JP2733259B2 - Porous microcellulose particles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial application field) The present invention relates to porous microcellulose particles, and more specifically, has a large specific surface area and a developed pore structure which are not available in the prior art, and The present invention relates to porous microcellulose particles having a crystalline form of I type. The substance of the present invention is used as an adsorption carrier for foods and pharmaceuticals, a compression molding aid, a fluidity improver, an additive for cosmetics, and the like.

(Prior Art) Porous cellulose particles have been conventionally used in various fields as gel filtration agents, raw materials for cellulosic ion exchangers, carriers for affinity chromatography, polymer carriers, cosmetic additives and the like. Examples of the production method include a method of obtaining porous regenerated cellulose particles of 16 to 170 mesh by dropping viscose in a granular form in a coagulation / regeneration bath and performing coagulation / regeneration (JP-A-48-60753).
A method in which cellulose is dissolved in an ammoniacal copper hydroxide solution and dropped into benzene containing an emulsifier to disperse the cellulose solution, and then poured into a regenerating bath to obtain cellulose globules (Japanese Patent Publication No. 52-11237), A method for obtaining porous cellulose spherical particles by saponifying cellulose triacetate particles (Japanese Patent Publication No. 63-12099) is disclosed.
However, since they are used as chromatographic supports, the products are usually in a wet state, and when dried, shrinkage occurs and a sufficient pore volume cannot be maintained.

In addition, since they carry out dissolving and regenerating operations of cellulose or cellulose derivatives, their crystal forms are II
It is a type.

As a dried porous cellulose particle,
No. 45254 discloses a method of solidifying a viscose suspension in a water-immiscible liquid by heating, followed by acid decomposition to obtain spherical cellulose particles.
Particles having the following porosity are dimensionally stable and can be dried. " Also, JP-A-63-90501
No. 3 discloses a method for obtaining porous cellulose particles by coagulating and neutralizing a fine particle dispersion of a mixture of cellulose xanthate and an aqueous alkali solution of a water-soluble polymer compound, and then removing the water-soluble polymer. However, there is no description about the specific surface area. Since these melting and regenerating operations are performed, the crystal form of the product is still type II.

The crystalline forms of cellulose are known as type I, type II, type III, type IV, etc. Among them, type I is particularly called "natural cellulose" and type II is called "regenerated cellulose". Natural cellulose has been used for food as plant fiber since ancient times,
At present, regenerated cellulose is widely used as a dispersion stabilizer for liquid foods and as an excipient for pharmaceuticals, and regenerated cellulose is used as rayon or cupra threads as clothing materials, and as spherical particles as a carrier for chromatography described above. ing. The fields of use are different between type I and type II, and the difference in crystal form is a problem to be noted depending on the purpose of use.

It is known that cellulose powder having a large specific surface area can be adjusted by using an organic solvent replacement method or a critical point drying method. (Masato Usuda, Journal of Paper and Technology Association, 36 (4), 423
-433 (1982)) However, they have pores of about 300 ° or less, do not have pores larger than that, and their pore volume is not sufficient.

(Problems to be solved by the present invention) The present inventor has a developed pore structure different from conventional ones, has a sufficient pore volume, and has a large specific surface area in a dry state. As a result of intensive efforts to obtain porous natural cellulose microparticles having the following, the present invention has been achieved. An object of the present invention is to provide a novel porous microcellulose particle.

As described above, all of the conventionally known porous cellulose particles have been subjected to dissolving and regenerating operations of cellulose or a cellulose derivative, so that the crystal form is II type, and the fine particles developed in a dry state. None had a combination of pore structure (large diameter pores and sufficient pore volume) and large specific surface area.

(Means for Solving the Problems) The present invention relates to a porous structure having a crystalline form of type I, a specific surface area of 20 m ² / g or more, and a pore volume of 0.01 μm or more and a pore volume of 0.3 cm ³ / g or more. Has an average particle size of at most 100 μm
The present invention relates to porous cellulose fine particles characterized by the following.

 Hereinafter, the present invention will be described in detail.

