WO2018062343A1 - 粒子およびその製造方法 - Google Patents

粒子およびその製造方法 Download PDF

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Publication number
WO2018062343A1
WO2018062343A1 PCT/JP2017/035102 JP2017035102W WO2018062343A1 WO 2018062343 A1 WO2018062343 A1 WO 2018062343A1 JP 2017035102 W JP2017035102 W JP 2017035102W WO 2018062343 A1 WO2018062343 A1 WO 2018062343A1
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Prior art keywords
particles
particle
cell wall
lignin
particle size
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PCT/JP2017/035102
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English (en)
French (fr)
Japanese (ja)
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桂一 小泉
鈴木　亮
丸山　一雄
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合同会社レビアスファーマ
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Priority to JP2018542823A priority Critical patent/JP7274863B2/ja
Publication of WO2018062343A1 publication Critical patent/WO2018062343A1/ja
Priority to JP2023038520A priority patent/JP2023063411A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to a particle having a maximum diameter of 1 to 800 nm obtained from a component constituting a cell wall, which is excellent in properties such as thermal stability.
  • fine particles for example, nanoparticles such as fullerenes and carbon nanotubes, and fine particles derived from natural products such as liposomes are known.
  • the former has physical properties such as heat resistance and solvent resistance, and the latter has a wide variety of physical properties such as being derived from natural products and being easily applicable to the human body.
  • over-the-counter drugs that do not require a doctor's prescription are displayed in pharmacies, etc., unlike ethical drugs that are strictly managed, and can be easily purchased by ordinary people.
  • the over-the-counter drugs tend to require more heat resistance and cold resistance than the prescription drugs.
  • foods, cosmetics and the like tend to require more heat resistance and cold resistance.
  • the present invention has been made in view of such circumstances, and by adding to the preparation, properties such as hardness and disintegration can be easily controlled, and heat resistance and cold resistance can be achieved without impairing these properties.
  • the present invention provides new fine particles that can enhance the properties and can sufficiently exhibit the characteristics even when blended with an over-the-counter drug.
  • the first gist of the present invention is particles having a maximum diameter of 1 to 800 nm obtained from components constituting the cell wall.
  • grains obtained from the component which comprises a cell wall among the particles of a 1st summary make a 2nd summary the particle
  • the particles obtained from the above are mainly composed of sugar as a third gist.
  • a method for producing particles according to any one of the first to third aspects comprising a step of lysing a cell wall and a step of separating particles from a lysate obtained by the step
  • a method for producing the particles according to any one of the first to third aspects comprising the steps of preparing a liquid containing a component constituting a cell wall and separating the particles from the liquid
  • a method for producing particles is a fifth aspect.
  • a composition containing any one of the particles of the first to third aspects is a sixth aspect, and among the compositions of the sixth aspect, a group consisting of a pharmaceutical composition, a food composition, and a cosmetic composition
  • a composition that is at least one selected from the above is defined as a seventh aspect.
  • the present inventors have made various studies in order to obtain fine particles applicable to various uses. As a result, they found new fine particles that have not been clarified so far. It has been clarified that the fine particles are excellent in dispersibility, heat resistance, cold resistance and the like by previous studies.
  • the particles of the present invention are obtained from the components constituting the cell wall, the health benefits derived from natural dietary fiber can be enjoyed.
  • the maximum diameter is as small as 1 to 800 nm, it has solubility in both water and oil, and it has excellent heat resistance, cold resistance, and drought resistance. be able to.
  • properties such as hardness and disintegration can be easily controlled, and a preparation having desired characteristics can be obtained.
  • the particles obtained from the components constituting the cell wall are spherical, so that the fluidity and dispersibility are excellent.
  • the particles obtained from the components that constitute the cell wall are mainly composed of sugar, the protein content that is relatively easy to become an allergen is relatively low or not at all, so that it should be safer when taken. Can do.
  • the method for producing the particles of the present invention comprising the step of lysing the cell wall and the step of separating the particles from the lysate obtained by the step, comprises selecting a living organism having a cell wall.
