JP2008545841A - Blends of inert particles and active particles - Google Patents

Abstract

  The present invention relates to a blend comprising two different types of particles: a. Particles comprising an active compound; and b. Inert particles comprising a coating. Inert particles are used to adjust the active strength of the particulate material comprising the active compound.

Description

Field of Invention:
The present invention relates to a blend comprising active particles and inert particles as a means for adjusting the active strength of the particulate material. The invention further relates to avoiding separation in the blend.

Background of the invention:
It is known in the art to inactivate core particles with an active compound in the production of a granulate comprising the active compound.

  WO2003 / 094899 relates to the production of a composition for the programmed release of enalapril. Inert nuclei are prepared from sugar and starch. A binder solution is added to the pulverized enalapril maleate active drug and subsequently to the core covered by talc. One part of the granulate is further coated, for example with ethylcellulose. Coated and uncoated granules are mixed to form the desired open profile.

  Coat the inert core particles with an inert material and use the coating as a means to adjust the size, density or appearance of the granulate, and adjust their activity to adjust the activity of the granulate comprising the active particles. The use of active coated granules is novel.

Summary of invention:
One object of the present invention is to provide a means for adjusting and controlling the activity intensity of a composition comprising active particles. Another object of the present invention is to provide a means for avoiding separation of the mixture. A third object is to prepare inert particles that have the same appearance as particles comprising the active compound.

Accordingly, in a first aspect, the present invention provides at least two different types of particles:
i) particles comprising the active compound; and
ii) inert particles comprising a coating,
A blend comprising is provided.
The present invention further provides a method for preparing the blend.

Specific description of the invention:
Definition:
The term “particle” or “granulate” is understood as a polymer-sized, mainly spherical or nearly spherical structure.

The term “ratio between the diameter of the particle and the diameter of the core unit” (hereinafter referred to as D _p / D _c ), as used herein, is divided by the diameter of the core unit only, It should be understood as the diameter of a granulate comprising core units and shell units. For example, if a core unit having a diameter of 100 μm is covered by a coating thickness of 200 μm, the grain has a diameter of (200 + 100 + 200) = 500 μm and D _p / D _c is 500 μm / 100 μm = 5 is there.

  The term “activity” refers to the relative ability of an enzyme in a preparation, granule, or core to react with a standard substrate under fixed standard conditions with respect to the enzyme preparation or for enzyme particles or enzyme cores. Measurement. Activity is measured in units defined as μmoles of substrate reacted per g of sample measured per minute under fixed standard conditions (hereinafter referred to as “standard assay”). Activity is also a measure of the amount of active enzyme protein.

  The enzyme has a specific activity that is the activity of a pure enzyme protein in a standard assay. Specific activity is also measured in units defined as μmoles of substrate reacted per gram of pure enzyme per minute under fixed standard conditions. If the specific activity of the enzyme is known, the amount of pure enzyme in the sample can be calculated. If a 1 g sample of pure enzyme reacts with 100 μmol substrate per minute in a standard assay, the specific activity of the enzyme is 100 units per g pure enzyme. If a 1 g sample of unknown enzyme activity reacts with 50 μmol substrate per minute in a standard assay, the sample activity is 50 units / g and 0.5 g of pure enzyme protein is present in the sample.

  The term “activity” should be understood as meaning the ability of an enzyme or granule to perform its intended work with respect to the enzyme, or with respect to the granule. For enzymes, this relates to its biocatalyst, for example metabolic processes. For granulate this relates to its overall intended work as planned in the overall formulation. The term “strength” relates to the activity of an enzyme or enzyme-containing particle with respect to its potency.

The particle size of the granulate means the diameter obtained by measurement with a sieve. When referring to “particle size” it can mean either the diameter of one particle or the average size of a particle batch depending on the contents.
The term “particle size ratio” is given by the particle size of the inert particles divided by the particle size of the particles comprising the active compound and is subsequently abbreviated as D _pI / D _pA .

The term “particle size distribution” is to be understood as a range of granule sizes due to a particular process; a range of particles or a gradient distribution with respect to their diameter.
The particle size distribution (PSD) can be represented by the mass average diameter of individual particles. The average mass diameter of D50 is the diameter where 50% by weight of the granulate has a smaller diameter and 50% by weight has a larger diameter. Values D10 and D90 are diameters where 10 and 90% by weight of the granulate respectively have a smaller diameter than the value in question. “Span” is the width of the PSD and is expressed as (D90-D10) / D50.

The term “particle density ratio” is the particle density of the inert particles divided by the density of the particles comprising the active compound and is _hereinafter abbreviated as ρ _pI / ρ _pA .
The term “separation count” is determined by a rolling bed test and Cs = | ((activity at the top) − (activity at the bottom)) | / | ((activity at the top) + (activity at the bottom) Activity)) |. The separation count is given as an absolute value.

  The separation according to the invention is measured in the rotating bed according to the following method: 600 ml of mixed particles are processed in the rotating bed. The rotating layer is present in a plastic cylinder 299 mm long x 89 mm wide. The cylinder opens at the top and is arranged with a tilt angle of 15 °. In order to reduce static electricity, the cylinder is cleaned by Rodalon and dried. The cylinder is rotated by the motor at 45-55 rpm for 5 minutes. After 5 minutes of rotation, the upper half of the granulate is removed from the cylinder. The average concentration of one type of particle at both the top and bottom is determined. The difference in the concentration of different particles between the top and bottom is a measure of the separation capacity of the granule mixture. The method described herein is similar to the method described by Williams J. C. and Khan M.I. (The Chemical Engineer, 19-25, January 1973).

  Another known method for measuring separation is a heap tester. A heap tester is a rectangular container with a transparent wall. Its dimensions are as follows: length 450mm, diameter 38mm and height 300mm. Because of the narrow diameter, it is also called a 2-dimensional heap. A funnel is placed in the center on the container. The funnel is filled with granular material and emptied into a container. The flow of material forms a two-dimensional heap with its top at the center of the so-called container. The heap is divided into sections or partitions with slicers. The slicer physically divides its slope into sections that are pushed down into the heap and evenly spaced along the granule flow method. Samples are taken from the top of individual sections by a suction system. The concentration of one component in each section is determined. The difference in concentration between the center and sides of the heap is a measure of the separation capacity of the granule mixture.

Introduction:
Compositions comprising specific active compounds are usually obtained with different activity strengths, depending on the application to which the composition is to be applied. In order to produce particles with a variety of different activity intensities for one particular active compound, new batches are expensive and time consuming, due to the individual different activity intensities required. Need to be generated. In addition, a large storage facility is required for all the different active concentration particles stored.

  In order to overcome these problems, the inventors have obtained a composition having the desired active strength by adding inert particles to the active particles; thereby to be prepared and one or a few It has been found that the number of different active granules is simply reduced to prepare particles with specific activity. It is therefore desirable to be able to use inert particles to produce particles comprising an active compound having significant activity and then dilute the composition to obtain the desired active strength of the batch.

  Another means of overcoming these problems is to produce high strength and low strength particles and use low strength particles to dilute the high strength particles to the desired active strength. .

  However, the use of a simple uncoated inert core in a batch of active compound-containing particles to adjust the activity intensity of the batch represents several negative aspects. One problem that arises when adding a simple inert core, such as salt particles, to the active compound-containing particles is the separation of the simple inert core and active compound-containing particles due to density and size differences; Another problem is that a simple inert core is found in the batch. Their negative aspects and solutions for the use of simple inert cores are adapted to the appearance of the active compound-containing particles to prevent separation, or on the other hand the particle density and / or size distribution / or surface properties It is to prepare inert particles that change (spherical, roughness, etc.). The main parameters used in the present invention to prevent separation are particle size and particle density control. One means of avoiding separation is to prepare particles comprising the active compound and inert particles having a more or less equivalent density and particle size.

  If the density of the inert particles results in separation because it is too high or too low, the separation can be prevented by adjusting the particle size of the particles. If the density of inert particles is higher than the particle density of the active particles that results in separation, the particle size of the inert particles should be increased to eliminate separation. If the density of inert particles is lower than the density of active particles that results in separation, the density of active particles should be increased to avoid separation. The density of the material used to change the particle size is also important.

The blends of the present invention are preferably premixes or intermediate products used in industrial processes to prepare the final product.
In a particular embodiment of the invention, the blend of the invention is in powder form.

Particles of the present invention :
One object of the present invention is to prevent separation.
Particle separation is mainly a problem with particles having a particle size of 50 μm or more. The particles of the present invention have a particle size of at least 50 μm in certain embodiments. In a more particular embodiment, the particle size is at least 100 μm. In the most specific embodiment, the particle size is at least 200 μm. In a particular embodiment of the invention, the particle size is between 100 μm and 2500 μm. In a more particular embodiment of the invention, the particle size is between 200 μm and 1200 μm. In an even more specific embodiment, the particle size is from 250 μm to 850 μm. In the most specific embodiment, the particle size is between 450 μm and 650 μm.

  When the surface characteristics, roughness, sphericity, etc. of inert and active particles are approximately equal, the main parameters that affect separation are particle size and particle density. If the particle density is not equal, the separation can be minimized by changing the size distribution to a larger or smaller size. Larger particle sizes make up for higher densities and vice versa.

  For the purposes of the present invention, the particle size distribution is usually as narrow as possible. Thus, the span of the particles of the present invention is typically about 2.5 or less, preferably about 2.0 or less, more preferably about 1.5 or less, and most preferably about 1.0 or less or even 0.5 or less. In certain embodiments, the particle span is from 0.1 to 0.9. One condition for obtaining a narrow particle size distribution of the particle blend is to coat the inert particles to obtain a particle size distribution of the inert particles that approximates the particle size distribution of the active particles.

  One means to avoid separation is to adjust the density of the inert particles to match the active compound-containing particles. Another means of avoiding separation can be to increase or decrease the density of the inert particles, depending on the particle size of the active compound-containing particles and the inert particles. If a size difference between the active and inactive particles is not desired, the particle density should be approximately equal to avoid separation. In a particular embodiment of the invention, the density of inert particles and active particles is 1.5 g / ml or less, such as 1 g / ml or less, further 0.5 / ml or less. In certain embodiments, the difference in density between the inert particles and the active particles is 0.25 g / ml or less. In a more specific embodiment of the present invention, the difference in density between the inert particles and the active particles is 0.1 g / ml or less.