The crystalline form of the porous cellulose microparticles according to the present invention is I
It has the same crystal structure as natural cellulose such as ramie, cotton linter and wood pulp. Furthermore, the porous cellulose microparticles according to the present invention often have a spherical shape in which the ratio of the major axis to the minor axis is relatively close to 1, and the surface thereof has a countless number of minute pores of 1 μm or less, or The porous surface and rod-like cellulose particles are mixed. The porosity extends not only to the surface but also to the inside.It has a fine pore structure in which the volume of pores with a diameter of 0.01 μm or more is 0.3 cm ³ / g or more and the specific surface area is 20 m ² / g or more. ing.

If any of these three conditions that define the fine pore structure is missing, the effects intended by the present invention cannot be achieved. Generally, when the pore diameter is large, for example, 0.1 μm or more, the pore volume tends to be large, and when the pore diameter is small, the specific surface area tends to be large. However, especially in the case of natural cellulose particles which cannot be dissolved and regenerated,
Although it was difficult to control these three physical properties, the porous cellulose particles according to the present invention have both of them, and therefore exhibit extremely excellent properties as an adsorption carrier for pharmaceuticals and a compression molding aid for powders. Can be done.

The porous cellulose particles according to the present invention have an average particle size.
100 μm or less. This generally means that the average particle size is 100 μm
This is because the above powder has poor mixing properties with other powders and causes a disadvantage as a powder.For example, when the product of the present invention is used as a fluidity improver for a mixed powder of a pharmaceutical preparation. On the other hand, if the average particle size is large, separation from other powders occurs, and the function cannot be sufficiently exhibited.

The porous cellulose microparticles of the present invention are produced, for example, by the following methods, but are not limited to these methods.

The porous cellulose fine particles of the present invention can be obtained by granulating and drying particulate fine cellulose dispersed in an organic solvent by a spray drying method.

The organic solvent slurry of the cellulose fine particles can be adjusted by various methods. For example, natural cellulose raw material is finely divided into cellulose particles by chemical treatment (acid hydrolysis, etc.) and / or mechanical treatment (pulverization, milling, etc.), and at this time, water serving as a dispersion medium is replaced with an organic solvent. And
Further, the slurry to be spray-dried can be adjusted by adjusting the solid content concentration. At this time, since it is essential that the particulate cellulose is dispersed in the organic solvent, the purpose may be achieved by subjecting the slurry after the replacement with the organic solvent to a grinding treatment. Rather, the workability of the organic solvent replacement operation (repetition of organic solvent dispersion and filtration) is better. It is suitable that the size of the dispersed fine particles is 10 μm or less, preferably 1 μm or less as an intermediate material in the present invention. As a natural cellulose raw material, ramie, cotton linter, wood pulp or the like having a cellulose I type crystal form is used, and as an organic solvent, acetone, methanol, ethanol, isopropyl alcohol, n-hexane, n-pentane, cyclohexane, pentane One or more of these are used. (In the case of using two or more types, it becomes a stepwise sequential replacement.) Spray drying is a closed system considering explosion proof, such as a nitrogen gas circulation type spray dryer because the dispersion medium of the slurry is an organic solvent. Must be done using

(Effect of the Invention) The porous cellulose fine particles obtained by the present invention are natural cellulose particles having a pore structure, a pore volume, and a specific surface area which have not been known so far. Excellent self-fluidity as a body. When mixed with other powders, particularly when the particle size distribution of the product of the present invention is sharp, the fluidity of the mixed powder is extremely improved, for example, tablets incorporated by direct powder compression in a pharmaceutical formulation In this case, the weight variation of the tablet is significantly reduced. In addition, because it has a developed pore structure and a sufficient specific surface area, it has excellent compression moldability, which is a property required as an additive in the direct powder compression method. Becomes noticeable. Furthermore, when a main drug having a sublimability such as aspirin and the present invention are physically mixed, the main drug is adsorbed to the pores, and the dissolution rate of the main drug is significantly increased. Is also possible.

Since the product of the present invention is natural cellulose, it can be used freely as food, and because it is chemically inert, it contributes to the stabilization of pharmaceuticals and enzyme preparations.

Further, it is known that porous cellulose particles are used as a column filler for liquid chromatography, and among them, cellulose particles having a type I crystal structure can be used for optical resolution of optical isomers of amino acids. Since the porous cellulose fine particles of the present invention have a large specific surface area, they have excellent performance as such a column packing.

