WO2009128543A1 - Process for producing silica-containing tablet, tablet, and composite particle for tablet - Google Patents

Process for producing silica-containing tablet, tablet, and composite particle for tablet Download PDF

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Publication number
WO2009128543A1
WO2009128543A1 PCT/JP2009/057792 JP2009057792W WO2009128543A1 WO 2009128543 A1 WO2009128543 A1 WO 2009128543A1 JP 2009057792 W JP2009057792 W JP 2009057792W WO 2009128543 A1 WO2009128543 A1 WO 2009128543A1
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Prior art keywords
tablet
silica
drug
tablets
excipient
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PCT/JP2009/057792
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French (fr)
Japanese (ja)
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洋文 竹内
洋平 帆足
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ニプロ株式会社
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Priority to JP2010508265A priority Critical patent/JPWO2009128543A1/en
Publication of WO2009128543A1 publication Critical patent/WO2009128543A1/en

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    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/10—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic in stationary drums or troughs, provided with kneading or mixing appliances

Definitions

  • the present invention relates to a method for producing a tablet containing silica. Furthermore, the present invention extends to tablet-containing composite particles for producing tablets, and tablets containing silica produced by the production method.
  • Patent Document 1 discloses that the drug elution can be improved by blending silica as a dispersant.
  • the problem of the tablet of Patent Document 1 is that the hardness of the tablet to be produced is low.
  • Patent Document 2 solves the problem of Patent Document 1 by manufacturing including a step of previously combining silica and one or more components other than silica to form composite particles.
  • a technique is disclosed in which the hardness of a manufactured tablet is improved by combining an excipient with silica.
  • the compounding in Patent Document 1 is mainly performed by a spray drying method.
  • the spray drying method is a method of producing by spraying a liquid in which silica or one or more components other than silica are dissolved or dispersed in some solvent.
  • a liquid in which silica or one or more components other than silica are dissolved or dispersed in some solvent when compositing silica, (1) prepare a solution in which one or more components other than silica and silica are dissolved or dispersed in some solvent, and (2) dry the solvent in the solution sprayed with silica. 2 steps are performed. For this reason, there are many problems in that the number of manufacturing steps for complexing silica is high and the manufacturing cost is high.
  • the solvent used is not water but an organic solvent.
  • further problems such as toxicity problems due to the remaining organic solvent and environmental load may be caused.
  • An object of the present invention is to provide a method for producing a tablet containing silica containing silica that is simple and inexpensive to produce.
  • the solution to the problem in the prior art of the present invention is the following tablet manufacturing method.
  • the production method of the present invention includes [1] a step of obtaining composite particles for tablets by kneading silica and a melted drug or an excipient other than silica and returning to normal temperature.
  • the number of manufacturing steps for compounding silica is only one.
  • Silica refers to an inorganic compound called silicon dioxide under the IUPAC name and also called quartz or silicic anhydride.
  • the shape of the silica used in the production method of the present invention is preferably a powder or a particle having a particle diameter smaller than that of the powder.
  • the quality of the silica is preferably a pharmaceutical additive standard compliant grade. Examples of such silica include Cylicia (registered trademark) series manufactured by Fuji Silysia Chemical Ltd. and Aerosil (registered trademark) manufactured by Degussa.
  • Silica is preferably porous from the viewpoint of easy compounding. Examples of the commercially available porous silica include Silicia (registered trademark) series manufactured by Fuji Silysia Chemical Ltd.
  • the tablet component kneaded with silica is a drug or an excipient.
  • silica and a drug are kneaded, the dissolution property of the drug in the manufactured tablet is improved.
  • fillers other than a silica the hardness of the manufactured tablet improves. That is, those skilled in the art can determine the tablet components to be kneaded with silica according to the drug or excipient used.
  • the drug may be a compound that can be formulated into a tablet, and is not particularly limited as long as it is an individual at room temperature.
