Ceremyl^TM, Citrozyme^TM, Denimax^TM, Dezyme^TM, Dextrozyme^TM, Finizym^TM, Fungamyl^TM, Gamanase^TM, Glucanex^TM, Lactozym^TM, Maltogenase^TM, Pentopan^TM, Pectinex^TM, Promozyme^TM, Pulpzme^TM, Novamyl^TM, Termamyl^TM, AMG^TM (Amyloglucidase Novo), Maltogenase^TM, Sweetzyme^TMAnd Aquazym^TM (All are available from Novo Nordisk A / S).
[0026]
The amount of enzyme to be incorporated into the granules of the present invention will depend on the intended use of the granules. For many applications, the enzyme content will be as high or practicable as possible.
The enzyme content (calculated as the percentage of pure enzyme protein per granule weight) in the granules of the present invention will typically range from about 0.5 to 50% by weight of the enzyme-containing granules, Higher amounts, for example 50-90% w / w, are also possible.
[0027]
For example, when a protease (peptidase) is incorporated into the granules according to the present invention, the enzymatic activity (proteolytic activity) of the finished granules will typically range from 1 to 20 KNPU / g. This protease activity unit isKiloNovoProtationUIt is a sample of nits / g (KNPU / g). This activity is determined relative to an enzyme standard of known activity (KNPU / g). For a given amount of enzyme, the enzyme standard is standardized by measuring the rate of formation (μmol / min) of free amino groups released by digestion of dimethyl casein (DMC) in solution with the enzyme.
[0028]
The rate of formation is monitored by recording the linear absorption at 420 nm of the simultaneous reaction between the amino groups formed and the added 2,4,6-trinitrobenzenesulfonic acid (TNBS). The digestion and color reaction of DMC is carried out at 50 ° C. in boric acid solution at pH 8.3, the reaction time is 9 minutes and the measurement time is 3 minutes. The folder AF 220/1 is available on request from Novo Nordisk A / S (Denmark), and this folder is incorporated herein by reference.
[0029]
Similarly, for example, in the case of α-amylase, an activity of 10-500 KNU / g is typical. This activity is determined relative to an enzyme standard of known activity (KNU / g). For a given amount of enzyme, 2-chloro-4-nitrophenyl-β-D-maltoheptaside substrate is digested with enzyme and auxiliary α- and β-glucosidase enzymes in solution to release 2-chloro-4- Enzyme standards are standardized by measuring the rate of formation of nitrophenyl (μmol / min). Kits for performing the α-amylase assay are commercially available. One description of the α-amylase assay can be found in the print AF318 / 1-GB, which is available on request from Novo Nordisk A / S (Denmark). For example, for ligase, an activity in the range of 50-400 KLU / g is usually adequate.
[0030]
Usually, the enzyme is applied to the granulation process as an enzyme-containing liquid. The enzyme-containing liquid may be applied as a purified product, wherein the enzyme is dissolved or dispersed as crystalline and / or amorphous proteins in an aqueous liquid in the form of an enzyme concentrate, or may be fermented. It can be in the form of a broth. Water in the liquid can be used as a liquid agent for the granulation process (supra).
[0031]
Preformed core particles
In making the granules of the present invention by applying an active ingredient layer around the preformed core particles, the preformed core particles are preferably carbohydrate-based core particles, such as plant flour or product (cassava). (Cassava), cassava (manioc), cereal powder, sugars, dextrin and others) or salts such as sulfuric acid, sulfurous acid, phosphoric acid, phosphonic acid, nitric acid, hydrochloric acid or carbonic acid alkali metal Preference is given to core particles based on salts made from salts or alkaline earth metal salts or salts of simple organic acids, for example salts made from citrate, malonate or acetate.
[0032]
filler
Suitable fillers are water-soluble and / or insoluble inorganic salts (eg,
Finely divided alkali sulfates, alkali carbonates and / or alkali chlorides), clays such as kaolin (e.g. Speswitte)^TM, English China Clay), bentonite, talc, zeolites, and / or silicates.
