WO2005073286A1 - 多孔質セルロース凝集体及びその成型体組成物 - Google Patents
多孔質セルロース凝集体及びその成型体組成物 Download PDFInfo
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- WO2005073286A1 WO2005073286A1 PCT/JP2005/001131 JP2005001131W WO2005073286A1 WO 2005073286 A1 WO2005073286 A1 WO 2005073286A1 JP 2005001131 W JP2005001131 W JP 2005001131W WO 2005073286 A1 WO2005073286 A1 WO 2005073286A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/02—Cellulose; Modified cellulose
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
- C08J2301/02—Cellulose; Modified cellulose
Definitions
- the present invention relates to a porous cellulose aggregate useful mainly as an excipient in the chemical industry, particularly in medicine and food, and a molded product composition thereof.
- Patent Document 1 discloses that a cellulose particle is mixed with a third component such as a crystalline substance which is insoluble or hardly soluble in water and soluble in an organic solvent, and this is mixed with an aqueous solution of a water-soluble organic solvent. After extracting and removing the third component with an organic solvent after granulation and drying using an organic solvent, the crystal form is Form I, the pore size is 0.1 ⁇ or more, and the porosity is 20% or more. It describes porous cellulose particles (corresponding to Comparative Example 6 of the present application) having fine pores and a fraction of 350 mesh or more of 90% by weight or more.
- the primary cellulose particles form a dense and strong film-like cellulose wall structure that is uniformly continuous so that the boundaries of the particles are unclear.
- the particle structure is completely different from that of the porous cellulose aggregate.
- the cellulose particles of Patent Document 1 are excellent in fluidity, water does not easily penetrate into a dense and continuous cellulose wall, so that they do not disintegrate in water and sometimes hinder the rapid release of the active ingredient.
- the cellulose particles of Patent Document 1 have poor moldability due to poor plastic deformation during cellulose compression, and furthermore, in the manufacturing process, an organic solvent or a crystalline substance soluble in an organic solvent such as a crystalline substance.
- the use of the components not only increases the production cost, but also may deactivate the active ingredients, and is insufficient for stable use as an excipient.
- Patent Document 2 discloses that the crystalline form is obtained by granulating and drying particulate natural cellulose dispersed in an organic solvent by a spray drying method, and the crystalline form is I type, and the specific surface area is 20 m 2 / g, a porous structure with a pore volume of at least 0.01 ⁇ and a pore structure of at least 0.3 cm 3 / g, and having a mean particle diameter of at most 100 ⁇ m. Comparative Example 7) is described. These fine cellulose particles also have the above-mentioned cellulose wall structure, and are completely different from the porous cellulose aggregate of the present invention in particle structure. In addition, the cellulose particle of Patent Document 2 has a large pore volume itself.
- the porous cellulose aggregate particles Since the particle structure is different from that of the porous cellulose aggregate of the present invention, it is inferior in disintegration that water hardly penetrates into the particle. Problem. As a matter of fact, the porous cellulose aggregate particles also use an organic solvent in the production process, which not only increases the production cost, but also promotes the interaction between the active ingredient and water because the specific surface area is too large. In some cases, the active ingredient was deactivated, which was insufficient for stable use as an excipient.
- Patent Document 3 as disintegration good cellulose powder and moldability, the average polymerization degree of 150 one 375, see force, only];.. ⁇ product force 84-8 92cm 3 / g, particle size force 300 Senorelose powder of ⁇ or less (corresponding to Comparative Example 8 of the present application) is described.
- Patent Document 4 discloses a cellulose powder having good flowability and disintegrability, an average degree of polymerization of 60 to 375, an apparent specific volume of 1.6 to 3. lcm 3 / g, and an apparent tapping specific volume of 1.4 cm 3.
- Microcrystalline cellulose aggregates (corresponding to Comparative Example 9 of the present application) having a repose angle of 35-42 ° and a component of 200 mesh or more of 2-80% by weight are described.
- the cellulose powder obtained by the examples described in these patent documents is intentionally formed as in the present invention, in which the pore volume in the particles is small. It is completely different from the pore structure. Therefore, these cellulose powders have a small specific surface area of 0.6-1.2 m 2 / g and have low compression moldability.
- These patent documents disclose adjusting the value of the apparent specific volume to control the moldability, flowability, and disintegration of the cellulose particles, but the apparent specific volume is 2.0 to 2. In a relatively small range of 9 cm 3 Zg, the fluidity and disintegration are excellent, but the moldability is satisfactory, and it is not a good thing, but the apparent specific volume is 3.0-3.2 cm 3 / g. When the size is large, the moldability is excellent, but there is a problem that the fluidity and the disintegration property are deteriorated.
- Patent Document 5 as a good cellulose powder moldability, a 30 zm even larger average particle size, and specific surface area of 1. 3m 2 / g and a j3 _l, 4-glucan powder (application of Comparison Example 1) is described.
- the i3-l, 4-gunolecan powder described in this document does not have a secondary aggregated structure, and individual primary particles exist alone.
- This gnorecan powder has good moldability, but is inferior in disintegration, and has a problem of poor fluidity due to a small average particle size.
- Patent Document 6 describes that cellulose powder has excellent compression moldability and disintegration properties.However, when the angle of repose was measured for the specifically disclosed example with the best balance, the angle of repose exceeded 55 °, Fluidity is not sufficiently satisfactory.In the case of formulas containing many active ingredients with poor fluidity, the coefficient of variation in tablet weight becomes large, affecting the uniformity of drug content. . Further, in the cellulose powder of this document, although high hardness can be imparted when molded under high pressure, the collapse of water due to the low permeability of water into the particles formed by the intentionally formed pores is low. There was a problem of delay.
- Patent Document 7 discloses that as a cellulose powder having good moldability, flowability and disintegration property, particles passing through a sieve having an average polymerization degree of 00-375 and 75 ⁇ m and remaining on a 38 ⁇ m sieve have a total weight of 70%. % Or more, and the average value of the ratio of the major axis to the minor axis of the particles is 2.0 or more, which describes crystalline cellulose (corresponding to Comparative Example 11 of the present application).
- Patent Document 8 discloses that as a cellulose powder having good moldability, disintegration, and fluidity, particles having an average polymerization degree of 50, 450 and 75 zm or less have an average LZD (major axis / minor axis ratio) of 2.04.5, Cellulose powder having an average particle size of 20 250 xm, an apparent specific volume of 4.0 to 7.0 cm 3 / g, an angle of repose of 54 ° or less, and a specific surface area of 0.5 to 4 m 2 / g Comparative Examples 2 and 3).
- the cellulose powders described in these documents also have a small intraparticle pore volume measured by mercury porosimetry, and thus are completely different from the intentionally formed pore structure as in the present invention.
- Cellulose powders described in these documents provide a molded product with high hardness by elongating the shape of the particles, but due to the elongated shape, the apparent specific volume is increased and the moldability is increased. The higher the level, the lower the fluidity.
- the angle of repose was measured to be 44 ° for the one with the best fluidity, and it was, for example, a formulation containing many active ingredients with poor fluidity and a high repose rate.
- the coefficient of variation of the tablet weight becomes large and affects the uniformity of the content of the drug, so that it is not satisfactory in terms of flowability.
- the cellulose powders described in these documents can also provide high hardness when molded under high pressure, but water permeability into the particles formed by the intentionally formed pores in the particles is low. Due to the low temperature, there was a problem that the collapse was delayed.
- Patent Document 9 discloses a pharmaceutically inert spherical nucleus containing 10-70% of microcrystalline cellulose having an average degree of polymerization of 60-375 and 10-90% of a water-soluble additive as cellulose particles having good flowability. Is described. In Patent Document 10, distilled water is added and kneaded while mixing a powder containing 50% or more of crystalline cellulose with a mixing and stirring granulator, and the water absorption capacity is 0.5 to 1.5 ml / g.
- Active spherical nuclei (corresponding to Comparative Example 12 of the present application) are described.
- Patent Document 11 discloses that hydrolyzed cellulose particles are mechanically reduced in particle size and spray-dried at least 0.4 g / cm 3 of looseness ⁇ density (2.5 cm 3 / g in apparent specific volume) Microcrystalline cell opening particles having a smooth surface having a spherical surface and an average particle diameter of 5-35 zm are described.
- Patent Document 12 discloses that a cellulosic material is hydrolyzed with kagami until the average degree of polymerization reaches 60 to 350, and then mechanically ground until the average particle size becomes 15 am.
- the resulting dispersion is dried in the form of droplets, Contains 10% or more of crystalline cellulose with a degree of polymerization of 60-350, an apparent specific volume of tapping of 0.60-0.95g / mL, a sphericity of 0.7 or more, and a shape factor of 1.10-1.50.
- cellulose-based particles having an average particle diameter of 10 to 400 ⁇ m (corresponding to Comparative Example 13 of the present application).
- the cellulose particles described in these publications also do not have a secondary aggregated structure, and the cellulose particles obtained by the method of Examples described in these patent documents have an apparent specific volume. 2.5 cm 3 / g or less, has a shape close to a sphere, and has excellent fluidity, but is inferior in compression moldability and does not have a practically sufficient hardness at a commonly used compression pressure of 10 to 20 MPa. .
- the moldability, flowability, and disintegration are mutually contradictory properties, and it is desired to realize cellulose particles having all these physical properties in a well-balanced manner. I was rare.
- the cellulose particles described in Patent Documents 3 to 12 do not have intentionally formed pores in the particles and have a small pore volume in the particles, so that almost no active ingredient can be supported in the particles.
- the cellulose particles described in Patent Documents 1 and 2 have pores within the particles that have a certain force. The pore size is small, so that it is difficult for water to penetrate into the dense and continuous cellulose wall. Had a problem.
- these cellulose particles do not have intentionally formed pores in the particles and have a small pore volume in the particles, so that almost no active ingredient can be supported in the particles.
- the active ingredient elutes slowly and is not practical for practical use unless a complicated process such as granulation and drying is performed once with water or an organic solvent.
- the active ingredient had drawbacks such as recrystallization during storage and loss of commercial value.
- the active ingredient in the solid preparation for internal use elutes from the preparation into the body fluid in the gastrointestinal tract, is absorbed from the gastrointestinal tract, enters the systemic blood, and exerts its medicinal effect. Since the active ingredient that is hardly soluble in water has low solubility, the administered active ingredient may not be completely eluted and may be excreted outside the body before it exhibits sufficient drug efficacy. Total amount entering the systemic blood with respect to the amount of active ingredient administered The ratio of the active ingredients is generally known as bioavailability. For the purpose of improving the bioavailability and the rapid effect of the active ingredient, various methods have been studied for improving the dissolution of the poorly soluble active ingredient.
- Patent Document 13 describes a method of co-milling an active ingredient that is hardly soluble in water with 4-glucan powder. This method requires long-term pulverization until the crystallinity of the ⁇ -1,4-glucan powder disappears, and also requires continuous application of a strong shear for a long time using a roll mixer, which results in a decrease in actual production. There was a problem of inefficiency. Further, ⁇ -1,4-glucan, which has lost crystallinity, has a problem that its compression moldability is low.
- Patent Document 14 discloses that when a poorly water-soluble active ingredient is used as a solid preparation for oral administration by direct tableting, ⁇ -1,4-glucan, a disintegrant and a surfactant are added to increase the strength, and It describes a method of eliminating the variation in the amount and increasing the disintegration degree of the tablet and the dissolution rate of the active drug.
- this publication there is no description about improving the water solubility of a drug by blending a poorly water-soluble active ingredient and a porous cellulose particle, which does not describe the pores in the particles.
- it is necessary to incorporate a surfactant in order to promote the elution of the poorly water-soluble active ingredient and there has been a problem that when the solid preparation is taken, the surfactant causes inflammation in the gastrointestinal mucosa. .
- Patent Document 15 discloses that, when a tablet is manufactured by a wet-blending method through powder mixing, kneading, granulating, and drying processes using a poorly water-soluble active ingredient and i3-l, 4-gnorecan, It is described that by adding a water-soluble polymer solution, a tablet having a high tablet hardness, a short disintegration time, and a high drug dissolution rate is produced. This document also does not describe porous cellulose particles having large pores in the particles, and it is completely known to improve the water solubility of a drug by blending a porous cellulose particle with a poorly water-soluble active ingredient. What was it.
- Patent Document 16 discloses a porous cellulose particle having a specific specific surface area and a specific pore volume, which is obtained by granulating and drying fine-particle natural cellulose dispersed in an organic solvent by a spray drying method. Is mixed with a poorly soluble drug, and Methods for improving the dissolution of drugs are described.
- the porous cell source particles described in the document have a high specific surface area and a large pore volume in the particles, and thus, when sublimation-adsorption of the poorly water-soluble active ingredient is performed, the elution is improved.
