sign in sign up
<<
Home , Diprophylline

USOO9446137B2

(12) United States Patent (10) Patent No.: US 9.446,137 B2 Magome et al. (45) Date of Patent: *Sep. 20, 2016

(54) COMPOSITE PARTICLES WHICH CONTAIN (58) Field of Classification Search BOTH CELLULOSE AND NORGANIC CPC ...... CO8L 1/O2 COMPOUND USPC ...... 428/402, 308.4, 319.1, 407, 532 (71) Applicant: ASAHI KASEI CHEMICALS S ee appl1cauonlication Illefile fIor completelet searcnh historv.n1story CORPORATION, Tokyo (JP) (56) References Cited (72) Inventors: Takumi Magome, Tokyo (JP); Kazuhiro Obae, Tokyo (JP) U.S. PATENT DOCUMENTS (73) Assignee: ASAHI KASEI CHEMICALS 4,744.987 A 5/1988 Mehra et al. CORPORATION, Tokyo (JP) 5,585,115 A 12/1996 Sherwood et al. Continued (*) Notice: Subject to any disclaimer, the term of this ( ) patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. JP 63-267731 * 11, 1988 ...... A61K 47.00 This patent is Subject to a terminal dis- JP 3-52823 3, 1991 Ca10. (Continued) (21) Appl. No.: 14/591,514 OTHER PUBLICATIONS (22) Filed: Jan. 7, 2015 DL-alpha Tocopheryl Acetate-Kyowa Hakko Europe GmbH (65) Prior Publication Data (1990)1990). US 2015/0174255 A1 Jun. 25, 2015 (Continued) Related U.S. Application Data (63) Continuation of application No. 13/807,373, filed as Primary Examiner — Holly Le application No. PCT/JP2011/064420 on Jun. 23, (74) Attorney, Agent, or Firm — Greenblum & Bernstein, 2011, now Pat. No. 8,951,636. P.L.C. (30) Foreign Application Priority Data (57) ABSTRACT

Jun. 29, 2010 (JP) ------2010-147663 Provided are composite particles which exhibit excellent (51) Int. Cl. fluidity and high liquid retentivity and which exhibit high B32B5/16 (2006.01) fluidity even in a liquid-holding state. Also provided are B32B5/18 (2006.01) composite particles which permit direct compressing in an open feed manner and which Suffer from little compressing (Continued) trouble and exhibit high shapability. When shaped together (52) U.S. Cl. with an active ingredient, the composite particles provide CPC ...... A61K 47/38 (2013.01); A23L I/00 shaped bodies which have uniform weight, uniform active (2013.01); A23L I/002 (2013.01); A23L 1/304 ingredient content, and high hardness and which Suffer from (2013.01); A61K 9/14 (2013.01); A61 K9/2054 less galling. (2013.01); (Continued) 12 Claims, 3 Drawing Sheets

US 9,446,137 B2 Page 2

(51) Int. Cl. 5,858.412 A 1/1999 Staniforth et al. A6 IK 47/38 (2006.01) 5.948,438 A 9, 1999 Staniforth et al. 6,103,219 A 8, 2000 Sherwood et al. C83/12 (2006.01) 6,358,533 B2 3/2002 Sherwood et al. COSL I/02 (2006.01) 6,521,261 B2 2/2003 Sherwood et al. A6 IK 47/02 (2006.01) 6,858,231 B2 2/2005 Sherwood et al. A 6LX 3L/355 (2006.01) 7,514,552 B2 4/2009 Yamasaki et al. C08K 3/34 (2006.01) 8,221,789 B2 7/2012 Obae et al. 8,951,636 B2 * 2/2015 Magome et al...... 428/402 A2.3L I/304 (2006.01) 2004.0053887 A1 3/2004 Obae et al. A6 IK 9/14 (2006.01) 2007/0028801 A1 2/2007 Yamasaki et al. A6 IK 47/36 (2006.01) 2009/0022791 A1 1/2009 Obae et al. A61 K9/20 (2006.O1 ) 2010.0045636 A1 2/2010 Noguchigu et al. 2010/0291161 A1 11/2010 Obae et al. A 2.3L I/00 (2006.01) 2011 OO62630 A1 3/2011 Honda et al. (52) U.S. Cl. 2011/00648.05 A1 3f2011 Obae et al. CPC ...... A61 K3I/355 (2013.01); A61K 47/02 (2013.01); A61K 47/36 (2013.01); C08J 3/122 FOREIGN PATENT DOCUMENTS (2013.01); C08K 3/34 (2013.01); C08L I/02 (2013.01); A23L 1/0035 (2013.01); A23V JP 10-500426 1, 1998 2002/00 (2013.01); A61K 92009 (2013.01); E. 2.93.3 '38. C08.J 2301/02 (2013.01); Y10T 428/24999 JP 2009-137892 6, 2009 (2015.04): Y10T 428/249958 (2015.04): Y10T WO O2/O2643 1, 2002 428/2982 (2015.01); Y10T 428/2991 WO 2004/106416 12, 2004 (2015.01); Y10T 428/2998 (2015.01); Y10T WO 2006/115,198 11 2006 428/31971 (2015.04) WO 2009, 142255 11/2009 (56) References Cited OTHER PUBLICATIONS

U.S. PATENT DOCUMENTS Search report from International Application No. PCT/JP2011/ 064420, mail date is Aug. 30, 2011. 5,725,883 A 3, 1998 Staniforth et al. 5,725,884 A 3, 1998 Sherwood et al. * cited by examiner U.S. Patent Sep. 20, 2016 Sheet 1 of 3 US 9,446,137 B2