The particle size ratio (D _pI / D _pA ) of the immortalizable particles and the active particles is 0.5-2, such as 0.6-1.4, in a particular embodiment of the present invention. In a more specific embodiment of the present invention, the particle size ratio is 0.7 to 1.3. In an even more specific embodiment of the invention, the particle size ratio is 0.8 to 1.2. In a further embodiment, the particle size ratio is from 0.9 to 1.1. In the most specific embodiment of the invention, the particle size is 0.95 to 1.05.

Reduce the separation of blends in which the particles differ significantly in either size and / or density by carefully planning the size or density so that the light particles have a larger diameter (and vice versa) Has been found to be possible. Regarding the separation, it was found that the diameter and density are almost equally important, ie the ratio ρ _pI / ρ _pA should be close to D _pI / D _pA in order to minimize the separation. . To obtain low separation, the density and diameter are 0.9 <(ρ _pI / ρ _pA ) · (D _pI / D _pA ) <1.1, preferably 0.95 <(ρ _pI / ρ _pA ) · (D _pI / D _pA ) should be selected to meet <1.05.

For example, ρ _pI / ρ _pA or D _pI / D _pA is greater than or equal to 1.1, or less than or equal to 0.9, or even greater than or equal to 1.2, or greater than 0.9 Is less than or equal to, or even greater than or equal to 1.2, or less than or equal to 0.8, or even greater than or equal to 1.2, or less than or equal to 0.8 It has been found that even when equal, this equation can be used to optimize the corresponding particle size or density to minimize separation by the described coating technique. This supplement can lower the separation factor below 0.3. In a specific correspondence, (ρ _pI / ρ _pA ) · (D _pI / D _pA ) is 0.9 to 1.1. In a more specific embodiment, (ρ _pI / ρ _pA ) · (D _pI / D _pA ) is 0.95 to 1.05.

  In a particular embodiment of the invention, the separation factor is 0.3 or less. In a more particular embodiment of the present invention, the separation factor is 0.2 or less. In an even more specific embodiment, the separation factor is 0.15 or less. In a further embodiment, the separation count is 0.1 or less. In the most specific embodiment, the separation factor is 0.08 or less, further 0.06 or less, such as 0.05 or less. The separation count is determined by a rotating bed test.

  Application of a thick fluid layer film to small core particles will provide a combination of possibilities for adjusting the particle density as both the core density and the coating density change. Variations in coating density can be achieved by applying materials with different densities, or by changing processing conditions that impart different porous coatings, for example by spraying solutions or suspensions onto the core ( Here, the suspension is typically obtained when applied on the core, which will increase the porosity of the applied phase over the solution).

  In a particular embodiment of the invention, the average particle density is 0.3 to 3.0 g / ml. In a more particular embodiment of the present invention, the average particle density is 0.8 to 2.5 g / ml. In an even more specific embodiment of the invention, the average particle density is from 1.5 g / ml to 2.1 g / ml.

  In a particular embodiment of the invention, the particle density ratio of inert particles and active particles is 0.5-2. In a more specific embodiment of the present invention, the particle density ratio between the inert particles and the active particles is 0.6 to 1.4. In an even more specific aspect of the present invention, the particle density ratio of inert particles and active particles is 0.7 to 1.3. In an even more specific aspect, the particle density ratio between the inert particles and the active particles is 0.8 to 1.2. In an even more specific aspect of the present invention, the particle density ratio of inert particles and active particles is from 0.9 to 1.1. In the most specific embodiment of the present invention, the particle density ratio between the inert particles and the active particles is 1.05 to 0.95.

  The particle density is measured by specific gravity methods well known in the art. A 150 ml dose flask is used and tested for 20-70 g samples. Flask is non-ionic surfactant (linear secondary alcohol ethoxylate, 12-14 moles alkyl carbon, 4.5-5.5 moles EO, 25-40 cPs viscosity at 25 ° C, 26-30 dynes / cm surface tension HLB9-12, specific gravity of 0.93 to 0.99 g / ml at 20 ° C., eg Softand 50 from Ineos Oxide), and particle density is measured volume of flask, nonionic surfactant only Is calculated from the weight of the flask filled with (the density of the surfactant), the weight of the sample and the weight of the flask containing the sample and the nonionic surfactant.

Appearance :
It is very important that the batch of particles have a homogeneous appearance, which is often a customer requirement. It is important that the particles be similar to the particles that are mixed into the composition, eg, detergent particles. However, in some cases it is important to be able to visually distinguish between active and inactive particles, which provides a quick identification of how well mixed.

To measure for appearance, the Hunter Lab color analysis method is used, where delta values, ΔL, Δa, Δb and ΔE are used. These values indicate how the standard and sample differ in color from each other.
The total difference in color is given by ΔE as follows:

  The color difference should be as low as possible, which means that ΔE should be as low as possible.

  In a particular embodiment of the invention, the color difference ΔE between the inert particles and the particles comprising the active compound is 6 or less. In a more particular embodiment of the present invention, the color difference ΔE between the inert particles and the particles comprising the active compound is 5 or less. In an even more specific embodiment of the invention, the color difference ΔE between the inert particles and the particles comprising the active compound is 4 or less. In the most specific embodiment of the invention, the color difference ΔE between the inert particles and the particles comprising the active compound is 3 or less.

Material :
The particles of the present invention can comprise one or more of the following components, but are not limited thereto:
Binders, polysaccharides, synthetic polymers, waxes, fillers, fiber materials, enzyme stabilizers, solubilizers, crosslinking agents, suspending agents, clay regulators, light spheres, plasticizers, pigments, salts and lubricants.
The particles of the present invention are preferably spherical or nearly spherical.

Polysaccharides:
The polysaccharide of the present invention may be a non-modified naturally occurring polysaccharide or a modified naturally occurring polysaccharide.
Suitable polysaccharides include cellulose, pectin, dextrin and starch. The starch can be soluble in water or insoluble.
In a particular embodiment of the invention, the polysaccharide is starch. In a particular embodiment of the invention, the polysaccharide is an insoluble starch.

  Naturally occurring starches from a wide variety of plant sources are suitable in the present invention (as starch itself or as a starting point for modified starches), and suitable starches are from Includes starches: rice, corn, wheat, potato, oats, cassava, sago palm, yucca, barley, sweet potato, sorghum, yam, rye, awa, buckwheat, kuzukon, taro, tannia, and, for example, powdered Can exist in form.

Among these, tapioca starch is a preferred starch in the present invention; in this regard, tapioca and tapioca starch are known as various similar terms, such as tapioca, manioc, mandioca and manihot.
As used herein, the term “modified starch” has undergone at least partial chemical modification, enzymatic modification and / or physical or physiochemical modification, and is generally referred to as “parent Naturally occurring starches exhibiting altered properties relative to “starch”.
In a particular embodiment of the invention, the granule comprises a polysaccharide.

Synthetic polymer:
The synthetic polymer means a polymer in which the main chain is synthetically polymerized. Suitable synthetic polymers according to the invention are in particular polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate, polyacrylates, polymethacrylates, polyacrylamides, polysulfonates, polycarboxylates and copolymers thereof, in particular aqueous polymers or Includes copolymers.
In a particular embodiment of the invention, the synthetic polymer is a vinyl polymer.

wax:
“Wax” as used herein should be understood as a polymeric material having a melting point of 25-150 ° C., in particular 30-100 ° C., more particularly 35-85 ° C., most particularly 40-75 ° C. is there. The wax is preferably present in the solid state at room temperature, ie 25 ° C. The lower limit sets an appropriate interval from the temperature at which the wax begins to melt to the temperature at which the granule or composition comprising the granule is typically stored, ie 20-30 ° C.

As used herein, “wax composition” should be understood as a mixture comprising a plurality of waxes. Such compositions usually have a solubility range rather than a melting point. The temperature at which the wax composition begins to melt is called T _{m, i,} and the median melting point for the wax composition is called T _{m, m,} and the temperature at which all wax solids are melted is T called _{m, e} . The median melting point herein is defined as the temperature at which 50% (w / w) of the solids in the wax is melted.

In a particular embodiment of the invention, the T _{m, i} of the wax composition is 25 ° C. or higher. In a more specific embodiment of the present invention, the T _{m, i} of the wax composition is 30 ° C. or higher. In the most specific embodiment of the present invention, the T _{m, i} of the wax composition is 35 ° C. or higher.
The melting range is calculated as the difference (° C.) between the temperature at which all wax solids are melted (T _{m, e} ) and the temperature at which the wax composition begins to melt (T _{m, i} ).

  For some granules, such as those used in the detergent industry, the preferred characteristic of waxes is that the wax should be water soluble or water dispersible, especially in neutral and alkaline solutions, so that When the coated particles of the invention are introduced into an aqueous solution by diluting it with water, the wax separates and / or dissolves and the quick release and solubility of the active compound incorporated in the aqueous solution by the particles Is to provide. An example of a water-soluble wax is polyethylene glycol (PEG). Among these, water-insoluble waxes that can be dispersed in an aqueous solution are triglycerides and oils. For some granules, it is preferred that the coating contains some insoluble wax, such as feed granules.

Preferably, the wax composition is a hydrophilic composition. In certain embodiments, the wax composition contains at least 25% w / w, preferably at least 50% w / w, preferably at least 75% w / w, preferably at least 85% w / w, preferably at least 95 % W / w, preferably at least 99% w / w of the component is water soluble.
In another embodiment, the wax composition is hydrophilic and is dispersible in aqueous solution.

In certain embodiments, the wax composition comprises 75% w / w or less, preferably 50% w / w or less, preferably 25% w / w or less, preferably 15% w / w or less, preferably 5% w / w. / w or less, preferably 1% w / w or less of hydrophobic components.
In certain embodiments, the wax composition comprises 75% w / w or less, preferably 50% w / w or less, preferably 25% w / w or less, preferably 15% w / w or less, preferably 5% w / w. / w or less, preferably 1% w / w or less of water-insoluble components.

Suitable waxes are one or more organic compounds having the above properties, or salts thereof.
The wax composition is preferably a component of at least 10% by weight coating material, more preferably at least 20% by weight coating material.
The wax composition of the present invention comprises any chemically synthesized wax. It can also equally well contain wax isolated from natural sources or derivatives thereof. Accordingly, the wax composition of the present invention comprises a wax selected from the following non-limiting list of waxes:

  -Polyethylene glycol, PEG. Different PEG waxes with different molecular sizes are commercially available, where PEG with a low molecular size also has a low melting point. Examples of suitable PEGs are BASF (Pluriok E series) or PEG 1500, PEG 2000, PEG 3000, PEG 4000, PEG 6000, PEG 8000, PEG 9000, etc. from Clariant or Ineos. Derivatives of polyethylene glycol can also be used.