- Sublimable active ingredients have a problem of leaching from solid preparations during storage, and many of these solid preparations have been coated with a film or sugar coating to prevent such problems.
- the active ingredient in the drug product is dispersed by passing through the film layer and escaping to the outside of the drug product.
- the commercial value was remarkably reduced due to a pungent odor or recrystallization in a storage container such as a bottle.
- sublimation recrystallization is more remarkable than in the case of a coating.
- Patent Document 16 as described above, cellulose particles having an excessively high specific surface area are used, and since the active ingredient adsorbed on the surface by sublimation is amorphous, the storage stability of the active ingredient is poor.
- Patent Document 17 also discloses a method for preventing recrystallization due to sublimation of ibuprofen in a solid preparation, as one or two of the group consisting of a solid preparation containing ibuprofen, polyvinylpyrrolidone, magnesium oxide and sodium bicarbonate.
- a method is described in which more than one stabilizing substance is stored in a closed container such as a bottle. According to this method, the adhesion of crystals to the sealed container and the pungent odor of the drug product during storage of the drug product are certainly improved, but it is necessary to put polyvinylpyrrolidone, magnesium oxide, sodium carbonate, etc. as a separate drug product in the container. , The process becomes complicated. Therefore, by substituting porous cellulose in the preparation, it is completely different from the preparation containing a sublimable active ingredient of the present invention, which is a single preparation in which sublimation is prevented.
- a composition containing an oily, liquid, or semi-solid active ingredient is particularly tabletable because the liquid ingredient leaches out of the preparation during compression molding as compared to the solid active ingredient.
- problems such as the occurrence of an obstacle, spotting of liquid components on the surface of the obtained preparation immediately, and poor flowability in the case of a granular preparation.
- Patent Documents 18-29 teach that in tablet production, a liquid or semi-solid active ingredient at room temperature is directly retained on an adsorption carrier, or the active ingredient is water, an organic solvent, oils and fats, a water-soluble polymer, and a surfactant.
- a method is described in which a solution obtained by dissolving, emulsifying, and suspending in water is subjected to a drying step, and the obtained dry powder or granule is compression-molded.
- a liquid or semi-solid active component at room temperature at the time of compression oozes out, causing tableting failure, and a sufficient compression molded product may not be obtained. .
- Patent Document 30 discloses a method of mixing microcrystalline cellulose and an active ingredient, increasing the uniformity of mixing of the active ingredient, and reducing the dispersion of the active ingredient.
- a method of mixing a drug for mixing light silicic anhydride, hydrated silicon dioxide, and a stearate and then mixing the mixed powder with other additives is disclosed. It is described as having excellent mixing properties.
- the porous cellulose aggregate particles as described in the present invention in which the description of the pores in the particles of cellulose such as crystalline cellulose is completely eliminated, the active components are retained in the particles, and the What can improve the mixing uniformity is Was not known.
- the document states that it is preferable to apply the compound to a highly cohesive drug in the form of a fine powder having an average particle size of 40 / m or less as a drug, because the effect becomes remarkable and is preferred.
- the average particle size of the drug described in the examples is 16 ⁇ m at the smallest.
- a drug that has been pulverized to about 10 zm or less for the purpose of enhancing the dispersibility of the poorly water-soluble active ingredient when taking it However, since the cohesiveness of the active ingredient is significantly increased, sufficient mixing uniformity may not be obtained with the existing crystalline cellulose having small pores in the particles (Comparative Example 31 of the present invention).
- Patent document 1 Japanese Patent Application Laid-Open No. 1-272643
- Patent Document 2 JP-A-2-84401
- Patent Document 3 Japanese Patent Publication No. 40-26274
- Patent Document 4 Japanese Patent Publication No. 53-127553
- Patent Document 5 JP-A-63-267731
- Patent Document 6 JP-A-6-316535
- Patent Document 7 JP-A-11-152233
- Patent Document 8 WO02 / 02643 pamphlet
- Patent Document 9 JP-A-4-283520
- Patent Document 10 JP-A-7-173050
- Patent Document 11 Japanese Patent Publication No. 7-507692
- Patent Document 12 pamphlet of W02 / 36168
- Patent Document 13 Japanese Patent Publication No. 53-22138
- Patent Document 14 JP-A-53-0444617
- Patent Document 15 JP-A-54-0552718
- Patent Document 16 Japanese Patent Application Laid-Open No. 03-264537
- Patent Document 17 Japanese Patent Application Laid-Open No. 08-193027
- Patent Document 18 JP-A-56-7713
- Patent Document 19 JP-A-60-25919
- Patent Document 20 JP-A-61-207341
- Patent Document 21 JP-A-11-193229
- Patent Document 22 JP-A-11-35487
- Patent Document 23 JP-A-2000-16934
- Patent Document 24 JP-A-2000-247869
- Patent Document 25 JP 2001-181195 A
- Patent Document 26 JP 2001-316248 A
- Patent Document 27 JP-T-2002-534455
- Patent Document 28 JP-A-2003-161
- Patent Document 29 JP 2003-55219 A
- Patent Document 30 JP 2003-81876 A
- the present invention provides excellent moldability and fluidity for producing molded articles containing various active ingredients by using cellulose particles as a porous cellulose aggregate having a specific pore size and pore volume. Another object of the present invention is to provide an excipient having disintegration properties.
- the present inventors have controlled the particle structure of the cellulose aggregate, developed a secondary aggregate structure, increased the intracellular pore volume of the cellulose aggregate, and
- the present invention has been accomplished by controlling the physical properties of the powder to a specific range. That is, the present invention is as follows.
- a molded product composition comprising one or more active ingredients finely pulverized to a particle size of 40 ⁇ m or less, and the porous cellulose aggregate according to any one of (1) to (4) above,
- a molded article composition comprising one or more active ingredients finely pulverized to a particle diameter of 10 ⁇ m or less, and the porous cellulose aggregate according to any one of the above (1)-(4).
- the porous cellulose aggregate of the present invention is extremely excellent in moldability, fluidity, and disintegration. Therefore, when the porous cellulose aggregate of the present invention is used as an excipient in the production of a molded article containing various active ingredients, the uniformity of the active ingredient and the uniformity of the active ingredient content with less weight variation can be obtained by using the excipient as an excipient. It is possible to provide a molded product having excellent friability, sufficient hardness, no tableting trouble, low friability and excellent disintegration by a simple method.
- the porous cellulose aggregate of the present invention can be used in a solid preparation containing a poorly water-soluble active ingredient because the active ingredient has extremely good dissolution, tableting and disintegration properties.
- liquid or semi-solid active ingredients are prevented from leaching out and have good disintegration properties.
- the average particle size is small and the adhesion and cohesion is high
- mixing of the active ingredient with a component other than the active ingredient and solid preparations using the same can contribute to reducing the mixing speed and the concentration variation of the active ingredient.
- recrystallization due to sublimation of the sublimable active ingredient can be prevented, and a decrease in commercial value can be prevented.
- Excipients for solid dosage forms It is particularly useful in applications.
- the porous cellulose aggregate of the present invention needs to have a secondary aggregated structure in which primary particles are aggregated.
- This refers to a secondary aggregate structure in which the boundaries of primary particles are clear when the particle surface is observed with a scanning electron microscope (SEM) at 250 ⁇ and Z or 1500 ⁇ .
- SEM scanning electron microscope
- the secondary aggregated structure in which the primary particles are aggregated is closely related to the disintegration property, and the absence of this particle structure is not preferable because the disintegration property is deteriorated.
- the boundaries of primary particles are not clear.For example, when the film has a dense and continuous cellulose partition wall, the cellulose primary particles are densely continuous and strongly bonded. It is not preferable because the disintegration of the body also deteriorates.
- the secondary aggregated structure in which the primary particles are aggregated is closely related not only to the disintegration property but also to the dissolution property of the active ingredient.
- Porous cellulose particles having a secondary aggregated structure in which primary particles are aggregated, in water the disintegration into primary particles, in which water quickly penetrates between the primary particles, is promoted, and when the active ingredient is retained,
- the contact area between the active ingredient and water is increased, there is an effect of improving the dissolution of the active ingredient that is hardly soluble in water.
- this secondary aggregate structure is uniformly distributed irrespective of the inner 'surface' of the particles, and when mixed with the active ingredient, the active ingredient can be retained even in the cellulose primary particle gap, In particular, it is preferable because oozing of the liquid component can be prevented.
- this secondary aggregation structure can hold the active ingredient not only on the surface of the particles but also inside it, contributing to the improvement of the mixing speed of the active ingredients, the improvement of the mixing uniformity, and the drastic reduction of the concentration variation. It is preferable because it is possible.
- the porous cellulose aggregate of the present invention is required to have a pore volume in particles of 0.265 cm 3 /g-2.625 cm 3 Zg. Porous particles having a large intraparticle pore volume are excellent in plastic deformability, and are liable to be crushed during compression, and thus are excellent in moldability.
- the porous cellulose aggregate of the present invention is obtained by intentionally increasing the pore volume in the aggregated particles in addition to the one derived from the original cellulose. It has improved deformability. Therefore, regardless of the apparent specific volume of the particles, high compression molding Expresses sex.
- the intracellular pore volume is less than 0.265 cm 3 / g, the intracellular pores inherent in the primary cellulose particles or the natural aggregation of the cell source instead of the intentionally formed ones Poor plastic deformability because only the formed intra-pores are present.
- the apparent specific volume of the particles must be increased, resulting in poor fluidity of the particles.
- the porous cellulose aggregate of the present invention can ensure good moldability with its relatively small apparent specific volume, and as a result, excellent in fluidity can be obtained.
- the particles have sufficient pore volume in the particles, so the activity once incorporated into the particles or in the pores on the particle surface during the mixing process and the compression process.
- the preferred solid active ingredient is used because it is difficult for the active ingredient to be desorbed and a sufficient amount of the liquid ingredient can be retained in the pores within the particles, it is excellent in preventing leaching.
- the drug concentration variation coefficient which is an index of the concentration variation of the active ingredient, is preferably 3.0% or less during the mixing time, more preferably 2.0% or less, particularly preferably 1.5% or less.
- the active ingredient has an average particle diameter of 10 ⁇ or less and the active ingredient has a very high cohesiveness and is mixed, the intracellular pores like the porous cellulose aggregate of the present invention are used.
- the one having a volume of 0.265 cm 3 / g or more because the active ingredient is retained not only on the surface of the particles but also inside the particles, so that the coefficient of variation of the drug concentration can be 2.0% or less. .
- the pore volume in the particles is less than 0.265 cm 3 Zg, the dispersion uniformity and retention of the solid active ingredient and the liquid active ingredient will be impaired, resulting in a variation in the active ingredient concentration, aggregation of the solid preparation, and compression. It is not preferable because the above effects are not obtained, such as deterioration of moldability and recrystallization of a sublimable active ingredient during storage, resulting in deterioration of stability and commercial value.
- the pore volume in the particle exceeds 2.625 cm 3 Zg, the apparent specific volume increases and the fluidity decreases. Is not preferred.
- the pore size distribution of the porous cellulose aggregate of the present invention is measured, for example, by mercury porosimetry. In particular, it is preferable to be able to identify "clear peaks" in the range of 0.1-1 10 / m.
- the central pore diameter which is the peak top of the pore distribution, is closely related to the permeability of water into the particles, and the central pore diameter is preferably 0.3 x m or more. When the median pore diameter is 0.3 x m or more, the penetration rate of water increases, and the disintegration property is further improved. The larger the central pore diameter, the better, but considering its distribution range, it is at most about 5 x m.
- the crystalline form of the porous cellulose aggregate of the present invention must be Form I.
- Known types of cellulose crystal are type I, type II, type III, type IV, etc. Among them, type I is called “natural cellulose” and type II is called “regenerated cellulose”. But types III and IV are available on a laboratory scale but not widely used on an industrial scale
- Natural cellulose has been used for food as vegetable fiber since ancient times, and is now widely used as a dispersion stabilizer for liquid foods and as a pharmaceutical excipient.
- regenerated cellulose is a regenerated cellulose whose chemical structure has been changed by removing chemical solutions such as carbon disulfide and sodium hydroxide, and solvents, and has been partially used as a wet-type food preservative.
- Regenerated cellulose which is a crystalline form, is different from the crystalline form of natural cellulose in that its crystal form changes, the particles become rigid, the plastic deformability during compression decreases, and the molded body has sufficient hardness. It is not preferable because it cannot be provided.