[0033]
Binder
Suitable binders are binders with or without a high melting point in all or part of the non-wax properties, such as polyvinylpyrrolidone, dextrin, polyvinyl alcohol, cellulose derivatives such as hydroxypropylcellulose, methylcellulose or CMC It is. Suitable binders are carbohydrate binders, such as Glucidex 21D (available from Roquette Frares, France).
[0034]
Fiber material
Pure or impure cellulose in the form of fibers can be sawdust, pure fibrous cellulose, cotton, or pure or impure fibrous cellulose. Also, filter aids based on fibrous cellulose can be used. Several brands of cellulose in the form of fibers are sold, for example, CEPO and ARBOCELL. In the publication "Cepo Cellulose Powder" from Svenska Traejolsfavrikerna AB, for Cepo S / 20 cellulose, the approximate maximum fiber length is 500 μm, the approximate average fiber length is 160 μm, and the approximate maximum fiber width is Is 50 μm and the estimated average fiber width is 30 μm.
[0035]
It is also stated that Cepo SS / 200 cellulose has an estimated maximum fiber length of 150 μm, an estimated average fiber length of 50 μm, a maximum fiber width of 45 μm, and an estimated average fiber width of 25 μm. . Cellulose fibers having these dimensions are very well suited for the purposes of the present invention. The languages "Cepo" and "Arbocel" are trademarks. Preferred fibrous cellulose is Arbocel^TM BFC200. Also, as described in EP 304331 B1, synthetic fibers can be used, and typical fibers can be made from polyethylene, polypropylene, polyester, especially nylon, polyvinyl format, poly (meth) acrylic compounds. it can.
[0036]
Liquid agent
Liquid agents are used in conventional mixer granulation processes to granulate the accumulation or agglomeration of conventional granulated component particles. Liquid agents are water and / or waxy substances. Liquid agents are always used in the liquid phase in the granular process, but can later solidify; thus, the waxy material, if present, is dissolved or dispersed in water or melts. The term “waxy material” as used herein means a material having all of the following properties: 1) a melting point of 30-100 ° C., preferably 40-60 ° C., 2) the material is tough and Has a non-brittle character, and 3) the material is somewhat plastic in the greenhouse.
[0037]
Both water and wax are liquid agents, i.e., they are both active during the formation of granules; the wax remains as a component in the finished granules, but the water Portions are removed during the drying process. Examples of waxy substances are polyglycols, fatty alcohols, ethoxylated fatty alcohols, mono-, di- and triglycerol esters of higher fatty acids, such as glycerol monostearate, alkylaryl ethoxylates, and coconut ethanolamide. is there.
[0038]
If a large amount of wax is used, a relatively small amount of water is added, and vice versa. Thus, the liquid agent can be water alone, a waxy substance alone or a mixture of water and a waxy substance. When using a mixture of water and a waxy substance, the water and the waxy substance can be added in any order, for example, adding water first and then the waxy substance, or first adding the waxy substance Then, a solution or suspension of water or a waxy substance in water can be added. Also, when using a mixture of water and a wax, the wax can be soluble or insoluble (but dispersible) in the water. When water is used as the liquid agent, the water cannot be part of the finished mixer granules, since usually the majority of the water is dried off during subsequent drying of the mixer granules.
[0039]
Active ingredient stabilizer or active ingredient protectant
Enzyme stabilizers or protectants fall into several categories: alkaline or neutral substances, reducing agents, antioxidants and / or salts of metal ions of the first transition series. Each of these can be the same or used in combination with different categories of other protective agents. Examples of alkaline protectants are silicates, carbonates or bicarbonates of alkali metals, which provide a chemical scavenging action, for example, by actively neutralizing oxidants.
[0040]
Examples of reductive protecting agents are sulfites, thiosulfites or thiosulfates, while examples of antioxidants are methionine, butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA). The most preferred stabilizer or protecting agent is a thiosulfate, for example, sodium thiosulfate. Enzyme stabilizers can also be borates, borax, formate, dicarboxylic acids, tricarboxylic acids and reversible enzyme inhibitors, such as organic compounds with sulfhydryl groups or alkylated or arylated borates.