  -Polypropylene (eg, polypropylene glycol Pluriol P series from BASF), or polyethylene, or mixtures thereof. Polypropylene and polyethylene derivatives may also be used.

  -Nonionic surfactants that are solid at room temperature, e.g. ethoxylated fatty alcohols with high levels of ethoxy groups, e.g. Lutensol AT series from BASF, C16-C18 fats with different amounts of ethylene oxide per molecule Alcohols such as Lutensol AT11, AT13, AT25, AT50, AT80 (where the numbers indicate the average number of ethylene oxide groups). On the other hand, polymers of ethylene oxide, propylene oxide, or copolymers thereof, such as block polymers such as Pluronic PE6800 from BASF are useful. Derivatives of ethoxylated fatty alcohols are useful.

  Waxes isolated from natural sources, such as Carnauba wax (melting point 80-88 ° C.), Candelilla wax (melting point 68-70 ° C.) and beeswax. Other natural waxes or derivatives thereof are waxes of animal or plant origin, for example marine origin. Hydrogenated vegetable oil or beef tallow, hydrogenated coconut oil, hydrogenated cotton seeds and / or hydrogenated soybean oil, where the term “hydrogenated” is used herein When used, it should be construed as, for example, a saturated or unsaturated carbohydrate chain in triglycerides, where the carbon = carbon double bond is converted to a carbon-carbon single bond. Hydrogenated coconut oil is available from Hobum OeIe und Fette GmbH-Germany or Deutche Cargill GmbH-Germany.

A fatty alcohol, for example the linear long chain alcohol NAFOL 1822 (C18, 20, 22) from Condea Chemie GMBH-Germany, having a melting point of 55-60 ° C Derivatives of fatty alcohols.
-Monoglycerides and / or diglycerides such as glyceryl stearate (where the stearate is a mixture of stearic acid and palmitic acid) are useful waxes. An example of this is Dimodan PM from Danisco Ingredients, Denmark.
-Fatty acids such as hydrogenated linear long chain fatty acids and derivatives of fatty acids.
-Paraffin, ie solid hydrocarbon.
A microcrystalline wax.

In a further aspect, the waxes useful in the present invention are CM. McTaggart et al., Int. J. Pharm. 19, 139 (1984) or Flanders et al., Drug Dev. Ind, incorporated herein by reference. Pharm. 13, 1001 (1987).
In a particular embodiment of the present invention, the wax of the present invention is a mixture of a plurality of different waxes.

In a particular embodiment of the invention, the wax is selected from the group consisting of PEG, ethoxylated fatty alcohol, fatty acid, fatty alcohol and glyceride.
In another particular embodiment of the invention, the wax is selected from synthetic waxes. In a more particular embodiment, the wax of the present invention is PEG or a nonionic surfactant. In the most specific embodiment of the invention, the wax is PEG.

filler:
Suitable fillers are water-soluble and / or water-insoluble inorganic salts such as finely ground alkyl sulfates, alkyl carbonates and / or alkyl chlorides, clays such as kaolin (eg SPESWHITE ^™ , English China Clay), bentonite Talc, zeolite, chalk, calcium carbonate and / or silicate.

Textile material:
Pure or impure cellulose in fiber form, such as sawdust, pure fiber cellulose, cotton, or other forms of pure or impure fiber cellulose may be used. Also, a filling aid based on fiber cellulose can be used. Several types of cellulose in fiber form are commercially available, such as CEPO ^™ and ARBOCELL ^™ . Suitable examples of fiber cellulose filler aids are ARBOCELL BFC 200 ^™ and ARBOCELL BC 200 ^™ . Synthetic fibers can also be used as described in EP304331B1, and typical fibers can be made from polyethylene, polypropylene, polyester, in particular nylon, polyvinylformate, poly (meth) acrylic compounds.

Oxygen stabilizer:
Enzymatic stabilizers or protective agents usually used in the field of granulation can be core or coating elements. Stabilizers or protective agents are usually used in the field of granulation. Stabilizers or protective agents can be divided into several categories: alkaline or neutral materials, reducing agents, antioxidants, and / or salts of metal ions of the first transition series. Each of them can be used with other protective agents of the same or different categories. Examples of alkaline protectants are alkali metal silicates, carbonates or bicarbonates that provide chemical removal, for example by actively neutralizing the oxidizing agent. Examples of reducing protectants are sulfites, thiosulfites, thiosulfates or MnSO ₄ and examples of antioxidants are methionine, butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA). ). In particular, the stabilizer may be a thiosulfate, such as sodium thiosulfate or methionine.

  Enzyme stabilizers can also be organic compounds including borates, borax, formates, di- and tricarboxylic acids, and reversible enzyme inhibitors such as sulfhydryl groups, or alkylated or arylated boric acids. Examples of boron-based stabilizers are found in WO 96/21716, and a preferred boron-based stabilizer is 4-formyl-phenyl-boric acid or its derivatives described in WO 96/41859. (The disclosures of those documents are incorporated herein by reference). Still other examples of useful enzyme stabilizers are gelatin, casein, polyvinylpyrrolidone (PVP) and nonfat milk powder. The amount of protective agent in the coating can be 5-40% by weight of the coating, in particular 5-30% by weight, for example 10-20%.

Solubilizer:
The solubility of the coating is particularly critical when the coated particles are a component of a detergent formulation. As known by those skilled in the art, many agents act to increase the solubility of the formulation through various methods, and typical agents known in the art are found in National Pharmacopeia's. obtain.

Light sphere:
Light spheres are small particles with a low true density. Typically, they are hollow sphere particles with air or gas inside. Such materials are usually prepared by foaming solid materials. These light spheres are of inorganic nature, such as SCOTCHLITE ^™ Glass Bubbles (hollow glass spheres) from 3M ^™ , Q-CEL ™ (borosilicate glass hollow spheres) available from The PQ Corporation and / or Ex -may be tendospheres ™ (ceramic hollow spheres). Light spheres are also of organic nature, eg PM-series (plastic hollow spheres) available from The PQ Corporation, Expancel ™ (plastic hollow spheres) from AKZO Nobel, Luxsil ™ from Potters Industries And Sphericel ™ and / or Styrocell ™ from SHELL (which is a polystyrene sphere). Styrocell ™ polystyrene is based on heating, boiling the material and foaming or repelling (this reaction is equivalent to foaming corn seeds into popcorn), a low true density light polystyrene material. Includes free pentane. Also preferred are polysaccharides such as starch or derivatives thereof. Biodac ™ is an example of a non-hollow lightweight material made from cellulose (waste from paper manufacture) available from GranTek Inc. These materials can be included in the granules of the present invention alone or as a mixture of different light materials.

Cross-linking agent:
Crosslinkers, such as enzyme-compatible surfactants, such as ethoxylated alcohols, in particular those having 10 to 80 ethoxy groups, can be present. They can be found in both coatings and core particles.

Anti-precipitation agent:
Anti-settling agents, mediators (to enhance the bleaching action based on dissolution of the particles in cleaning applications) and / or solvents can be incorporated into the particles.
Viscosity modifier:
Viscosity modifiers can be present in the particles.

Plasticizer:
Plasticizers useful in the coating layers of the present invention include polyols such as sugars, sugar alcohols, glycerin, glycerol trimethylolpropane, neopentyl glycol, triethanolamine, mono-, di- and triethylene glycol or polyethylene glycol (PEG). (Having a molecular weight of 1000 or less); ureas, phthalate esters such as dibutyl or dimethyl phthalate; thiocyanates, nonionic surfactants such as ethoxylated alcohols and ethoxylated phosphates, and water.

Pigment:
Suitable pigments include finely divided white extender pigments such as titanium dioxide or kaolin, colored pigments, water soluble colorants, and combinations of one or more pigments and water soluble colorants. It is not limited to. Granules comprising an enzyme, and if the granules are additives for detergents, whitening agents, for example, TiO ₂ may be incorporated in the granules. If the granules are intermittently performed at different positions in the granulator, or if granulation is performed continuously, TiO ₂ can be obtained by adding TiO ₂ at various times during the granulation process. , Distributed within the wax coating or on the surface of the wax coating, or optionally both.

salt:
Salts are inorganic salts such as sulfates, sulfites, phosphates, phosphonates, nitrates, hydrochlorides or carbonates, or simple organic acid salts (less than 10 carbon atoms, such as 6 or less carbons). Atom), for example citrate, malonate or acetate. Examples of cations in these salts are alkali or alkaline earth metal ions, but also include ammonium ions or metal ions of the first transition series such as sodium, potassium, magnesium, calcium, zinc or aluminum. Examples of anions are chloride, iodide, sulfate, sulfite, bisulfite, thiosulfate, phosphate, monobasic phosphate, dibasic phosphate, hypophosphite, dihydrogenpyrroline Acid salt, carbonate, bicarbonate, metasilicate, citrate, malate, maleate, malonate, succinate, lactate, formate, acetate, butyrate, propionate, Includes benzoate, tartrate, ascorbate or gluconate.

In particular, sulfate, sulfite, phosphate, phosphate, nitrate, chloride or carbonate alkali or alkaline earth metal salts, or simple organic acid salts such as citrate, malonate or acetic acid Salts can be used. Specific examples are NaH ₂ PO ₄ , Na ₂ HPO ₄ , Na ₃ PO ₄ , (NH ₄ ) H ₂ PO ₄ , K ₂ HPO ₄ , KH ₂ PO ₄ , Na ₂ SO ₄ , K ₂ SO ₄ , KHSO ₄ , ZnSO ₄ , MgSO ₄ , CuSO ₄ , Mg (NO ₃ ) ₂ , (NH ₄ ) ₂ SO ₄ , sodium borate, magnesium acetate and sodium citrate.

The salt can also be a hydrated salt, ie a crystalline hydrate with crystallized bound water as described in WO99 / 32595. Examples of hydrated salts are magnesium sulfate heptahydrate (MgSO ₄ (7H ₂ O)), zinc sulfate heptahydrate (ZnSO ₄ (7H ₂ O)), sodium phosphate dibasic Heptahydrate (Na ₂ HPO ₄ (7H ₂ O)), copper sulfate nitric acid hexahydrate (CuSO ₄ (6H ₂ O)), magnesium hexahydrate (Mg (NO ₃ ) ₂ (6H ₂ O)), sodium borate decahydrate, sodium citrate dihydrate and magnesium acetate tetrahydrate.

