WO2010095494A1 - Granules contenant une substance peu soluble, comprimé et procédé de solubilisation d'une substance peu soluble - Google Patents

Granules contenant une substance peu soluble, comprimé et procédé de solubilisation d'une substance peu soluble Download PDF

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Publication number
WO2010095494A1
WO2010095494A1 PCT/JP2010/051076 JP2010051076W WO2010095494A1 WO 2010095494 A1 WO2010095494 A1 WO 2010095494A1 JP 2010051076 W JP2010051076 W JP 2010051076W WO 2010095494 A1 WO2010095494 A1 WO 2010095494A1
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functional substance
carrier
nonionic surfactant
granule
weight
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PCT/JP2010/051076
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English (en)
Japanese (ja)
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静男 齊藤
和幸 石川
伸明 平井
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アサヒビール株式会社
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Publication of WO2010095494A1 publication Critical patent/WO2010095494A1/fr

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to granules and tablets and methods for producing them, and more particularly to granules and tablets containing a hardly soluble substance as a functional substance and methods for producing them.
  • compositions for taking functional substances which are active ingredients of pharmaceuticals and health foods, include powders, granules, capsules and tablets. Of these, tablets are the most commonly used because they are easy to handle and take.
  • tablets are granulated by adding water and / or an organic solvent to a mixed powder containing a functional substance, an excipient, and an optional component of a binder. Or synthetic or naturally-occurring polymer additives) and lubricants to make granules for tableting.
  • This granule is quantified from a hopper (a container containing the granules for tableting) onto the rotary table of the tableting machine. It is produced by compressing the granulated granules in a hole (mortar) formed in a rotating disk with two sets of upper and lower steel bars (upper and lower irons).
  • the functional substance Since tablets are compressed and shaped in this way, if the functional substance is an oily liquid or a low-melting-point solid in a normal temperature environment, if the functional substance is an oily liquid, it can be molded into a tablet as it is. It is difficult to cause tableting troubles such as sticking and capping when it is a low melting point solid. Therefore, when the functional substance has such a property, a process for converting the form into a solid or powder is performed.
  • Patent Document 1 a liquid drug dissolved in a non-volatile solvent is simply mixed with a pre-calculated amount of a carrier substance such as crystalline cellulose and a coating substance such as light anhydrous silicic acid, A method for providing a compressible liquid / powder mixture (Liquisolid) is described.
  • this liquid solid has a small amount of liquid that can be carried and the liquid drug content is insufficient.
  • Patent Document 2 describes a liquid solid system using calcium silicate as a carrier for adsorbing and powdering a functional substance which is an oily liquid or a low melting point solid, and using starches or sugars as a binder. By doing so, the loose bulk density of the powder obtained was appropriately adjusted, and it became possible to make a thick tablet with a tableting machine. As a result, an appropriate diameter and thickness that can withstand actual use and an appropriate weight can be imparted to a tablet using calcium silicate as a carrier.
  • Calcium silicate can carry a relatively large amount of liquid, and a tablet using calcium silicate as a carrier can contain a functional substance such as a liquid drug at a high concentration.
  • a functional substance such as a liquid drug at a high concentration.
  • it is required to improve the dissolution of the functional substance from the preparation into water and the transferability to the digestive fluid.
  • Patent Document 3 describes a technique for increasing the absorbability of fat-soluble or water-soluble difficult / low-absorbable drugs in the body.
  • a surfactant that exhibits an absorption improving action in the body is solidified by using a porous adsorbent, and this is combined with a difficult / low absorbable drug to form a solid preparation.
  • Patent Document 3 is a technique for increasing the absorbability of a drug in a living body by the effect of a surfactant, and does not describe the solubility of a poorly soluble drug in water.
  • the effect of the surfactant to increase the passage of the drug through the biological membrane does not necessarily mean to increase the solubility in water. This is because surfactants often affect the interaction with biological membranes, and the mechanism of action is not necessarily the same. Therefore, it can be said that the technique described in Patent Document 3 is basically an invention in a region different from the technique described in the present invention.
  • the present invention solves the above-mentioned conventional problems, and the object of the present invention is to absorb a large amount of a poorly soluble functional substance and solidify it, while the functional substance is soluble in water. It is to provide a novel granule excellent in the above.