  • examples of such drugs include indomethacin, fenofibrate, acetaminophen, famotidine, cimetidine, ranitidine hydrochloride, roxatidine acetate, nizatidine, lafutidine, omeprazole, omeprazole sodium, lansoprazole, rabeprazole sodium, pirenzepine hydrochloride, proglumide , Ugastron, phenytoin, phenobarbital, phenobarbital sodium, primidone, sodium valproate, carbamazepine, trimethadione, Zomig, granisetron hydrochloride, azesetron hydrochloride, ondasetron hydrochloride, ramosetron hydrochloride, tropisetron hydrochloride, triazolam
  • Excipients other than silica refer to tablet components other than silica that are added so as to be an appropriate amount for handling as a tablet when the effective amount of the drug in the tablet is small, and refers to those having no physiological activity.
  • Excipients other than silica may be any compound that can be formulated into tablets, and are not particularly limited as long as they are solid at room temperature. Examples of such excipients include sugar alcohols such as mannitol, erythritol, sorbitol, xylitol, trehalose, maltitol and lactitol, and crystalline cellulose, powdered cellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and ethylcellulose. And the like.
  • the silica described above corresponds to a so-called excipient, but an excipient other than silica is added to improve tablet hardness in the tablet produced as described above.
  • the above-mentioned drugs or excipients other than silica are kneaded with silica in a melted or crystal hydrated state.
  • the temperature condition for melting it is desirable to be near the melting point.
  • the drug when it is indomethacin, it may be around 155 degrees, and when the drug is fenofibrate, it may be around 80 degrees.
  • the excipient when the excipient is mannitol, it may be around 166 degrees, when the excipient is erythritol, around 121.5 degrees, and when the excipient is trehalose, it may be around 97 degrees.
  • the temperature condition in the kneading may be slightly lower than the melting point of the excipient other than the drug or silica. If this temperature condition is expressed qualitatively, it means a condition equal to or higher than the temperature at which the endotherm attributed to the melting point in differential scanning calorimetry (DSC) of excipients other than drugs or silica begins.
  • DSC differential scanning calorimetry
  • crystal hydration is a case where excipients other than the drug or silica have water of crystallization, and the excipient other than drug or silica dissolves in the crystal water as the temperature rises.
  • Crystal hydration is preferably in a state where all of the excipients other than the drug or silica are dissolved in water of crystallization, but a partially dissolved state is also included in the crystal hydration in the present invention.
  • the temperature condition in crystal hydration is expressed qualitatively, it means a condition equal to or higher than the temperature at which the endotherm attributed to the melting point of crystal water in differential scanning calorimetry (DSC) starts.
  • DSC differential scanning calorimetry
  • Kneading is performed, for example, by a method according to the stirring granulation method, rolling granulation method, and extrusion granulation method.
  • An excipient other than the drug or silica is melted or crystal hydrated and kneaded.
  • the method according to the stirring granulation method, the rolling granulation method and the extrusion granulation method is a granulation apparatus that enables these granulation methods, as long as it has a mechanism capable of heating the apparatus. It is not limited.
  • the silica and the drug or excipients other than silica are granulated by returning to normal temperature.
  • the granulated silica and drug or excipient other than silica are combined with silica as a base material with the drug or excipient other than silica adsorbed around the silica.
  • the granulated particles are referred to as “composite particles for tablets”.
  • poorly water-soluble drug examples include indomethacin and fenofibrate.
  • poorly water-soluble in the present invention refers to a drug having a solubility in water of 1 mg / mL or less.
  • the remaining of the organic solvent in the tablet does not become a problem, which is why a poorly water-soluble drug is mentioned as a desirable drug. .
  • sugar alcohol is preferable from the viewpoint of being a low-molding excipient and applicable to orally disintegrating tablets, and mannitol, erythritol, and trehalose are more preferable.
  • the apparatus for the agitation granulation method is preferable from the viewpoint that the apparatus is small.
  • mixer-type devices and screw-type devices for the stirring granulation method.
  • the former apparatus include a Pugmill mixer, a Henschel mixer, and an Eirich (registered trademark) mixer.
  • the latter device include a uniaxial device and a biaxial device.
  • a screw type biaxial one (biaxial kneader) is preferable.
  • the biaxial kneader include the KRC (registered trademark) series manufactured by Kurimoto Steel Works.