In addition, the product of the present invention can be used as a compounding agent for cosmetics. For example, when incorporated into a solid foundation, it is porous, and its particles are not too large, so that it has good spreadability, and because of the characteristics of cellulose (such as hygroscopicity), it contains other cosmetic ingredients and sebum or sweat. Is good, the makeup is hardly distorted, and a light feeling of use can be obtained. When incorporated into emulsified cosmetics such as creams and emulsions, the emulsifying properties are stable, the spread at the time of use is light, and after use the product has an excellent refreshing and moist feeling.

Prior to Examples, a method for evaluating physical properties of product particles and a method for measuring physical properties of tablets will be described.

<Average particle system (μm)> A 50 g sample was sieved for 30 minutes using a JIS standard sieve (Z8801-1987) using a Yanagimoto low tap sieve shaker, and accumulated.
The particle size of 50% by weight is defined as the average particle size. When the average particle size was not determined by the sieving method due to the small particle size, the measurement was performed using a microscope. Microscopy involves dispersing an appropriate amount of a sample powder in a mixed solution of equal weights of water, ethanol and glycerin, taking a photograph with an optical microscope, measuring the particle size of each particle in the photograph, and averaging the average particle size. Is defined as the average particle size. Measurement of particle size can be made in any one direction.
The number of samples was determined as the distance between the parallel lines, and the number of samples was 200.

<Pore diameter (μm) and pore volume (cm ³ / g)> The pore distribution was determined by mercury porosimetry using Shimadzu Corporation's Pore Sizer 9300, and the pore volume was expressed as the mercury penetration volume in the particles. .

<Specific surface area (m ² / g)> It was measured by the BET method using nitrogen as an adsorbing substance.

<Crystal Form> X-ray diffraction was performed with an X-ray diffractometer, and the determination was made based on the diffractogram.

<Angle of Repose (゜)> The angle of repose was measured using a cone angle deposition method with a repose angle measuring instrument (turntable type) manufactured by Tsutsui Physical and Chemical Instruments. The number of repetitions is 3, and the average value is taken.

<Tablet strength (kg)> A load is applied in the radial direction of a tablet with a Schleinger gauge measured by Proint Sangyo Co., Ltd., and is expressed as the load when broken. The number of repetitions is 10 and the average is taken.

<Tablet weight variation (%)> Ten tablets are precisely weighed, and the coefficient of variation is determined.

(Example) Example 1 Commercially available DP pulp was cut and placed in a 7% hydrochloric acid aqueous solution at 105 ° C for 2 hours.
Wet cake (50% moisture content) obtained by neutralizing, washing, filtering and dehydrating the acid-insoluble residue obtained by hydrolysis for 0 minutes 3.
0 kg was kneaded and milled in a 10 kneader for about 1 hour. The water in the milled wet cake was replaced with isopropyl alcohol (hereinafter abbreviated as IPA), and finally the solid content (cellulose content) concentration was 5.5% by weight, the water content was 0.4% by weight, and the IPA was 94.
The slurry was adjusted to 1% by weight. At this time, most of the particulate cellulose was in a state of being ground to 1 μm or less.

When this slurry was spray-dried using a nitrogen circulation type spray drier, it was possible to obtain a powder composed of extremely spherical particles. A coarse particle of 45 μm or more of this powder was cut (according to JIS Z 8801 45 μm) and the sieved fraction was used as Sample A. Table 1 shows the basic physical properties of Sample A.

Example 2 The wet cake obtained in the same manner as in Example 1 was subjected to IPA
The mixture was subjected to filtration, dehydration and redispersion twice, and further subjected to a dispersion treatment three times at a processing pressure of 400 kg / cm ² using a Gorin homogenizer 15M type manufactured by Nippon Seiki Seisakusho Co., Ltd. Spray-dried in the same manner as described above. The slurry before drying had a composition having a solid content of 9.8% by weight, a water content of 2.5% by weight, and an IPA of 87.7% by weight. The obtained sample was cut into coarse particles of 250 μm or more using a standard sieve (JIS Z 8801 250 μm), and the spherical sample of 250 μm or less was used as Sample B. The basic physical properties of Sample B are shown in Table 1.