F.G. 1

FIG. 2

FG. 3

FIG. 4 U.S. Patent Sep. 20, 2016 Sheet 2 of 3 US 9,446,137 B2

FIG. 5

F.G. 7

FIG. 8 U.S. Patent Sep. 20, 2016 Sheet 3 of 3 US 9,446,137 B2

FIG. O US 9,446,137 B2 1. 2 COMPOSITE PARTICLES WHICH CONTAIN cellulose is blended based on silicate. According to BOTH CELLULOSE AND NORGANIC the description, even if a drug having poor compactibility COMPOUND Such as phenacetin and acetaminophen is directly tableted, 70 to 90 parts by weight of the drug can be blended without CROSS REFERENCE TO RELATED capping. APPLICATIONS CITATION LIST This application is a Continuation of application Ser. No. 13/807,373 filed Jun. 23, 2011 now U.S. Pat. No. 8,951,636, Patent Literature which is a National Stage of International Application No. 10 PCT/JP2011/064420, filed Jun. 23, 2011, which claims Patent Literature 1: U.S. Pat. No. 4,744,987 priority to Japanese Application No. 2010-147663, filed Jun. Patent Literature 2: JP 10-500426 A 29, 2010. The disclosures of application Ser. No. 13/807,373 Patent Literature 3: JP 2005-232260 A and PCT/JP2011/064420 are expressly incorporated by ref Patent Literature 4: JP 3-52823 A erence herein in their entirety. 15 SUMMARY OF INVENTION TECHNICAL FIELD The present invention relates to composite particles hav Technical Problem ing high fluidity and liquid carrying properties, and keeping compactibility and fluidity of the particles even after reten Usually, a tablet is produced by tableting by filling a tion of the liquid to prevent tableting problems. powder into a die and compressing the powder with a punch. In the case where the drug easily adheres to the punch, it BACKGROUND ART causes a phenomenon called Sticking Such that the Surface of 25 the molded article is peeled off. Usually, a single inorganic Conventionally, in the fields of pharmaceuticals, foods, compound is used as an excipient, but the single inorganic and other chemical industries, cellulose powder is widely compound cannot always prevent the Sticking. Moreover, used as an excipient for molding when a molded article because the single inorganic compound has a large apparent containing an active ingredient is prepared. In addition, in specific Volume, flushing properties of the powder are the case where the active ingredient is a liquid ingredient, 30 increased in tableting to reduce filling properties into the die, the liquid ingredient is carried by a single inorganic com leading to problems such as variation in the weight of the pound to obtain a powder. The obtained powder is molded molded article and a phenomenon called capping: part of the into a molded article by using a cellulose powder as an molded article is peeled off. For this reason, a large amount excipient. of the inorganic compound cannot be added. Unfortunately, the single inorganic compound has an 35 Cellulose powder is an excipient having high compact excessively large apparent specific Volume, which limits the amount of the active ingredient to be powdered at one time. ibility. Once the cellulose powder gets wet, however, the There is also a handling problem Such that the inorganic compactibility is reduced, the function as the excipient is no compound scatters, or the like. For this reason, use of longer demonstrated. Moreover, compared to the inorganic cellulose-inorganic compound porous composite particles as 40 compound, the cellulose powder has lower liquid retention. the excipient has been examined. Moreover, the composite products of cellulose and an inor Patent Literature 1 describes an invention of fine particles ganic compound known in the related art have a low liquid produced by co-processing a microcrystalline cellulose par retention rate, and low fluidity of the particle after retention ticle and calcium carbonate having a particle size less than of the liquid. In addition, problems such as Sticking and 30 um in a specific mass ratio in order to reduce cost of a 45 capping cannot be sufficiently eliminated. pharmaceutical excipient. An object of the present invention is to provide composite Patent Literature 2 describes an invention of an excipient particles having a high liquid retention rate and having high composition composed of a fine particle agglomerates fluidity of the particles even after retention of a liquid. In including a microcrystalline cellulose and silicon dioxide as addition, another object of the present invention is to provide a pharmaceutical excipient having improved compressibil 50 composite particles that can be tableted with gravity feeder ity. in a direct tableting method, hardly cause tableting prob Patent Literature 3 describes an invention of cellulose lems, and have high compactibility. Further another object inorganic compound porous composite particles which are of the present invention is to provide a molded article in an aggregate of a specific cellulose dispersed particle and a which the weight of the molded article and the content of an water-insoluble inorganic compound particle, and having an 55 active ingredient are uniform, hardness is high, and friability intraparticle pore volume of 0.260 cm/g or more. According is low when the composite particles and the active ingredient to Patent Literature 3, the cellulose and the inorganic com are formed into the molded article. pound are formed into composite particles to obtain a particle having a large intraparticle pore Volume, and high Solution to Problem compactibility, disintegration properties, and fluidity. 