[0041]
Crosslinking agent
Crosslinking agents are active compatible surfactants, such as ethoxylated alcohols, especially alcohols having 10 to 80 ethoxy groups.
Other suspending agents, mediators (eg, to facilitate the bleaching action when dissolving the granules in the wash) and / or solvents can be incorporated into the granule core.
[0042]
coating
One or more coatings can be applied to the granules of the present invention to protect the desired properties of the granules, for example, the active ingredients in the core. The components of the coating may suitably be those described above, used in the core, preferably excluding enzymes.
[0043]
Conventional coatings known in the art, such as those described in the following patent applications, may be suitably used: WO 89/08694, WO 89/08695, 270 608 B1 and / or PA 1998 00876. (Prior application in the Netherlands, closed to the priority date of the present invention). Other examples of conventional coating materials can be found in the following patent applications: US Pat. No. 4,106,991, EP 170360, EP 304332, EP 304331, EP 458849, EP 458845, WO 97/39116, WO 92 / 12645A, WO 89/08695, WO 89/08694, WO 87/07292, WO 91/06638, WO 92/13030, WO 93/07260, WO 93/07263, WO 96/38527, WO 96/16151, WO 97/23606, U.S. Pat. No. 5,324,649, U.S. Pat. No. 4,689,297, EP 206417, EP 193829, DE 4344215, DE 4322229 A, DD 263790, JP 61162185 A and / or Or JP 58179492.
[0044]
In certain embodiments, the coating can comprise a small amount of a protective agent, wherein the protective agent can react with a component that can inactivate (inhibit) the active ingredient, wherein the inhibitory component surrounds From the matrix, i.e. before the components come into contact with the active ingredient and deactivate the active ingredient, they can enter the granules. Thus, the protective agent can, for example, neutralize and reduce the inhibitory component or otherwise react with the inhibitory component and render it harmless to the active ingredient. Typical ingredients capable of inactivating the active ingredients are oxidants, such as perbromates, percarbonates, organic peracids and others.
[0045]
Protecting agents fall into several categories: alkaline or neutral substances, reducing agents, antioxidants and / or salts of metal ions of the first transition series. Each of these can be the same or used in combination with different categories of other protective agents. Examples of alkaline protectants are silicates, carbonates or bicarbonates of alkali metals, which provide a chemical scavenging action, for example, by actively neutralizing oxidants. Examples of reductive protecting agents are sulfites, thiosulfites or thiosulfates, while examples of antioxidants are methionine, butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA). The most preferred stabilizer or protecting agent is a thiosulfate, for example, sodium thiosulfate. The amount of protective agent in the coating is 5-40% w / w of the coating, preferably 5-30% w / w, for example 10-20% w / w.
[0046]
The coating should encapsulate the active ingredient-containing granules by forming a substantially continuous homogeneous layer.
The coating can perform a number of functions on the granules, depending on the intended use of the granules. Thus, for example, a coating can achieve one or more of the following effects:
(I) slightly reduce the formation of active dust in the active ingredient-containing granules;
(Ii) protect one or more active ingredients in the active ingredient-containing granules against oxidation by bleaching substances / systems (eg, perbromates, percarbonates, organic peracids and others);
(Iii) when the granules are introduced into a liquid medium (eg, an aqueous medium), they dissolve at a desired rate;
(Iv) provide granules having better physical strength.
[0047]
The coating may further comprise one or more of the following substances: antioxidants, chlorine scavengers, plasticizers, pigments, additional enzymes and fragrances.
Useful plasticizers in the coating layer in the context of the present invention include, for example: polyols, such as sugars, sugar alcohols or polyethylene glycols (PEGs) having a molecular weight of less than 1000; ureas, phthalate esters, For example, dibutyl or dimethyl phthalate; and water.
Suitable pigments include, but are not limited to, finely divided white extenders, such as titanium dioxide or kaolin, colored pigments, water-soluble colorants, and one or more pigments and water-soluble colorants. Combination with.
[0048]
In a preferred embodiment of the invention, the granules according to the invention are coated with a protective coating having a high constant humidity, for example in Dutch patent application WO 00/01793, p. 5-9 and coated as described in the Examples, which are incorporated herein by reference.
