Patent Description:
Microcrystalline cellulose is a free-flowing fine powder made by hydrolyzing natural cellulose to the levelling off degree of polymerization (LODP) in dilute acid. It is white or near-white, odorless and tasteless. Its levelling off degree of polymerization (LODP) is usually <NUM>-<NUM>. It is not dissolved in water, dilute acid, organic solvent or grease. Partial dissolution and swelling are carried out in a dilute alkali solution. The microcrystalline cellulose is stable in property under the condition of high temperature, high humidity and strong light irradiation, and is widely applied to various industries such as medicine, food, daily chemicals and light industry.

Microcrystalline cellulose serves as a medicinal auxiliary material and is widely applied to the medical industry. It is mainly used as an adhesive, a disintegrating agent or a filler in the pharmaceutical industry, and is mainly used in a tabletting process. It can be used for wet granulation, dry granulation or direct tabletting. It is good in pressure resistance and plays a role in disintegration and lubrication. It is an important medicinal auxiliary material. Microcrystalline cellulose can also play a slow release effect on medicine because of its unique porous structure. Microcrystalline cellulose can be used as dietary fiber which is an important functional food base material in the food industry. It is an ideal food additive and can be used as a substitute for fat.

There are many types of microcrystalline cellulose products on the market, such as PH <NUM> (average particle size of <NUM>-<NUM>, loose density of <NUM>-<NUM>/mL), PH <NUM> (average particle size of <NUM>-<NUM>, loose density of <NUM>-<NUM>/mL), PH <NUM> (average particle size of <NUM>-<NUM>, loose density of <NUM>-<NUM>/mL) and PH <NUM> (average particle size of <NUM>-<NUM>, loose density of <NUM>-<NUM>/mL). There are also special types of microcrystalline cellulose products with a higher density or a small particle size, such as PH <NUM> (the average particle size is <NUM>-<NUM>, the loose density is <NUM>-<NUM>. <NUM>/ml), PH <NUM> (the average particle size is <NUM>-<NUM>, the loose density is <NUM>-<NUM>/ml) and PH <NUM> (the average particle size is <NUM>-<NUM>, the loose density is <NUM>-<NUM>/mL).

The following table is cited as an ASAHI product manual from Japan, and is a product parameter marked on the packaging of common microcrystalline cellulose products on the market:.

Microcrystalline cellulose products with different particle sizes or densities have different application properties. Generally speaking, the smaller the particle size of microcrystalline cellulose, the more favorable it is to mix evenly with other ingredients such as medicines, which is suitable for it to mix with materials with small particle size or low active ingredient content to improve the content uniformity. The traditional microcrystalline cellulose with small particle size has also a unique advantage that the smaller the particle size is, the higher the strength performance of the tablet is. However, the smaller the particle size of microcrystalline cellulose is, the smaller the fluidity tends to be, which is not conducive to the process of direct compression and other preparations, and greatly limits its application in medicine and food.

Small particle size microcrystalline cellulose products are traditionally produced by dry powder grinding, sieving or ball milling, especially in the presence of grinding aids. Chinese invention patent <CIT> discloses that microcrystalline cellulose is degraded with <NUM>Co-γ irradiation and ultrafinely treated, and then mechanically pulverized or/and chemically degraded to obtain ultra-fine crystalline cellulose with a particle size less than <NUM>. However, the density of the microcrystalline cellulose products produced by these methods did not increase significantly. Commercially available microcrystalline cellulose products with small particle size generally have an average particle size D50 of about <NUM>-<NUM> and a loose density of <NUM>-<NUM>/ml. Therefore, there is a problem that the smaller the particle size, the poorer the fluidity of the product. It greatly limits its application in industry.