  • the component which comprises a desired cell wall can be used, and the freedom degree of the particle design obtained can be raised.
  • a method for producing the particles of the present invention comprising a step of preparing a liquid containing a component constituting the cell wall and separating the particle from the liquid, is a contaminant other than the component constituting the cell wall in advance. Therefore, particles can be produced efficiently.
  • composition containing the particles of the present invention can enjoy health benefits derived from natural dietary fiber.
  • the composition is at least one selected from the group consisting of a pharmaceutical composition, a food composition and a cosmetic composition
  • the particles of the present invention have a low protein content or no protein at all. Therefore, safety can be further increased.
  • the “main component” means a component that affects the properties of the material, and the content of the component is usually 50% by weight or more of the whole material.
  • FIG. (A) is the photograph which showed the aggregate
  • (b) is the transmission electron micrograph of the said particle
  • (c) is the particle
  • FIG. (A) is a photograph showing a state in which the particles A dispersed in ultrapure water are freeze-dried, and (b) is a photograph in which the particles A are dispersed again in ultrapure water.
  • (C) is a transmission electron micrograph of the particle A, and (d) is a view showing the particle size distribution of the particle A.
  • FIG. 3 is a view showing a particle size distribution of the particles A.
  • A) is a photograph showing a state after a lapse of one week after dispersion of freeze-dried particles A in ultrapure water
  • (b) is a transmission electron micrograph of the particles A
  • FIG. 3 is a view showing a particle size distribution of the particles A.
  • A) is the transmission electron micrograph of the particle
  • (b) is the figure which showed distribution of the particle diameter of the particle
  • FIG. (A) is the photograph which showed the aggregate
  • (b) is the transmission electron micrograph of the particle
  • (A) is the photograph which showed the aggregate
  • (b) is the transmission electron micrograph of the said particle
  • (c) is the particle
  • 4 is a diagram showing a Raman analysis spectrum of the particle D.
  • FIG. (A) is a photograph showing a lyophilized state of the particles D dispersed in ultrapure water, and (b) is a photograph showing a state in which the particles D are dispersed again in ultrapure water.
  • FIG. 4 is a view showing the particle size distribution of the particles D.
  • A) is a photograph showing a state after a lapse of one week after dispersing particles D after freeze-drying in ultrapure water
  • (b) is a transmission electron micrograph of the particles D
  • FIG. 4 is a view showing the particle size distribution of the particles D.
  • the “component constituting the cell wall” refers to a substance that forms a cell wall found in cells of organisms belonging to the plant kingdom, organisms belonging to the fungal kingdom, organisms belonging to the protist kingdom, organisms belonging to the prokaryotic kingdom, etc. This means that it also includes the sugars that make up this substance.
  • Examples of organisms belonging to the plant kingdom include red algae, brown algae, green algae, axle algae, moss plants, fern plants, seed plants, and the like.
  • examples of the organism belonging to the above-mentioned fungal kingdom include algae fungi, larvae, basidiomycetes, lichens, and the like, and examples of organisms belonging to the protozoan kingdom include diatoms.
  • examples of organisms belonging to the prokaryotic world include bacteria and cyanobacteria.
  • organisms belonging to the fungal kingdom, protist kingdom, prokaryotic kingdom, so-called algae red algae, brown algae, green algae, axle algae, Diatoms, cyanobacteria, etc.
  • yeasts belonging to Ascomycomycetes, Basidiomycetes, etc. are particularly preferably used in the fungal kingdom.
  • yeasts belonging to the genus Saccharomyces or Schizosaccharomyces are preferably used.
  • the component which comprises a cell wall, and its composition differ greatly with living things. Therefore, the proportion of the constituent sugars in the particles varies depending on the organism used as the material.
  • the cell walls of organisms belonging to the plant kingdom are usually of a two-layer structure, and cellulose, lignin and hemicellulose are typical components. And among the living organisms belonging to the plant kingdom, the content ratio of hemicellulose is greatly different for each race. Some algae do not have lignin which is a secondary cell.