  • the present invention is a granule comprising a carrier containing porous calcium silicate, a functional substance adsorbed on the carrier and a nonionic surfactant, and a binder,
  • the functional substance provides a granule that is at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid, and a herbal extract containing a sparingly soluble active ingredient. Is achieved.
  • the carrier further contains cellulose.
  • the functional substance is at least one selected from the group consisting of vitamin E, coenzyme Q10, docosahexaenoic acid, eicosapentaenoic acid, lipoic acid, lutein, saw palmetto extract, ginkgo biloba extract, St. John's wort and royal jelly. It is.
  • the said nonionic surfactant corresponds to a food additive or a pharmaceutical additive, and contains the compound which has a polyether chain as a hydrophilic part.
  • the nonionic surfactant contains at least one selected from the group consisting of polysorbates and polyoxyethylene hydrogenated castor oil.
  • the nonionic surfactant further contains at least one selected from the group consisting of a sucrose fatty acid ester and a polyglycerol fatty acid ester.
  • the surfactant is a mixture of polysorbates and polyoxyethylene hydrogenated castor oil in a ratio of 1: 1 to 1: 3, or polysorbates and sucrose fatty acid esters in a ratio of 1: 1 to 1. : 3 or a mixture of polysorbates and polyglycerol fatty acid esters in a ratio of 1: 1 to 1: 3.
  • the surfactant is blended in an amount of 20 to 1000 parts by weight with respect to 100 parts by weight of the functional substance.
  • the binder is at least one selected from the group consisting of sugars and sugar alcohols.
  • the carrier is blended in an amount of 50 to 400 parts by weight with respect to 100 parts by weight of the functional substance
  • the binder is blended in an amount of 50 to 1500 parts by weight with respect to 100 parts by weight of the carrier
  • the loose bulk density is 0.20 to 0.80 g / ml.
  • the present invention provides a functional substance and a nonionic surfactant that are at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid and a herbal extract containing a sparingly soluble active ingredient.
  • the functional substance and the nonionic surfactant are adsorbed to the carrier by dissolving or dispersing the functional substance and the nonionic surfactant in ethanol to lower the viscosity, and mixing with the carrier. By evaporating the ethanol.
  • the present invention also provides a method for producing a tablet comprising the step of tableting any of the granules described above.
  • the present invention also provides a tablet obtained by the above method.
  • the present invention provides a functional substance that is at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid and a sparingly active active ingredient, together with a nonionic surfactant, Adsorbing to a carrier containing porous calcium silicate; and eluting the functional substance in water;
  • a method for solubilizing a hardly soluble substance including
  • the granule of the present invention is excellent in water elution even if the solidified functional substance is hardly soluble. Therefore, this problem can be solved by using the granule according to the present invention even if it is a functional substance that is hardly transferred to the digestive juice.
  • the granule of the present invention comprises a carrier, a functional substance, a nonionic surfactant, and a binder. At least the functional substance and the nonionic surfactant are adsorbed on the carrier.
  • the carrier is a solid substance that can be solidified by supporting a liquid.
  • fine powders and porous materials excellent in chemical stability are used as the carrier.
  • inorganic substances such as silicic acids and celluloses are widely known.
  • porous calcium silicate has an average particle size of 18 to 32 ⁇ m, a loose bulk density of 0.07 to 0.15 g / ml, and an oil absorption of 300 to 550 ml / 100 g.
  • Calcium silicate powder having such characteristics is represented by the formula
  • a gyrolite-type calcium silicate powder having a petal-like crystal structure as observed with an electron microscope.
  • Flowlight of Tokuyama Corporation.
  • the carrier is blended at a ratio of preferably 20 to 200 parts by weight, more preferably 50 to 150 parts by weight with respect to 100 parts by weight of the functional substance.
  • the amount of the carrier is less than 20 parts by weight, the functional substance is likely to be leached from the carrier, and problems such as capping and sticking when tablets are compressed, insufficient hardness of the tablet, and poor appearance occur.
  • the amount of the carrier exceeds 200 parts by weight, it can be made into a tablet, but the content of the active ingredient is reduced, resulting in a large tablet that is difficult to drink.
  • the carrier it is preferable to use a non-porous substance such as crystalline cellulose in addition to porous calcium silicate. This is because the poorly soluble substance held in the porous part has poor water penetration and is difficult to elute, which can avoid this problem.