Lubricant:
As used herein, the term “lubricant” refers to any agent that reduces surface friction, lubricates the surface of the granules, reduces the tendency to build up static electricity, and / or reduces the friability of the granules. Mention. Lubricants can also play a related role in improving the coating process by reducing the tackiness of the binder in the coating. Thus, the lubricant can act as an anti-aggregant and humectant. Examples of suitable lubricants are low molecular weight polyethylene glycol (PEG), ethoxylated fatty alcohols and mineral oils. The lubricant is in particular a mineral oil or a nonionic surfactant, and more particularly the lubricant is immiscible with other coating materials.

Inert particles:
The composition of the inert particles is a homogenous mixture of particles or it can be stacked particles. In a particular embodiment of the invention, the inert particles comprise inert core particles, on which at least one coating is applied.

Inert core particles :
An inert core particle, such as a placebo particle, a carrier particle, an inert nucleus, an inert particle, a non-ballein particle, a non-active particle, or a seed is a particle that does not contain an active compound, and further comprises an active compound The coating mixture can be laminated. They are formulated with organic or inorganic materials such as inorganic salts, sugars, sugar alcohols, small organic molecules such as organic acids or salts, starches, celluloses, polysaccharides, minerals such as clays or silicates, or combinations thereof. obtain.

  In a particular embodiment of the invention, the particles to be coated are inert particles. In a more particular embodiment of the present invention, the core particle material is selected from the group consisting of inorganic salts, sugar alcohols, small organic molecules, starch, cellulose and minerals. In certain embodiments of the invention, the particles are not made from alkyl metal silicates.

  In a particular embodiment of the invention, the core particles have a particle size of at least 50 μm. In a more particular embodiment, the core particle size is at least 100 μm. In the most specific embodiment, the core particle size is at least 150 μm. In a particular embodiment of the invention, the core particle size is 50-1200 μm. In a more particular embodiment of the present invention, the core particle size is 100-800 μm. In a more specific embodiment of the invention, the core particle size is 125-450 μm. In the most specific embodiment of the invention, the core particle size is 150-350 μm.

Coating :
The coating applied to the non-immobilizable core particles is used to obtain the desired characteristics of the inert particles, for example a specific density or a specific size or size distribution. The coating can further be used to obtain the same or similar appearance as the particles comprising the active compound.
The coating applied to the inert core particles can be any coating known from pharmaceutical and enzyme products, but is not limited thereto.

  The coating may comprise one or more conventional shells or coating components as described in WO 89/08694, WO 89/08695, 270 608 B1 and / or WO 00/01793. Other examples of conventional coating materials are US 4,106,991, EP 170360, EP 304332, EP304331, 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, WO96 / 38527, WO 96/16151, WO 97 / No. 23606, US Pat. No. 5,324,649, US Pat. No. 4,689,297, EP 206417, EP 193829, DE 4344215, DE 4322229 A, DD 263790, JP 61162185 A and / or JP 58179492. In certain embodiments, the coating is not an organic diphosphonate.

  For some inert core particles, it is difficult to obtain the desired characteristics of the particles by simply encapsulating the inert core particles with a thin coating, and therefore some coatings, or thick coatings such as It is desired to apply a coating known from WO 01/25412 which is incorporated herein by reference.

In a particular embodiment of the present invention, the inert granule of the present invention comprises a structure wherein D _p / D _c is at least 1.1, meaning that the thickness of the shell unit is at least 5% of the core unit diameter. Have. In certain embodiments, for D _p / D _c of granules, at least 1.05, more particularly at least 1.25, more particularly at least 1.5, at least 2 and even more identified, most particularly is at least 3. However, _Dp / _Dc is especially about 100 or less, especially about 50 or less, more particularly 25 or less, and most particularly 10 or less.

In order to obtain an appearance that is the same as or similar to particles comprising the active compound, it is necessary to apply a coating of minimal thickness to ensure a normal surface appearance.
In certain embodiments of the invention, the coating is at least 10 μm thick. In more particular embodiments, the thickness is at least 25 μm, such as at least 50 μm, at least 75 μm, at least 100 μm, at least 150 μm, at least 200 μm, or most particularly at least 300 μm.

  In certain aspects of the invention, the coating comprises at least 5% by weight of the total granule. In a more particular embodiment of the invention, the coating constitutes at least 10% by weight of the total granules. In an even more specific embodiment of the present invention, the coating comprises at least 25%, such as 50% by weight of the total granule. In a further embodiment, the coating comprises at least 75% by weight of the total granule. In the most particular embodiment of the invention, the coating constitutes at least 90%, for example 95% by weight of the total granules.

  In certain aspects of the invention, the coating comprises at least 5% by weight of the total granule. In a more particular embodiment of the invention, the coating constitutes at least 10% by weight of the total granules. In an even more specific embodiment of the present invention, the coating comprises at least 25%, such as 50% by weight of the total granule. In a further embodiment, the coating comprises at least 75% by weight of the total granule. In the most particular embodiment of the invention, the coating constitutes at least 90%, for example 95% by weight of the total granules.

  The density of the inert core particles is usually higher than the density of the particles comprising the active compound. Accordingly, it is often beneficial that the coating used to change the size and density of the inert particles have a density that is lower than the density of the inert core to achieve the desired effect.

  In a particular embodiment of the invention, the difference between the coating density and the particle core is at least 5%. In a more particular embodiment of the invention, the difference between the density of the coating and the core of the particles is at least 10%. In an even more specific embodiment, the difference between the density of the coating and the core of the particles is at least 25%. In the most specific embodiment, the difference between the density of the coating and the core of the particles is at least 50%.

  In certain embodiments of the invention, the density of the coating is at least 5% less than the density of the core. In a more particular embodiment of the invention, the density of the coating is at least 10% lower than the density of the core. In an even more specific embodiment of the present invention, the density of the coating is at least 25% lower than the density of the core. In the most specific embodiment of the invention, the density of the coating is at least 50% lower than the density of the core.

The particle density ρ _p of the coated particles is obtained from the particle density and diameter of the core ρ _c and the coating ρ _coationg :
ρ _p = (ρ _c · Dc ³ + ρ _coating · (Dp ³ −Dc ³ )) / Dp ³
In fact, the particle size density and particle size, as well as the core density and size of the coated particles are measured. The coating density can be calculated using the above formula.

Granules comprising active compound:
A granule comprising the active compound can be any granule formulated to comprise the active compound.

  One object of the present invention is to provide a means for obtaining the desired active strength of any of the granules comprising the active compound by easy means. Ideally, high strength granules (high activity granules) are produced and mixed with granules with low or low activity compared to high activity granules, eg high strength Is to provide a method for diluting a granule of any desired active strength. In a particular embodiment of the invention, the activity intensity of the high activity granules is at least 4 times higher than the activity of the low activity granules. In a more particular embodiment of the invention, the activity intensity of the high activity granules is at least 10 times higher than the activity of the low activity granules. In the most specific embodiment of the invention, the activity intensity of the high activity granules is at least 100 times higher than the activity of the low activity granules. If the low activity granules are used to dilute the high activity granules instead of the inert granules, anything associated with the inactivating granules disclosed in this description can also be applied to the low activity granules .

Active compound :
The active compound of the present invention present in the core or coating can be any active compound or mixture of active compounds, which is significant in that it is separated from the environment surrounding the granules. The term “active” includes all compounds that fulfill the purpose of improving said process based on the release from the coated granule based on the application of the coated granule of the present invention in one process. . The active compound can be of inorganic or organic nature.

  In particular, the active compounds are biologically active compounds that are usually very sensitive to the surrounding environment, for example compounds obtainable from microorganisms. More particularly, the active compound is a peptide or polypeptide or protein. Most particularly, the active compound is a protein, such as an enzyme. Further suitable active compounds are bleaches, growth promoters, antibiotics, antigenic determinants used as vaccines, constructed polypeptides with increased content of essential amino acids, hormones and other therapeutic proteins . In a particular embodiment of the invention, the active compound is a protein. In a more particular embodiment, the protein is an enzyme.

The enzyme in the present invention can be any enzyme or a combination of different enzymes. Thus, when referring to “enzymes” it will be understood that this generally encompasses one enzyme or a combination of enzymes.
It should be understood that enzyme variants (eg, produced by recombinant techniques) are encompassed within the meaning of the term “enzyme”. Examples of such enzyme variants are for example disclosed in EP 251,446 (Genencor), WO 91/00345 (Novo Nordisk), EP 525,610 (Solvay) and WO 94/02618 (Gist-Brocades NV) .

  Enzymes can be classified based on a handbook (Enzyme Nomenclature from NC-IUBMB, 1992). Also see the ENZYME site on the Internet: http://www.expasv.ch/enzvme/. ENZYME is a repository for information on enzyme nomenclature. It is mainly based on the recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUB-MB), Academic Press, Inc., 1992, and it is provided with an EC (Enzyme Commission) number Describes individual types of characterized enzymes (Bairoch A. The ENZYME database, 2000, Nucleic Acids Res 28: 304-305). This IUB-MB enzyme nomenclature is based on the substrate specificity of the enzymes and sometimes their molecular mechanism; such a classification does not affect the structural features of those enzymes.

  Another class of glycoside hydrolase enzymes, such as endoglucanase, xylanase, galactanase, mannanase, dextranase and α-galactosidase, based on amino acid sequence similarity has been proposed several years ago. They are currently classified into 90 different families: CAZy (ModO) Internet site (Coutinho, PM & Henrissat, B. (1999) Carbohydrate-Active Enzymes server at URL: http: //afmb.cnrs-mrs. fr / ~ cazy / CAZY / index.html (Corresponding document: Coutinho, PM & Henrissat, B. (1999) Carbohydrate-active enzymes: an integrated database approach. In "Recent Advances in Carbohydrate Bioengineehng", HJ. Gilbert, G Davies, B. Henrissat and B. Svensson eds., The Royal Society of Chemistry, Cambridge, pp. 3-12; Coutinho, PM & Henrissat, B. (1999) The modular structure of cellulases and other carbohydrate-active enzymes: an "integrated database approach. In" Genetics, Biochemistry and Ecology of Cellulose Degradation "., K. Ohmiya, K. Hayashi, K. Sakka, Y. Kobayashi, S. Karita and T. Kimura eds., Uni Publishers Co., Tokyo , pp. 15-23).