  • the cell wall of yeast is usually a monolayer, and ⁇ -glucan and galactomannan are typical components.
  • the cell walls of lactic acid bacteria classified as bacteria are usually monolayers, and dextran, teichoic acid and cell wall polysaccharides are typical components.
  • the fact that the particles of the present invention are obtained from the components constituting the cell wall can be derived from the fact that the proportion of the constituent sugars of the obtained particles is determined for each type of organism used as the material.
  • the cell wall has a large amount of cellulose, lignin and hemicellulose.
  • glucose is about 60% by weight as constituent sugar, 10-30% by weight of lignin, and others. It is 10 to 30% by weight.
  • Example 1 the particles of the present invention using licorice have 64.8% by weight of glucose as a constituent sugar and the content of other sugars is also small. Has 14.0% by weight of lignin.
  • the cell walls of licorice and the particles of the present invention made from licorice are very similar in the proportions of constituent sugar and lignin.
  • all the component compositions shown below are shown on a weight basis (parts by weight, weight%).
  • chlorella belongs to green algae, its cell wall has a lot of cellulose, lignin and hemicellulose, like licorice.
  • grains of this invention which use chlorella as a material have 59.8 weight% of glucose as a component saccharide
  • the lignin content of chlorella is lower than that of licorice, lignin is a representative component that appeared last in the process of plant evolution, and is based on the type difference between chlorella and licorice Conceivable.
  • yeast usually belongs to Aspergillus or basidiomycetes, and its cell wall has a large amount of ⁇ -glucan and galactomannan, but hardly contains lignin.
  • the particles of the present invention using yeast as a material have almost all the constituent sugars as glucose and lignin as 0.6. It has almost no sugar other than glucose except for having a weight percentage.
  • the particles of the present invention need only be obtained from components that constitute such a cell wall, and it is not necessary to specify these components.
  • specific examples of components that constitute such cell walls include cellulose, hemicellulose, pectin, glycoprotein, and phenolic compounds.
  • Examples of the hemicellulose include xyloglucan, 1,3-1,4- ⁇ -D-glucan, xylan, glucomannan, callose and the like.
  • Examples of the pectin include homogalacturonan, rhamnogalacturonan I, rhamnogalacturonan II, apiogalacturonan, arabinogalactan, arabinan, galactan and the like.
  • Examples of the glycoprotein include extensin and arabinogalactan protein.
  • Examples of the phenol compound include lignin.
  • the components constituting the cell wall include a large number of components in which a plurality of sugars are combined.
  • Such constituent sugars include glucose, xylose, galactose, fucose, cellotriose, cellotetraose, xylan, arabinose, mannose, rhamnose and the like.
  • the components constituting the cell wall include these sugars.
  • the term “particle” means that the structure can be seen as a two-layer structure, a double film structure, a multilayer structure, or a multilayer structure when observed with an electron microscope. That is, the particles of the present invention have an electron density different from at least the outermost layer and the inside.
  • the particles of the present invention have a maximum diameter of 1 to 800 nm, more preferably 10 to 800 nm, more preferably 30 to 500 nm, and further preferably 40 to 300 nm.
  • the “maximum diameter of the particle” refers to the diameter when the particle is a sphere, and the maximum length when the particle is in another shape.
  • the particle diameter can be measured, for example, by dispersing the obtained particles in ultrapure water and using the concentrated particle size analyzer.
  • the calculated average particle size should be the maximum size of the particle, and the calculated average particle size should be within the range defined by the maximum size .
  • the particles of the present invention usually have a shape with no sharp parts such as carbon nanotubes, and preferably have a spherical shape.
  • the sphere includes not only a true sphere but also an ellipsoid.
  • the shape of the particles can be determined by, for example, photographing negatively stained particles with a transmission electron microscope and observing the appearance. For example, particles assembled in a pellet form are dispersed in ultrapure water, the dispersion is adsorbed on a mesh, and a staining solution is placed thereon. Then, the appearance of the particles can be observed by taking an image of the excess dyed liquid that has been sucked with a filter paper and dried with a transmission electron microscope.