  • the kneading time is not particularly limited because it depends on the size of the apparatus, but it is about 1 to 10 minutes.
  • the present invention also extends to composite particles for tablets produced by kneading [6] silica with a melted or crystal hydrated drug or an excipient other than silica and returning to normal temperature.
  • the steps up to obtaining composite particles for tablets are as described above.
  • This composite particle for tablets can be used as a tablet component for producing a tablet.
  • the present invention provides [7] silica, a melted or crystal hydrated drug, or an excipient other than silica to knead to obtain composite particles for tablets, and the composite particles for tablets and other tablet components It extends to tablets produced by mixing and tableting. The steps up to obtaining composite particles for tablets are as described above.
  • the manufacture of a tablet using the above-described composite particle for tablets is easily performed by mixing the composite particles for tablet and other tablet components, and tableting.
  • tablet components include excipients, disintegrants, binders, solubilizers, lubricants, fragrances, foaming agents, surfactants, pH adjusters, preservatives, and coloring agents.
  • the present invention is not limited by the types of these additives.
  • Such other tablet components are appropriately selected by those skilled in the art as long as they do not affect the drug efficacy of the active ingredient.
  • the disintegrant is preferably used.
  • excipients are no different from those combined with silica described above. It should be noted that the excipients as other tablet components mentioned here are used even when the excipient is used as a composite with the above-mentioned silica. It means you may do it. The excipient as the other tablet component may be the same or different from the excipient complexed with the silica described above.
  • Disintegrants include, for example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, synthetic aluminum silicate, low substituted hydroxy
  • examples include propylcellulose, croscarmellose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose and hydroxypropyl starch. The present invention is not limited to the types of these disintegrants.
  • binders examples include gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, pullulan, and partially pregelatinized.
  • examples include starch and saccharides. The present invention is not limited to these binder types.
  • solubilizer examples include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, and sodium hydrogen carbonate.
  • the present invention is not limited to these types of solubilizers.
  • lubricants examples include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated rapeseed oil, hydrogenated castor oil, glycerin fatty acid ester, sodium stearyl fumarate, benzoic acid Examples include sodium acid, L-leucine and L-valine. The present invention is not limited to these types of lubricants.
  • fragrances include mint, lemon and orange.
  • the present invention is not limited to these types of fragrances.
  • foaming agent examples include tartrate, citrate and bicarbonate.
  • the present invention is not limited to these types of foaming agents.
  • surfactant examples include anionic surfactants such as sodium alkyl sulfate, nonionic surfactants such as sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, and polyoxyethylene castor oil derivative. Agents and the like. The present invention is not limited to these surfactant types.
  • pH adjuster examples include inorganic salts such as sodium hydrogen carbonate, calcium hydrogen phosphate and sodium hydrogen phosphate, organic acids such as glycine, acetic acid, succinic acid, tartaric acid, fumaric acid and citric acid, or salts of these organic acids. Etc.
  • the present invention is not limited to these types of pH adjusters.
  • preservative examples include benzoic acid, paraoxybenzoic acid and salts thereof.
  • the present invention is not limited to these types of preservatives.
  • colorant examples include yellow iron oxide, yellow ferric oxide, ferric oxide (red), orange essence, brown iron oxide, caramel, light anhydrous silicic acid, edible blue No. 5, edible yellow No. 4, and edible yellow 4 No. aluminum lake, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, talc, sodium fluorescein, green tea powder, vitamin C and the like.
  • the present invention is not limited to these types of colorants.
  • the mixing of the composite particles for tablets and other tablet components can be performed, for example, by using an apparatus such as a V-type mixer or a container blender. Thereby, the mixture of the composite particle for tablets and other tablet components is obtained.
  • the present invention is not limited by these mixing techniques.
  • a tableting device for example, a tableting mortar used for tablet molding, an upper punch and a lower punch for tableting, a hydraulic hand press machine, a single-shot tableting machine, a rotary tableting machine, etc. Can be used.
  • the present invention is not limited by these tableting techniques.