60 Patent Literature 4 describes an invention of a solid In order to solve the problems above, the present inven formulation which is not a composite product but a physical tors have found out that if cellulose and an inorganic mixture of an inorganic compound and a microcrystalline compound are formed into a composite product, the appar cellulose, and comprises a drug, calcium silicate, and starch ent specific volume, the pore Volume, and the liquid reten and/or microcrystalline cellulose, in which 10 to 45% by 65 tion rate can be increased, and compactibility and fluidity of weight of calcium silicate is blended based on the drug, and the particles even after retention of a liquid can be increased. 40 to 250% by weight of starch and/or microcrystalline Thus, the present invention has been made. US 9,446,137 B2 3 4 Namely, the present invention is as follows. FIG. 2 is an enlarged SEM photograph at a magnification (1) Composite particles comprising a cellulose and an inor of 500 times of Composite Particles D according to Example ganic compound, and having an apparent specific volume 4. of 7 to 13 cm/g. FIG. 3 is an enlarged SEM photograph at a magnification (2) The composite particles according to (1), wherein the 5 of 500 times of Composite Particles G according to Example cellulose has an average width of 2 to 30 um and an average thickness of 0.5 to 5 Lum. 7. (3) The composite particles according to (1) or (2), com FIG. 4 is an enlarged SEM photograph at a magnification prising 10 to 60 parts by mass of the cellulose and 40 to of 500 times of Composite Particles I according to Example 90 parts by mass of the inorganic compound. 9. (4) The composite particles according to any one of (1) to 10 FIG. 5 is an enlarged SEM photograph at a magnification (3), wherein the inorganic compound is at least one of 200 times of a dried product of a cellulose WET cake. Selected from the group consisting of silicon dioxide FIG. 6 is an enlarged SEM photograph at a magnification hydrate, light anhydrous silicic acid, synthetic aluminum of 500 times of calcium silicate according to Reference silicate, hydroxide-aluminum hydroxide co Example 2. precipitate, magnesium aluminometasilicate, magnesium 15 aluminosilicate, calcium silicate, non-crystalline silicon FIG. 7 is an enlarged SEM photograph at a magnification oxide hydrate, magnesium silicate, and magnesium sili of 500 times of Composite Particles Kaccording to Example cate hydrate. 11. (5) The composite particles according to any one of (1) to FIG. 8 is an enlarged SEM photograph at a magnification (4), wherein the inorganic compound is calcium silicate. of 500 times of Composite Particles M according to (6) The composite particles according to any one of (1) to Example 13. (5), wherein a pore size is 0.003 to 1 um, and a pore FIG. 9 is an enlarged SEM photograph at a magnification volume is 1.9 to 3.9 cm/g. of 200 times of Composite Particles Haccording to Example (7) The composite particles according to any one of (1) to 8 (6), wherein a retention rate of tocopherol acetate is 500 25 FIG. 10 is an enlarged SEM photograph at a magnification to 1000%. (8) The composite particles according to any one of (1) to of 100 times of a mixture of cellulose and calcium silicate. (7), wherein a weight average particle size is 30 to 250 DESCRIPTION OF EMBODIMENTS lm. (9) The composite particles according to any one of (1) to (8), further comprising starch. 30 Hereinafter, an embodiment for implementing the present (10) A molded article comprising the composite particles invention (hereinafter, simply referred to as “the present according to any one of (1) to (9) and an active ingredient. embodiment”) is described in detail with reference to the (11) The molded article according to (10), wherein the active drawings when necessary. The present embodiment below is ingredient is an ingredient for a medicament or an ingre only an example for describing the present invention, and is dient for health food. 35 not intended to limit the present invention to the contents (12) A molded article comprising composite particles com below. Moreover, the attached drawings show an example of prising a cellulose and an inorganic compound, and an the embodiment, and the present embodiment should not be active ingredient, wherein the active ingredient is a liquid construed to be limited to the drawings. The present inven having a viscosity at 25°C. of 3 to 10000 mPas, and the tion can be properly modified without departing from the molded article contains 105 to 250 mg of the active 40 gist, and implemented. ingredient per 500 mg of one molded