  • the particles of the present invention have a good dispersibility in both aqueous and oily liquids, and in particular, are highly dispersible in aqueous liquids. Moreover, the excellent dispersibility is maintained for a long time.
  • the dispersibility of the particles can be determined, for example, by dispersing the obtained particles in ultrapure water, photographing the dispersion with a transmission electron microscope, and observing the degree of dispersion. In addition, the degree of dispersibility retention can be determined by comparing the dispersion liquid with that after storage for a certain period.
  • the particles of the present invention are excellent in pressure resistance and heat resistance, and there is almost no change in particle diameter due to pressurization up to at least 2 atmospheres and heating up to 121 ° C.
  • the pressure resistance and heat resistance of the particles for example, the particle size distribution of the particles dispersed in the ultrapure water and the particles that are obtained by pressurizing and heating the dispersion liquid is analyzed with a concentrated particle size analyzer. When the two are calculated and compared, it can be determined from the fact that the particle size distribution does not change in both.
  • the particles of the present invention are excellent in cold resistance and drying resistance, and there is almost no change in particle diameter by cooling and drying from ⁇ 50 to ⁇ 80 ° C.
  • the cold resistance and drying resistance of particles include, for example, particles dispersed in ultrapure water and those obtained by freeze-drying this dispersion ( ⁇ 50 ° C.) and redispersing the dried product in ultrapure water. It can be determined that the particle size distribution is not changed when the particle size distribution is calculated with a dense particle size analyzer and the two are compared. Further, even if the particles contained in the lyophilized product stored at ⁇ 80 ° C. for 7 days and dispersed in ultrapure water are compared in the same manner, the particle size distribution does not change.
  • the structure of the particles of the present invention does not change even when pressurization, heating, cooling, and drying are performed. This means that particles dispersed in ultrapure water, those obtained by pressurizing and heating this dispersion, or those obtained by cooling and drying again in ultrapure water are dispersed in them using an electron microscope. This can be determined by comparative observation of the structure of the contained particles.
  • Such particles can be produced, for example, by a method comprising a step of lysing the cell wall and a step of separating the particles from the lysate obtained by the step.
  • Examples of the step of lysing the cell wall include heat treatment, ultrasonic treatment, treatment with a degrading enzyme, and alkali decomposition treatment. These can be used alone or in combination. Among these, from the viewpoint of efficiency and consideration of health, heat treatment and treatment with a degrading enzyme are preferable, and heat treatment is particularly preferable.
  • Examples of the heat treatment include immersing a living organism having a cell wall in a liquid and heating the organism together with the liquid to dissolve the components constituting the cell wall in the liquid to obtain a lysate. More specifically, first, an organism having a cell wall as a material is prepared. This organism may be in any state, but is preferably dried and pulverized from the viewpoint of efficiency. The prepared organism is immersed in a separately prepared liquid and heated at 60 ° C. or higher for 3 minutes or longer to obtain a lysate, but the prepared organism is heated and dried in a state of being immersed in the liquid. If so, it is not necessary to further heat when immersed in a liquid. However, since the yield tends to increase as the heating time increases, the heating may be performed. As said liquid, you may use the liquid used as various solvents, such as water and alcohol, individually or in mixture of 2 or more types. However, in consideration of taking particles or the like, water or an aqueous liquid is preferably used from the viewpoint of health.
  • dissolving the component constituting the cell wall in the liquid means that the structure of the cell wall is disrupted by separating the basic skeleton and the substrate to form a system in which the component is dispersed in the liquid.
  • the polysaccharide, which is one of the components is dispersed in a liquid, for example, by decomposing it into small-sized ones.
  • examples of the step of separating the particles of the present invention from the lysate obtained in the above step include centrifugation, filter filtration, ultrafiltration, ultracentrifugation and the like. More suitable ones are used depending on the type of organism having a cell wall as a material. Of these, centrifugation and filter filtration are preferable from the viewpoint of ease of operation, and these are preferably used in combination from the viewpoint of increasing the degree of purification.