Comparative Example 1 1 kg of the wet cake obtained in the same manner as in Example 1 was dispersed in acetone 2, filtered and dehydrated. This acetone-replaced wet cake is a high-speed mixing granulator manufactured by Gohashi Seisakusho
The mixture was placed in an NSK 250 type and crushed and granulated for 1 minute at a rotation speed of a stirring blade of 500 rpm. This fraction of 710 μm or less (JIS Z 8801
(According to 710 μm) was dried at 50 ° C. for 18 hours to obtain a spherical sample C. Table 1 shows the basic physical properties of Sample C.

Comparative Example 2 Commercially available microcrystalline cellulose “AVICEL PH-101” (manufactured by Asahi Kasei Kogyo Co., Ltd.) was used as Sample D. The basic physical properties of Sample D are shown in Table 1.

As can be seen from Table 1, the IP of finely divided cellulose
Samples A and B, which are spray-dried products of A slurry, have a sufficiently large pore volume and specific surface area, and an average particle size of 100 μm.
m or less. Incidentally, the reason that the specific surface area is small even though the pore volume of the sample B is larger than that of the sample A is because the pore size is different. (The pores of sample A are smaller than those of sample B.) Sample C, which is a cellulose particle prepared without milling or spray drying, has a sufficient pore volume but a low specific surface area. However, the existing cellulose powder, Sample D, is not satisfactory in both the pore volume and the specific surface area.

As described above, by performing the operation shown in the example, the crystal form of which the existence was not known until now was
To obtain novel porous cellulose microparticles having a specific surface area of 20 m ² / g or more, a pore volume of 0.01 μm or more having a pore volume of 0.3 cm ³ / g or more and an average diameter of 100 μm or less. Was completed.

 Hereinafter, the effects of the present invention will be described with use examples.

Usage Example 1 90 g of sample AB and 60 g of phenacetin pharmacological agent (Yamamoto Kagaku Kogyo Co., Ltd.) pulverized finely with a bantam mill AP-B type (use screen diameter 0.5 mmφ) manufactured by Hosokawa Ironworks Co., Ltd. After mixing 30 g of Nisseki Chemical Co., Ltd. and 120 g of lactose (DMV, 100 mesh) in a plastic bag for 3 minutes, 1.5 g of magnesium stearate (Taipei Chemical Industry Co., Ltd.) was obtained. In addition, the mixture was further mixed for 30 seconds, and the mixture was mixed with an RT-S-9 type rotary tableting machine manufactured by Kikusui Seisakusho Co., Ltd.
φ, rotation speed 25rpm using a 12R punch, molding pressure 1000kgf / cm
^The resulting mixture was compression-molded to obtain a tablet weighing 200 mg. Table 2 shows the physical properties of the tablets.

Comparative Use Example 1 A sample CD was tableted in the same manner as in Use Example 1. The results are shown in Table 2.

Comparative Use Example 2 A commercially available microcrystalline cellulose “Avicel PH-301” (manufactured by Asahi Kasei Kogyo Co., Ltd.) was tablet-formed as Sample E in the same manner as in Use Example 1. The results are shown in Table 2.

Table 2 shows that the angle of repose of sample AB is lower than the others. (Here, the angle of repose is a measured value for the mixed powder used for tableting.) A low angle of repose is expected to mean that the weight variation of the tablets obtained by compression is also low, but the sample AB Is also lower than others. The value of the weight variation indicates the quality of the filling of the powder into the mill of the tableting machine rather than the fluidity of the powder, and the adaptability of the powder to the direct powder compression method is determined based on this value. It is common that the weight variation is large even if the angle of repose is low, for example, as in the relationship between samples D and E. Sample AB, which is an invention, has a higher value than sample DE, which is a commercially available excipient for direct hitting. Sample C has a moderate value for each value, but its large particle size makes it less compatible with other powders, and causes separation and segregation problems.

As described above, the porous cellulose microparticles according to the present invention have excellent properties as compression molding aids and flow improvers for direct compression of pharmaceutical preparations and the like.

Claims (1)

(57) [Claims] (1) a crystal form of type I, a porous structure having a specific surface area of at least 20 m ² / g and a volume of pores having a diameter of 0.01 μm or more of 0.3 cm ³ / g or more, and an average particle size of Is at most 100μ
m, the porous microcellulose particles