article. The composite particles according to the present embodi (13) The molded article according to (12), wherein the liquid ment comprise a cellulose and an inorganic compound ingredient is tocopherol acetate. formed into a composite product and having a specific apparent specific volume. Advantageous Effects of Invention 45 In the present embodiment, the cellulose refers to fibrous materials containing a natural polymer obtained from natural The composite particles according to the present inven products. In the present embodiment, the cellulose prefer tion have a large apparent specific volume and pore Volume, ably has a crystal structure of a cellulose type I. Preferably, and a high retention rate of tocopherol acetate as an index of the cellulose has an average width of 2 to 30 um and an the liquid retention rate. Scattering properties are reduced by 50 average thickness of 0.5 to 5 um. If the average width and forming a composite product, providing good operability. average thickness of the cellulose are within the ranges Thereby, the composite particles of the present invention can above, preferably, the pore within the particle can be suffi be used as an adsorption carrier of the liquid ingredient. By ciently developed by forming a composite product. More forming a composite product, high fluidity after retention of preferably, the cellulose has an average width of 2 to 25um the liquid can be provided, a uniformity in weight of the 55 and an average thickness of 1 to 5 Lum. molded article and content of the active ingredient can be The cellulose in the present invention includes microc provided among molded articles, and a large content of the rystalline cellulose. The microcrystalline cellulose used in liquid ingredient can be contained in the molded article. In the present invention is a white crystalline powder obtained addition, the molded article according to the present inven by partially depolymerizing C-cellulose obtained as pulp tion has sufficient hardness, can prevent sticking and cap 60 obtained from a fibrous plant with mineral acid, and puri ping, and provide a molded article having low friability. fying the partially depolymerized product. The microcrys talline cellulose has various grades. In the present invention, BRIEF DESCRIPTION OF DRAWINGS the microcrystalline cellulose having a polymerization degree of 100 to 450 is preferable. As a commercially FIG. 1 is an enlarged SEM photograph at a magnification 65 available product, “Ceolus' PH grade, “Ceolus' KG grade, of 500 times of Composite Particles B according to Example and “Ceolus' UF grade (all made by Asahi Kasei Chemicals 2. Corporation) can be used. The UF grade is most preferable. US 9,446,137 B2 5 6 Preferably, the cellulose has a volume average particle improved, and further, the properties of the cellulose are size of 10 to 100 um. The volume average particle size is Successfully given to the composite particles. Thereby, the preferably 10 to 50 um, and more preferably 10 to 40 um. composite particles having a high liquid retention rate and The cellulose preferably has an average polymerization given compactibility and fluidity that the cellulose has can degree of 10 to 450. The average polymerization degree is be provided. more preferably 150 to 450. Preferably, the composite particles according to the pres In the present embodiment, the inorganic compound is not ent embodiment contain 10 to 60 parts by mass of the particularly limited as long as the inorganic compound is cellulose and 40 to 90 parts by mass of the inorganic insoluble in water and has an apparent specific volume of 10 compound. More preferably, the composite particles accord to 50 cm/g. For example, silicon dioxide hydrate, light 10 anhydrous silicic acid, synthetic aluminum silicate, magne ing to the present embodiment contain 15 to 45 parts by sium hydroxide-aluminum hydroxide co-precipitate, mag mass of the cellulose and 55 to 85 parts by mass of the nesium aluminometasilicate, magnesium aluminosilicate, inorganic compound. If the inorganic compound is 40 parts calcium silicate, non-crystalline silicon oxide hydrate, mag by mass or more, a large intraparticle pore Volume can be nesium silicate, and magnesium silicate hydrate are prefer 15 given to the obtained composite particles including the able. Preferably, the inorganic compound has a volume cellulose and the inorganic compound to provide Sufficient average particle size of 10 to 50 um because the concentra liquid retention. Moreover, compression compactibility after tion of the dispersion liquid of the cellulose and the inor retention of the liquid is improved. If the inorganic com ganic compound can be increased. Particularly preferably, pound is 90 parts by mass or less, flushing properties can be the inorganic compound is calcium silicate. Calcium silicate Suppressed, and variation in the weight of the molded article is composed of CaO, SiO, and HO. Those represented by and the content of the active ingredient and reduction in the formula 2CaO.3SiOmSiOnH2O (1