  • the supernatant may be filtered through a filter having a pore size of 0.22 to 0.45 ⁇ m to obtain a filtrate (precision separation step).
  • the particles of the present invention adopt a method (for example, a method using caustic soda, hydrochloric acid, or the like) for the purpose of substituting terminal molecules for the components constituting the cell wall, such as cellulose. Because it is not, it is excellent in safety.
  • a living organism having a cell wall is used as a material.
  • a specific component that constitutes a cell wall such as cellulose, hemicellulose, pectin, glucan, pullulan, glycoprotein, and phenolic compound is used as a material.
  • pectin and glucan are preferable. That is, at least one component among the components constituting the specific cell wall is dissolved in a liquid, a liquid containing the component constituting the cell wall is prepared, and the particles of the present invention are separated from the liquid. Good. According to this, since impurities derived from living organisms other than the components constituting the cell wall can be eliminated in advance, particles can be produced efficiently.
  • the particles of the present invention when the particles of the present invention are blended in preparations such as pharmaceuticals, foods, and cosmetics, it becomes possible to control various properties such as hardness and disintegration as additives.
  • additives it is important that the additive does not limit the blending amount of the main agent.
  • the particles of the present invention can control each characteristic by adding a relatively small amount to the composition constituting the preparation, the amount of the main ingredient is not limited, and the degree of freedom of the composition is reduced. Can be increased.
  • the particles of the present invention are blended in a preparation, it is preferably contained in an amount of 0.01 to 95% by weight, more preferably 0.01 to 90% by weight, further based on the total composition constituting the preparation. It is preferably 0.1 to 50% by weight, and more preferably 1 to 20% by weight.
  • Examples 1 to 4 the particles of the present invention were examined (Examples 1 to 4), and then formulations using these particles were examined (Examples 5 to 7 and Comparative Examples 1 to 3).
  • the present invention is not limited to this.
  • the particles of the present invention were prepared by the following procedure. For each of the particles obtained, the appearance was observed (Examples 1 to 4), the particle size distribution was calculated (Examples 1, 2, and 4), and the constituent sugars and lignin were analyzed (implemented) according to the following items. Examples 1, 3, 4), Raman analysis (Examples 1, 4), evaluation of heat resistance, cold resistance and drying resistance (Examples 1, 4), evaluation of water dispersibility and storage stability (Example 1, 4) was performed.
  • Example 1 Licorice (roots and strons, sometimes excluding pericytes (peeled licorice), Tochimoto Amikado, Tochimoto licorice P) was boiled and then immersed in water at 95 ° C and heated for 50 minutes. To obtain a lysate. Next, this lysate was centrifuged at 20,000 G to obtain a supernatant from which relatively large contaminants were removed. The supernatant was centrifuged at 140,000 G to obtain particles A assembled in a pellet form.
  • the particles A assembled in a pellet form are dispersed in water, this dispersion is centrifuged at 20,000 G for 20 minutes to remove impurities, and the supernatant is 0.45 ⁇ m filter (Merck). Manufactured by Millex-HV, 0.45 ⁇ m, PVDF), and the filtrate is further filtered through a 0.22 ⁇ m filter (Millex-GV, 0.22 ⁇ m, PVDF gamma sterilized). Centrifugation was performed at 000 G to obtain a pellet which is an aggregate of particles A with an increased degree of purification [FIG. 1 (a)].
  • FIG. 1 A photograph of this particle A negatively stained and taken with a transmission electron microscope is shown in FIG. That is, the particles A, which are aggregated in a pellet form and have a high degree of purification, are dispersed in ultrapure water, and this dispersion is adsorbed onto a collodion affixed mesh (manufactured by Nisshin EM Co., Ltd.). Put it on. The surplus uranyl acetate was absorbed with a filter paper and dried, and photographed with a transmission electron microscope (JEM-1400TC, manufactured by JEOL Ltd.). A typical particle A was a sphere having a maximum diameter of about 200 nm as shown in FIG.