The cores and coatings constituting the active ingredient-containing granules to be lubricated are suitably spherical or nearly spherical, suitably in their longest dimension from 50 to 2000 μm, preferably from 200 to 1200 μm, more preferably from 400 to 1200 μm. It can have an average diameter in the range of 800 μm or 50-200 μm.
[0049]
lubricant
The lubricant of the present invention forms a non-aqueous liquid at 25 ° C., preferably less than 5000 centipoise at 25 ° C., for example 500-5000 cP, preferably less than 4000 centipoise, for example 500-4000 cP, more preferably Is a compound or mixture of compounds having a viscosity of less than 3000 centipoise, eg, 500-3000 cP, most preferably less than 2500 centipoise, eg, 500-2500 cP. One advantage of using lubricants with low viscosities is that they are fairly easy to apply as a thin layer in small quantities on the granules, and the low viscosities result in a small amount of lubricant on all surfaces on the granules. Is promoted to be homogeneously distributed. When using a lubricant having a higher viscosity, the lubricant tends to adhere heterogeneously to the granule surface in the form of a sticky mass.
[0050]
Another advantage of the low viscosity lubricant is that the low viscosity lubricant, when applied to the outer surface of the granules, reduces the friction of the granules. The reduction in particulate friction can be easily measured with a rheometer. Accordingly, one aspect of the present invention, as described above, relates to active ingredient-containing granules comprising a lubricant on the outer surface of the granules, wherein a tip speed of 50 rpm, a twist angle of 3 ° ( Lubricated granules are compared to unlubricated granules when measured with a rheometer using a 46 mm rotor and weighing 170 g of granules into a 50 mm test vessel using a 46 mm rotor. Have a relative coefficient of friction lower than 80%, for example, 5 to 80%. Preferably, the relative coefficient of friction is less than 78%, such as 5 to 78%, more preferably less than 75%, such as 5 to 75%, most preferably less than 70% compared to the unlubricated granules. For example, it has a relative coefficient of friction of 5 to 70%.
[0051]
Preferably, the lubricant is an organic compound or a mixture of organic compounds that meets the requirements of low viscosity. Preferred lubricants are nonionic surfactants, such as Softanol (eg, Softanol 50) and / or Dobanol, natural refined mineral oils, such as Whiteway T15 (alkane oil), synthetic mineral oils, such as silicone oil, animal oil, Vegetable oil or any suitable mixture.
[0052]
As a further feature, certain advantages are achieved when using a lubricant that is substantially insoluble in the particulate material to which the lubricant is applied. One advantage of this embodiment is that the lubricant does not dissolve and / or mix with the particulate surface, for example, disappears from the particulate surface by absorption, where the lubricant is Functioning. Another advantage of this embodiment is that after mixing the lubricant and coating material, the lubricant and coating can be applied to the granules. Thus, the mixture or dispersion can be applied to the granules simultaneously, and since the lubricant is insoluble in the coating material, the lubricant can be separated from the coating material to form an outer lubricant layer. it can.
[0053]
The term "substantially insoluble" in this context means that less than 1 g of lubricant can be dissolved in 1 kg of the granular material to which the lubricant is applied. The particulate material on which the lubricant is applied, eg, the coating layer, is usually a hydrophilic, water-soluble material. Thus, in these embodiments, the preferred lubricant is hydrophobic. In particular, mineral oil lubricants are suitable, and in one aspect, therefore, the present invention relates to active ingredient-containing granules comprising a mineral oil lubricant on the granule surface. The most preferred lubricant is a mineral oil lubricant having a viscosity of less than 5000 centipoise, which reduces the relative coefficient of friction of the lubricated granules to less than 80% when compared to unlubricated granules.