A broad leaf tree was Subjected to known pulping and 65 Composite particles L (number of rotation of an atomizer bleaching treatments to obtain a pulp (the average width of of 8000 rpm) and Composite Particles M (number of rota the cellulose primary particle was approximately 19 um, and tion of an atomizer of 30000 rpm) were obtained in the same US 9,446,137 B2 27 28 manner as in Examples 2 and 3 except that the mass ratio anhydrous silicic acid=50/50 (based on the solid content), was starch/cellulose/calcium silicate=3/60/37 (based on the and the concentration of the total solid content was 4% by Solid content), the concentration of the total Solid content mass. The physical properties of Composite Particles O are was 11.7% by mass, and the number of rotation of an shown in Table 1. atomizer was 8000 rpm and 30000 rpm. The physical 5 Example 16 properties of Composite Particles L and M are shown in Table 1. Composite particles P (number of rotation of an atomizer 1 of 15000 rpm) were obtained in the same manner as in Example 14 10 Example 4 except that the mass ratio was cellulose/magne sium aluminometasilicate=30/70 (based on the solid con Composite particles N (number of rotation of an atomizer tent), and the concentration of the total solid content was 5% of 15000 rpm) were obtained in the same manner as in by mass. The physical properties of Composite Particles P Example 2 except that the mass ratio was starch/cellulose/ are shown in Table 1. calcium silicate=2.5/72.5/25 (based on the solid content), 15 and the concentration of the total solid content was 11.7% by Example 17 mass. The physical properties of Composite Particles N are shown in Table 1. Composite particles Q (number of rotation of an atomizer of 15000 rpm) were obtained in the same manner as in Example 15 2O Example 4 except that the mass ratio was cellulose/magne sium silicate hydrate=50/50 (based on the solid content), and Composite particles O (number of rotation of an atomizer the concentration of the total solid content was 5% by mass. of 30000 rpm) were obtained in the same manner as in The physical properties of Composite Particles Q are shown Example 5 except that the mass ratio was cellulose/light in Table 1. TABLE 1. Inorganic compound Cellulose volume Cellulose Cellulose volume average Inorganic average average average particle Cellulose compound width thickness particle size size parts by parts by Kind of inorganic lm In In In 3.SS mass compound Example 1 A. 9 3 25 25 28.6 71.4 Calcium silicate Ca Example 2 B 9 3 25 25 2O 70 Calcium silicate Ca Example 3 C 9 3 25 25 2O 70 Calcium silicate Ca Example 4 D 9 3 25 25 2O 8O Calcium silicate ca. Example 5 E 9 3 25 25 2O 8O Calcium silicate Ca Example 6 F 9 3 25 25 40 55 Calcium silicate Ca Example 7 G 9 3 25 25 40 55 Calcium silicate Ca Example 8 H 9 3 25 25 43 50 Calcium silicate Ca Example 9 I 9 3 25 25 43 50 Calcium silicate Ca Example 10 J 9 3 25 25 60 40 Calcium silicate Ca Example 11 K 9 3 25 25 60 40 Calcium silicate Ca Example 12 L 9 3 25 25 60 37 Calcium silicate Ca Example 13 M 9 3 25 25 60 37 Calcium silicate Ca Example 14 N 9 3 25 25 72.5 25 Calcium silicate Ca Example 15 O 9 3 2O O.O16 50 50 Light anhydrous silicic acid Example 16 P 9 3 25 12 30 70 Magnesium aluminometasilicate Example 17 Q 9 3 50 O.O7 50 50 Magnesium silicate hydrate Mg Weight Retention Apparent average rate of Starch specific Repose Pore particle tocopherol Hardness parts by volume angle volume Porosity size acetate of tablet mass (cm/g) II (cm/g) (9%) Llm % N Example 1 10.8 35 2.71 33.1 48 860 240 Example 2 10 10.4 34.5 2.70 32.4 38 830 233 Example 3 10 10.7 37.5 2.81 33.1 55 860 244 Example 4 11.5 35 3.15 35.5 31 915 325 Example 5 11.6 36.5 3.15 35.5 32 875 312 Example 6 5 8.7 32 1.97 27.4 8O 703 243 Example 7 5 8.8 34 2.09 28.2 60 738 261 Example 8 7 9.4 30 2.32 29.8 90 725 264 Example 9 7 8.7 33 2.05 28.0 70 760 240 Example 10 8.2 35 1.84 26.5 65 575 239 Example 11 7.7 39 1.63 2SO 50 520 220 Example 12 3 7.1 35 1.43 23.8 210 590 190 Example 13 3 7.2 35.5 148 24.1 61 530 200 Example 14 2.5 7.1 38.5 1.44 23.9 49 485 236 Example 15 12.5 41 1...SO 25.1 29 500 150 US 9,446,137 B2 30 TABLE 1-continued Example 16 1O.S 37 1.55 24.9 40 510 170 Example 17 11.6 38 1.21 2O2 38 450 148