The types of enzymes that can be incorporated into the granules of the present invention include oxidoreductase (EC1 .-.-.-), transferase (EC2 .-.-.-), hydrolase (EC3 .-.-.-), lyase ( EC4 .-.-.-), isomerase (EC5 .-.-.-) and ligase (EC6 .-.-.-).
Preferred oxidoreductases herein include peroxidase (EC 1.1.11.), Laccase (EC 1.10.3.2) and glucose oxidase (EC 1.1.3.4). An example of a commercially available oxidoreductase (EC1 ...) is Gluzyme ^™ (an enzyme available from Novozymes A / S).

In addition, oxidoreductases are available from other suppliers. Preferred transferases are transferases in any of the following subclasses:
a) 1-carbon group transfer transferase (EC 2.1);
b) a transferase that transfers an aldehyde or ketone residue (EC 2.2); an acyltransferase (EC 2.3);
c) Glycosyltransferase (EC 2.4);
d) transferases that transfer aryls other than alkyl or methyl groups (EC 2.5); and e) transferases that transfer nitrogen groups (EC 2.6).

The most preferred type of transferase in the present invention is transglutaminase (protein-glutamine γ-glutamyltransferase; EC 2.3. 2.13).
Further examples of suitable transglutaminases are described in WO 96/06931 (Novo Nordisk A / S).

Preferred hydrolases in the present invention are the following: carboxylate ester hydrolase (EC 3.1.1), such as lipase (EC 3.1.1), phytase (EC 3.1.3) -), E.g. 3-phytase (EC 3.1.3.8) and 6-phytase (EC 3.1. 3.26); glycosidase (EC 3.2, a group designated herein as "carbohydrase") For example, α-amylase (EC 3.2.1.1); peptidase (EC 3.4, also known as protease); and other carbonyl hydrolases. Examples of commercially available phytases include Bio-Feed ^TM phytase (Novozymes), Ronozyme ^TM P (DSM Nutritional Products), Natuphos ^TM (BASF), Finase ^TM (AB Enzymes), and the Phyzyme ^TM product series (Danisco) . Other preferred phytases include those described in WO 98/28408, WO 00/43503, and WO 03/066847.

  As used herein, the term “carbohydrase” refers specifically to an enzyme (ie, glycosidase, EC 3.2) that can degrade carbohydrate chains (eg, starch) of 5- and 6-membered ring structures. Rather, it is used to indicate an enzyme that can isomerize a carbohydrate, such as a 6-membered structure, such as D-glucose, into a 5-membered ring structure, such as D-fructose.

  Suitable carbohydrases include (EC numbers in parentheses): α-amylase (3.2.1.1.1), β-amylase (3.2.1.2), glucan 1,4-α-glucosidase ( 3.2.1.3), endo-1,4-β-glucanase (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), chitinase (3.2.1.14), polygalacturonase (3.2.1.15), lysozyme (3.2.1.17), β-glucosidase (3.2. 1.21), α-galactosidase (3.2.2.12), β-galactosidase (3.2.2.13), amylo-1,6-glucosidase (3.2.2.13), xylan 1,4-β-xylosidase (3.2.2.1.37), glucan endo -1,3-β-D-glucosidase (3.2.2.1.39), α Dextrin endo-1,6-α-glucosidase (3.2.1.41), sucrose α-glucosidase (3.2.1.48), glucan endo-1,3-α-glucosidase (3.2.1.59), glucan 1,4-β-glucosidase (3.2.1.74), glucan endo-1,6-β-glucosidase (3.2.1.75), galactanase (EC 3.2.1.89), arabinan endo-1,5-α-arabinosidase (3.2.1.99), Lactase (3.2.1.108), chitosanase (3.2.1.132) and xylose isomerase (5.3.1.5).

Examples of commercially available proteases (peptidases) include Kannase ^™ , Everlase ^™ , Esperase ^™ , Alcalase ^™ , Neutrase ^™ , Durazym ^™ , Savinase ^™ , Ovozyme ^™ , Pyrase ^™ , Pancreatic Traypsin NOVO (PTN), Bio-Feed ^™ Pro and Includes Clear-Lens ^TM Pro (all available from Novo Noridisk A / S, Bagsvaerd, Denmark). Other preferred proteases include those described in WO 01/58275 and WO 01/58276.

Other commercially available proteases include Ronozyme ^™ Pro, Maxatase ^™ , Maxacal ^™ , Maxapem ^™ , Opticlean ^™ , Propease ^™ , Purafect ^™ and Purafect Ox ^™ (available from Genencor International Inc. or Gist-Brocades).
Examples of commercially available ^{lipases, Lipex TM, Lipoprime TM, Lipopan} TM, Lipolase TM, Lipolase TM Ultra, Lipozyme TM, Palatase TM, Resinase TM, Novozym TM 435 andLecitase TM ( all available from Novo Nordisk A / S) Is included.

Other commercially available lipases are Lumafast ^™ (Pseudomonas mendocina lipase from Genencor International Inc.); Lipomax ^™ (Ps. Pseudoalcaligenes from Gist-Brocades / Genencor Int. Inc.) ) Lipase; and Bacillus sp. Lipase from Salvay Enzyme,). Additional lipases are available from other suppliers.

Examples of commercially available carbohydrases include: Alpha-Gal ^™ , Bio-Feed ^™ Alpha, Bio-Feed ^™ Beta, Bio-Feed ^™ Plus, Bio-Feed ^™ Wheat, Bio-Feed ^™ Z, Novozyme ^{TM 188, Carezyme TM, Celluclast TM} , Cellusoft TM, Celluzyme TM, Ceremyl TM, Citrozym TM, Denimax TM, Dezyme TM, Dextrozyme TM, Duramyl TM, Energex TM, Finizym TM, Fungamyl TM, Gamanase TM, Glucanex TM, Lactozym TM , Liquezyme ^TM , Maltogenase ^TM , Natalase ^TM , Pentopan ^TM , Pectinex ^TM , Promozyme ^TM , Pulpzyme ^TM , Novamyl ^TM , Termamyl ^TM , AMG ^TM (Amyloglucosidase Novo), Maltogenase ^TM , Sweetzyme ^TM and Aquazym ^TM (Available from Nordisk A / S). In addition, carboxymethyl hydrolases, other companies, for example Roxazyme ^TM and Ronozyme ^TM product series (DSM Nutritional Products), the Avizyme TM, Porzyme TM and Grindazyme ^TM product series (Danisco, Finnfeeds), and Natugrain ^TM (BASF), Purastar ^TM And from Purastar ^™ OxAm (Genencor).

Other commercially available enzymes include Mannaway ^™ , Pectaway ^™ , Stainzyme ^™ and Renozyme ^™ .

  Lipases: Suitable lipases include those of bacterial or fungal origin. Chemically modified or protein engineered variants are included. Examples of useful lipases are Humicola (also known as Thermomyces), for example Humicola Lauginosa (T. Lauginosa) as described in European Patent Nos. 258068 and 305216, or Humicola as described in WO96 / 13580.・ Insolens, P. Alkalinenes or P. pseudoalkaligenes (European Patent No. 218272), P. Sephacia (European Patent No. 331376), P. Stutzeri (UK Patent No. 1,372,034), P. Full Olesense, pseudomonas sp. SD705 strain (WO75 / 06720 and WO96 / 27002), lipase from P. Wisconsinensis (WO96 / 12012), for example B. subtilis (Dartois et al. (1993) , Biochemica et Biophysica Acta, 1131, 253-360), B. stearothermophilus (Japanese Patent 64/744992) or B. pumilas (WO91 / 16422).

Other examples are lipase variants such as WO92 / 05249, WO94 / 01541, European Patent 407225, European Patent 206105, WO95 / 35381, WO96 / 00292, WO95 / 30744, WO94 / 25576. No., WO95 / 14783, WO95 / 22615, WO97 / 04079 and WO97 / 0720.
Examples of commercially available lipases include LIPEX, LIPOPRIME ^™ , LIPOLASE ^™ , LIPOLASE ^™ Ultra, LIPOZYME ^™ , PALATASE ^™ , NOVOZYM ^™ 435 and LECITASE ^™ (all available from Novozymes A / S).

Other commercially available lipases are LUMAFAST ^™ (Pseudomonas mendocina lipase from Genencor International Inc.); LIPOMAX ^™ (Ps. Pseudoalcaligenes lipase from DSM / Genencor Int. Inc.). And Bacillus sp. Lipase from Genencor enzymes. Additional lipases are available from other suppliers.

Examples of commercially available ^{carbohydrases, ALPHA-GAL TM, BIO-} FEED TM Alpha, BIO-FEED TM Beta, BIO-FEED TM Plus, BIO-FEED TM Plus, NOVOZYME TM 188, CELLU- CLAST TM, CELLUSOFT TM, CEREMYL TM ^{, CITROZYM TM, DENIMAX TM, DEZYME} TM, DEX- TROZYME TM, FINIZYM TM, FUNGAMYL TM, GAMANASE TM, GLUCANEX TM, LACTOZYM TM, MALTOGENASE TM, PENTOPAN TM, PECTINEX TM, PROMOZYME TM, PULPZYME TM, NOVA- MYL TM, Includes TERMAMYL ^™ , AMG ^™ (Amyloglucosidase Novo), MALTOGENASE ^™ , SWEETZYME ^™ and AQUAZYM ^™ (all available from Novozymes A / S). Additional carbohydrases are available from other suppliers.

  Amylase: Suitable amylases (α- and / or β) include those of bacterial or fungal origin. Chemically modified or protein engineered variants are included. Amylases include Bacillus, for example α-amylase obtained from the patent strain of B. lichenylformis, which is described in more detail in British Patent 1,296,839.

Examples of useful amylases are the variants described in WO94 / 02597, WO94 / 18314, WO96 / 23873 and WO / 43424, in particular variants having substitutions at one or more of the following positions: : 15, 23, 105, 106, 124, 128, 133, 154, 156, 181, 188, 190, 197, 202, 208, 209, 243, 264, 304, 305, 391, 408 and 444.
Commercially available ^{amylases, NATALASE TM, STAINZYME TM, DURAMYL} TM, TERMAMYL TM, TERMAMYL TM ULTRA, FUNGAMYL TM and ^{BAN TM (Novozymes A / S)} , RAPI- DASE TM, PURASTAR TM and PURASTAR OXAM ^TM (Genencor International Inc Is from).