Chinese invention patent <CIT> discloses a method for preparing microcrystalline cellulose by acid hydrolysis after high shear mechanical pretreatment. During the pretreatment process, the high shear mechanical force cuts the fibers, which improves the accessibility of the acid solution to the cellulose, increases the speed at which the acid solution penetrates into the cellulose, increases the acid hydrolysis rate of the acid solution to the cellulose amorphous region and reduces chemical usage or reaction time. The density of the microcrystalline cellulose prepared by this method is not improved, and the average particle size of the microcrystalline cellulose product is still above <NUM>.

Chinese invention patent <CIT> discloses microcrystalline celluloses with high loose density and their production process. The filter cake obtained by acid hydrolysis is kneaded by a kneader and spray-dried to obtain a microcrystalline cellulose product with a loose density of <NUM>-<NUM>/cm<NUM>. However, the particle size of the microcrystalline cellulose product is also larger and the average particle size D50 reaches <NUM>-<NUM>.

Chinese invention patents <CIT>, <CIT> and <CIT> also disclose methods for preparing microcrystalline cellulose. However, the particle size or the loose density of the microcrystalline cellulose products prepared by these methods is not within the scope of the present invention. For example, the particle size is above <NUM>, or the loose density is much lower than <NUM>/ml.

US patent application <CIT> discloses microcrystalline cellulose having a mean particle size of <NUM>-<NUM> and a loose bulk density of <NUM>-<NUM>/ml. The method for preparing microcrystalline cellulose involves aggregating smaller particles.

In order to overcome the defects of microcrystalline cellulose products of the prior art, the present invention provides a manufacturing method for a microcrystalline cellulose product with ultra-fine particle size and extremely high density. The microcrystalline cellulose product has better performance and wider field of application.

The technical scheme of the present invention is as follows:
The present invention provides a manufacturing method for a microcrystalline cellulose particle, which is characterized in that the average particle size D50 of the microcrystalline cellulose particle is <NUM>-<NUM> and the loose density is <NUM>-<NUM>/ml. Preferably, the average particle size D50 of the microcrystalline cellulose particle is <NUM>-<NUM> and the loose density is <NUM>-<NUM>/ml. More preferably, the average particle size D50 of the microcrystalline cellulose particles is <NUM>-<NUM> and the loose density is <NUM>-<NUM>/ml.

The above-mentioned microcrystalline cellulose particles are obtained from ordinary microcrystalline cellulose by high shear mechanical action, and the solid content of ordinary microcrystalline cellulose is <NUM>%-<NUM>% in the high shear mechanical action. Preferably, the solid content of ordinary microcrystalline cellulose is <NUM>%-<NUM>% in the high shear mechanical action.

The said high shear machine action is to use a high shear force equipment with a torque greater than <NUM> N·m. The said high shear force equipment is a screw extrusion equipment with high strength and high shear force, such as a screw extruder, a screw kneader or a screw extrusion kneader and the like. The said high shear force equipment can be continuous or intermittent, and can also be divided into multiple stages, multiple times or repeated processing.

The ordinary microcrystalline cellulose mentioned above refers to the microcrystalline cellulose product whose average particle size D50 and/or loose density is different from those of the present invention. Its average particle size D50 exceeds <NUM> and/or loose density below <NUM>/ml. For example, microcrystalline cellulose products prepared by the raw materials for preparing microcrystalline cellulose in the prior art through conventional methods in the art, or microcrystalline cellulose filter cake or semi-finished product prepared from natural cellulose pulp which is subjected to conventional hydrolysis methods or electron beam irradiation methods, or existing commercially available microcrystalline cellulose products. As an example of the said conventional hydrolysis methods, the cellulose pulp is acid hydrolyzed at a temperature of <NUM>-<NUM> and an acid concentration of <NUM>-<NUM>. 35mol/L to obtain the filter cake by washing and filtering. As an example of the said electron beam irradiation methods, microcrystalline cellulose is produced by electron beam irradiation with the radiation dose of <NUM>. 2Mrad-10Mrad. The raw materials of the natural cellulose pulp is not particularly limited and can be materials commonly used in the art for producing microcrystalline cellulose, which includes but is not limited to the following raw materials or pulps: wood pulp, hemp pulp, bamboo pulp, cotton, cotton linter, straw, reed, straw pulp, cane bagasse, algae, bacterial microorganisms, etc. The said existing commercially available microcrystalline cellulose products include but are not limited to microcrystalline cellulose products with code names such as PH101, PH102, PH112, PH301, PH302, PH105 or PH103.