  • the amount of the non-porous substance used is up to 50% by weight, preferably up to 40% by weight of the whole carrier. If the amount of crystalline cellulose used exceeds 60% by weight, the amount of liquid that can be supported decreases, and subsequent granulation becomes difficult.
  • non-porous substance examples include crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose / light silicic acid anhydride, and the like.
  • the preferred non-porous material is crystalline cellulose.
  • “Functional substance” refers to a substance that exhibits the desired action in the body after ingestion into the human body, and is a concept that includes active ingredients in medicines and health foods.
  • the functional substance is not limited as long as it can be adsorbed to the carrier by any method, but preferred functional substances are herbal medicines containing a hardly soluble liquid, a low melting point and hardly soluble solid and a hardly soluble active ingredient. It is at least one selected from the group consisting of extracts. This is because a hardly soluble functional substance is inherently difficult to dissolve in digestive fluid and is poorly absorbed in the body.
  • the liquid refers to a substance that exhibits fluidity at room temperature (20 ° C.), and the solid refers to a substance that does not exhibit fluidity at room temperature.
  • the low melting point means that the melting point is 100 to 120 ° C. or less.
  • hardly soluble liquids include vitamin A, vitamin A derivatives, vitamin E, docosahexaenoic acid, eicosapentaenoic acid and the like.
  • a hardly soluble liquid derived from a natural product is a substance extracted from a natural product, and generically refers to an oily extract mainly composed of fat-soluble components.
  • a specific example of a hardly soluble liquid derived from a natural product is a saw palmetto extract.
  • low melting point solids often cause sticking, so it is difficult to compress them into tablets in the same way as hardly soluble liquids. Therefore, a low melting point solid is also useful as the functional substance of the present invention. Specific examples of the low melting point solid include coenzyme Q10, ⁇ lipoic acid, ribose and the like.
  • Particularly preferred poorly soluble functional substances for use in combination with porous calcium silicate and nonionic surfactant include, for example, vitamin E, coenzyme Q10, docosahexaenoic acid, eicosapentaenoic acid, lipoic acid, lutein, saw palmetto extract, It is at least one selected from the group consisting of ginkgo biloba extract, St. John's wort and royal jelly.
  • the nonionic surfactant is preferably a compound having a polyether moiety such as a polyoxyethylene chain and a polyoxypropylene chain as the hydrophilic portion. This is because the nonionic surfactant having a polyether chain as the hydrophilic portion improves the dissolution property of the solidified hardly soluble substance in an aqueous environment. Moreover, what corresponds to a food additive or a pharmaceutical additive is preferable so that a nonionic surfactant may not have a bad influence on a human body.
  • Preferred nonionic surfactants include, for example, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene polyoxypropylene glycol, and polysorbates.
  • particularly preferred nonionic surfactants are polysorbate 80 and polyoxyethylene hydrogenated castor oil.
  • fatty acid esters may be used as nonionic surfactants. This is because a synergistic effect between those having a polyether chain and those having a fatty acid ester can be expected. In that case, the amount of the fatty acid ester used is 90% by weight, preferably 80% by weight of the entire nonionic surfactant. When the usage-amount of fatty acid ester exceeds 90 weight%, a synergistic effect with what has a polyether chain will become weak.
  • fatty acid esters include sucrose fatty acid esters and polyglycerin fatty acid esters.
  • the nonionic surfactant is blended at a ratio of 20 to 1000 parts by weight, preferably 50 to 600 parts by weight, more preferably 200 to 500 parts by weight with respect to 100 parts by weight of the functional substance.
  • the amount of the nonionic surfactant is less than 20 parts by weight, the functional substance is hardly eluted from the carrier in an aqueous environment.
  • the amount of the nonionic surfactant exceeds 1000 parts by weight, the amount of the functional substance to be blended becomes small, so that the intake quantity increases and becomes impractical.
  • the binder is a component used to bind the carrier particles into granules. From the standpoint of elution as in the present invention, the types of binders preferred for use are limited to some extent.
  • a preferred binder is a saccharide.
  • calcium silicate when only calcium silicate is used as a carrier, calcium silicate is light and difficult to granulate, but by adding saccharides and granulating in this way, appropriate loose bulk density, particle size Granules with a distribution can be obtained.