  • the particles A which are aggregated in the above pellet form and have a high degree of purification, are dispersed with ultrapure water, and the dispersion is analyzed by a histogram method using a concentrated particle size analyzer (FPAR-1000, manufactured by Otsuka Electronics Co., Ltd.). The particle size distribution was calculated. The result is shown in FIG. As shown in FIG. 1C, the particle diameter of the particles A showed a normal distribution with an average particle diameter of 193 nm.
  • the decomposition solution and the residue were separated by filtration, and the filtrate and the residue washing solution were added to make a constant volume of 100 mL.
  • a recovery rate test using a monosaccharide was performed in parallel.
  • Monosaccharides rhamnose, ribose, xylose, arabinose, fructose, mannose, glucose, galactose
  • the instrument used for the analysis is a GL-7400 HPLC system manufactured by GL Sciences.
  • the amount of constituent sugar in the sample was calculated from the monosaccharide concentration of the obtained decomposition solution and the sample decomposition amount.
  • the obtained results are shown in Table 1 below.
  • the result of Table 1 correct
  • Sf sugar excessive decomposition correction coefficient
  • the particle A has an analysis result of its constituent sugars, and glucose of about 65% by weight of the constituent sugars, and also contains fructose, galactose, arabinose, rhamnose and the like. .
  • This result correlates with the fact that many of the components constituting the cell walls of licorice are cellulose and hemicellulose. That is, cellulose is a natural polymer in which a number of ⁇ -glucose molecules are linearly polymerized by glycosidic bonds, and is decomposed into glucose by thermal decomposition. Hemicellulose is a generic name for polysaccharides in which glucose and ⁇ -glucan, etc.
  • the analysis of the lignin of the particle A was performed as follows. Originally, in lignin measurement, soluble components (oil, tannin, polyphenol, etc.) in a sample are removed in advance with an organic solvent or the like, but extraction is not performed in the analysis of lignin. That is, in the above lignin analysis, as a quantitative determination of acid-insoluble lignin, the residue obtained by filtration in the above constituent sugar analysis is dried at 105 ° C. and weighed to calculate the decomposition residue rate, and the ash content in the residue is measured. As a result, the acid-insoluble lignin concentration was calculated.
  • the filtrate obtained by filtration by the above constituent sugar analysis was measured at a wavelength of 210 nm using a double beam spectrophotometer (manufactured by Hitachi High-Tech Science Co., Ltd., U-2001 type).
  • the concentration was calculated using the extinction coefficient of the acid-soluble lignin of hippopotamus (plant name) according to the formula (1).
  • Table 2 It is known that the extinction coefficient of hippo lignin is around 110 L ⁇ g ⁇ 1 cm ⁇ 1 .
  • the particle A has about 14.0% by weight of acid-insoluble and acid-soluble lignin. This result also confirms that the particle A is derived from the cell wall of an organism belonging to the plant kingdom.
  • the Raman analysis of the particle A was performed on an inVia Reflex Raman microscope using the inVia Reflex Raman microscope on a small amount (about 0.5 mm square) of the particle A placed on a slide glass. That is, using an LD-excited grain laser (wavelength of 532 nm), an objective lens used 50 times, an irradiation laser beam diameter of 1.5 ⁇ m, an irradiation laser power of 1 mW or less, a photometric Raman shift range of 4000 to 150 cm ⁇ 1 , a wave number resolution of 6 cm ⁇ 1 , and integration The number of times was 10, and the analysis was performed by library search by spectral waveform comparison and collation with the database. The obtained spectrum is shown in FIG.
  • the particles A have a spectrum close to that of cellulose.
  • Cellulose is a polysaccharide component that constitutes the cell wall, and the constituent sugar is glucose.
  • a broad peak centered at 3500 to 3300 cm ⁇ 1 is mainly attributed to a hydroxyl group, and a peak observed in the vicinity of 2900 cm ⁇ 1 is attributed to a C—H bond. Since both the hydroxyl group and the C—H bond are groups found in saccharides, it can be seen that the particle A is derived from the cell wall of an organism belonging to the plant kingdom.