  Cellulases: Suitable cellulases include those of bacterial or fungal origin. Chemically modified or protein engineered variants are included. Suitable cellulases are cellulases from the genera Bacillus, Humicola, Fusarium, Thielavia, Acremonium, e.g., U.S. Patent No. 4,435,307, U.S. Patent No. 5,648,263, U.S. Patent No. 5,691,178, U.S. Patent No. 5,776,757, and WO 89/09259. Including the disclosed Humicola insolens, fungal cellulases produced from Myseriopsola thermophila / oxysporum.

  Particularly suitable cellulases are alkali or neutral cellulases with color protection benefits. Examples of such cellulases are those described in European Patent No. 0495257, European Patent No. 0531372, WO96 / 11262, WO96 / 29397, WO98 / 08940. Examples of examples are WO94 / 07998, European Patent No. 053315, US Patent No. 5,457,046, US Patent No. 5,685,593, US Patent No. 5,763,254, WO95 / 24471, WO98 / 12307 and PCT / DK98 / 0299. Are those described in.

Commercial cellulases include CELLUZYME ^™ , ENDOLASE ^™ , RENOZYME ^™ and CAREZYME ^™ (Novozymes A / S), CLAZINASE ^™ and PURADAX HA ^™ (Genencor International Inc.) and KAC-500 (B) ^™ (Kao Corporation).

Oxidoreductase: Specific oxidoreductases herein are peroxidase (EC 1.11.1), laccase (EC 1.10.3.2) and glucose oxidase (EC 1.1.3.4). An example of a commercially available oxidoreductase (EC 1 .-.-.-) is GLUZYME ^™ (available from Novozymes A / S). Additional oxidoreductases are available from other suppliers.

Peroxidase / oxidase: Suitable peroxidases / oxidases include those of plant, bacterial or fungal origin. Chemically modified or protein engineered variants are included. Examples of useful peroxidases include peroxidases from coprinas, such as Coprinus cinereus, and variants thereof such as those described in WO93 / 24618, WO95 / 10602 and WO98 / 15257.
Commercially available peroxidases include Guardzyme ^™ (Novo Nordisk A / S).

Mannanase: Any mannanase suitable for use in an alkaline solution can be used. Suitable mannanases include those of bacterial or fungal origin. Chemically or genetically modified variants are included.
In a preferred embodiment, the mannanase is a strain of the genus Bacillus, particularly Bacillus sp.1633 or Bacillus agarodhaerens disclosed in SEQ ID NO: 2 positions 31-330 of WO99 / 64619 or SEQ ID NO: 5, For example, derived from the DSM873721 strain. In a more preferred embodiment of the invention, the mannanase is derived from an alkalophilic Bacillus.
Suitable mannanases include MANNAWAY ^™ (Novozymes A / S).

Pectate lyase: Any pectate lyase suitable for use in alkaline solutions can be used. Suitable pectate lyases include those of bacterial or fungal origin. Chemically or genetically modified variants are included.
In a preferred embodiment, the pectate lyase is a strain of the Bacillus family, in particular a strain of Bacillus subtilis, in particular the Bacillus subtilis DSM14218 disclosed in SEQ ID NO: 2, or a variant thereof disclosed in Example 6 of WO02 / 092741. Derived from the body. In a more preferred embodiment of the invention, the pectate lyase is derived from Bacillus licheniformis. In a particular embodiment of the invention the active compound is not a medicament.

Granule preparation:
The particles of the present invention can be formulated by any conventional compounding method known in the art. Methods for preparing the particles include known enzyme compounding techniques such as spray drying, fluidized bed, fluidized bed spray drying, mixer granulation and extrusion. Other suitable particles are laminated products, adsorbed products, pelletized products, prilled products. The particles can optionally be dried after granulation.

Methods for preparing particles can be found in Handbook of Powder Technology; Particle size enlargement by CE Capes; Volume 1; 1980; Elsevier. Preparation methods include known feed and granule blending techniques, ie:
a) A spray-dried tower in which the spray-dried product, here a liquid enzyme-containing solution, forms small droplets descending the drying tower drying between these means to form an enzyme-containing particulate material Is atomized. Very small particles can be produced by this means (Michael S. Showell (editor); Powdered detergents; Surfactant Science Series; 1998; vol. 71; page 140-142; Marcel Dekker).

  b) Laminated product, where the enzyme is coated as a layer around the preformed inert core particles, and the enzyme-containing mixture is typically atomized in a liquid bed apparatus, where the pre- The formed core particles are fluidized and dried so that the enzyme-containing mixture adheres to the core particles and leaves a layer of dry enzyme on the surface of the core particles. The desired size particles are obtained by this means if useful core particles of the desired size can be found. This type of product is described, for example, in WO 97/23606.

  c) Rather than coating the absorbed core particles where the enzyme is coated as a layer around the core, the enzyme is absorbed on and / or in the surface of the core. Such a method is described in WO 97/39116.

  d) Extruded or pelletized product, where the enzyme-containing paste is compressed into pellets or extruded under pressure through small openings and cut into particles followed by drying. Such particles are usually of considerable size because the material from which the extrusion opening is made (usually a plate with a lumen hole) sets a limit for an acceptable pressure drop over the extrusion opening. Also, when using a small opening, a very high extrusion pressure increases the heat generation in the active compound paste, which is detrimental to the active compound ((Michael S. Showell (editor); Powdered detergents; Surfactant Science Series; 1998; vol. 71; page 140-142; Marcel Dekker).

  e) Spray granulated product, where enzyme powder is suspended in molten wax, and the suspension is sprayed into a cooling chamber where the solution quickly solidifies, for example through a rotating disk jet (Michael S. Showell (editor); Powdered detergents; Surfactant Science Series; 1998; vol. 71; page 140-142; Marcel Dekker). The resulting product is a product in which the active compound is evenly distributed throughout the inert material instead of being concentrated on the surface of the inert material. U.S. Pat. Nos. 4,016,040 and 4,713,245 are documents relating to this technique.

  f) A mixer granulation product, where the enzyme-containing liquid is added to a conventional dry powder composition of granulation compound. As the liquid and powder in the proper proportions are mixed and the moisture of the liquid is absorbed into the dry powder, the components of the dry powder begin to adhere and agglomerate and the particles constitute and contain the active compound. A granulate is formed. Such a method is described in U.S. Pat. (NOVO NORDISK) and WO 90/09428 (NOVO NORDISK). In a particular product of this process in which various high shear mixers can be used as granulators, a granulate consisting of enzymes as active compounds, fillers and binders, etc. is used to obtain a so-called T-granulate. , Mixed with cellulose fibers to reinforce the particles. Reinforced particles strengthen more and release little enzyme dust.

  g) Size reduction, where the core is produced by comminution or grinding of large particles, pellets, tablets, briquettes, etc. containing the active material. The desired core particle fraction is obtained by sieving the finely divided or ground product. Particles that are too small and too large can be recycled. Size reduction is described in Martin Rhodes (editor); Principles of Powder Technology; 1990; Chapter 10; John Wiley & Sons.

  h) Fluidized bed granulation. Fluidized bed granulation involves suspending the granulate in a stream of air and spraying the enzyme liquid through the nozzle onto the fluidized particles. Particles that are impacted by the spray droplets become wet and become sticky. This stickiness collides with other particles, adheres to them and forms granules.

  i) The core can be subjected to drying, for example in a fluid bed dryer. Known methods for drying granules in the feed or enzyme industry can be used by those skilled in the art. Drying preferably occurs at a product temperature of 25-90 ° C. For some enzymes, it is important that the core comprising the enzyme contains a low amount of water prior to salt coating. If the water sensitive active ingredient is coated with salt before the excess water is removed, it becomes trapped within the core and it can negatively affect the activity of the enzyme. After drying, the core preferably contains 0.1-10% w / w water.

Conventional coatings and methods as known in the art, for example coatings described in WO 03/080827, WO 89/08694, WO 89/08695, EP 270608 B1 and / or WO 00/01793 Can be used appropriately. Other examples of conventional coating materials are US 4,106,991, EP 170360, EP 304332, EP 304331, EP 458849, EP 458845, WO 97/39116, WO 92 / 12645A, WO 89/08695 No., 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, WO 01/25412, WO 02/20746, WO 02/28369, US 5879920, US 5,324,649, US 4,689,297, US 6,348,442, EP 206417, EP 193829, DE 4344215 No., DE 4322229 A, DE 263790, JP 61162185 A and / or JP 58179492.
The resulting granules can be subjected to spheronization (eg spheronization), for example in Marumeriser ^™ , or compression.

Adjusting the active strength of granulate:
The active strength of the final granulate is obtained by mixing inert particles with particles comprising an active compound.
The particles can be mixed before or after application of the coating to the particles. If a different amount of coating is to be applied or is just one type of particle to be coated, it is necessary to coat the particles that require the coating before blending the different particles. If both types of particles are coated the same, it is advantageous to coat them together after blending to obtain a particle with the most similar appearance to avoid one step.

In certain aspects of the invention, the invention further comprises
i) preparing inert particles;
ii) preparing particles comprising the active compound;
iii) relates to a process for preparing a blend comprising inert particles and particles comprising a chemical compound comprising mixing i) particles and ii) particles into a granular composition. Thus, the activity can be adjusted by changing the% of inert particles.

The present invention further comprises a coating step in i) and / or ii) or it may comprise a coating step iv).
The method of the present invention further comprises
v) determining the desired specific activity intensity of the final particulate composition; and
vi) selecting the amount of i) particles and ii) particles in the correct proportions to obtain the desired specific activity intensity determined in v) above.

In certain embodiments, the method includes adjusting the amount of coating applied to the particles in order to reduce separation when blending the two types of particles.
The blends of the present invention are particularly suitable for premixes or intermediates suitable for mixing with other granular or liquid formulations to produce final products such as detergent compositions, animal feed or dough compositions. It is a sex organism.

Accordingly, the present invention includes a method for preparing particles comprising an active compound and a first particulate composition of inert particles, wherein the method comprises:
i) preparing particles comprising a chemical compound;
ii) preparing inert particles comprising a coating;
iii) blending the particles of i) and ii) to obtain a first granular composition;
iv) mixing the first granular composition of iii) and the second composition at least one day after the preparation of the first granular composition.

In a particular embodiment of the invention, the first granular composition of iii) is at least 7 days after the preparation of the first granular composition, for example at least 14 days after the preparation of the first granular composition, After at least one month of preparation of the composition, it is mixed with the second composition.
The blends of the present invention are expected to be transported from the mixing location of the two particles to another geographically remote location for processing into the final product. In a specific embodiment of the present invention, the mixing of the first granular composition and the second composition of iii) is performed in a region different from the region where the first granular composition is prepared. In a more particular embodiment of the present invention, the first particulate composition is stored and / or transported to another geographical location prior to mixing it with the second composition.