Reference Example 1 formed at 116° C. for 1 hour to obtain an acid insoluble residue (the volume average particle size of the cellulose 100 g of pure water was introduced into a stainless steel dispersed particle was 51 um, and L/D was 3.4). The obtained acid insoluble residue and silicon dioxide (made by jug. While pure water was stirred by a 3-1 motor, calcium 10 Tokuyama Corporation, trade name, FINESEAL, volume silicate (made by Tokuyama Corporation, product name: average particle size of 5um) as a water insoluble inorganic Florite R, Volume average particle size of 25 to 30 um) was compound were introduced into a 90 L plastic bucket at an added little by little with a dispensing spoon and stirred. amount ratio of 30/70 (based on the solid content). Pure When the amount of calcium silicate added reached 10.7 g. water was added such that the concentration of the total solid stirring became impossible. 15 content became 20% by weight. While the materials were stirred by a 3-1 motor, the materials were neutralized with Reference Example 2 aqueous ammonia (pH after neutralization was 7.5 to 8.0). The obtained product was spray dried (dispersion liquid feed Pure water was introduced into a stainless steel jug. While rate of 6 kg/hr, inlet temperature of 180 to 220° C., outlet pure water was stirred by a 3-1 motor, the Wet cake obtained temperature of 50 to 70° C., number of rotation of an in Example 1 was added and mixed. Next, while SiO, (trade atomizer of 30000 rpm) to obtain Composite Particles S name: Aerosil 200, made by Nippon Aerosil Co., Ltd., (corresponding to Example 2 in Patent Literature 3). The volume average particle size of 0.016 um) was added little physical properties of Composite Particles S are shown in by little with a dispensing spoon, the materials were stirred Table 2. and mixed. The mass ratio was cellulose/light anhydrous 25 silicic acid=29.3/70.7 (based on the solid content), and the Comparative Example 4 concentration of the total solid content was 8.5% by mass (pH was 10.2). The obtained product was gluey, and could 2 kg of a chipped commercially available pulp (acicular not be spray dried. tree pulp, average width of the cellulose primary particle 30 was approximately 39 Lim, average thickness of the cellulose Reference Example 3 primary particle was approximately 8 um) and 30 L of a 0.2% hydrochloric acid aqueous solution were put into a low Pure water was introduced into a stainless steel jug. While speed stirrer (made by Ikebukuro Horo Kogyo Co., Ltd., pure water was stirred by a 3-1 motor, the Wet cake obtained trade name, 30LGL reactor). While the chipped pulp and the in Example 1 was added and mixed. Next, magnesium 35 aqueous solution were stirred, hydrolysis was performed at aluminometasilicate (trade name: Neusilin, made by Fuji 116° C. for 1 hour to obtain an acid insoluble residue (the Chemical Industry Co., Ltd.) was mixed. The mass ratio was Volume average particle size of the cellulose dispersed cellulose/magnesium aluminometasilicate=31.0/69.0 (based particle was 72 lum, and L/D was 4.0). The acid insoluble on the solid content), and the concentration of the total solid residue (solid content) and talc (made by Wako Pure Chemi content was 11.7% by mass (pH was 10.2). The obtained 40 cal Industries, Ltd., prepared so as to have a volume average product was creamy, and could not be spray dried. particle size of 5 um) were introduced into a 90 L plastic bucket at an amount ratio of 98/2 (based on the solid Comparative Example 1 content). Pure water was added such that the concentration of the total solid content became 10% by weight. While the The physical properties of calcium silicate (made by 45 materials were stirred by a 3-1 motor, the materials were Tokuyama Corporation, product name: Florite R, Volume neutralized with aqueous ammonia (pH after neutralization average particle size of 25 um) are shown in Table 2. was 7.5 to 8.0). The obtained product was spray dried in the same manner as that in Comparative Example 3 to obtain Comparative Example 2 Composite Particles T (corresponding to Example 6 in 50 Patent Literature 3). The physical properties of Composite Composite particles R were obtained in the same manner Particles T are shown in Table 2. as in Example 4 except that the mass ratio was starch/ cellulose/calcium silicate=2.5/72.5/25 (based on the solid Comparative Example 5 content), and the concentration of the total Solid content was 11.7% by mass. The physical properties of Composite 55 Ceolus PH-101 (made by Asahi Kasei Chemicals Corpo Particles R are shown in Table 2. ration) was used as a microcrystalline cellulose. The cellu lose and calcium silicate at a mass ratio of cellulose? calcium Comparative Example 3 silicate=28.6/71.4 were sufficiently mixed in a plastic bag for 3 minutes to obtain Mixture U of cellulose? calcium 2 kg of a chipped commercially available dissolved pulp 60 silicate (the mixture having the largest amount of silicic acid (acicular tree pulp, average width of the cellulose primary to be blended which is described in Patent Literature 4). The particle was approximately 39 um, average thickness of the physical properties of Mixture U are shown in Table 2. cellulose primary particle was approximately 8 um) and 30 Lofa 0.4% hydrochloric acid aqueous solution were put into Comparative Example 6 a low speed stirrer (made by Ikebukuro Horo Kogyo Co., 65 Ltd., trade name, 30LGL reactor). While the chipped pulp Ceolus PH-101 (made by Asahi Kasei Chemicals Corpo and the aqueous solution were stirred, hydrolysis was per ration) was used as a microcrystalline cellulose. The cellu US 9,446,137 B2 31 32 lose and calcium silicate at a mass ratio of cellulose/calcium NIPPON STARCH CHEMICAL CO.,LTD.) were weighed silicate=71.4/28.6 were sufficiently mixed in a plastic bag and mixed in a polyethylene bag for 3 minutes. Then, the for 3 minutes to obtain Mixture V of cellulose? calcium mixture was placed in a vertical granulator (made by Powrex silicate (the mixture having the Smallest amount of silicic Corporation, FM-VG-10P type) and mixed (blade at 200 acid to be blended which is described in Patent Literature 4). 5 rpm, chopper at 2100 rpm). 200 g of a hydroxypropyl The physical properties of Mixture V are shown in Table 2. cellulose (trade name: HPC-L, made by NIPPON SODA TABLE 2 Inorganic Cellulose Cellulose compound Inorganic average average Cellulose particle Cellulose compound width thickness particle size size parts by parts by Kind of inorganic Llm Lim Lim Lim 3.SS mass compound Comparative — 25 1OO Calcium silicate Ca Example 1 Comparative R 19 3 22-27 25 72.5 25 Calcium silicate Ca Example 2 Comparative S 39 8 51 5 30 70 Silicon dioxide Example 3 Comparative T 39 8 72 5 98 2 Talc Example 4 Comparative U 39 8 38 25 28.6 71.4 Calcium silicate Ca Example 5 Comparative V 39 8 38 25 71.4 28.6 Calcium silicate Ca Example 6