[0054]
Lubrication of the active ingredient-containing granules lubricate the granules, reduce friction between the granules, reduce dusting and reduce the risk of breakage, but in some cases too much lubricant is applied In some cases, the lubricating properties of the lubricant have also been found to make the dry granules sticky and cohesive. As described in U.S. Pat. No. 4,106,911, Example 22, a dry particulate material such as TiO.₂Aggregation can be suppressed by subjecting the particles to powder treatment. However, this counteracts or even negates the lubricating action, and if the amount of lubricant is preferably less than 1% w / w of the lubricated granules, significant agglomeration is prevented while It has been discovered that beneficial lubrication is maintained.
[0055]
Thus, to prevent agglomeration and / or stickiness of the granules, which is a problem in handling the active ingredient-containing granules, and to avoid the cost and problems of adding various anti-agglomeration agents, 1% w / W, for example, 0.01-1% w / w, preferably less than 0.75% w / w, for example, 0.1-0.75% w / w, more preferably about 0.5 It is preferred to apply the additional lubricant as a very thin layer, comprising% w / w, for example 0.1-0.5% w / w. By using a lubricant that is substantially insoluble in the low viscosity lubricant and / or the particulate material to which the lubricant is applied, as described above, the application of a very thin lubricant layer is facilitated. There will be.
[0056]
As mentioned above, due to the nature and small amount of lubricant on the granules of the present invention, the use of an anti-cake agent to prevent agglomeration during manufacture or storage of the granules should be successfully omitted. Can be. Therefore, in a preferred embodiment of the invention, the granules of the invention do not contain an anti-cake agent applied on the lubricating layer.
[0057]
Method for producing lubricated granules
Properly applying the lubricant to the enzyme granules by adding the lubricant to the granules in an appropriate amount, mixing the composition and depositing and distributing the lubricant on the granule surface. it can. Mixing can be accomplished by spraying the lubricant onto the enzyme granules in a high speed mixer or fluid bed coater. As described above, in a preferred embodiment, the method for producing the granules of the present invention does not include a step of adding an anti-agglomeration agent to the lubricant layer.
[0058]
Application of lubricated granules
The lubricants of the present invention can be suitably incorporated into compositions for industrial and domestic use. Such compositions include cleaning and / or disinfecting compositions, for example, cleaning compositions that further comprise a surfactant. Such compositions are described, for example, in WO 00/01793, section "Disclosure of cleaning agents". Other compositions are antimicrobial compositions, wherein the enzyme is optionally an antimicrobial oxidoreductase, and compositions for treating microbial biofilms, wherein the enzyme is optionally an antimicrobial oxidoreductase. And the composition optionally further comprises a hydrolase enzyme. Other compositions can be feed or food compositions, such as animal feed or bread and confectionery flour.
[0059]
Example
Example 1 .
Uncoated Savinase (protease) -containing granules were prepared as described in US Pat. No. 4,106,991, Example 1, with the following exclusion:
・ Sodium sulfate was used instead of sodium chloride as the filling material.
-The enzyme concentrate was an aqueous suspension of a crystalline enzyme that also contained a carbohydrate binder (Glucidex) and methionine as an antioxidant.
[0060]
As described in U.S. Pat. No. 4,106,991, Example 22, 6.9% PEG 4000 and 12.5% 1: 1 TiO.₂The granules were coated by applying a solution of the / kaolin mixture. The granules were further coated by mixing the granules with 2.0% PEG 4000 in a Ladige mixer and then powdering the granules with 1.5% kaolin.
[0061]
A portion of the granules was lubricated by adding the nonionic surfactant into a Ladige mixer (mixing for 5 minutes in a greenhouse) as described in the table below. Using the conventional Heubach attrition method known in the art (see, for example, WO 93/07263), the total dust generated (as mg dust / 20 g granules) and enzyme dust (ng protein as ng) The final granules were tested for dust by measuring both (g / g of granules). The values given in the table are the average of three measurements.
[0062]
[Table 1]

As demonstrated in this example, the final lubrication of the granules using a nonionic surfactant in an amount of 0.25% w / w or 0.50% w / w significantly reduces dust levels.
[0063]
Example 2 .
As in Example 1, uncoated enzyme granules were produced.
As described in Example 1, 5.0% PEG 4000 and 12.5% 1: 1 TiO.₂The granules were coated by applying a solution of the / kaolin mixture. The granules were further coated by coating the granules with 1.5% PEG 4000 in a Reggae mixer and then powdering the granules with 1.5% kaolin.