  • saccharide a known saccharide can be used without limitation, and may be a sugar alcohol obtained by hydrogenating these saccharides, such as glucose and malt-strehalose.
  • sugar alcohol is used.
  • any of sorbitol, erythritol, xylitol and maltitol can be used.
  • the amount of binder used is not particularly limited. If the amount used is too small, the granule becomes light. It is difficult to produce a granule, and it is not practical.
  • the binder is blended in a ratio of 20 to 500 parts by weight, preferably 30 to 300 parts by weight, more preferably 50 to 200 parts by weight with respect to 100 parts by weight of the carrier. When the amount of the binder is less than 20 parts by weight, the loose bulk density of the granules becomes too small, and the tablet is difficult to be meat pressure. When the amount of the binder exceeds 500 parts by weight, the amount of the functional substance that can be blended becomes small, and the concentration of the functional substance contained in the tablet becomes too low.
  • the granule of the present invention may contain additives such as a lubricant and a disintegrant as required in addition to the carrier, the functional substance, the nonionic surfactant and the binder.
  • additives such as a lubricant and a disintegrant as required in addition to the carrier, the functional substance, the nonionic surfactant and the binder.
  • low-substituted hydroxypropylcellulose, carmellose, Carboxymethyl starch sodium, crospovidone, croscarmellose sodium, starch, agar and the like may be added.
  • the content of the functional substance is 10 to 50% by weight, preferably 25 to 35% by weight, which greatly increases the content of the functional substance. be able to.
  • the granules of the present invention have a loose bulk density of 0.20 to 0.80 g / ml, preferably 0.30 to 0.60 g / ml.
  • a tablet having an appropriate diameter and thickness and an appropriate weight can be obtained using an ordinary tableting machine. That is, if the granule of the present invention is used, a tablet having a shape and size that is practically sufficient in strength and convenient for handling can be provided.
  • the granules of the present invention may be coated with a water-soluble polymer as necessary.
  • a water-soluble polymer By applying the coating, it is possible to reduce the odor and taste derived from the water-soluble antioxidant component. In addition, the dosage and moisture resistance of the granules are improved.
  • the method and the raw material to be used are not limited. Examples of water-soluble polymers generally include hydroxypropyl methylcellulose.
  • the functional substance-containing liquid is converted into a hardly soluble liquid or a low melting point solid by a conventional method or a method described in JP-A No. 2001-97858, JP-A No. 2007-15970 or JP-A No. 6-32774. Prepare by dissolving or dispersing.
  • Adsorption and loading of a functional substance on a carrier is performed by dissolving or dispersing the functional substance in a solvent, if necessary, to lower the viscosity, mixing with the carrier, granulating with a binder, and then drying. To do.
  • the functional material after granulation is held tightly in the pores of the carrier, and at the time of tableting, the functional material does not exude to the granule surface, the compression moldability is improved, the hardness is reduced, A capping or sticking phenomenon is suppressed.
  • ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Ethanol is preferred as the organic solvent used to lower the viscosity of the functional substance. This is because safety is high.
  • the organic solvent in which the functional substance is dissolved or dispersed and the carrier are usually mixed under stirring using a mixer or a stirring granulator used in the granulation step described later.
  • the amount of the organic solvent in which the functional substance is dissolved or dispersed is sufficient if it dissolves or disperses the functional substance to be dissolved to reduce the viscosity. If the amount of the organic solvent is too small, the functional substance will not be adsorbed uniformly, and if it is too large, the supported material will be wetted.
  • Adsorption and loading of the nonionic surfactant on the carrier is performed by adding a nonionic surfactant and a functional substance dissolved in ethanol to the carrier and stirring and mixing. Moreover, you may heat as needed, when melt
  • the granulation and granulation of the obtained support are performed.
  • the granulation of the support is performed by a usual method using a binder and water.
  • Granulation is preferably performed by stirring granulation. This is because a strong stirring force is required for the interaction between the surfactant and the functional substance, and granules with a higher bulk density can be obtained.
  • Agitation granulation has various forms, and there are one using a rotating arm at the top of the container, one using a rotary blade at the bottom of the container, and one obtained by adding stirring in a different direction.
  • Examples of the apparatus used for granulation include a vertical granulator, a high shear mixer, a high speed mixer, a planetary mixer, a collet granal granulator, and a chopper type planetary mixer.