Retention Apparent Average rate of Starch specific Repose Pore particle tocopherol Hardness parts by volume angle volume Porosity size acetate of tablet mass (cm/g) () (cm/g) (96) Lim (9%) N Comparative 13.7 40 3.95 41.O 56 885 348 Example 1 Comparative 2.5 6.9 4O.S 1.37 23.3 50 440 215 Example 2 Comparative S.1 32 1.25 22.1 52 400 45 Example 3 Comparative 6 45 O.29 17.2 45 204 110 Example 4 Comparative 11 42 1.88 27.1 29 687 26S Example 5 Comparative 7.4 38 1.OO 20.4 39 390 145 Example 6

40 CO., LTD.) 6% solution was poured over 30 seconds. Using a "JSM-551OLV type' electron microscope made Further, the ingredients were mixed (granulated) for 3 by JEOL, Ltd., Composite Particles B, D, G, I, K, and M minutes, and taken out from the granulator. Next, the mix were observed by SEM. ture was dried using a MULTIPLEX (made by Powrex 45 Corporation, MP-01 type). The drying was completed when It is found that the particle has relatively few irregularities the temperature of exhaust air reached 40° C. Then, a on the Surface, and has a shape close to a sphere in granulated product was extracted. The granulated product Composite Particles B in Example 2 (see FIG. 1), Composite was sieved with a sieve having an opening of 710 um, and Particles D in Example 4 (see FIG. 2), Composite Particles used as a test sample (hereinafter, referred to as granulated G in Example 7 (see FIG. 3), and Composite Particles I in 50 granules). Example 9 (see FIG. 4). It is also found that the cellulose WET cake (see FIG. 5) and calcium silicate in Reference Example 18 Example 2 (see FIG. 6) are formed into a composite product which has gaps. The gaps can provide a molded article 88% by mass of the granulated granules, 2% by mass of croscarmellose sodium (made by NICHIRIN CHEMICAL having high liquid retention rate and hardness. 55 INDUSTRIES, LTD.), “KICCOLATE ND-2HS), and 10% Meanwhile, the particle has irregularities on the surface in by mass of Composite Particles C of Example 3 were mixed Composite Particles K in Example 11 (FIG. 7) and Com in a polyethylene bag for 3 minutes. Next, based on the total posite Particles M in Example 13 (see FIG. 8). weight of the mixed powder, 0.5% by mass of magnesium stearate (made by TAIHEI CHEMICAL INDUSTRIAL Ibuprofen is a representative example of a drug easy to 60 CO., LTD.) was added, and mixed slowly for 30 seconds. Stick. Using ibuprofen, comparison was made about the Using a rotary tableting machine (made by Kikusui Sei sakusho Ltd., CLEANPRESS CORRECT 12HUK), the Sticking-preventing effect. Granulated granules having ibu mixed powder was tableted with a punch having a diameter profen blended were produced by the following method. of 0.8 cm and 12 R on the condition of the number of In the total amount of ingredients of 1000 g, 45% of rotation of the turn table of 54 rpm, a compression force of ibuprofen (made by API Corporation), 38% of lactose 65 5 to 15 kN, and open feed. Thus, a tablet having a weight of hydrate (trade name: lactose 200M, made by DMV Inter 180 mg was produced. The physical properties of the tablet national), and 17% of corn starch (GRDE: ST-C, made by are shown in Table 3. US 9,446,137 B2 33 34 Example 19 In Examples 18 and 19, tablets having a practical hardness of 50 N or more, the weight CV value of 1.0% or less, and The operation was performed in the same manner as that no tableting problems (sticking, capping) were obtained. in Example 18 except that Composite Particles C used in Meanwhile, in Comparative Example 7, tableting problems Example 18 were replaced by Composite Particles H of 5 (no Sticking, but two cappings) were occurred. The weight Example 8. The physical properties of the tablet are shown CV value was more than 1.0%. Accordingly, the tablet in in Table 3. Comparative Example 7 is not suitable for practical use. In Comparative Examples 8 to 11, the weight CV value was Comparative Example 7 more than 1.0%, and tableting problems (sticking, capping) 10 were remarkable. Accordingly, the tablets in Comparative The operation was performed in the same manner as that Examples 8 to 11 are not suitable for practical use. in Example 18 except that Composite Particles C used in In Comparative Example 9, a practical hardness of 50 N Example 18 were replaced by light anhydrous silicic acid or more was obtained at the compression force of 15 kN (made by Nippon Aerosil Co., Ltd., Aerosil 200). The while the friability was 0.8% and did not satisfy the practical physical properties of the tablet are shown in Table 3. 15 level of 0.5% or less. The disintegrating time of the tablet was measured in the Comparative Example 8 respective tablets, but no remarkable difference was found among the tablets. The operation was performed in the same manner as that in Example 18 except that Composite Particles C used in 20 360 g of Riken tocopherol acetate (Riken Vitamin Co., Example 18 were replaced by Composite Particles S of Ltd.) as an liquid active ingredient, Tween 80 (Wako Pure Comparative Example 3. The physical properties of the Chemical Industries, Ltd.), and 1000 g of pure water were tablet are shown in Table 3. weighed, and stirred and mixed with a TK homomixer Comparative Example 9 25 E.PRIMIX minutes Corporation, tproduce anMARK2 NiSA. 2.5 type) at 10000 rprpm for The operation was performed in the same manner as that Example 20 in Example 18 except that Composite Particles C used in Example 18 were replaced by Composite Particles T of 360 g of Composite Particles C of Example 3 was put into Comparative Example 4. The physical properties of the 30 a vertical granulator (made by Powrex Corporation, tablet are shown in Table 3. FM-VG-10P). While Composite Particles C were mixed on the condition of a blade at 200 rpm and a chopper at 2100 Comparative Example 10 rpm, 360 g of the emulsified solution produced above was poured in 30 seconds. The obtained mixture was granulated The operation was performed in the same manner as that 35 for 6 minutes, and discharged. Next, the granulated product in Example 18 except that Composite Particles C used in was dried with an oven (made by Tabai Espec Corp., ESPEC Example 18 were replaced by Mixture U of Comparative Oven PV-211), and passed through a sieve having an open Example 5. The physical properties of the tablet are shown ing of 710 um (made by Iida Seisakusho K.K., sieve for a in Table 3. test) to obtain a dried product. The dried product was used 40 as a test sample (hereinafter, referred to as VE granules). The Comparative Example 11 repose angle of the VE granules was 35° and good. 35% by mass of the VE granules, 45% by mass of a The operation was performed in the same manner as that microcrystalline cellulose (made by Asahi Kasei Chemicals in Example 18 except