- the porous cellulose aggregate of the present invention needs to have an average particle diameter of more than 30 ⁇ m and not more than 250 ⁇ m. If the average particle size is 30 ⁇ 30 ⁇ or less, the cellulose particles agglomerate, so that when mixed with the active ingredient, the active ingredient in the obtained molded article has a large dispersion due to the uniform dispersion of the active ingredient. As soon as possible, the weight variation of the molded body during continuous production tends to increase. On the other hand, if the average particle diameter exceeds 250 x m, poor flowability and separation and segregation are liable to occur when the formulated powder mixed with the active ingredient is continuously compressed.
- the specific surface area of the porous cellulose aggregate of the present invention must be 1.3 m 2 Zg 20 m 2 / g.
- the specific surface area is less than 1.3 m 2 / g, the compression moldability becomes low, High hardness and low friability.
- the specific surface area exceeds 20 m 2 / g, the contact area between cellulose and the active ingredient becomes excessively large when mixed with the active ingredient. It is not preferable because it is easy.
- the angle of repose of the porous cellulose aggregate of the present invention must be not less than 25 ° and less than 44 °.
- the active ingredient is prepared in such a manner that it diffuses in the gastric juice and intestinal fluid medium when taken and rapidly enhances its efficacy, and is often pulverized or originally finely divided. Since they are fine powder, they have poor fluidity.However, when the repose angle of cellulose powder is 44 ° or more, the fluidity of the mixed powder when a large amount of active ingredients with poor fluidity are blended is considered. Preferred les. In particular, there is a tendency that the weight variation of the molded body during high-speed tableting of several hundred thousand tablets / hour becomes large. The smaller the angle of repose, the better the fluidity, but the one with 25 42 ° is particularly excellent. More preferably, it is 25 40 °. If the angle of repose is less than 25 °, it is not preferable in terms of separation and deviation from the active ingredient.
- the apparent specific volume of the porous cellulose aggregate of the present invention must be 2.0-6. Ocm 3 / g. Since the porous cellulose aggregate of the present invention has a porous structure, it has a good balance of hardness, fluidity and disintegration over almost the entire area of the apparent specific volume as compared with the conventional one. In order to impart high compression moldability, the apparent specific volume is preferably 2.Ocm 3 / g or more, and in order to impart high fluidity, the apparent specific volume is preferably 6.Ocm 3 / g or less. Particularly preferred is 2.5-5. Ocm 3 / g.
- the porous cellulose aggregate of the present invention preferably has a bound water amount measured by DSC of at least 0.1 Olg. It is said that there are three types of water in cellulose particles: free water, bound water, and antifreeze water.
- the free water and bound water shown here are measured by differential scanning calorimetry (DSC) (measured at PERCIN ELMER DSC7 at a measurement temperature of -50 30 ° C and a temperature rise rate of 10 ° CZ).
- the peak area around ° C and the peak area between -30 ° C and 40 ° C are shown.
- Antifreeze water corresponds to the peak that does not appear in DSC, and is free from the total water content measured by Karl-Fisher method. Equivalent to water and water bound.
- the preferred upper limit of the bound water is not particularly limited because the larger the amount, the higher the compression moldability.
- the amount of bound water is more preferably 0.15 g or more, and even more preferably 0.20 g or more.
- the porous cellulose aggregate of the present invention has a surface free energy ( ⁇ d ) of 65 mj / m, as measured by an inverse gas chromatograph (IGC: manufactured by Surfacure Measurement System Ltd., 303K, relative humidity: 0%). Les, preferably less than 2 .
- IOC inverse gas chromatograph
- the particle surface has surface free energy.
- the surface free energy is measured by charging a sample to an IGC column and adding organic solvent gases of different polarities such as decane, nonane, octane, hexane, chlorophonolem, ethyl acetate, acetone, 1,4-dioxane, ethanol, and methane.
- the surface free energy is particularly preferably 60 mj / m 2 or less.
- the surface free energy contributes to the fluidity of the cellulose particles, and the smaller the smaller, the better the lower limit is not particularly limited.
- the porous cellulose aggregate of the present invention is prepared by weighing 0.5g of cellulose powder, placing it in a mortar (made of Kikusui Seisakusho, using material SUS2, 3), and using a circular flat punch with a diameter of 1.1cm (Kikusui Seisakusho). (Material: SUS2, 3 used) and compressed until the pressure reaches 10MPa and 20MPa (manufactured by Aiko Engineering Co., Ltd., use PCM-1A, compression speed is 1cmZ), and can be obtained under the condition of holding at the target pressure for 10 seconds
- the hardness of the columnar molded body is preferably 60N or more and 165N or more, respectively.
- the porous cellulose aggregate of the present invention is particularly excellent when the hardness of the molded article on a cylinder obtained by compressing the above-mentioned pressure to 20 MPa is 165 to 410 N, preferably 200 to 410 N.
- the porous cellulose aggregate of the present invention is compressed to 20 MPa by the above-described method, and the disintegration time of the columnar molded body obtained under the condition of maintaining the target pressure for 10 seconds is 75 seconds in terms of disintegration.
- the following is preferred. Especially preferably, it is 50 seconds or less. The shorter the collapse time, the better.
- the active ingredient is prepared in such a way that it diffuses in the gastric fluid and intestinal fluid medium when taken, and rapidly enhances the efficacy.However, as the disintegration time of the molded body increases, the drug elutes from the molded body. Tend to be delayed and not immediately absorbed in the gastrointestinal tract, resulting in reduced immediate efficacy.
- the porous cellulose aggregate of the present invention is obtained by mixing 55 parts of acetaminophen (powder type, manufactured by API Co., Ltd.) and light caffeic anhydride (trade name, aerosil 200, manufactured by Nippon Aerosil Co., Ltd.).
- excipients with high moldability are required.
- excipients with high fluidity are required.
- the porous cellulose aggregate of the present invention is a dispersion liquid containing two or more kinds of cellulose dispersed particle groups having different average particle diameters and a liquid medium, and the average particle diameter of the cellulose dispersed particles is 110 ⁇ m. It is obtained by drying the cellulose dispersion.
- the cellulose dispersed particle group referred to in the present invention comprises a natural cellulosic substance.
- Natural cellulosic substances include those derived from natural products such as wood, bamboo, straw, rice straw, cotton, ramie, bagasse, kenaf, beet, sea squirt, and bacterial cellulose, which can be plant or animal. It is preferably a fibrous substance and has a cellulose I type crystal structure.
- the raw material one of the above-mentioned natural cellulosic substances may be used, or a mixture of two or more may be used.
- the pulp is preferably used in the form of refined pulp.
- the pulp purification method is not particularly limited, and any pulp such as dissolved pulp, kraft pulp, and NBKP pulp may be used.
- the natural cellulosic material may or may not be used to decompose raw materials such as pulp into kamitsu water.
- hydrolysis two or more kinds may be used regardless of acid hydrolysis, alkali oxidative decomposition, hydrothermal decomposition, steam explosion, etc. You may use together.
- water is preferable as a medium used when the solid content containing the cellulosic material is subsequently dispersed in an appropriate medium, but there is no particular limitation as long as it is used industrially.
- water and Z or an organic solvent may be used.
- the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; and acetone. And ketones such as ethyl methyl ketone.
- organic solvents are classified as solvents in the Pharmaceutical Additives Encyclopedia (published by Yakuji Nippo Co., Ltd.), which is preferably used for pharmaceuticals.
- Water and organic solvents can be used alone or in combination of two or more. After once dispersing in one type of medium, the medium may be removed and dispersed in a different medium.
- the porous cellulose aggregate of the present invention is obtained by drying a cellulose dispersion obtained by mixing two or more kinds of cellulose dispersed particles having different average particle diameters.
- the average particle diameter of each cellulose dispersed particle group is not particularly limited, but is preferably 110 to 110 x m.
- the present invention is not limited to the case where two or more kinds of cell-mouth dispersed particle groups having different average particle diameters in the average particle diameter range are included, except that each of them has the same average particle diameter. Those having a particle size may be blended. For example, when mixing two types of cellulose dispersed particles having different average particle diameters, the larger the average particle diameter, the larger the average particle diameter, and the smaller the average particle diameter.
- the average particle diameter is preferably 0.005 to 0.99 times. More preferably, the smaller one has an average particle diameter 0.01-0.8 times the larger average particle diameter. Most preferably, the smaller one has an average particle diameter 0.01 to 0.7 times the larger average particle diameter.
- Mixing two or more kinds of cellulose dispersed particle groups having different average particle diameters means that when the cellulose dispersion is dried, the cellulose dispersed particles having a small average particle diameter are interposed between the cellulose dispersed particle components having a large average particle diameter. This contributes to suppressing excessive agglomeration of cellulose dispersed particles having a large average particle diameter, and forms a secondary agglomeration structure in which each is a primary particle, thereby providing a large pore volume within the particle. Can be.
- the weight ratio between the cellulose particle group having a large average particle diameter and the cellulose particle group having a small average particle diameter is usually preferably in the range of 5:95 to 95: 5, depending on the purpose. More preferably, the ratio is 10: 90-90: 10, and even more preferably, the ratio is 20: 80-80: 20. By selecting an appropriate weight ratio, the value of the pore volume of the present invention can be controlled.
- the particle shape of the cellulose particle composition having a large average particle diameter is such that the ratio (L / D) of the average value of each of the major axis and the minor axis is 2.0 or more. It is preferable to use them.
- the greater the L / D the greater the effect of suppressing excessive particle agglomeration during drying, which contributes to providing a large pore volume in the particles.
- the treatment method used here may be either a wet method or a dry method.Each of the wet methods may be mixed before drying, or each of the dry methods may be mixed before drying. It is also possible to combine those obtained by wet or dry methods. Although there is no particular limitation on known methods, for example, classification using a sieve that can be crushed and pulverized, cyclone, centrifugation using a centrifugal separator, and the like may be used in combination. It's also a way.
- Examples of the grinding method include stirring blades such as a one-way rotating type such as a portable mixer, a three-dimensional mixer, and a side mixer, a multi-axis rotating type, a reciprocating reversing type, a vertical moving type, a rotation + vertical moving type, and a pipe type.
- stirring blades such as a one-way rotating type such as a portable mixer, a three-dimensional mixer, and a side mixer, a multi-axis rotating type, a reciprocating reversing type, a vertical moving type, a rotation + vertical moving type, and a pipe type.
- Grinding method using a jet mixer such as a line mixer, grinding method using a high-shear homogenizer, a high-pressure homogenizer, an ultrasonic homogenizer, etc., for example, an axial rotary extrusion grinding method such as a kneader It's also a way.
- the pulverization method includes screen-type pulverization methods such as screen mills and hammer mills, blade-type rotary pulverization methods such as flash mills, air-flow-type pulverization methods such as jet mills, and ball-type pulverization methods such as ball mills and vibrating boring mills. Method, blade stirring type pulverization method, etc.
- the cellulose dispersed particle aggregate obtained by the above operation be a dispersion having a concentration of 5 to 40% by weight before drying. If the concentration is less than 5% by weight, the average particle diameter of the obtained cell source particles becomes small, and self-fluidity is likely to be impaired. On the other hand, if the concentration exceeds 40% by weight, the apparent specific volume of the cellulose particles becomes small, and the compression moldability tends to be impaired. More preferably, it is 10-40% by weight, and still more preferably, 1540% by weight.
- the average particle diameter of the cellulose dispersed particles present in the cellulose dispersion having a concentration of 5 to 40% by weight is preferably 110 to 110 zm. If the average particle size exceeds 110 xm, the dried cellulose particles become excessively large, and depending on the type of active ingredient, Separation and knitting may occur when mixed with them. On the other hand, when the average particle size is less than ⁇ , the cellulose particles after drying become excessively small, and it becomes difficult to maintain good fluidity. More preferably, it is 5-90 / im, and still more preferably 10-80 / im.
- the average particle diameter here is determined by a commonly used method of measuring the volume particle size distribution measured by, for example, a laser diffraction type particle size distribution meter (manufactured by HORIBA, trade name, LA-910 type). Can be.
- the average particle size can be controlled to a desired range by adjusting the degree of polymerization of the raw material cellulose by hydrolysis and the stirring force in the hydrolysis and Z or dispersion steps of the cellulose.
- the degree of cellulose polymerization tends to decrease, and the average particle diameter of the cellulose in the dispersion tends to decrease, and the stirring power of the solution is increased.
- the average particle size of the cellulose dispersed particles tends to be small.
- drying method for example, freeze drying, spray drying, drum drying, shelf drying, flash drying, or vacuum drying may be used.
- the above may be used in combination.
- the spraying method used for spray drying may be any of spraying methods such as a disk type, a pressurized nozzle, a pressurized two-fluid nozzle, and a pressurized four-fluid nozzle. May be used in combination.
- a blowing agent or a gas is used for the purpose of accelerating the vaporization rate of the medium. It may be added to the dispersion.