After cooling, a portion of the granules was lubricated by adding mineral oil (mixing for 5 minutes in a greenhouse) into a reggae mixer as described in the table below. The final granules were tested for dust using the Heubach method. The values given in the table are the average of three measurements.
[0064]
[Table 2]

As evidenced in this example, the final lubrication of the granules using mineral oil significantly reduces dust levels.
[0065]
Example 3 .
As in Example 1, uncoated enzyme granules were produced.
As described in Example 1, 4.5% PEG 4000 and 12.5% 1: 1 TiO.₂The granules were coated by applying a solution of the / kaolin mixture. The granules were further coated by coating the granules with a pre-blended mixture of PEG 4000 and lubricant (see table below) in a Reggae mixer and then powdering the granules with 1.5% kaolin. . Both a lubricant soluble in PEG 4000 (Softanol 50) and a lubricant insoluble in PEG 4000 (Whiteway T15) were used. The final granules were tested for dust using the Heubach method. The values given in the table are the average of three measurements.
[0066]
[Table 3]

As demonstrated in this example, when the lubricant is mixed with the coating material (PEG 4000), the best effect is obtained from the lubricant which is insoluble in the coating material.
[0067]
Example 4 .
The relative coefficient of friction of the lubricated granules from Example 1 was measured using a powder rheometer from a Manumit Powder Rheometer (Freeman Technology FT3 Powder Rheometer). Torque measured by rheometer by weighing 170 g of granules into a 50 mm test vessel using a tip speed of 50 rpm, a twist angle of 3 ° (compression mode), a 46 mm rotor and a 50 mm test vessel. The coefficient of friction is proportional to the force divided by (). The relative coefficient of friction is calculated by dividing by the coefficient of friction from unlubricated granules:
(FORCE / TORQUE)_sample / (FORCE / TORQUE)_reference
[0068]
result:
[Table 4]

As demonstrated in this example, the relative coefficient of friction is significantly reduced by lubrication.

Claims (17)

Comprising a lubricant on the outer surface of the active ingredient-containing granules,
(A) the lubricant is liquid at 25 ° C. and has a viscosity of less than 5000 centipoise at 25 ° C. or (b) a tip speed of 50 rpm, a twist angle of 3 ° (compression mode), a rotor of 46 mm. When used and measured with a rheometer by weighing 170 g of granules into a 50 mm test container, the lubricated granules have a relative coefficient of friction lower than 80% compared to the unlubricated granules. Has or (c) the lubricant is mineral oil;
Alternatively, active ingredient-containing granules characterized by a combination thereof. The granule according to claim 1, wherein the active ingredient is a biologically active substance. 3. Granules according to claim 2, wherein the active ingredient is a pharmaceutically or catalytically active substance. 4. The granule according to claim 3, wherein the active ingredient is a peptide or a polypeptide. The granule according to claim 4, wherein the active ingredient is an enzyme. Granules according to claim 1, wherein the lubricant comprises less than 1% w / w of the granules, preferably less than 0.75% w / w. 2. The granule of claim 1, further comprising one or more coating layers. The granule according to claim 7, wherein the lubricant is insoluble in the coating layer on which the lubricant is applied. The granule according to claim 1, wherein the lubricant is an organic compound or a mixture of organic compounds. The granule according to claim 9, wherein the lubricant is a hydrophobic compound. 11. The granule according to claim 10, wherein the lubricant is selected from mineral, animal and vegetable oils or mixtures thereof. The granule according to claim 11, wherein the lubricant is a mineral oil. The granule according to claim 9, wherein the lubricant is a nonionic surfactant. The method for producing granules according to any of claims 1 to 13, wherein the granules containing the active ingredient are brought into contact with a lubricant, and the lubricant is deposited on the outer surface of the granules. A composition comprising the granules according to claim 1. The composition according to claim 15, wherein the composition is a detergent composition further comprising a surfactant. Use of the lubricating active ingredient-containing granules according to any one of claims 1 to 13.