Compositions comprising coated particles and their application:
The present invention also relates to a composition comprising the particle mixture of the present invention. The composition can be any beneficial composition comprising a particle blend. A suitable composition may be a detergent composition, a pharmaceutical composition, a composition for use in the textile, leather or paper industry, a composition for use in the feed or food industry and the baking industry, provided that It is not limited only to them. Thus, the composition can be a feed composition, a food composition, a baking composition, a detergent composition, a pharmaceutical composition, or an additive introduced into such a composition. The particles of the present invention can be used in the pharmaceutical field, in detergent compositions for washing objects, in the textile industry, in baking to improve bread, in feed compositions for improving feed and food products. It can be used for nursing care products.

  In a particular embodiment of the invention, the invention is not used for tablets. In a more particular embodiment of the invention, the inventive blend is not used for further processing, for example compression of the blend into tablets.

Detergent :
The particle blend of the present invention is added to the detergent composition and can therefore be a component thereof.
The particle blend of the present invention is preferably not a detergent composition.
The detergent compositions of the present invention may be formulated as manual or machine laundry detergent compositions, such as laundry additive compositions and rinse cloth softener compositions suitable for pretreatment of dyed fabrics, or It can be formulated as a detergent composition for use in general household hard surface cleaning operations, or it can be formulated for manual or machine dishwashing operations.

In a particular aspect, the present invention provides a detergent additive comprising the particle blend of the present invention. The detergent additive and detergent composition may comprise one or more other enzymes such as proteases, lipases, cutinases, amylases, carbohydrases, cellulases, pectinases, mannanases, arabinases, galactanases, xylanases, oxidases such as laccases and / or poloases. It may comprise a xidase.
In general, the nature of the selected enzyme should be compatible with the selected detergent (ie pH-optimal compatibility with other enzymes and non-enzymatic components, etc.) and the enzyme is effective Should be present in quantity.

  Proteases: Suitable proteases include those of animal, plant or microbial origin. Microbial origin is preferred. Chemically modified or protein engineered variants are included. The protease can be a serine protease or a metalloprotease, preferably an alkaline microbial protease or a trypsin-like protease. Examples of alkaline proteases are subtilisins, in particular those derived from Bacillus, such as subtilisin Novo, subtilisin Carlsberg, subtilisin 309, subtilisin 147 and subtilisin 168 (described in WO 89/06279). Examples of trypsin-like proteases are trypsin (eg of porcine or bovine origin) and the Fusarium protease described in WO89 / 06270 and WO94 / 25583.

Examples of useful proteases are variants described in WO92 / 19729, WO98 / 20115, WO98 / 20116 and WO98 / 34946, in particular variants having substitutions at one or more of the following positions: : 27, 36, 57, 76, 87, 97, 101, 104, 120, 123, 167, 170, 194, 206, 218, 222, 224, 235 and 274.
Preferred commercially available protease ^{enzymes, EVERLASE TM, OVOZYME TM, SAVOZYME} TM, ALCALASE TM, SAVINASE TM, PRIMASE TM, DURALASE TM, ESPERASE TM and ^{KANNASE TM (Novozymes A / S)} , MAXATASE TM, MAXACAL TM, MAXAPEM TM, PROPERASE It encompasses ^{TM, PURAFECT TM, PURAFECT OXP TM} , FN2 TM, and FN3 ^TM, FN4 ^TM and (Genencor International Inc.).

  Lipases: Suitable lipases include those of bacterial or fungal origin. Chemically modified or protein engineered variants are included. Examples of useful lipases are Humicola (also known as Thermomyces), for example Humicola Lauginosa (T. Lauginosa) as described in European Patent Nos. 258068 and 305216, or Humicola as described in WO96 / 13580.・ Insolens, P. Alkalinenes or P. pseudoalkaligenes (European Patent No. 218272), P. Sephacia (European Patent No. 331376), P. Stutzeri (UK Patent No. 1,372,034), P. Full Olesense, pseudomonas sp. SD705 strain (WO75 / 06720 and WO96 / 27002), lipase from P. Wisconsinensis (WO96 / 12012), for example B. subtilis (Dartois et al. (1993) , Biochemica et Biophysica Acta, 1131, 253-360), B. stearothermophilus (Japanese Patent 64/744992) or B. pumilas (WO91 / 16422).

Other examples are lipase variants such as WO92 / 05249, WO94 / 01541, European Patent 407225, European Patent 206105, WO95 / 35381, WO96 / 00292, WO95 / 30744, WO94 / 25576. No., WO95 / 14783, WO95 / 22615, WO97 / 04079 and WO97 / 0720.
Preferred commercially available lipase enzymes include Lipolase ^™ and Lipolase Ultra ^™ (Novozymes A / S).

  Amylase: Suitable amylases (α- and / or β) include those of bacterial or fungal origin. Chemically modified or protein engineered variants are included. Amylases include Bacillus, for example α-amylase obtained from the patent strain of B. lichenylformis, which is described in more detail in British Patent 1,296,839.

Examples of useful amylases are the variants described in WO94 / 02597, WO94 / 18314, WO96 / 23873 and WO / 43424, in particular variants having substitutions at one or more of the following positions: : 15, 23, 105, 106, 124, 128, 133, 154, 156, 181, 188, 190, 197, 202, 208, 209, 243, 264, 304, 305, 391, 408 and 444.
Commercially available amylases are DURAMYL ^™ , TERMAMYL ^™ , FUNGAMYL ^™ and BAN ^™ (Novozymes A / S), RAPIDASE ^™ , PURASTAR ^™ and PURASTAR OXAM ^™ (from Genencor International Inc.).

  Cellulases: Suitable cellulases include those of bacterial or fungal origin. Chemically modified or protein engineered variants are included. Suitable cellulases are cellulases from the genera Bacillus, Humicola, Fusarium, Thielavia, Acremonium, e.g., U.S. Patent No. 4,435,307, U.S. Patent No. 5,648,263, U.S. Patent No. 5,691,178, U.S. Patent No. 5,776,757, and WO 89/09259. Including the disclosed Humicola insolens, fungal cellulases produced from Myseriopsola thermophila / oxysporum.

  Particularly suitable cellulases are alkali or neutral cellulases with color protection benefits. Examples of such cellulases are those described in European Patent No. 0495257, European Patent No. 0531372, WO96 / 11262, WO96 / 29397, WO98 / 08940. Examples of examples are WO94 / 07998, European Patent No. 053315, US Patent No. 5,457,046, US Patent No. 5,685,593, US Patent No. 5,763,254, WO95 / 24471, WO98 / 12307 and PCT / DK98 / 0299. Are those described in.

Commercial cellulases include Celluzyme ^™ and Carezyme ^™ (Novozymes A / S), Clazinase ^™ and Puradex HA ^™ (Genencor International Inc.) and KAC-500 (B) ^™ (Kao Corporation).

Peroxidase / oxidase: Suitable peroxidases / oxidases include those of plant, bacterial or fungal origin. Chemically modified or protein engineered variants are included. Examples of useful peroxidases include peroxidases from coprinas, such as Coprinus cinereus, and variants thereof such as those described in WO93 / 24618, WO95 / 10602 and WO98 / 15257.
Commercially available peroxidases include Guardzyme ^™ (Novozymes A / S).

Mannanase: Suitable mannanases include MANNAWAY ^™ (Novozymes A / S).
The detergent composition can be present in any convenient dry form, such as sticks, tablets, powders, granules or pastes. It can also be a liquid detergent, in particular a non-aqueous liquid detergent.
The detergent composition comprises one or more surfactants which may be nonionic, for example semi-polar and / or anionic and / or cationic and / or zwitterionic. Surfactants are typically present at levels of 0.1-60% by weight.

  When included therein, the detergent is typically from about 1% to about 40% anionic surfactant, such as linear alkyl benzene sulfonate, α-olefin sulfonate, alkyl sulfate (fatty acid sulfate), alcohol ethoxy sulfate, second Alkane sulfonates, alpha-sulfo fatty acid methyl esters, alkyl- or alkenyl succinic acids or soaps will be included.

  When included, the surfactant is typically about 0.2% to about 40% nonionic surfactant, such as alcohol ethoxylates, nonylphenol ethoxylates, alkylpolyglycosides, alkyldimethylamine oxides, ethoxylated fatty acids. It may include monoethanolamide, fatty acid monoethanolamide, polyhydroxyalkyl fatty acid amide, or N-acyl N-alkyl derivatives of glucosamine (“glucosamide”).

  Detergents are 0-65% detergent builders or complexing agents such as zeolites, diphosphates, triphosphates, phosphonates, carbonates, citrates, nitrilotriacetic acid, ethylenediaminetetraacetic acid, diethylenetriaminehexaacetic acid, alkyl- or alkynyl succinic acid, Soluble silicates or layered silicates (eg SKS-6 from Hoechst) can be included.

  The detergent comprises one or more polymers. Examples include carboxymethylcellulose, poly (vinyl pyrrolidone), poly (ethylene glycol), poly (vinyl alcohol), poly (vinyl pyridine-N-oxide), poly (vinyl imidazole), polycarboxylate (eg, polyacrylate, malein). Acid / acrylic acid copolymer and lauryl methacrylate / acrylic acid copolymer.

The detergent can comprise a perborate or percarbonate that can be combined with a bleaching system comprising a source of H ₂ O ₂ , such as a peracid-forming bleach activator, such as tetraacetylethylenediamine or nonanoyloxybenzenesulfonate. . On the other hand, the bleaching system can comprise peroxyacids of the amide, imide or sulfone type, for example.

  The enzyme of the detergent composition of the present invention comprises conventional stabilizers such as polyols such as propylene glycol or glycerol, sugars or sugar alcohols, lactic acid, boric acid or boric acid derivatives such as aromatic boric acid esters or phenylboric acid derivatives such as 4- It can be stabilized with formylphenylboronic acid and the composition can be formulated as described, for example, in WO92 / 19709 and WO92 / 19708.