- water-soluble polymer examples include pharmaceutical additives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacrylic acid, carboxybutyl polymer, polyethylene glycol, polybutyl alcohol, polybutylpyrrolidone, methylcellulose, gum arabic, and starch. Encyclopedia "(published by Yakuji Nippo Co., Ltd.). One type may be used alone, or two or more types may be used in combination.
- surfactant examples include phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyoxyethylene stearyl ether.
- foaming agent examples include “tartaric acid, sodium bicarbonate, potato starch, citric anhydride, medicinal stones, sodium lauryl sulfate, lauric diethanolamide, laumacrogol, etc.”, a dictionary of pharmaceutical additives (published by Yakuji Nippo Co., Ltd.). And the like. One of these may be used alone, or two or more of them may be used in combination.
- use of bicarbonates that generate gas upon thermal decomposition such as sodium bicarbonate and ammonium bicarbonate, and carbonates that generate gas by reacting with acids such as sodium carbonate and ammonium carbonate, etc. May be. However, when using the above carbonates, it is necessary to use them together with the acid.
- the acid examples include organic acids such as citric acid, acetic acid, ascorbic acid, and adipic acid; protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; and acid substances such as Lewis acid such as boron fluoride. Those used as foods are preferred, but otherwise they have the same effect. Dispersions may be impregnated with gases such as nitrogen, carbon dioxide, liquefied petroleum gas, and dimethyl ether, which are not foaming agents.
- gases such as nitrogen, carbon dioxide, liquefied petroleum gas, and dimethyl ether, which are not foaming agents.
- the timing of the addition of these water-soluble polymers, surfactants, and substances that generate gas is not particularly limited as long as they are added before drying.
- the molded product composition referred to in the present invention is not particularly limited in the amount as long as it contains one or more active ingredients and the porous cellulose aggregate of the present invention.
- the components are 0.001 99%, and the cellulose powder of the present invention is 1-199%.
- the molded article composition of the present invention can be processed by a known method such as mixing, stirring, granulation, sizing, and tableting. If the active ingredient is less than 0.001%, a therapeutically effective amount cannot be secured, and if it exceeds 99%, the porous cellulose aggregate of the present invention is less than 1%, and practical hardness, friability, It is difficult to obtain a molded body showing collapse.
- the molded composition of the present invention comprises an active ingredient, a cell
- they can contain excipients, disintegrants, binders, fluidizers, lubricants, flavoring agents, flavors, coloring agents, and sweetening agents as necessary.
- Examples of the molded product composition according to the present invention include tablets, powders (including tableting powders), fine granules (including tableting fine granules), granules, extracts, Pills and the like. In addition, these are not limited, as long as they are prepared by a general production method, regardless of the shape and weight that may be coated.
- the present invention is not limited to pharmaceuticals, but includes those used in foods such as confectionery, health foods, texture improvers, dietary fiber enhancers, solid foundations, bath agents, animal drugs, diagnostics, agricultural chemicals, fertilizers, ceramic catalysts, and the like. include.
- the active ingredient referred to in the present invention means a pharmaceutical active ingredient, an agricultural chemical ingredient, a fertilizer ingredient, a feed ingredient, a food ingredient, a cosmetic ingredient, a pigment, a fragrance, a metal, a ceramic, a catalyst, a surfactant, and a solid form (powder form). , Crystalline, etc.), oil, liquid, semi-solid, etc., and may be coated for the purpose of controlling elution, reducing bitterness, etc.
- the active ingredient may be used alone or in combination of two or more.
- the active ingredient may be dissolved, suspended, or emulsified in a vehicle before use.
- Pharmaceutical active ingredients include, for example, antipyretic analgesics and anti-inflammatory drugs, hypnotics and sedatives, drowsiness drugs, anti-analgesics, pediatric analgesics, stomach drugs, antacids, digestive drugs, inotropic drugs, antiarrhythmic drugs, antihypertensive drugs, and vasodilators. Orally administered drugs, diuretics, anti-ulcer drugs, intestinal drugs, osteoporosis drugs, antitussive expectorants, anti-asthmatic drugs, antibacterial agents, pollakiuria, nourishing tonics, vitamins, etc. It becomes.
- the medicinal ingredient may be used alone or in combination of two or more.
- compositions used in the present invention include, for example, aspirin, aspirin aluminum dimethyl, acetaminophen, ethenzamide, sazapyrine, salicinoleamide, lactyl phenetidine, isothibenzyl hydrochloride, diphenylviraline hydrochloride, diphenhydramine hydrochloride, diphen hydrochloride Etherol, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine difurodisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylhydranyl methacrylate, napadimetyl methacrylate Salt, carbinoxamine maleate, cH_chlorpheniramine maleate, d_chlorpheniramide maleate , Diphthelo
- the poorly water-soluble active ingredient referred to in the present invention is, for example, a pharmaceutically active ingredient and refers to an ingredient in the Japanese Pharmacopoeia, 14th Edition, which requires a water volume of 30 mL or more to dissolve solute lg. If it is hardly soluble in water, the effect can be obtained by adding it as an active ingredient to the composition of the present invention regardless of the degree of sublimation and surface polarity.
- Examples of the hardly water-soluble and solid active ingredient include acetoaminophen, ibuprofen, benzoic acid, ethenzamide, caffeine, camphor, quinine, calcium dalconate, dimethylcaprol, sulfamine, theophylline, theopromine, riboflavin, mefeneci Antipyretic analgesics, nervous system drugs, sedative-hypnotics, etc.
- Antibiotics such as colistin sulfate, methyltestosterone, methylandrostone longione, progesterone, estradio-norenzozoate, ethinylestradio-one, deoxyconoreticosterone 'acetate, cortisone acetate, hide mouth cortisone, hide mouth Steroid hormones such as cortisone acetate and blednisolone, non-steroidal yolks such as dienst mouth-nore, hexast mouth-nore, jetinorestinolebestero-nore, jetinorestinolebestero-lujib-mouth honate, chlorotriacene, etc.
- Antibiotics such as colistin sulfate, methyltestosterone, methylandrostone longione, progesterone, estradio-norenzozoate, ethinylestradio-one, deoxyconoreticosterone 'acetate, cor
- Hormone ij other fats
- Pharmaceutical active ingredients described in ⁇ Japanese Pharmacopoeia '', ⁇ Extratopic group '', ⁇ USP '', ⁇ NF '', and ⁇ EP '' such as soluble vitamins, etc. It is also possible to use two or more types together.
- Examples of the poorly water-soluble oily or liquid active ingredient used in the present invention include vitamins such as teprenone, indomethacin 'phnarnesyl, menatetrenone, phytonadione, vitamin A oil, fenpentol, vitamin D, vitamin E and the like. , DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), higher unsaturated fatty acids such as liver oil, coenzyme Q, oil-soluble flavors such as orange oil, lemon oil, and peppermint oil. , “External groups”, “USP", “NF”, and "EP”.
- Vitamin E has various homologs and derivatives, but is not particularly limited as long as it is liquid at normal temperature.
- dl-hypertocopherolone, acetic acid dl-hypertocopherolone, d-hypertocopherolone, acetic acid d-hypertocopherol, and the like may be mentioned. Even if used, two or more types can be used together.
- Examples of the poorly water-soluble semi-solid active ingredient include, for example, ground dragon, kanzo, keihi, shakuyaku, botan, ryokoso, sansho, shokyo, chimpi, mao, nantenzi, ohi, onji, kikyo, shazenshi, shazenso.
- the solid pharmaceutical composition of the present invention may further contain other physiologically active ingredients in addition to the above-mentioned poorly water-soluble active ingredients.
- the finely pulverized active ingredient used in the present invention is used for the purpose of improving the dispersibility of a hardly water-soluble solid active ingredient, and improving the uniformity of mixing of a trace amount of a medicinal active ingredient. It refers to what is finely pulverized to ⁇ m or less.
- the average particle size of the active ingredient is more preferably 1 1-20 ⁇ m, and still more preferably 1 10 xm.
- the sublimable active ingredient referred to in the present invention is not particularly limited as long as it has sublimability, and may be solid at normal temperature, liquid, or semi-solid. However, the state may be any.
- sublimable active ingredient for example, benzoic acid, ethenzamide, caffeine, camphor, salicylic acid, phenacetin, ibuprofen, etc., ⁇ Japanese Pharmacopoeia '', ⁇ external group '', ⁇ USP '', ⁇ NF '', ⁇ EP ''
- Sublimable medicinal active ingredients described in (1) above, and one of the above-mentioned powers may be used alone, or two or more of them may be used in combination.
- the solid pharmaceutical composition of the present invention may further contain other active ingredients in addition to the above-mentioned sublimable active ingredients.
- Examples of the active ingredient that is liquid at normal temperature used in the present invention include vitamins such as teprenone, indomethacin 'huanesyl, menatetrenone, futonadione, vitamin A oil, phenypentenole, vitamin D, vitamin E, and the like, DHA ( "Japanese Pharmacopoeia”, such as docosahexaenoic acid), EPA (eicosapentaenoic acid), higher unsaturated fatty acids such as liver oil, coenzyme Qs, oil-soluble flavors such as orange oil, lemon oil, peppermint oil, etc.
- Vitamin E is not particularly limited as long as it has various homologs and derivatives with a certain strength S and is liquid at normal temperature.
- dl_a_tocopherol nore dl_ct-tocopherol acetate
- d_hytotocopherol nole d_hytotocopherol acetate
- d_hytotocopherol acetate etc. can be mentioned. It is free to use more than one species.
- the semi-solid active ingredient at room temperature used in the present invention includes, for example, ground dragon, kanzo, keihi, shakuyaku, botanpi, ryokoso, sansho, shokyo, chimpi, mao, nantenzi, ohihi, onji, kikiyou.
- Excipients include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoaminoacetic acid, candy (powder), gum arabic, gum arabic, alginic acid, sodium alginate, alpha-monitized starch, pumice granules, inositol, Ethyl cellulose, ethylene acetate butyl copolymer, sodium salt, olive oil, kaolin, cocoa butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrous silicon dioxide, dried yeast, dried aluminum hydroxide gel, dried sulfuric acid Sodium, dried magnesium sulfate, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerate, sodium dal
- Disintegrators include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, celluloses such as low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch. Is classified as a disintegrant in the “Medical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as starches such as starch, potato starch and partially alpha starch, and synthetic polymers such as crospovidone and crospovidone copolymer. Things can be mentioned. One type selected from the above may be used alone, or two or more types may be used in combination.
- binder examples include sugars such as sucrose, glucose, lactose and fructose, mannitol, xylitol , Sugar alcohols such as maltitol, erythritol, sorbitol, gelatin, pullulan, carrageenan, locust bean gum, agar, darcomannan, xanthan gum, tamalin gum, pectin, sodium alginate, water-soluble polysaccharides such as gum arabic, crystals Synthesis of celluloses such as senorelose, powdered senorelose, hydroxypropinoresenorelose, methinoresenololose, starches such as alpha-monostarch, starch paste, polybutylpyrrolidone, carboxybutyl polymer, polybutyl alcohol, etc.
- sugars such as sucrose, glucose, lactose and fructose
- mannitol xylitol
- Sugar alcohols such as malt
- superplasticizers include those that are classified as superplasticizers in the Pharmaceutical Additives Encyclopedia (published by Yakuji Nippo Co., Ltd.), such as silicon compounds such as hydrous silicon dioxide and light silicic anhydride.
- Power S can. One type selected from the above may be used alone, or two or more types may be used in combination.
- lubricants examples include those classified as lubricants in the “Medical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, and talc. be able to.
- One type selected from the above may be used alone, or two or more types may be used in combination.
- flavoring agents examples include “Guideline for Pharmaceutical Additives” such as gnoretamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, and menthol. ) Can be listed as flavoring agents. One kind selected from the above may be used alone, or two or more kinds may be used in combination. Examples of flavoring agents include “oils such as orange, vanilla, strawberry, gnogoreto, mentonore, fennel oil, keihi oil, spruce oil, and coconut oil” and “Medical additive dictionary” such as green tea powder (published by Yakuji Nippo Co., Ltd.) And fragrances and fragrances. One type selected from the above may be used alone, or two or more types may be used in combination.
- Coloring agents include food colors such as Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, etc., and the Pharmaceutical Additives Dictionary (National Pharmaceutical Daily) such as copper chlorophyll sodium, titanium oxide, and riboflavin. That are classified as colorants. Selected from the above
- One type may be used alone, or two or more types may be used in combination.
- Sweeteners include those classified as "sweeteners" in the Pharmaceutical Additives Dictionary (published by Yakuji Nippo Co., Ltd.), such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and powdered amateur. Can be mentioned. One kind selected from the above may be used alone, or two or more kinds may be used in combination.