  • a vertical granulator a high shear mixer, a high speed mixer, a planetary mixer, a collet granal granulator, and a chopper type planetary mixer.
  • any device capable of appropriately mixing powders may be used, and the stronger the stirring force, the faster the granulation proceeds.
  • the granules thus obtained are dried to remove the contained water and organic solvent.
  • the drying temperature is 20 to 90 ° C, preferably 25 to 75 ° C, more preferably 30 to 60 ° C.
  • the dried granule is sized, added with a polymer additive, a disintegrant and a lubricant to give granules for tableting, and compressed into tablets.
  • a polymer additive those generally used for making granules and tablets can be used. Specific examples include celluloses such as crystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; synthetic polymers such as polyvinylpyrrolidone; and natural polymers such as gum arabic, agar, and pullulan.
  • Polymer additives are used alone or in combination of two or more, but it is desirable to use them separately in excipients, binders and disintegrants according to their applications.
  • the tablets produced as described above may be appropriately provided with a coating process for applying film coating or sugar coating.
  • the tableting granules for production are made into tablets using a tableting machine.
  • the method of making the granule for tableting into a tablet is the same as that of the past, the description is abbreviate
  • the functional substance adsorbed on the carrier is brought into contact with water.
  • the water is not limited to pure water and may be a liquid containing water.
  • a body fluid such as digestive fluid is included in the water here.
  • the temperature of water can be appropriately adjusted according to the type of functional substance, but is generally about 15 to 25 ° C.
  • the adsorbed functional substance comes into contact with water.
  • the adsorbed functional substance comes into contact with water.
  • Examples 1 to 21 and Comparative Examples 1 to 3 Step 1 A volatile solvent such as ethanol and a nonionic surfactant such as polysorbate were mixed using a stirrer. While stirring, functional substances such as vitamin E, coenzyme Q10 or herbal extract were gradually added, and stirred sufficiently to dissolve or disperse uniformly.
  • coenzyme Q10 does not dissolve at room temperature, it was dissolved by raising the temperature to around 45 ° C.
  • a crude drug extract since it contains substances insoluble in ethanol, it is difficult to dissolve 100%, but the temperature was raised to around 50 ° C., and it was dispersed and partially dissolved over time.
  • a non-volatile solvent such as glycerin was used in combination, it was added and mixed here.
  • Step 2 On the other hand, the amount of florite used was charged into a vertical granulator (granulator, manufactured by Paulex Co., Ltd.). When using crystalline cellulose together, it was put together and mixed well using the mixing function of the vertical granulator.
  • a vertical granulator granulator, manufactured by Paulex Co., Ltd.
  • Step 3 The liquid produced in Step 1 was charged into florite (or mixed powder of fluorite and crystalline cellulose), stirred using the mixing function of a vertical granulator, and uniformly adsorbed.
  • Step 4 A predetermined amount of water was added to the adsorbed powder.
  • Step 5 sugar alcohol was added and granulation was started.
  • Some crude herbal extracts contain ingredients that are necessary for granulation, so some sugar alcohols do not need to be added at this stage. However, granulation is essential.
  • Step 6 Drying was performed using a fluidized bed. Ethanol was completely removed at this stage.
  • Step 7 To the obtained granules, 5 parts by weight of agar and 1 part by weight of sucrose fatty acid ester are added to obtain granules for tableting, and tableting is performed using a tableting machine (manufactured by Hata Ironworks Co., Ltd., model number: HT-AP12SS-U). A tablet was obtained.
  • a tableting machine manufactured by Hata Ironworks Co., Ltd., model number: HT-AP12SS-U.
  • Step 8 About the obtained tablet, the dissolution property of the functional substance in water was tested. That is, first, a tablet corresponding to a single intake of a functional substance was used for the test. For the dissolution test, the test method listed in the Japanese Pharmacopoeia was used. The test was performed by the paddle method, and the paddle was rotated at a speed of 50 revolutions per minute, and the active ingredient eluted from the tablet into water was measured by the liquid chromatography method.
  • Table 1 shows the sources of materials used in each example.
  • Table 2 shows the types and amounts of materials used and the results of the dissolution test.