Wherein the above-mentioned method, the microcrystalline cellulose particles are obtained from the material processed by the high shear force equipment, which further optionally includes the steps of dilution, dispersion, drying, sieving and/or fine grinding.

As another object of the present disclosure, uses of the above-mentioned microcrystalline cellulose particles as an adjuvant or carrier in pharmaceuticals, health products, food, industry, light industry, daily chemicals, petroleum, personal care, agricultural chemistry and other industries are provided.

The said particles in the microcrystalline cellulose particles prepared by the present invention can also be understood as powder and the like. They refer to microcrystalline cellulose products with the granular or powdery particles having an average particle size D50 of <NUM>-<NUM> and a loose density of <NUM>-<NUM>/ml.

The high shear force device or equipment used in the present invention can reduce the particle size of the particles through extremely high shear force and mechanical action such as pressure or friction. Different from the traditional manufacturing method of fine microcrystalline cellulose, the present invention does not use solid grinding aids, nor does it use water-soluble grinding aids such as salts during the high shearing process.

The high shear force device or equipment of the present invention can be a continuous or intermittent device, and can also be divided into multiple repeated processes. In general, if a screw device such as an extruder or a kneader is used, its torque should be more than <NUM> N·m. The torque is more than <NUM> N·m and controlled among <NUM>-<NUM> N·m in the examples of the present invention. In the actual extrusion operation, the torque is variable. It is low at the beginning and will increase later. For example, it is about <NUM> N·m at the beginning and reaches more than <NUM> N·m later. The microcrystalline cellulose products prepared by this method can reach the particle size and the density described in the present invention.

In the high shear mechanical processing used in the present invention, the solid content of the material is generally <NUM>%-<NUM>%, preferably <NUM>%-<NUM>%. If the material to be processed is a hydrolyzed microcrystalline cellulose filter cake and the solid content is too high, an appropriate amount of water can be added before or during processing until it reaches a suitable solid content. If the solid content is too low, the material can be dehydrated before or during the high shear processing. The dehydration method can be centrifugation, filtration, pressing, infrared radiation, hot blowing, air blowing or a combination thereof. It can also be obtained by adding dry powder of microcrystalline cellulose or high solid content of hydrolyzed microcrystalline cellulose filter cake to make a suitable solid content of the final mixture. If the material to be processed is an existing microcrystalline cellulose powder, an appropriate amount of water can be added before or during processing until a suitable solid content is achieved. The solid microcrystalline cellulose powder can be factory-made microcrystalline cellulose powder or existing products on the market, such as but not limited to PH101, PH102, PH112, PH301, PH302, PH105, PH103, etc..

Different from traditional methods such as grinding to prepare microcrystalline cellulose products, the method of the present invention significantly increases the density of microcrystalline cellulose while reducing the particle size by controlling the mechanical action of high shear force, so as to obtain high-performance microcrystalline cellulose products with small particle size and high density.

In the present invention, the material processed by the high shear device can be further diluted and dispersed according to an appropriate amount of water, and the general solid content during the dispersion process can be controlled at <NUM>%-<NUM>%. The dispersing device used includes, but is not limited to, any high shear dispersing device, such as high shear mixers, homogenizers, homogenizer pumps and the like.

The diluted and dispersed materials can be further dried by spray drying, fluidized bed drying, airflow drying, flash drying and the like. According to needs, the dried material can be further screened or finely ground.