- a method for producing a tablet containing one or more active ingredients and the porous cellose aggregate of the present invention as a main component will be described. However, this is an example, and the effects of the present invention are not described. However, the method is not limited to the following method.
- a method a method of mixing the active ingredient and the porous cell aggregate of the present invention, followed by compression molding can be employed.
- other additives which may be blended with other additives as necessary include, for example, the above-mentioned excipients, disintegrants, binders, fluidizing agents, Lubricants, flavoring agents, flavors, coloring agents, sweeteners, and one or more components selected from solubilizers may be added.
- each component there are no particular restrictions on the order of addition of each component.i) A method in which the active ingredient, the porous cellulose aggregate of the present invention, and other additives are mixed together and compression-molded, if necessary, ii) The active ingredient, and the flow Pretreatment and mixing of additives such as an agent and / or a lubricant, mixing the porous cellulose aggregate of the present invention with other additives as required, and then compression molding.
- additives such as an agent and / or a lubricant, mixing the porous cellulose aggregate of the present invention with other additives as required, and then compression molding.
- a lubricant may be added to the compression molding mixture powder obtained in i) and ii), and after mixing, compression molding may be performed.
- the active ingredient is adsorbed to the porous cellulose aggregate used in the present invention and Z or other additives as necessary.
- any of the methods of mixing with the porous cellulose aggregate of the present invention and Z or other additives as necessary, distilling off water and Z or an organic solvent as necessary, and performing compression molding may be used.
- the porous cellulose aggregate of the present invention is mixed with other components as necessary, and compression molding is performed. It is preferable in terms of moldability and fluidity.
- the crystalline form of the active ingredient before compression molding may be the same as or different from the state before the preparation, but it is preferable that the crystalline form be the same in terms of stability.
- an active ingredient that is hardly soluble in water it is effective to use a water-soluble polymer and a surfactant in combination as a solubilizing agent, and to disperse the active ingredient in a medium.
- the other additives are additives other than the porous cellulose aggregate of the present invention, and include, for example, the above-mentioned excipients, disintegrants, binders, fluidizers, lubricants, and flavors. Additives such as agents, flavors, coloring agents, sweeteners, and solubilizing agents.
- additives may be used alone or in combination of two or more.
- a step of once dissolving or dispersing the active ingredient which is hardly soluble or insoluble in water is performed, there is also an effect of improving the elution of the active ingredient.
- a liquid dispersion such as polyethylene render alcohol
- the dispersion in which the active ingredient is dispersed becomes liquid or semi-solid. Therefore, a tablet cannot be formed unless it is excellent in compression moldability and fluidity like the porous cellulose aggregate of the present invention.
- the method of adding each component is not particularly limited as long as it is a commonly used method, but a small suction transport device, a pneumatic transport device, a bucket conveyor, a pressure transport device, a vacuum conveyor, and a vibrating quantitative feeder are used. , Spray, funnel, etc., or may be added all at once.
- the active ingredient is a solution, suspension, or emulsion
- the method of spraying it onto porous cellulose aggregates or other additives reduces dispersion of active ingredient concentration in the final product. Is preferred.
- Spraying methods include spraying the active ingredient solution / dispersion using a pressure nozzle, two-fluid nozzle, four-fluid nozzle, rotating disk, ultrasonic nozzle, etc., and dropping the active ingredient solution / dispersion from a tubular nozzle. Either may be used.
- the porous cellulose Porous cellulose aggregates using active ingredient solution / dispersion as a binding liquid that can be layered or coated such that active ingredients are laminated on the surface of body particles, or can be supported inside porous cellulose aggregate particles.
- a mixture of particles or porous cellulose and other additives may be granulated in a matrix. Layering and coating may be wet or dry.
- the mixing method is not particularly limited as long as it is a commonly used method, but a container rotary mixer such as a V-type, W-type, double-cone type, container-tack type mixer, or a high-speed stirring type, a universal A stirring mixer such as a stirring mixer, a ribbon mixer, a bag mixer, a Nauter mixer, a high-speed fluid mixer, a drum mixer, or a fluid bed mixer may be used. Further, a container-shaking mixer such as a shaker can be used.
- the method of compression molding of the composition is not particularly limited as long as it is a commonly used method, but a method of compression molding to a desired shape using a mortar and a punch, a method of compression molding in a sheet shape in advance, and a desired shape It may be a method of cleaving.
- a roller type press machine such as a static pressure press machine, a briquetting roller type press machine, a smooth roller type press machine, a single press tableting machine, a rotary tableting machine etc. are used. it can.
- the method for dissolving or dispersing the active ingredient in the medium is not particularly limited as long as it is a commonly used dissolving and dispersing method.
- One-way rotating type such as portable mixer, three-dimensional mixer, side mixer, multi-axial rotating type, reciprocating method, etc.
- a mixing method using a homogenizer, an ultrasonic homogenizer, or the like, or a container shaking mixing method using a shaker or the like may be used.
- the solvent used in the above-mentioned production method is not particularly limited as long as it is used for pharmaceuticals, but for example, water and / or an organic solvent may be used.
- Alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane and cyclohexane; ketones such as acetone and ethyl methyl ketone Etc., are classified as solvents in the Pharmaceutical Excipients Dictionary (published by Yakuji Nippo Co., Ltd.) It is possible to use it alone or to use two or more kinds in combination. After dispersing once in one kind of medium, the medium may be removed and dispersed in a different medium.
- water-soluble polymer as a solubilizer examples include, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacryloleic acid, carboxyvinyl polymer, polyethylene glycol, polybutylalcohol, polybutylpyrrolidone, methylcellulose, and ethylcellulose. , Gum arabic, starch glue, etc., and water-soluble polymers listed in the “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.). You are free.
- fats and oils as solubilizers include, for example, stearic acid monoglyceride, stearic acid triglyceride, stearic acid sucrose ester, paraffins such as liquid paraffin, carnauba wax, hardened oils such as hardened castor oil, castor oil, stearic acid, Fats and oils such as stearyl alcohol, polyethylene glycol, and the like described in the “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) can be used alone or in combination of two or more. is there.
- surfactant as a solubilizer examples include phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyoxyethylene stearyl ether.
- sorbitan monostearate, polyoxyethylene sorbitan monooleate, sorbitan monopalmitate, and sodium lauryl sulfate Pressurizing agent Encyclopedia "(Yakujinipposha Corporation published) those classified as a surfactant can be mentioned, even using it alone, it is free to combination of two or more
- the tablet according to the present invention is a tablet containing the porous cellulose aggregate of the present invention, one or more active ingredients and, if necessary, other additives, and is obtained by compression molding.
- the tablet composition containing the porous cellulose aggregate of the present invention is particularly complex. Practical hardness can be obtained by a simple method such as direct compression without the need for additional steps.However, if necessary, dry granule compression, wet granulation, post-dispersion, and pre-compressed tablets may be used.
- a method of manufacturing a multi-core tablet as an inner core, a method of manufacturing a multi-layer tablet in which a plurality of pre-compressed molded bodies are stacked and compressed again, or any other manufacturing method may be used.
- the porous cellulose aggregate of the present invention is excellent in various physical properties required as a compression moldability, a self-flowing property, and a disintegrating excipient.
- Tablets containing many or many kinds of drugs that are susceptible to tableting troubles such as peeling from the inside and cracks, etc. are equally compressed under pressure such as tablets containing over-the-counter medicines, tablets containing extract powders such as Chinese medicine, small tablets, edge necking, etc. It is effective for drugs such as enzymes, proteins, etc., which are easily deactivated due to friction with the compression and excipients, tablets containing coated granules, etc. .
- the cellulose powder of the present invention has excellent compression moldability and disintegration properties, tablets exhibiting practical friability at a relatively low compression pressure can be obtained. Therefore, a void (water pipe) can be maintained in the tablet, which is also effective for an orally disintegrating tablet that rapidly disintegrates in the oral cavity. Furthermore, in the case of multi-layer tablets and dry-coated tablets in which several types of components are compression-molded in one step or in another step, in addition to the above-mentioned hardness imparting and suppressing general tableting troubles, delamination and cracks between layers are suppressed. There is also the effect of doing.
- the porous cellulose aggregate of the present invention has a secondary aggregate structure in which primary particles are aggregated, the particles themselves are excellent in dividability, and when used in a scored tablet or the like, the tablet is easily divided uniformly. Become. Furthermore, the porous cellulose aggregate of the present invention has a developed porous structure, and the cellulose particles themselves are used because of their excellent retention of particulate drug, suspended liquid drug, and solution component. Tablets also have excellent retention of solid, suspension and solution components. For this reason, the suspension and solution components are layered on tablets, and coated tablets, and sugar-coated tablets, in which components such as sugar and calcium carbonate are suspended in a suspended state, are coated. It is also effective to use for prevention of peeling and reinforcement.
- the solid, liquid or semi-solid active ingredient and the porous cellulose aggregate particle composition obtained by the method described above may be used in the form of a powder or granule, even if used as a solid preparation.
- Coating a coating agent on the object Ingredients may be used as powders or granular solid preparations.
- the coated or uncoated powder or granular composition obtained here may be used by filling in capsules or compression-molding them and used as tablet-type solid preparations. Further, capsules or tablets may be used after coating.
- Examples of the coating agent in the case of applying a coating include, for example, ethyl acrylate 'methyl methacrylate copolymer dispersion, acetyl glycerin fatty acid ester, amino phenol methacrylate copolymer, gum arabic powder, ethyl cellulose,
- the porous cellulose aggregate of the present invention has a developed porous structure and the particles themselves are excellent in drug retention, even if the particles carrying the drug in the pores are used as fine particles as they are.
- they may be granulated and used as granules, or they may be compression molded.
- the granules, granules and tablets may be further coated thereon.
- the method of loading is not particularly limited as long as it is a known method.However, i) a method of mixing with a particulate drug and loading it in pores, ⁇ ) mixing with a powdered drug at a high shear, and forcing finely Iii) After mixing with the drug once in a solution or dispersion, and supporting it in the pores, drying it if necessary Iv) A method of mixing with a sublimable drug and sublimating and adsorbing it into pores by heating and / or reducing the pressure. V) Mixing and melting the drug before or during heating and melting Any one of the methods of supporting in the pores may be used alone, or two or more may be used in combination.
- the porous cellulose aggregate of the present invention has a developed pore structure, and has moderate water retention and oil retention properties, so that it can be used as a core particle for layering and coating in addition to excipients. In this case, there is an effect of suppressing aggregation between particles in the layering and coating processes.
- Layering and coating may be dry or wet.
- the active ingredient is a solution, a suspension, or an emulsion
- the active ingredient may be a porous cellulose aggregate particle or a mixture of the porous cellulose aggregate particle and other additives, such as a dipping method using a carrier as a carrier. Immerse in a solution, suspension, or emulsion to retain the active ingredient.
- the liquid immersion method such as divebing is excellent in that the uniformity of the active ingredient is practically maintained and the process is simpler than the above spraying.
- the active ingredient is a solution, a suspension, or an emulsion
- the active ingredient solution, the suspension, the porous cellulose aggregate particles or a mixture of the porous cellulose aggregate particles and other additives is used as a carrier.
- the dispersion may be spray-dried to form a composite.
- Granulation methods in the case of performing granulation in the manufacturing process include dry granulation, wet granulation, heat granulation, spray granulation, and microencapsulation.
- the wet granulation method is, for example, a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, a crushing granulation method, or a tumbling granulation method.
- the fluidized powder is granulated by spraying the binding liquid in a fluidized bed granulator.
- the stirring granulation method mixing, kneading, and granulation of powders are simultaneously performed in a closed structure by rotating stirring blades in a mixing tank while adding a binding liquid.
- the wet mass kneaded by the addition of the binding liquid is screw-type or basket-type.
- Granulation is performed by forcibly extruding from an appropriately sized screen by a method such as a cut type.
- the crushing granulation method the wet mass kneaded by the addition of the binding solution is sheared and crushed by a rotary blade of a granulator, and is then granulated by being repelled from a peripheral screen by centrifugal force.
- tumbling granulation method tumbling is performed by the centrifugal force of a rotating rotor. At this time, spherical granules having a uniform particle size are grown in the form of a snowman using a binder solution sprayed from a spray gun. Granulate.
- the method of drying the granulated material can be any of hot air heating type (shelf drying, vacuum drying, fluidized bed drying), conduction heat transfer type (flat pan type, tray box type, drum type), and freeze drying Can also be used.
- hot air heating type the material is brought into direct contact with hot air, and at the same time, the evaporated water is removed.