Detergents also include other conventional detergent compositions such as fabric conditioners such as clays, foam enhancers, soap foam inhibitors, anticorrosives, soil suspensions, anti-soil re-deposition agents, dyes, fungicides, fluorescent Brightening agents, hydrotropes, haze inhibitors, or fragrances can be included.
In the detergent composition, any enzyme, in particular the enzyme of the invention, is 0.01-100 mg enzyme protein per liter of washing liquid, preferably 0.05-5 mg enzyme protein per liter of washing liquid, especially 0.1-1 mg per liter of washing liquid. It is currently planned that it may be added in an amount corresponding to that enzyme protein.

  The blends of the present invention can further be introduced into the detergent formulations disclosed in WO 97/07202 (incorporated herein by reference).

  The particle size can be changed by passing the coating and changing the density. The density of the final particles is between the density of the core and the density of the coating. Several different coating layers can also be applied. Variations in core and coating size will provide a particle density that varies between core and coating density. Inert granules can be produced with the required particle density to avoid separation. Furthermore, the thick coating also provides an equal appearance between the inert and active particles.

Example 1 :
A sodium sulfate core having a density of 2.67 g / ml was coated with a sodium sulfate slurry. The density of the coating was 2.03 g / ml. The particle size was increased from the initial 300μ to 400μ by coating to induce a final particle density of 2.3 g / ml.
This is an example of how low density can be obtained by increasing the size of the coating relative to the size of the core.

Example 2 :
56% of the volume of the salt coating was replaced by a starch coating having a coating density of 1.43 g / ml. This resulted in a final particle density of only 2.1 g / ml. The size of the coated particles was 400μ.
This is an example of how low particle density can be obtained by applying a low density coating to high density core particles.

Example 3 :
A 10% (v / v) coating of sodium sulfate slurry applied on the salt core slightly changed the appearance of the inert core particles. 200% (v / v) of the sodium sulfate slurry was applied onto the salt core and the appearance changed completely so that the inert particles could not be visually distinguished.
The coating changed the appearance of the sodium sulfate core particles from translucent crystals to non-transparent particles. When mixed with other coated active particles, the inert particles were not visually distinguishable from the active particles in the mixture.

Example 4 :
Inactive particles differ in particle density from particles comprising an active ingredient. If the difference is large enough, the separation of the two components occurs for equally sized granules. Separation can be reduced by changing the size of the inert particles relative to the size of the active particles.

The table below shows the separation factor for a 50:50 mixture of active and inert particles with a particle density ratio of 0.8.
The particle size of the active particles is 450μ. The particle size of the inert particles is 450 to 650 μm. The particle density of the active particles is 2.1 g / ml and the density of the inert particles is 2.67 g / ml.

Table 1 shows the separation factor measured by both the heap test and the rotating layer as a function of the size ratio between the inert and active granules. The particle density ratio of the two types of granulate is 0.8.
From Table 1, it is found that separation can be avoided by changing the particle size when having different particle densities of inert and active particles.

Example 5 :
The particle density of the active particles is 2.1 g / ml and the density of the non-active particles is changed from 2.67 g / ml to 2.3 and 2.1 g / ml, where particles having a density of 2.67 g / ml are 400 μ salt particles Met.
Particle density was reduced by coating; 300μ core particles having a density of 2.67g / ml were coated to 400μ with sodium sulfate slurry. A 56% exchange of the coating with the starch coating resulted in particles having a density of 2.1 g / ml. The particle sizes of the active and non-active particles were all 400μ. The table below shows the separation factor for a 1: 1 mixture of active and inactive particles.

Example 6 :
The color of the particles comprising the enzyme and the color of the simple salt core were measured. The size of the particles was 300-400μ. Color Lab-values were measured with a HunterLab DP 9000 Model D25M Optical sensor. Before coating, the difference in the appearance of the two granulates is very large, as can be seen from the ΔE in the table below.

  After coating with 200% salt coating, the difference is negligible and ΔE is 6 or less.

Example 7 :
Preparation of protease / placebo products and mixtures:
P1: Sabinase globules (activity)
Spray dried protease (sabinase) powder is mixed with sodium sulfate powder and molten Lutensol AT-80 wax and spray cooled to obtain spherical spherules:
Average particle size: 273μ
Particle density: 1.51g / ml
Color L, a, b: 78.1, -0.29, 19.1

P2: Uncoated sodium sulfate spherical beads (placebo) from Minera Santa Marta:
Average particle size: 370μ
Particle density: 2.71 g / ml
Color L, a, b: 93.6, -0.17, 1.69

P3: coated sabinase (activity):
The sabinase microspheres (P1) are coated on the fluidized bed (Aeromatic MP-1) by spraying 50% sodium sulfate and 2% Avebe W80 dextrin aqueous slurry onto the microspheres to produce the following product: Brought about:
Average particle size: 443μ
Particle density: 2.27g / ml
Color L, a, b: 87.7, -0.66, 11.0
(The coating is composed of 85% final particles)

P4: Coated sodium sulfate beads (placebo):
Sodium sulfate beads (P2) are coated on the fluidized bed (Aeromatic MR-1) by spraying 33% sodium sulfate, 5% TiO ₂ and 2.5% Avebe W80 dextrin aqueous slurry onto the beads. Bring the following products:
Average particle size: 524μ
Particle density: 2.55g / ml
Color L, a, b: 91.0, 0.33, 4.13
The coating is composed of 63% final particles.
A mixture of activity and placebo was prepared:

From this example, the active granule (P1 or P3) and uncoated placebo (P2) have a large ΔE value, a ratio not close to 1.0 (ρ _pI / ρ _pA ) · (D _pA / D _pI ), And it is apparent that this leads to a visible heterogeneous mixture. By producing a concentrated coating of placebo (P4), a lower ΔE, approaching 1.0 (ρ _pI / ρ _pA ), (D _pA / D _pI ) and a homogeneous mixture mixed with the coated active granules Obtained if you do.

Claims (43)

At least two different types of particles:
i) particles comprising the active compound; and
ii) inert particles comprising a coating,
A blend comprising.   The blend of claim 1, wherein the particles have an average particle size of 100-1500 μm.   The blend of claim 1, wherein the inert particles and particles comprising the active compound have a particle density ratio of 0.4 to 2.5.   The blend of claim 1 wherein the inert particles and particles comprising the active compound have a particle size ratio of 0.4 to 2.5.   The blend of claim 1, wherein the inert particles and particles comprising the active compound have a span of 2.5 or less.   The blend according to claim 1, wherein the color difference ΔE of the inert particles and the particles comprising the active compound is 6 or less. The blend according to claim 1, wherein (ρ _pI / ρ _pA ) · (D _pA / D _pI ) is between 0.9 and 1.1.   The blend of claim 1, wherein the inert particles and particles comprising the active compound have a ΔE of 6 or less.   The blend of claim 1, wherein the inert particles and particles comprising the active compound have a separation factor of 0.3 or less.   The blend of claim 1 wherein said particles comprising an active compound comprise a core and a coating comprising an active compound.   The blend of claim 1 wherein the two types of particles are coated with the same coating.   12. A blend according to claim 1, 10 and 11 wherein the coating is at least 25 μm thick.   12. A blend according to claim 1, 10 and 11 wherein the coating is at least 5% (w / w) of the total particles.   12. A blend according to claim 1, 10 and 11 wherein the ratio of the particle diameter to the core diameter is at least 1.1.   12. A blend according to claim 10 or 11, wherein the core comprises a component selected from the group consisting of salts, sugars, sugar alcohols, organic acids, organic salts, starches, celluloses, polysaccharides, clays and silicates.   12. A blend according to claim 10 or 11, wherein the core comprises a component selected from the group consisting of salts, polysaccharides, synthetic polymers, waxes and fats. 17. A process for preparing a blend according to any one of claims 1 to 16, comprising inert particles and particles comprising an active compound, comprising the steps of:
i) preparing inert particles comprising a coating;
ii) preparing particles comprising the active compound;
iii) A method comprising mixing the particles of i) and the particles of ii) into a granular composition.   The method of claim 17, wherein the coating is applied in step i).   The method of claim 17 wherein the particles comprising the active compound comprise a coating.   The method of claim 17, wherein step ii) comprises a coating step.   The method of claim 17, wherein steps i) and ii) comprise a coating step.   The method of claim 17, wherein the particles of iii) are coated in step iv).   18. The method of claim 17, wherein separation in the blend is reduced by adjusting the amount of coating applied to the inert particles.   18. The method of claim 17, wherein the inert particles and particles comprising the active compound have a separation factor of 0.3 or less. a) determining the desired specific activity intensity of the final granular composition; and b) to obtain the desired specific activity intensity determined in a) above for the particles of i) and ii) in the correct ratio 18. The method of claim 17, further comprising the step of selecting an amount.   18. A method according to claim 17, wherein the amount of coating is selected such that the inert particles and particles comprising the active compound have a particle size ratio of 0.6 to 1.4.   18. The method of claim 17, wherein when the amount of coating is blended, the inert particles and particles comprising the active compound are selected to have a separation factor of 0.3 or less.   18. A blend obtained by the method of claim 17.   29. A detergent composition comprising the blend of claim 1 or 28.   An animal feed composition comprising the blend according to claim 1 or 28.   A composition for baking comprising a blend according to claim 1 or 28.   29. Use of a blend according to any one of claims 1 to 16 or 28 in a detergent composition for laundry washing or dishwashing.   29. Use of a blend according to any one of claims 1-16 or 28 in a baking composition.   Use of a blend according to any one of claims 1 to 16 or 28 in an animal feed composition.   29. Use of a blend according to any one of claims 1 to 16 or 28 in a food composition.   Use of a blend according to any one of claims 1 to 16 or 28 for textile processing.   29. Use of a blend according to any one of claims 1-16 or 28 in a pharmaceutical composition. A method for preparing particles comprising an active compound and a first granular composition of inert particles comprising:
a) preparing particles comprising the active compound;
b) preparing inert particles comprising a coating;
c) blending the particles of a) and b) above to obtain a first granular composition;
d) A method comprising mixing the first granular composition of c) and the second composition at least one day after preparation of the first granular composition.   39. The method of claim 38, wherein the mixing of the first granular composition of c) and the second composition is at least 7 days after the preparation of the first granular composition.   40. The method of claim 38, wherein the mixing of the first granular composition of c) and the second composition is at least 14 days after the preparation of the first granular composition.   39. The method of claim 38, wherein the mixing of the first granular composition of c) and the second composition is at least one month after the preparation of the first granular composition.   39. The method of claim 38, comprising mixing the first granular composition and the second composition of c) in a region separate from the part where the first granular composition is prepared.   40. The method of claim 38, wherein the first particulate composition is stored and / or transported to another geographic location prior to mixing with the second composition.