  • Comparative Example 4 A commercially available St. John's wort tablet (“Sato St. John's wort” manufactured by Sato Pharmaceutical Co., Ltd.) was obtained, and a functional substance dissolution test in water was performed in the same manner as in the above Examples. The elution of hyperforin, an active ingredient of St. John's Wort Extract, was evaluated. The results are shown in Table 2.
  • Comparative Example 5 A commercially available soft capsule of saw palmetto extract (“Nature's Resource Saw Palmetto” manufactured by Otsuka Pharmaceutical Co., Ltd.) was obtained, and a functional substance dissolution test in water was performed in the same manner as in the above Examples. Since no specific active ingredient is determined for saw palmetto, the component dissolved in the eluate was subjected to pattern analysis, and the elution was evaluated based on the total area of the obtained peaks. The results are shown in Table 2.
  • the tablets of the examples were superior to those of the comparative examples in the dissolution of functional substances except for a part.
  • the formulation of Example 14 did not contain a solvent component, and the expected dissolution property was not obtained.
  • Example 14 It should be noted that the necessity of a solvent such as ethanol or ester, its preferred type and appropriate amount vary depending on the type of functional substance used. Therefore, the above-mentioned result that the expected dissolution property was not obtained in Example 14 does not indicate that the formulation containing no solvent is generally inappropriate for functional substances other than Coenzyme Q10. .

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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne de nouveaux granules capables d'adsorber et de solidifier une quantité importante d'une substance fonctionnelle peu soluble, et présentant d'excellentes propriétés de libération de ladite substance fonctionnelle dans un environnement aqueux. L'invention concerne en particulier des granules, chaque granule comprenant un support qui contient un silicate de calcium poreux, une substance fonctionnelle et un tensioactif non ionique adsorbés sur le support, et un agent de liaison. Les granules sont caractérisées en ce que la substance fonctionnelle est composée d'au moins une substance sélectionnée dans un groupe comprenant des liquides peu solubles, des solides peu solubles présentant un point de fusion bas et des extraits de médicaments bruts contenant un ingrédient actif peu soluble.
PCT/JP2010/051076 2009-02-19 2010-01-28 Granules contenant une substance peu soluble, comprimé et procédé de solubilisation d'une substance peu soluble WO2010095494A1 (fr)

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JP2009036785A JP2010189337A (ja) 2009-02-19 2009-02-19 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法
JP2009-036785 2009-02-19

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US9427402B2 (en) 2010-09-30 2016-08-30 Shionogi & Co. Ltd. Preparation for improving solubility of poorly soluble drug
WO2020218518A1 (fr) * 2019-04-25 2020-10-29 富士製薬工業株式会社 Préparation pharmaceutique et sa méthode de production
WO2020218517A1 (fr) * 2019-04-25 2020-10-29 富士製薬工業株式会社 Préparation médicinale et son procédé de fabrication

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CA2762939C (fr) * 2009-05-22 2017-07-18 Mochida Phamaceutical Co., Ltd. Composition auto-emulsifiante d'acide gras .omega.3
JP6344678B2 (ja) * 2013-09-27 2018-06-20 キョーリンリメディオ株式会社 テルミサルタン含有製剤及びその製造方法
KR101617119B1 (ko) * 2015-01-06 2016-05-03 아주대학교산학협력단 셀레콕시브를 포함하는 경구용 정제의 제조방법
KR20200004178A (ko) * 2018-07-03 2020-01-13 한국유나이티드제약 주식회사 펠라고니움 시도이데스 추출물을 포함하는 약학 조성물 및 이의 제조방법
KR102381839B1 (ko) * 2020-01-13 2022-04-04 한국유나이티드제약 주식회사 R-치옥트산 또는 이의 약학적으로 허용되는 염 및 유화제를 포함하는 약학조성물

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US9427402B2 (en) 2010-09-30 2016-08-30 Shionogi & Co. Ltd. Preparation for improving solubility of poorly soluble drug
WO2020218518A1 (fr) * 2019-04-25 2020-10-29 富士製薬工業株式会社 Préparation pharmaceutique et sa méthode de production
JPWO2020218518A1 (fr) * 2019-04-25 2020-10-29
WO2020218517A1 (fr) * 2019-04-25 2020-10-29 富士製薬工業株式会社 Préparation médicinale et son procédé de fabrication
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CN114126590B (zh) * 2019-04-25 2024-01-05 富士制药工业股份有限公司 医药制剂及其制造方法

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