- the heat transfer type the material is indirectly heated through the heat transfer wall. The freeze-dried by mosquitoes ⁇ in advance frozen material in one 10 40 ° C, then under high vacuum (1. 3 X 10- 5 2. 6 X 10- 4 MPa), sublimation of water And remove.
- a mixture of the active ingredient and the porous cellulose aggregate particles, or a mixture of one or more active ingredients and the porous cellulose aggregate particles, and other additives as necessary may be obtained by a usual method. And compression molding (direct compression method). Alternatively, ii) after mixing the active ingredient, the porous cellulose aggregate particles, and other additives as necessary, granulating them into granules, and compression-molding by a usual method (wet / dry method) Granule compression method).
- the active ingredient, the porous cellulose aggregate particles, and other additives, if necessary, are mixed and granulated to obtain granules, and the porous cellulose aggregate particles are further added, if necessary, to other granules.
- the mixture may be mixed and compression molded by a conventional method (wet / dry granulation followed by compression).
- the method of adding one or more active ingredients, porous cellulose aggregates, other additives, or granules is not particularly limited as long as it is a commonly used method.
- a bucket conveyor, a pressure-feeding transport device, a vacuum conveyor, a vibrating quantitative feeder, a spray, a funnel, or the like, and the mixture may be added continuously or may be added at once.
- the tableting composition of the present invention is also excellent in retention of solid and liquid components, so that it particularly improves fluidity, blocking resistance and coagulation resistance. It may be used as a granule or powder for the purpose.
- Granules and powders can be produced by, for example, dry granulation, wet granulation, heat granulation, spray drying, microcapsulation. You can use the shift and the shift.
- the sample dispersed in water was expressed as a 50% cumulative volume particle measured using a laser diffraction type particle size distribution analyzer (trade name, LA-910, manufactured by HORIBA, Ltd.) without ultrasonic treatment at a refractive index of 1.20. .
- this measured value is not necessarily correlated because the measurement principle is completely different from the particle size distribution of dry particles obtained by the following low tap method.
- dispersed cellulose particles take the form of elongated fibrous particles, and the average particle size measured by laser diffraction is such that fibrous particles are formed into spheres whose diameter is 80% of the major axis. Deemed to be measured by volume frequency relative to its diameter.
- the average particle diameter obtained by the low tap method is obtained by shaking the obtained powder on a sieve, fractionating the powder, and measuring the weight frequency with respect to the particle diameter.
- the value is larger than that of the laser diffraction type, which depends on the major axis of the fiber, and the rotor type, which depends on the minor axis of the fiber.
- X-ray diffraction was performed by an X-ray diffractometer, and the determination was made based on the X-ray pattern.
- the average particle size of the powder sample is determined by sieving 10 g of the sample for 10 minutes using a low-tap sieve shaker (trade name, Shibe Shaker A type, manufactured by Hira Kousakusho) and a JIS standard sieve (Z8801-1987). The particle size distribution was measured and expressed as a 50% cumulative weight particle size.
- the measurement was performed by the BET method using Trimer® (trade name, manufactured by Micromeritics Co., Ltd.) and nitrogen as an adsorption gas. Each sample powder was charged into a cell about lg and measured. Each sample powder used for the measurement was dried under reduced pressure at 110 ° C for 3 hours.
- Each cellulose sample was placed on a sample table on which a carbon tape was stuck, and platinum palladium was vacuum-deposited (at this time, the thickness of the deposited film was 20 nm or less), and the trade name of JASCO Corporation, JSM-5510LV was applied.
- the primary particles aggregate continuously, the boundaries of the primary particles are clear, and the central pore diameter of the pores that can be confirmed is 0.1 ⁇ m
- ⁇ Those having a secondary aggregated particle structure in which the primary particles were aggregated as described above were designated as ⁇ , and those having other structures were designated as X.
- Aspirin (Amorphous crystal aspirin, small crusher ⁇ ⁇ . 5mm, 1-pass treatment), and dry blending of powder samples at 5/5 (total amount: 0.5g) of each cell mouth sample were combined with glass sampler. After mixing in a bottle and storing it in an oven (trade name, Perfect Oven, manufactured by Tabai Espec) in a sealed stopper (60 ° C) for 2 weeks, the decomposition rate was measured. 8 g of sodium ferric (III) sulfate-12 hydrate was introduced into a 100 mL volumetric flask, and pure water was added to make 100 mL. Liquid.
- each cellulose powder is weighed and put into a mortar (made by Kikusui Seisakusho, using material SUS2, 3), and pressure is applied with a 1.1cm diameter circular flat punch (made by Kikusui Seisakusho, made of material SUS2, 3). Compressed to 10MPa and 20MPa (Aiko Ichi Engineering Co., Ltd., trade name, use PCM-1A, compression speed is lcm / min), hold at target pressure for 10 seconds, then take out cylindrical molded body.
- 10MPa and 20MPa Aiko Ichi Engineering Co., Ltd., trade name, use PCM-1A, compression speed is lcm / min
- acetaminophen produced by API Co., Ltd., powder type
- light anhydrous silicic acid manufactured by Nippon Aerosil Co., Ltd., trade name: aerodinole 200
- a prescription powder was obtained.
- the total charged amount of each powder was 25 kg.
- the obtained prescription powder is transferred to a rotary tableting machine (manufactured by Kikusui Seisakusho, trade name, LIBRA-II,
- the formulation powder was supplied by a stirring feeder using a diameter of ⁇ 410 ⁇ , 36 tubes).
- the tablets were tableted with a turntable rotation speed of 50 rpm and a compressive pressure of 7.5 kN using a 8R, 8 mm diameter 12R punch to obtain tablets weighing 200 mg.
- the cylindrical molded product or tablet is subjected to a Schroingel hardness tester (trade name, manufactured by Freund Corporation, 6D type), and a load is applied in the diameter direction of the cylindrical molded product or tablet to destroy the load. The average value of ten samples was measured.
- Disintegration tests were performed according to the 14th Revised Japanese Pharmacopoeia, General Test Methods, and Tablet Disintegration Test Methods.
- the disintegration tester manufactured by Toyama Sangyo Co., Ltd., trade name, NT-40HS type, with disk
- the average value of six samples was shown.
- Friability 1 OOx (Wa-Wb) / Wa
- the dried floc is crushed with a household mixer, and further pulverized using an air-flow crusher (trade name, manufactured by Seishin Enterprise Co., Ltd., trade name, Single Track Jet Minore STJ-200).
- the cellulose particle size at that time was 5 ⁇ m), and a pulverized product was obtained.
- the obtained pulverized product and the wet acid-insoluble residue in a wet state are introduced into a 90 L polybucket in a composition of 50 parts by weight and 50 parts by weight (dry base), and purified so that the total solid content concentration becomes 25% by weight.
- Example 2 In the same manner as in Example 1, the obtained acid-insoluble residue was sufficiently washed with pure water, and then filtered to obtain a wet floc. Of the obtained wet flocks, 60% by weight was further sufficiently washed with pure water, neutralized, filtered again, and air-dried to obtain a dried floc. The dried floc is crushed with a household mixer and then further pulverized using an air-flow crusher (trade name, single-track jet mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.). The cellulose particle diameter was 3 am) to obtain a pulverized product.
- an air-flow crusher trade name, single-track jet mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.
- the obtained pulverized material and the wet The acid-insoluble residue in the state is introduced into a 90 L bucket with a composition of 60 parts by weight and 40 parts by weight (dry base), and pure water is added so that the total solid concentration becomes 10% by weight. While stirring with a motor, the mixture was neutralized with aqueous ammonia (pH after neutralization was 7.5-8.0), and this was spray-dried in the same manner as in Example 1 to obtain cellulose particles B.
- Table 1 shows the physical properties of the cellulose particles B.
- the pore distribution was measured by mercury porosimetry, and scanning electron microscopy (SEM) observation revealed that, similarly to the case of cellulose aggregate A, 0.1 in the pore distribution by mercury porosimetry. — At 10 xm, a “clear peak” was confirmed. From the SEM photograph, a “secondary aggregated structure in which primary particles were aggregated” was confirmed, and the boundary between the primary particles was clear. In addition, disintegration of particles was observed in water.
- SEM scanning electron microscopy
- Example 2 In the same manner as in Example 1, the obtained acid-insoluble residue was sufficiently washed with pure water, and then filtered to obtain a wet floc. Of the obtained wet flocks, 40% by weight was further thoroughly washed with pure water, neutralized, filtered again, and air-dried to obtain a floc-dried product. The dried floc is crushed with a household mixer, and then further pulverized using an air-flow crusher (trade name, single-track jet mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.). The cellulose particle size was 8 ⁇ ), and a crushed product was obtained.
- an air-flow crusher trade name, single-track jet mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.
- the obtained milled material and the wet acid-insoluble residue in a wet state are introduced into a 90 L poly bucket with a composition of 40 parts by weight and 60 parts by weight (dry base) so that the total solid content concentration becomes 27% by weight.
- cellulose aggregate C was obtained.
- Table 1 shows properties of the cellulose aggregate C.
- the pore distribution was measured by mercury porosimetry, and scanning electron microscopy (SEM) observation revealed that, similarly to the case of cellulose aggregate A, 0.1 in the pore distribution by mercury porosimetry. — At 10 xm, a “clear peak” was confirmed. From the SEM photograph, a “secondary aggregated structure in which primary particles were aggregated” was confirmed, and the boundary between the primary particles was clear. In addition, disintegration of particles was observed in water.
- SEM scanning electron microscopy
- Example 4 Hydrolysis was performed in the same manner as in Example 1 except that the hydrolysis conditions were 3N aqueous hydrochloric acid, 40 ° C, and 24 hours, and the acid-insoluble residue (average of cellulose-dispersed particles in the acid-insoluble residue) was used. The particle size was 82 ⁇ m).
- the obtained acid-insoluble residue was purified in the same manner as in Example 1 to obtain a wet floc. Of the obtained wet flocks, 50% by weight was further sufficiently washed with pure water, neutralized, filtered again, and air-dried to obtain a dry floc.
- This floc-like dried product is pulverized by a household mixer, and further pulverized using a pneumatic pulverizer (trade name, single track jet mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.).
- the cellulose particle diameter at this time was 5 am) to obtain a pulverized product.
- the resulting pulverized product and the wet acid-insoluble residue are introduced into a 90 L poly bucket in a composition of 50 parts by weight and 50 parts by weight (dry base) so that the total solid content concentration becomes 16% by weight. Pure water was added, neutralized with ammonia water while stirring with a 3-1 motor (pH after neutralization was 7.5-8.0), and spray-dried in the same manner as in Example 1.
- Table 1 shows properties of the cellulose aggregate D.
- cellulose aggregate A As in the case of cellulose aggregate A, the pore distribution was measured by mercury porosimetry and observed by scanning electron microscope (SEM). A “clear peak” was confirmed in ⁇ , and a “secondary aggregate structure in which primary particles were aggregated” was confirmed from the SEM photograph, and the boundary between the primary particles was clear. In addition, disintegration of particles was observed in water.
- the acid-insoluble residue obtained in the same manner as in Example 4 was purified by the same operation as in Example 1 to obtain a wet floc. After 10% by weight of the obtained wet floc was further washed sufficiently with pure water, it was neutralized, filtered again, and air-dried to obtain a dry floc.
- the flocculent dried product is pulverized with a household mixer, and further pulverized using a pneumatic pulverizer (trade name, Single Track Jet Mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.). The cellulose particle size at that time was 3 zm), and a pulverized product was obtained.
- the obtained pulverized product and the wet acid-insoluble residue in a wet state are introduced into a 90 L polybucket in a composition of 10 parts by weight and 90 parts by weight (dry base), and purified so that the total solid content concentration becomes 35% by weight.
- Table 1 shows properties of the cellulose aggregate E.
- cellulose aggregate A As in the case of cellulose aggregate A, the pore distribution was measured by mercury porosimetry and observed by scanning electron microscope (SEM). A "clear peak” was confirmed at 10 xm, and a "secondary aggregate structure in which primary particles were aggregated” was confirmed from the SEM photograph, and the boundary between the primary particles was clear. In addition, disintegration of particles was observed in water.
- Example 2 Hydrolysis was carried out in the same manner as in Example 1 except that the hydrolysis conditions were 0.14N aqueous hydrochloric acid, 121 ° C, and 1 hour, and the acid-insoluble residue (the average particle size of cellulose-dispersed particles in the acid-insoluble residue) was used. The average particle size was 36 ⁇ m).
- the obtained acid-insoluble residue was purified in the same manner as in Example 1 to obtain a wet floc. Of the obtained wet flocks, 50% by weight was further sufficiently washed with pure water, neutralized, filtered again, and air-dried to obtain a dry floc.