In the present invention, if cellulose raw material or cellulose pulp is used to prepare hydrolyzed microcrystalline cellulose filter cake, any pulp and source of cellulose raw material can be applied. These raw materials or pulps include but are not limited to wood pulp, hemp pulp, bamboo pulp, cotton, cotton staple cashmere, straw, reed, straw pulp, cane bagasse, algae, bacterial microorganisms, etc..

The ultra-fine and high-density microcrystalline cellulose product manufactured by the present invention can be applied to any known application field of microcrystalline cellulose, and can also be applied to any potential or emerging application field, including pharmaceuticals, health products, food, industry, light industry, daily chemical, petroleum, personal care, agricultural chemical and other industries. In the pharmaceutical field, its applications can be, but not limited to, binders, disintegrants, excipients, taste-masking agents, dispersants, adsorbents and the like. The products of the present invention can be used in any formulation process, including but not limited to wet granulation, dry granulation, direct compression, extrusion spheronization, spray drying, pellets, microtablets, coatings, liquid formulations , creams, injections, sprays and more. Medicinal applications also include traditional Chinese medicine and the like. The fine microcrystalline cellulose powder prepared by the present invention is also widely used in the food field. For example, it can be applied to various dairy products such as milk beverages, solid beverages, coffee and tea beverages, carbonated beverages, meat products, jams, condiments, soups, frozen foods, yogurt, fermented milk, cheese, biscuits and the like. In addition to these traditional food applications, the ultra-fine microcrystalline cellulose prepared by the present invention can also be applied in some new fields. For example, ultra-fine microcrystalline cellulose can be used as a carrier of flavor substances, pigments or other nutrients due to its unique and delicate taste and taste-masking or taste-regulating functions, especially in compressed candies. Its superior functions and fluidity greatly improve the quality and performance of compressed candies. It can also reduce or replace the use of sugar alcohols. Still other examples of applications include, but are not limited to, being used as an encapsulating agent or an excipient for active microorganisms in spray drying or tableting.

The microcrystalline cellulose product prepared by the present invention has a small particle size and a high loose density at the same time, which enhances the fluidity, compressibility and other properties of the product, so that it has a wider field of application. Especially, the microcrystalline cellulose product prepared by the present invention has a unique particle shape which is spherical or quasi-spherical particles. The existing microcrystalline cellulose products on the market are all fibrous products in sections and there are no spherical particles. Furthermore, the angle of repose of the microcrystalline cellulose prepared by the present invention is also smaller than that of UF-<NUM> which is the microcrystalline cellulose product with the smallest angle of repose currently on the market. The microcrystalline cellulose product prepared by the present invention not only has the properties of good fluidity and strong compressibility which is very suitable for the tableting process, but also has a small particle size and a spherical or nearly spherical shape which endows the product with good taste and fineness as well as masking odor and is suitable for pharmaceutical and food molding.

The following examples are intended to explain and illustrate the content of the present invention. The content of the examples should not be construed as limiting the protection scope of the present invention.

The particle size, density, angle of repose and microscope measurement said in the present invention are as follows:.

In the actual extrusion operation, the torque is a variable. The torque is low at the beginning. For example, the torque is about <NUM> N·m at the beginning and will increase later, generally reaching <NUM>-<NUM> N·m. The torque will reach the limit of the equipment when it exceeds <NUM> N·m. The prepared microcrystalline cellulose products can all reach the particle size and the density described in the present invention when the torque reaches more than <NUM> N·m.

Take the cellulose pulp obtained from wood on the market, undergo high temperature acid hydrolysis (hydrolysis temperature <NUM>-<NUM>, acid concentration <NUM>-<NUM>. 35mol/L) for <NUM>-<NUM> hours to obtain hydrolyzed microcrystalline cellulose, filter and wash to pH to <NUM>-<NUM> and increase the solid content of the cake to <NUM>%. The filter cake of this solid content is extruded <NUM> times through a high shear extrusion device (continuous extruder with high shear blades), and the torque of the extrusion device is controlled between <NUM>-<NUM> N·m. In the interlayer of the extruder, cooling water is introduced for cooling. The extruded material is diluted with water and stirred, neutralized to pH <NUM>-<NUM>, and then spray-dried to obtain the microcrystalline cellulose product of the present invention.