  • FIG. 5 (a) shows a product obtained by dispersing the lyophilized product in ultrapure water [FIG. 4 (a)] and stored in an atmosphere at 4 ° C. for 1 week.
  • the particles A contained in the dispersion after storage were observed in the same manner as in the above-mentioned appearance observation (FIG. 5B), and the particle size distribution was calculated with the concentrated particle size analyzer [FIG. c)].
  • Example 2 Using a ginger (scientific name: Zingiber officinale, manufactured by Tochimoto Tenkaido Co., Ltd., ginger increment), a pellet which is an aggregate of particles B having a high degree of purification was obtained in the same manner as in Example 1.
  • Example 3 Using chlorella (Yaeyama Macrolla, manufactured by Yaeyama Shokusan Co., Ltd.), pellets that are aggregates of particles C having an improved degree of purification were obtained in the same manner as in Example 1.
  • FIG. 7 (a) shows a photograph when a pellet which is an aggregate of particles C having a high degree of purification is obtained.
  • Example 2 A photograph of the particle C taken with a transmission electron microscope in the same manner as in Example 1 is shown in FIG.
  • the particle C was a sphere having a maximum diameter of about 400 nm as shown in FIG.
  • the particle C contains about 6.1% by weight of lignin. This result also confirms that the particles C are derived from the cell walls of organisms belonging to the plant kingdom.
  • Example 4 Using the same amount of yeast (MC Food Specialties, dry beer yeast) and yeast (Nippon Garlic, natural beer yeast) mixed in the same manner as in Example 1, the degree of purification of particles D was increased. A pellet as an aggregate was obtained [FIG. 8 (a)].
  • the Raman analysis of the particle D was performed in the same manner as in Example 1. The obtained spectrum is shown in FIG. As a result of analysis, the particle D was found to have a spectrum close to that of cellulose, which is a kind of ⁇ -glucan, which is a constituent sugar of the cell wall of yeast. Also in FIG. 9, a broad peak centered at 3500 to 3300 cm ⁇ 1 mainly attributed to hydroxyl groups was observed, and a peak near 2900 cm ⁇ 1 attributed to C—H bonds was observed. Since both the hydroxyl group and the C—H bond are groups found in saccharides, it can be considered that the particle D is derived from the cell wall of yeast.
  • FIG. 12 (a) shows a product obtained by dispersing the lyophilized product in ultrapure water [FIG. 10 (b)] and storing it in an atmosphere at 4 ° C. for 1 week. Moreover, what observed the particle
  • FIG. 12C shows the particle size distribution calculated for the particles D contained in the dispersion after storage by the concentrated particle size analyzer.
  • Example 5 Comparative Example 1
  • the particles A prepared in Example 1 and the following materials were prepared, and the mixture obtained by stirring and mixing these materials was used as a tableting machine (Ichibashi Seiki Co., Ltd.) equipped with a mortar coated with magnesium stearate.
  • the product was compressed at 6 kN using HANDTAB-100, and Example 5 which was a 120 mg preparation (diameter 7 mm, curvature radius 10 mm) was obtained.
  • Comparative Example 1 a 120 mg preparation (preparation not using the particles of the present invention) was prepared in the same manner as in Example 5 except that lactose was used in place of the particles A.
  • Table 7 shows the composition of Example 5 and Comparative Example 1.
  • Example 5 For Example 5 and Comparative Example 1, the dissolution rate (%) was calculated according to the following items. The results are shown in Table 8 below.
  • Example 6 Comparative Example 2
  • the particle C prepared in Example 3 and the following materials were prepared, and a mixture obtained by stirring and mixing these materials was treated in the same manner as in Example 5 to prepare a 120 mg preparation (diameter 7 mm, curvature radius 10 mm).
  • Example 6 was obtained.
  • Comparative Example 2 a 120 mg preparation (preparation not using the particles of the present invention) was prepared in the same manner as in Example 6 except that lactose was used in place of the particles C.
  • Table 9 shows the formulation of Example 6 and Comparative Example 2.