- the dried floc is crushed with a household mixer, and then further pulverized using an air-flow-type pulverizer (trade name, Single Track Jet Mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.). Had a particle size of 5 ⁇ ), and a ground product was obtained.
- the obtained ground material and the acid-insoluble residue in the wet state are introduced into a 90 L poly bucket in a composition of 50 parts by weight and 50 parts by weight (dry base) so that the total solid content concentration becomes 30% by weight. Pure water was added, neutralized with ammonia water while stirring with a 3-1 motor (pH after neutralization was 7.5-8.0), and spray-dried in the same manner as in Example 1.
- Table 1 shows properties of the cellulose aggregate F.
- the pore distribution was measured by mercury porosimetry, and scanning electron microscopy (SEM) observation revealed that, similarly to the case of cellulose aggregate A, 0.1 in the pore distribution by mercury porosimetry. — At 10 xm, a “clear peak” was confirmed. From the SEM photograph, a “secondary aggregated structure in which primary particles were aggregated” was confirmed, and the boundary between the primary particles was clear. In addition, disintegration of particles was observed in water.
- SEM scanning electron microscopy
- Example 1 Using commercially available pulp (natural cellulose kraft pulp derived from cotton linter), It was hydrolyzed in the same manner as ⁇ 6, obtained acid insoluble residue (the average particle size of the cell openings over scan dispersion particle in the acid insoluble residue was 30 beta m) is the same manner as in Example 1 Purification was performed to obtain a wet floc. 90% by weight of the wet flocks were further washed with neutralized water and neutralized, and then ground with a planetary mixer (the average particle diameter of the cellulose dispersed particles in the ground wet flocks was lxm).
- Milled wet floc and non-milled wet floc are introduced into a 90-liter bucket with a composition of 90 parts by weight to 10 parts by weight (dry base), and pure water is added so that the total solid concentration becomes 30% by weight. While stirring with a 3-1 motor, the mixture was neutralized with aqueous ammonia (pH after neutralization was 7.5-8.0) and dried in the same manner as in Example 1 to obtain cellulose particles. G got. Table 1 shows properties of the obtained cellulose aggregate G.
- the pore distribution was measured by mercury porosimetry, and scanning electron microscopy (SEM) observation revealed that, similarly to the case of cellulose aggregate A, 0.1 in the pore distribution by mercury porosimetry. — At 10 xm, a “clear peak” was confirmed. From the SEM photograph, a “secondary aggregated structure in which primary particles were aggregated” was confirmed, and the boundary between the primary particles was clear. In addition, disintegration of particles was observed in water.
- SEM scanning electron microscopy
- the wet floc was dispersed in water, sedimented with a centrifugal force of 3000 G, and the sediment component was filtered to obtain an acid-free financial residue (the average particle size of the cellulose-dispersed particles at this time was 22 ⁇ m).
- Non-hydrolyzed and hydrolyzed wet floc are introduced into a 90-liter poly bucket with a composition of 50 parts by weight to 50 parts by weight (dry base), and purified to a total solid concentration of 39% by weight. Add water, neutralize with ammonia water while stirring with a 3-1 motor (pH after neutralization was 7.5-8.0), and put in a tray at 60 ° C. Dry for 18 hours and dry Got a lock.
- the dried floc was pulverized with a flash mill, and coarse particles were removed with a sieve of 500 / im to obtain a cellulose aggregate H. Table 1 shows properties of the obtained cellulose aggregate H.
- the pore distribution was measured by mercury porosimetry, and scanning electron microscopy (SEM) observation revealed that, similarly to the case of cellulose aggregate A, 0.1 in the pore distribution by mercury porosimetry. — At 10 xm, a “clear peak” was confirmed. From the SEM photograph, a “secondary aggregated structure in which primary particles were aggregated” was confirmed, and the boundary between the primary particles was clear. In addition, disintegration of particles was observed in water.
- SEM scanning electron microscopy
- Example 6 The acid-insoluble residue hydrolyzed in the same manner as in Example 6 was dispersed at a solid concentration of 17% by weight, and the dried cellulose aggregates in the same manner as in Example 1 were subjected to an air-flow grinder (Seishin Enterprise Co., Ltd.) Was manufactured using a single-track jet mill STJ_2 20 (trade name, manufactured by Toshiba Corporation) to obtain cell mouth powder 1 (corresponding to Example 1 of JP-A-63-267731).
- Table 1 shows the physical properties of the obtained cellulosic powder I.
- the product name of Avicel PH-200 manufactured by FMC was used as it was as cellulose powder M.
- Table 1 shows properties of the cellulose powder M.
- the acid-insoluble residue hydrolyzed in the same manner as in Example 6 was dispersed at a solid concentration of 17% by weight, and dried in the same manner as in Example 1 using a cellulose powder and a bantam mill (Screen used by Hosokawa Iron Works Co., Ltd.) Acetaminophen (manufactured by Merck Whey) pulverized to a composition of 50% by weight of cellulose and 50% by weight of acetoaminophen, and 500 g of a total of 500 g of a powder were mixed with a high-speed stirring granulator (5 mm in diameter).
- the physical properties of the obtained cellulose powder N are shown in Table 1. From the results of the pore distribution measurement by mercury porosimetry, the cellulose powder N showed a "clear peak" in the pore distribution of 0.1-1 10 / im. Was done. From the electron micrographs by SEM (Figs. 4 and 6), the particle structure is not "secondary aggregate structure in which primary particles are aggregated," but “uniformly dense and continuous film-like partition structure.” The boundaries of the partition walls were not clear, the particles did not disintegrate in water, and the cylindrical molded body obtained from the cellulose particles N was confirmed. (Compression pressure lOMPa) was very fragile.
- the cellulose particles O As for the cellulose particles O, a “clear peak” was confirmed at 0.1 zm or less from the pore distribution measurement result by mercury porosimetry. In addition, electron micrographs by SEM confirmed that the particle structure had a “uniformly dense and continuous film-like partition wall structure” rather than a “secondary aggregate structure in which primary particles were aggregated”. In the partition, the boundaries of the primary particles were unclear. The particles did not disintegrate in water, and the aspirin degradation rate was higher than that of the drug alone.
- Example 6 The acid-insoluble residue hydrolyzed in the same manner as in Example 6 was dispersed at a solid concentration of 17% by weight, dried as in Example 1, and dried with cellulose powder P (Example of Japanese Patent Publication No. 40-26274). Equivalent). Table 1 shows properties of the cellulose powder P.
- dissolved pulp is cut into pieces, hydrolyzed in a 10% by weight aqueous hydrochloric acid solution at 105 ° C for 30 minutes, and the resulting acid-insoluble residue is filtered, washed and neutralized, and the solid content concentration is 17% by weight. % Dispersion was obtained.
- the obtained cellulose dispersion was dried in a drum dryer (Kusuki Kikai Seisakusho Co., Ltd., trade name, KDD-1 type, steam pressure 0.35MPa, drum temperature 136 ° C, drum rotation speed 2i ⁇ pm, After drying at a water dispersion temperature of 100 ° C), the mixture was pulverized with a hammer mill, and coarse fractions were removed with a sieve having an opening of 425 ⁇ m to remove cellulose powder R (see Example 1 of JP-A-6-316535). Equivalent). Table 1 shows the physical properties of the obtained cellulose powder R.
- spherical spherical particles T (corresponding to Example 1 of Japanese Patent Application Laid-Open No. 07-173050) with 16 mesh (opening lmm).
- Table 1 shows the physical properties of the obtained spherical core particles T.
- the cellulose spherical core particles T were extremely heavy and had excellent fluidity, a specific surface area, and almost no pore volume in the particles, and did not become a molded product under a commonly used compression pressure of 10 or 20 MPa.
- a homomixer (trade name, TK homomixer MARKII type, manufactured by Tokushu Kika Kogyo Co., Ltd.) is used.
- the particle size, pH, and IC were adjusted.
- the cellulose dispersed particles in the obtained cellulose dispersion have a single average particle diameter, and the average particle diameter is 7 xm Met.
- the dispersion is spray-dried on a rotating disk of about 8 cm under the conditions of a rotating disk speed of 5000 i "pm, a flow rate of 6 L / hr, an intake temperature of 170 ° C, and an exhaust temperature of 85 ° C.
- the coarse particles were removed by a sieve of No. 1 to obtain cellulose powder U.
- Table 1 shows various physical property values of the obtained cellulose powder U (corresponding to Example 1 of WO 02/36168).
- Cellulose particles U are also heavy and have excellent fluidity. The specific surface area and the pore volume inside the particles are small.
- the molded body is formed under the commonly used compression pressure of 10, 20 MPa, but the molded body is brittle. It was worn out and easily broken by hand.
- acetaminophen produced by API Co., Ltd., powder type
- light caffeic anhydride trade name, aerodinole 200, manufactured by Nippon Aerosil Co., Ltd.
- Examples 2, 5, and 7 27 parts by weight of the cellulose powders B, E, and G obtained in the above or the cellulosic powders I, J, and L-S obtained in Comparative Examples 1, 2, and 4-11 were mixed with crospovidone (27 parts by weight).
- BASF trade name, Kollidon CL 2 parts by weight and granulated lactose (latatose New Zealand, trade name, Super-Tab) 15 parts are put into a 100-L scale V-type mixer (Dalton), 30 Then, 0.5 part by weight of magnesium stearate (manufactured by Taihei Chemical Co., Ltd., vegetable) was added and mixed for another 5 minutes to obtain a formulated powder.
- the total charged amount of each powder was 25 kg.
- the obtained powdered powder was turned using a 12 R punch with a diameter of 8 mm and a turntable. Tablets were compressed at 50 rpm and a compression force of 7.5 kN to obtain tablets weighing 200 mg. Tablets 60 minutes after the start of tableting were sampled, and the tablet weight, hardness, friability, and tableting failure rate were measured. Table 2 shows the physical properties of the obtained tablet.
- cellulose aggregate A 5 g was added to 20 g of a solution active ingredient obtained by diluting an ibuprofen-polyethylene glycol solution (amount ratio 1: 5) with ethanol (manufactured by Wako Pure Chemical Industries, Ltd., 10 times). Mix for 5 minutes with stirrer. The obtained mixed solution was vacuum-dried using an evaporator to obtain a powder. 0.2 g of the obtained powder is weighed and put into a mortar (made of Kikusui Seisakusho, using material SUS2, 3), and a 0.8 mm diameter circular flat punch (made by Kikusui Seisakusho, made of material SUS2, 3) ) And compress until the pressure reaches 100MPa.
- a solution active ingredient obtained by diluting an ibuprofen-polyethylene glycol solution (amount ratio 1: 5) with ethanol (manufactured by Wako Pure Chemical Industries, Ltd., 10 times). Mix for 5 minutes with stirrer. The obtained mixed solution was vacuum-
- Example 12 The same procedure as in Example 12 was carried out except that the cellulose aggregate A was changed to cellulose powder N (corresponding to Example 2 of JP-A-1-272643), to produce a liquid component-containing molded body, and to immerse the liquid component. The disintegration test was performed. Table 3 shows the results.
- a liquid component-containing molded article was produced in the same manner as in Example 12, except that the cell mouth agglomerate A was changed to cell mouth powder ⁇ (corresponding to Example 2 of JP-A-2-84401). Then, the liquid component was leached and a disintegration test was performed. Table 3 shows the results.
- Example 12 The same procedure as in Example 12 was carried out except that the cellulose aggregate A was changed to cellulose powder P (corresponding to the example of Japanese Patent Publication No. 40-26274) to produce a liquid component-containing molded product, and the liquid component was impregnated. And a disintegration test was performed. Table 3 shows the results.
- Example 12 The same procedure as in Example 12 was carried out except that the cellulose aggregate A was changed to cellulose powder Q (corresponding to Example 1 in Japanese Patent Publication No. 53-127553) to produce a liquid component-containing molded body, and the liquid component was impregnated. The disintegration test was performed. Table 3 shows the results.
- Example 12 The same procedure as in Example 12 was carried out except that cellulose aggregate A was changed to cellulose powder J (corresponding to Example 5 of WO02 / 02643) to produce a liquid component-containing molded body, and the liquid component was leached out and collapsed The test was performed. Table 3 shows the results.
- the force S which is half the particle size of the finely pulverized acetaminophen used in JP-A-2003-81876, and the drug concentration fluctuation during mixing by using the porous cellulose aggregate of the present invention
- the coefficient is less than 1.0% after 30 minutes, and extremely good mixing uniformity has been achieved.
- Example 14 The same procedure as in Example 13 was carried out except that the cellulose aggregate A was changed to cellulose powder N (corresponding to Example 2 of JP-A-1-272643), and the coefficient of variation of the drug concentration when mixed for 30 minutes and molding were performed. The breaking strength and disintegration time of the body were measured. Table 4 shows the results.