that Composite Particles C used in Corporation, UF-711), 18% by mass of anhydrous dibasic Example 18 were replaced by Mixture V of Comparative 45 calcium phosphate (made by Fuji Chemical Industry Co., Example 6. The physical properties of the tablet are shown Ltd., Fujicalin), and 2% by mass of croScarmellose sodium in Table 3. (made by NICHIRIN CHEMICAL INDUSTRIES, LTD, TABLE 3 Mass Sticking occurrence Number Hardness N CV (%) Friability (9%) rate (%) of cappings occurred - Compression force ISN Items 5 10 15 5 10 15 5 10 15 15 15 Example 18 Composite particles C 59 85 102 0.5 0.6 0.5 0.45 0.15 0.11 O None Example 19 Composite particles H 70 90 79 0.9 O.S. O.9 O.16 O.O8 O.17 O None Comparative Light anhydrous silicic 30 53 38 22 2.1 16 O.39 O.43 2.85 O 2 Example 7 acid Comparative Composite particles S 20 35 40 19 2.3 15 2SO 1.90 120 5 25 Example 8 Comparative Composite particles T 20 48 6O 28 1.8 3.4 2.40 1.OO O.80 2O 5 Example 9 Comparative Mixture U 26 40 3O 15 14 19 1.OO O.90 O.80 10 25 Example 10 Comparative Mixture V 2O 37 43 1.8 1.6 2.1 1.8 1.2O O.70 50 40 Example 11 US 9,446,137 B2 35 36 “KICCOLATEND-2HS) were mixed in a polyethylene bag reason, the composite particles according to the present for 3 minutes. Next, based on the total weight of the mixed invention have high uniformity of mixing with the active powder, 2.0% by mass of magnesium Stearate (made by ingredients when the composite particles according to the TAIHEI CHEMICAL INDUSTRIAL CO., LTD.) was present invention are used as an excipient mainly in the added, and further mixed slowly for 30 seconds. Using a rotary tableting machine (made by Kikusui Seisakusho Ltd., pharmaceutical field in production of a molded article con LIBRA2), the mixed powder was tableted using a punch taining a variety of active ingredients. Moreover, the com having a diameter of 0.8 cm and 12 R on the condition of the posite particles according to the present invention can keep number of rotation of the turn table of 30 rpm, the com the compactibility and fluidity of the particles even after pression force of 2 to 7 kN, and open feed to produce a tablet retention of the liquid to prevent tableting problems. In having a weight of 200 mg. The physical properties of the 10 addition, the weight of the molded article according to the tablet are shown in Table 4. present invention is hardly fluctuated. The molded article according to the present invention has high uniformity of the Comparative Example 12 active ingredients contained, high Sufficient hardness, and low friability. The operation was performed in the same manner as in 15 Example 20 except that Composite Particles C were replaced by calcium silicate (made by Tokuyama Corpora The invention claimed is: tion, product name: Florite Grade R, Volume average particle 1. Composite particles comprising a cellulose and an size (which was measured at the state of aggregated par inorganic compound, wherein an apparent specific volume ticles) of 25 to 30 Lum). The physical properties of the tablet of the composite particles is 7 to 13 cm/g, and a volume are shown in Table 4. The repose angle of the VE granules average particle size of the cellulose as a water-dispersed was 41. Fluidity was inferior to that in the case where cellulose is 10 to 40 um. Composite Particles C were used. 2. The composite particles according to claim 1, compris ing 10 to 60 parts by mass of the cellulose and 40 to 90 parts Comparative Example 13 25 by mass of the inorganic compound. 3. The composite particles according to claim 1, wherein The operation was performed in the same manner as in Example 20 except that Composite Particles C were the inorganic compound is at least one selected from the replaced by Composite Particles S. The physical properties group consisting of silicon dioxide hydrate, light anhydrous of the tablet are shown in Table 4. silicic acid, synthetic aluminum silicate, magnesium 30 hydroxide-aluminum hydroxide co-precipitate, magnesium Comparative Example 14 aluminometasilicate, magnesium aluminosilicate, calcium silicate, non-crystalline silicon oxide hydrate, magnesium The operation was performed in the same manner as in silicate, and magnesium silicate hydrate. Example 20 except that Composite Particles C were 4. The composite particles according to claim 1, wherein replaced by Mixture U. The physical properties of the tablet 35 the inorganic compound is calcium silicate. are shown in Table 4. 5. The composite particles according to claim 1, wherein a pore size of the composite particles is 0.003 to 1 um, and TABLE 4 a pore volume of the composite particles is 1.9 to 3.9 cm/g. 6. The composite particles according to claim 1, wherein Sticking occurrence rate % 40 a retention rate for the composite particles of tocopherol Compression force IkN acetate is 500 to 1000%. Items 2 3 4 S 6 7 7. The composite particles according to claim 1, wherein a weight average particle size of the composite particles is Example 20 Composite O O O particles C 30 to 250 um. Comparative Calcium silicate 31.O 113 75.O 45 8. The composite particles according to claim 1, further Example 12 comprising starch. Comparative Composite Powder cannot be obtained 9. A molded article comprising the composite particles Example 13 particles S Comparative Mixture U Powder cannot be obtained according to claim 1 and an active ingredient. Example 14 10. The molded article according to claim 9, wherein the 50 active ingredient is an ingredient for a medicament or an ingredient for health food. In Example 20, a tablet having a practical hardness of 50 11. A molded article comprising composite particles com N or more, a weight CV value of 1.0% or less, and no tableting problems (sticking, capping) were obtained. Mean prising a cellulose and an inorganic compound, wherein an while, in Comparative Example 12, the sticking occurrence apparent specific volume of the composite particles is 7 to 13 55 cm/g, and a volume average particle size of the cellulose as rate was not 0 at all of the compression forces. Accordingly, a water-dispersed cellulose is 10 to 40 um, and an active the tablet is not suitable for practical use. In Comparative ingredient, wherein the active ingredient is a liquid having Examples 13 and 14, the retention rate of tocopherol acetate a viscosity at 25° C. of 3 to 10000 mPas, and the molded was low, and powder could not be obtained. article contains 105 to 250 mg of the active ingredient per INDUSTRIAL APPLICABILITY 60 500 mg of one molded article. 12. The molded article according to claim 11, wherein the The composite particles according to the present inven active liquid ingredient is tocopherol acetate. tion have extremely high compactibility and fluidity. For this k k k k k