Through particle size, density and angle of repose measurement, the microcrystalline cellulose particle product obtained above has a loose density of <NUM>/ml and a tapped density of <NUM>/ml. Its particle size distribution is D10 of <NUM>, D50 of <NUM> and D90 of <NUM>. Its angle of repose is <NUM>°.

The microcrystalline cellulose particle products obtained above were observed under the optical microscope at <NUM> times and <NUM> times respectively. The results are shown in <FIG>. It can be seen that the product has a unique particle shape, which is spherical or quasi-spherical particle.

As a comparison, take the most representative AVICEL PH101 microcrystalline cellulose product on the market to observe the morphology under a 32x optical microscope. The result is shown in <FIG>, and it can be seen that it is in the form of a section of fiber.

Take commercially available Vivapur PH102 microcrystalline cellulose powder, its levelling off degree of polymerization is <NUM>. Through particle size and density measurement, the loose density is <NUM>/ml, the tapped density is <NUM>/ml and the particle size distribution D10 is <NUM> , D50 is <NUM> and D90 is <NUM>.

Weigh Vivapur PH102 microcrystalline cellulose powder <NUM>, add water <NUM> and mix to be <NUM>% of the solid content of the material. The filter cake of this solid content is extruded <NUM> times by the high shear extrusion device and the torque of the extrusion device is controlled between <NUM>-<NUM> N•m. In the interlayer of the extruder, it is cooled by cooling water. The extruded material is diluted with water and stirred, neutralized to pH <NUM>-<NUM>, and then spray-dried to obtain the microcrystalline cellulose product of the present invention.

Through particle size and density measurement, the microcrystalline cellulose product obtained above has a loose density of <NUM>/ml, a tapped density of <NUM>/ml, a particle size distribution D10 of <NUM>, D50 of <NUM>, and D90 of <NUM>.

Take the cellulose pulp obtained from bamboo on the market, and hydrolyze it with acid at high temperature (hydrolysis temperature <NUM>-<NUM>, acid concentration <NUM>-<NUM>. 35mol/L) for <NUM>-<NUM> hours to obtain hydrolyzed microcrystalline cellulose, filter and wash with water to pH <NUM>-<NUM>. The filter cake is diluted with water, neutralized to pH <NUM>-<NUM>, and then spray-dried to obtain the traditional microcrystalline cellulose product. After measurement to the microcrystalline cellulose powder obtained, the loose density was <NUM>/ml, the tapped density was <NUM>/ml, and the particle size distribution D50 was <NUM>.

Take the bamboo pulp microcrystalline cellulose filter cake obtained above, control the solid content at <NUM>%, extrude <NUM> times through a high shear extrusion device, and control the torque of the extrusion device between <NUM>-<NUM> N·m. In the interlayer of the extruder, cooling water is introduced for cooling. The extruded material is diluted with water and stirred, neutralized to pH <NUM>-<NUM>, and then spray-dried to obtain the microcrystalline cellulose product of the present invention.

Through particle size and density determination, the microcrystalline cellulose product prepared above has a loose density of <NUM>/ml, a tapped density of <NUM>/ml, a particle size distribution of D10 of <NUM>, D50 of <NUM>, and D90 of <NUM>.

Take the cellulose pulp obtained from hemp fibers on the market, and undergo high-temperature acid hydrolysis (hydrolysis temperature <NUM>-<NUM>, acid concentration <NUM>-<NUM>. 35mol/L) for <NUM>-<NUM> hours to obtain hydrolyzed microcrystalline cellulose. Wash with water to pH <NUM>-<NUM>, dilute the filter cake with water, neutralize to pH <NUM>-<NUM>, and then spray-dry to obtain the traditional microcrystalline cellulose product. After determination of the microcrystalline cellulose powder obtained, the loose density was <NUM>/ml, the tapped density was <NUM>/ml, and the particle size distribution D50 was <NUM>.