- Example 31 The same procedure as in Example 13 was carried out except that the cell mouth source aggregate A was changed to cell mouth powder (corresponding to Example 2 of JP-A-2-84401). The coefficient of variation of the concentration, the breaking strength of the molded body, and the disintegration time were measured. Table 4 shows the results. Comparative Example 31
- Example 14 The same procedure as in Example 13 was carried out except that the cellulose aggregate A was changed to cellulose powder P (corresponding to the example of Japanese Patent Publication No. 40-26274, equivalent to the crystalline cellulose “Avicel” PH-101). The coefficient of variation of the drug concentration, the breaking strength of the molded product, and the disintegration time after mixing for 30 minutes were measured. Table 4 shows the results. With the same formulation as that of Example 3 in JP-A-2003-81876, the average particle size of the finely divided acetaminophen used as the active ingredient was made half that used in the publication, whereby the active ingredient was reduced. Adhesive cohesion is significantly increased, which is worse than the mixing uniformity disclosed in Example 3 of the publication.
- Example 14 The same procedure as in Example 13 was carried out except that the cellulose aggregate A was changed to cellulose powder Q (corresponding to Example 1 of JP-B-53-127553, equivalent to crystalline cellulose “Avicel” PH-301).
- the coefficient of variation of the drug concentration, the breaking strength of the molded body, and the breaking time after mixing for 1 minute were measured. Table 4 shows the results.
- Example 14 The same procedure as in Example 13 was carried out except that the cellulose aggregate A was changed to cellulose powder J (corresponding to Example 5 of WO02 / 02643, trade name: crystalline cellulose “Seolas” KG-802), and mixed for 30 minutes.
- the coefficient of variation of the drug concentration, the breaking strength of the molded product, and the disintegration time were measured. Table 4 shows the results.
- cellulose aggregate A commercially available ibuprofen (active ingredient described as almost insoluble in water according to the Japanese Pharmacopoeia 14 revision) was added to polyethylene glycol (macrogol 400, manufactured by Sanyo Chemical Co., Ltd.). : Dissolved at a ratio of 5 and further added a solution diluted 10-fold with ethanol so as to be 10% by weight with respect to cellulose particles A, and stirred in a mortar.
- Example 14 The same procedure as in Example 14 was carried out except that the cellulose aggregate A was changed to cellulose powder N (corresponding to Example 2 of JP-A-1-272643), to produce a molded body and to obtain a liquid component on the surface of the molded body. Observation of leaching, measurement of drug dissolution rate from the columnar molded body, and observation of disintegration were performed. Table 5 shows the results. No leaching of the liquid component from the cylindrical molded body was observed, but in the dissolution test, it did not disintegrate for 3 minutes and floated on the liquid surface, and the disintegration was poor. Comparative Example 35
- Example 14 The same procedure as in Example 14 was carried out except that the cellulose aggregate A was changed to cellulose powder ⁇ (corresponding to Example 2 of JP-A-2-84401), to produce a molded article and the liquid component on the surface of the molded article. Observation of leaching, measurement of drug dissolution rate from the columnar molded body, and observation of disintegration were performed. Table 5 shows the results. No leaching of the liquid component from the cylindrical molded body was observed, but in the dissolution test, it did not disintegrate for 3 minutes and floated on the liquid surface, and the disintegration was poor. Comparative Example 36
- Example 14 The same procedure as in Example 14 was carried out except that the cellulose aggregate A was changed to cellulose powder P (corresponding to the example of Japanese Patent Publication No. 40-26274) to prepare a molded body and to immerse the liquid component on the surface of the molded body. Observation of protrusion, measurement of drug dissolution rate from the columnar molded body, and observation of disintegration were performed. Table 5 shows the results. Leaching of the liquid component was confirmed on the surface of the columnar molded body, and it did not become a tablet, and the dissolution test could not be performed.
- Example 14 The same procedure as in Example 14 was carried out except that the cellulose aggregate A was changed to cellulose powder Q (corresponding to Example 1 of JP-B-53-127553) to prepare a molded product and to examine the liquid components on the surface of the molded product. Observation of leaching, measurement of drug dissolution rate from the columnar molded body, and observation of disintegration were performed. Table 5 shows the results. Leaching of liquid components was confirmed on the surface of the cylindrical molded body As a result, it did not become a tablet and the dissolution test could not be performed.
- Example 14 The same procedure as in Example 14 was carried out except that the cellulose aggregate A was changed to cellulose powder J (corresponding to Example 5 of WO02 / 02643), to produce a molded body and to observe leaching of liquid components on the surface of the molded body.
- the drug dissolution rate from the columnar molded product was measured, and the disintegration was observed.
- Table 5 shows the results. Leaching of the liquid component was confirmed on the surface of the columnar molded body, and it did not become a tablet, and the dissolution test could not be performed.
- Ethenzamide produced by API Co., Ltd., powder grade was pulverized with a small pulverizer
- ethanol Woodo Pure Chemicals, reagent grade
- 5:95 10 mL of a solution of cellulose aggregates.
- Gig was added and stirred with a magnetic stirrer for 3 minutes.
- the obtained dispersion was introduced into an evaporator, and the solvent was completely removed to obtain a powder sample.
- the dissolution test was carried out by operating this powder in the same manner as in Example 14 except that the compression at the time of producing the cylindrical molded body was changed to 50 MPa. Table 6 shows the results.
- cellulose aggregate A a 1: 5 ratio of commercially available ibuprofen (active ingredient described as almost insoluble in water according to the Japanese Pharmacopoeia 14 revision) in ethanol (Wako Pure Chemical Industries, special grade reagent) was added to the cellulose aggregate A so as to be 10% by weight, followed by stirring in a mortar. Ethanol was completely removed from the obtained wet mixed powder using an evaporator to obtain a dry powder.
- Example 16 The same procedure as in Example 16 was carried out except that the cellulose aggregate A was changed to cellulose powder N (corresponding to Example 2 of JP-A-2-84401), to produce a columnar molded body, which was then sealed and stored. The bottle was observed for cloudiness, dissolution test, and disintegration. Table 7 shows the results. No clouding of the bottle was observed, but the tablet did not disintegrate in 1 minute and was floating above the liquid surface.
- a columnar molded body was prepared in the same manner as in Example 16 except that the cell mouth agglomerate A was changed to cell mouth powder (corresponding to Example 2 of JP-A-2-84401).
- the bottles were then observed for cloudiness after storage, sealed, tested for dissolution, and observed for disintegration.
- Table 7 shows the results. No clouding of the bottle was observed, but the tablets did not disintegrate in 1 minute and were floating above the liquid surface.
- Example 16 The same procedure as in Example 16 was carried out except that the cellulose aggregate A was changed to cellulose powder P (corresponding to the example of Japanese Patent Publication No. 40-26274) to produce a columnar molded body, and the bottle after storage in a sealed stopper. , A dissolution test and an observation of disintegration were performed. Table 7 shows the results. The bottle was clouded because the sublimed ibuprofen recrystallized in the bottle wall.
- Compressed molded article Cell sucrose particles S exudation of liquid component Occurrence Example 1 'i A No exudation Collapse Comparative example 2 4 N «Extruded without collapsing No collapsing Comparative example 2 5 0' Minamizashi Collapse Depth ratio K example 26 P i ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ 2 2 2 2 2 2 2 2
- the highly flowable porous cellulose aggregate excellent in moldability and disintegration of the present invention the molded body composition containing the cellulosic particles thereof and one or more active ingredients have an I-type crystal form.
- TECHNICAL FIELD The present invention relates to a molded product composition comprising a body and its cellulose particles and one or more active ingredients, and can be suitably used mainly in the field of pharmaceuticals.
- FIG. 1 is a pore distribution diagram of a porous cellulose aggregate A of the present invention (Example 1) measured by mercury porosimetry. From FIG. 1, a “clear peak” derived from the pores in the particles can be confirmed in the pore distribution of 0.1— ⁇ . This is about the same size as the pore size shown in the electron micrograph by SEM. The peak at 1050 x m shown in Fig. 1 is derived from the particle gap.
- FIG. 2 is a pore distribution diagram of cellulose powder K (Comparative Example 3) measured by mercury porosimetry. No "clear peak” as observed in the porous cellulose aggregate of the present invention was confirmed. The pores without such “clear peaks” are those of the original cellulose primary particles. The peak observed at 10-50 x m is due to the particle gap, considering the particle size distribution of the powder.
- FIG. 3 is an electron microscopic photograph of the porous cellulose aggregate of the present invention (Example 1) at a magnification of 250 times. "Secondary aggregate structure in which primary particles aggregated" was observed.
- FIG. 4 is an electron micrograph of cellulose particles N (Comparative Example 6) at a magnification of 250 ⁇ .
- the particle structure of the cellulose particles N is not a “secondary aggregate structure in which the primary particles are aggregated”, but rather, because the primary cellulose particles are refined and the refined particles are firmly bonded during drying. It can be seen that the more indistinct the boundary is, the “continuous and strong film-like cellulose partition walls”.
- Electron micrograph of cellulose powder P (Comparative Example 8) at 250 ⁇ magnification. According to the photograph, the particle structure of the cellulose powder P was obtained by drying a dispersion of cellulose particles having a single average particle diameter, which had a ⁇ secondary aggregate structure in which primary particles aggregated ''. The pore volume in the particles was small. The pore distribution was measured by mercury porosimetry. As a result, no “clear peak” was observed at 0.1 to 10 ⁇ m in the pore distribution.
- FIG. 10 The angle of repose and hardness of the cellulose particles A-H in Example 18 and the cell mouth powder or particles I-U in Comparative Example 1-113 (0.5 g each were weighed and compressed at 20 MPa). Is a graph showing the relationship between the pressure and the hardness of a columnar molded body having a diameter of 1.1 cm. In Examples 18 to 18, the hardness is 165 N or more even in a region where the angle of repose is less than 44 °, and it can be seen that the balance between fluidity and formability is excellent.
- FIG. 11 Hardness and disintegration of cellulose particles A-H in Example 18 and the cellulosic powder or particles I-U in Comparative Example 113 (in each case, 0.5 g of each cellulose was weighed).
- a graph showing the relationship between hardness and collapse of a columnar molded body having a diameter of 1.1 cm at a compression pressure of 20 MPa.
- the disintegration time is 75 seconds or less in all the regions where the hardness is 160N to 400N or more, and it can be seen that the balance between the hardness and the disintegration is excellent.
- Comparative Example 113 there was a system in which the disintegration was extremely delayed when the hardness was increased, and none of the systems showed disintegration of 75 seconds or less at 160 N or more.
- the entire apparent specific volume used as the excipient as in the present invention for example, in the range of 2.0 to 6.0 cm 3 Zg, the hardness at 20 MPa is 165 N or more and the disintegration time is 75 seconds or less. None had excellent disintegration properties.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Manufacture Of Porous Articles, And Recovery And Treatment Of Waste Products (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
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JP2005517489A JP4969104B2 (ja) | 2004-01-30 | 2005-01-27 | 多孔質セルロース凝集体及びその成型体組成物 |
BRPI0507139-9A BRPI0507139A (pt) | 2004-01-30 | 2005-01-27 | agregado de celulose porosa, processo para produzir o mesmo, e composição de produto moldado |
US10/587,827 US8597686B2 (en) | 2004-01-30 | 2005-01-27 | Porous cellulose aggregate and formed product composition comprising the same |
EP05709405.4A EP1712583B1 (en) | 2004-01-30 | 2005-01-27 | Porous cellulose aggregate and formed product composition comprising the same |
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JP2004-024875 | 2004-01-30 | ||
JP2004024875 | 2004-01-30 |
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US (1) | US8597686B2 (ja) |
EP (1) | EP1712583B1 (ja) |
JP (1) | JP4969104B2 (ja) |
CN (1) | CN100402585C (ja) |
BR (1) | BRPI0507139A (ja) |
TW (1) | TWI291877B (ja) |
WO (1) | WO2005073286A1 (ja) |
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Also Published As
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EP1712583B1 (en) | 2020-09-16 |
JP4969104B2 (ja) | 2012-07-04 |
TW200538162A (en) | 2005-12-01 |
US20070190017A1 (en) | 2007-08-16 |
US8597686B2 (en) | 2013-12-03 |
EP1712583A1 (en) | 2006-10-18 |
JPWO2005073286A1 (ja) | 2007-09-06 |
TWI291877B (en) | 2008-01-01 |
BRPI0507139A (pt) | 2007-06-19 |
CN100402585C (zh) | 2008-07-16 |
EP1712583A4 (en) | 2009-04-15 |
CN1926175A (zh) | 2007-03-07 |
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