  • Example 6 the elution rate (%) after t minutes from the start of the test was calculated according to the above items as in Example 5 and Comparative Example 1. The results are shown in Table 10 below.
  • Example 7 Comparative Example 3
  • the particles D prepared in Example 4 and the following materials were prepared, and a mixture obtained by stirring and mixing these materials was compressed at 8 kN using a tableting machine (manufactured by Ichihashi Seiki Co., Ltd., HANDTAB-100).
  • Example 7 was obtained which was a 200 mg formulation (diameter 8 mm, curvature radius 12 mm).
  • Comparative Example 3 a 200 mg preparation (preparation not using the particles of the present invention) was prepared in the same manner as in Example 7 except that lactose was used in place of the particles D. Table 11 below shows the formulation of Example 7 and Comparative Example 3.
  • the addition of only 10% by weight of the particles D with respect to the entire mixture can confirm an increase in the dissolution rate of about 2 times from the time point 5 minutes after the start of the test to the time point 40 minutes later. It was. From this, it was found that the particle D has a function as an additive for a fast dissolving / disintegrating tablet.
  • Example 7 Further, with respect to Example 7 and Comparative Example 3, hardness and disintegration time were measured according to the following items. The results are shown in Table 13 below.
  • the disintegration time (disintegration) was measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd., NT-200) according to the 16th revised Japanese Pharmacopoeia disintegration test method. In the above test, 1000 mL of purified water was used as a test solution, and the measurement temperature was 37 ⁇ 2 ° C. The time required for the preparation to disintegrate and disperse in the test solution was taken as the disintegration time.
  • Example 7 had higher hardness than Comparative Example 3. However, although Example 7 has high hardness, the time until the preparation collapses is shorter than that of Comparative Example 3. That is, it has been found that the use of the particles of the present invention in a preparation can be an extremely superior additive that controls properties such as hardness, disintegration, and drug dissolution.
  • the particles of the present invention are suitable as additives for preparations such as pharmaceuticals, foods and cosmetics.

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WO2019156174A1 (ja) * 2018-02-09 2019-08-15 合同会社レビアスファーマ 粒子、粒子含有組成物および粒子の製造方法
WO2019189795A1 (ja) * 2018-03-30 2019-10-03 合同会社レビアスファーマ 酵母由来の微細な粒子の製造方法
JP2022507710A (ja) * 2018-11-15 2022-01-18 プシグリフ インク． 植物組織由来ナノ粒子及び食物粉末
WO2022045371A1 (ja) * 2020-08-31 2022-03-03 合同会社レビアスファーマ 組成物およびその組成物の製造方法、脂溶性成分の吸収性を向上させる方法、脂溶性成分の抽出効率を向上させる方法、脂溶性成分
WO2023210722A1 (ja) * 2022-04-28 2023-11-02 学校法人帝京大学 免疫機能活性化剤、ワクチンアジュバントおよび免疫誘導方法

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JP2002539147A (ja) * 1999-03-12 2002-11-19 バイオテク エイエスエイ ナノスカラー水溶性β−（１，３）グルカンの使用
WO2002087603A1 (fr) * 2001-04-27 2002-11-07 Ajinomoto Co., Inc. Immunostimulants
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019156174A1 (ja) * 2018-02-09 2019-08-15 合同会社レビアスファーマ 粒子、粒子含有組成物および粒子の製造方法
WO2019189795A1 (ja) * 2018-03-30 2019-10-03 合同会社レビアスファーマ 酵母由来の微細な粒子の製造方法
JP2022507710A (ja) * 2018-11-15 2022-01-18 プシグリフ インク． 植物組織由来ナノ粒子及び食物粉末
WO2022045371A1 (ja) * 2020-08-31 2022-03-03 合同会社レビアスファーマ 組成物およびその組成物の製造方法、脂溶性成分の吸収性を向上させる方法、脂溶性成分の抽出効率を向上させる方法、脂溶性成分
WO2023210722A1 (ja) * 2022-04-28 2023-11-02 学校法人帝京大学 免疫機能活性化剤、ワクチンアジュバントおよび免疫誘導方法

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