Take the hemp pulp microcrystalline cellulose filter cake obtained above, control the solid content at <NUM>%, extrude it three times through a high-shear extrusion device, and control the torque of the extrusion device to be between <NUM>-<NUM> N·m. In the interlayer of the extruder, cooling water is passed into it for cooling. The extruded material is diluted with water and stirred, neutralized to pH <NUM>-<NUM>, and then spray-dried to obtain the microcrystalline cellulose product of the present invention.

After particle size and density determination, the microcrystalline cellulose product prepared above has a loose density of <NUM>/ml, a tapped density of <NUM>/ml, a particle size distribution of D10 of <NUM>, D50 of <NUM>, and D90 of <NUM>.

Take the cellulose pulp obtained from wood on the market, undergo acid hydrolysis at high temperature (hydrolysis temperature <NUM>-<NUM>, acid concentration <NUM>-<NUM>. 35mol/L) for <NUM>-<NUM> hours to obtain hydrolyzed microcrystalline cellulose, filter and wash to pH to <NUM>-<NUM> and increase the solid content of the cake to <NUM>%. The filter cake of this solid content is extruded <NUM> times through a high shear extrusion device (continuous extruder with high shear blades), and the torque of the extrusion device is controlled between <NUM>-<NUM> N·m. In the interlayer of the extruder, cooling water is introduced for cooling. The extruded material is diluted with water and stirred, neutralized to pH <NUM>-<NUM>, and then spray-dried to obtain the microcrystalline cellulose product of the present invention.

After the measurement of particle size, density and angle of repose, the microcrystalline cellulose particles obtained above have a loose density of <NUM>/ml, a tapped density of <NUM>/ml, and a particle size distribution of D10 of <NUM>, D50 of <NUM>, D90 of <NUM>, and the angle of repose of <NUM>°.

Take the cellulose pulp obtained from wood on the market, undergo acid hydrolysis at high temperature (hydrolysis temperature <NUM>-<NUM>, acid concentration <NUM>-<NUM>. 35mol/L) for <NUM>-<NUM> hours to obtain hydrolyzed microcrystalline cellulose, filter and wash to pH to <NUM>-<NUM> and increase the cake the solid content to <NUM>%. The filter cake of this solid content is extruded <NUM> times through a high shear extrusion device (continuous extruder with a high shear blade), and the torque of the extrusion device is controlled between <NUM>-<NUM> N·m during the extrusion process. The torque will gradually increase with the volatilization of water during the extrusion process, and the torque will be kept below <NUM> N·m by adding an appropriate amount of water. In the interlayer of the extruder, cooling water is introduced for cooling. The extruded material is diluted with water and stirred, neutralized to pH <NUM>-<NUM>, and then spray-dried to obtain the microcrystalline cellulose product of the present invention.

Claim 1:
A method of preparing microcrystalline cellulose particles, wherein the microcrystalline cellulose particle has an average particle size D50 of <NUM>-<NUM>, and loose density of <NUM>-<NUM>/ml, characterized in comprising the step of mechanical action on ordinary microcrystalline cellulose by high shear force of a high shear force device, and the solid content of the ordinary microcrystalline cellulose is <NUM>%-<NUM>% in the high shear mechanical action, wherein the said high shear mechanical action is a high shear force device selected from screw extruder, a screw kneader or a screw extrusion kneader, with a torque controlled among <NUM>-<NUM> N·m, and the said ordinary microcrystalline cellulose is the microcrystalline cellulose product with average particle size D50 above <NUM> and/or loose density below <NUM>/ml; the average particle size D50 and loose density being measured as specified in the description.