  • the shape of the tablet is not particularly limited because it is a matter appropriately designed by those skilled in the art.
  • the shape may be a disk shape, a donut shape, a polygonal plate shape, a spherical shape, an elliptical shape, a caplet shape, or the like.
  • the shape is preferably a disc shape which is a normal tablet shape.
  • the size of the orally disintegrating tablet is not particularly limited because it is a matter appropriately designed by those skilled in the art. However, it is suitable to be slightly larger so as not to be swallowed directly, and for example, it is preferable that the diameter is about 3 to 30 mm and the thickness is about 1 to 10 mm.
  • the production method of the present invention is simpler and less expensive to manufacture because the number of steps in the composite of silica is reduced as compared with the conventional production method.
  • an inexpensive tablet composite particle and a tablet using the tablet composite particle can be provided.
  • an organic solvent is not used. It can also be provided. Thereby, the safer composite particle for tablets and the composite particle for tablets can be provided.
  • silica porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used.
  • indomethacin commercially available product
  • the porous silica powder and indomethacin are kneaded at a weight ratio of 1: 1 using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of 160 ° C. near the melting point of indomethacin. It was. Thereby, composite particles for tablets were obtained.
  • Example 1 The composite particles for tablets obtained in Example 1 and the indomethacin bulk powder of Comparative Example 1 were subjected to a dissolution test according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method (Paddle Method, 50 rpm).
  • the Japanese Pharmacopoeia General Test Method Disintegration Test Method Second Solution pH 6.8 was used, and the measurement was performed by the ultraviolet-visible absorbance measurement method (measurement wavelength: 320 nm).
  • the test results are shown in FIG.
  • the dissolution properties of indomethacin from tablet composite particles were greatly improved compared to the indomethacin bulk powder.
  • silica porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used. Moreover, fenofibrate (commercially available product), which is a poorly water-soluble drug, was used as a drug kneaded with silica or an excipient other than silica.
  • the porous silica powder and fenofibrate are kneaded at a weight ratio of 1: 1 using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of about 80 ° C. near the melting point of fenofibrate. I went. Thereby, composite particles for tablets were obtained.
  • Example 2 The composite particles for tablets obtained in Example 2 and the fenofibrate bulk powder of Comparative Example 2 were subjected to a dissolution test according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method (Paddle Method, 50 rpm). A 0.1M sodium lauryl sulfate solution was used as a test solution, and measurement was performed by an ultraviolet-visible absorbance measurement method (measurement wavelength: 290 nm). The test results are shown in FIG. The dissolution properties of fenofibrate from the tablet composite particles were greatly improved compared to the fenofibrate bulk powder.
  • silica porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used. Moreover, erythritol (commercially available product) was used as a drug to be kneaded with silica or an excipient other than silica. The porous silica powder and erythritol are kneaded at a weight ratio of 1: 2, using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of 120 ° C. near the melting point of erythritol. It was. Thereby, composite particles for tablets were obtained.
  • a twin-screw kneader trade name: KRC Jr., Kurimoto Seiko
  • the composite particles for tablets and other tablet components were mixed and tableted to produce tablets.
  • erythritol excipient as another tablet component
  • magnesium stearate lubricant
  • Erythritol is mixed with 10% by weight of tablet composite particles and 1% by weight of magnesium stearate, and a tablet with a total weight of 200 mg is produced using a single-punch tableting machine at a compression pressure of 150 MPa at 8 mm flat plate. did.
  • erythritol excipients as other tablet components
  • magnesium stearate lubricant
  • 10% by weight of silica / erythritol mixture and 1% by weight of magnesium stearate are mixed with erythritol, and the total weight is obtained using a single tableting machine under a tabletting pressure of 150 MPa in an 8 mm flat plate. 200 mg tablets were produced.
  • Example 3 The tablet hardness of the tablets produced in Example 3 and the tablets produced in Comparative Examples 3 and 4 were measured. Tablet hardness was measured using a portable checker (Okada Seiko Co., Ltd.). The measurement results are shown in Table 1. The tablet produced in Example 3 was significantly improved in tablet hardness as compared with the tablet produced in Comparative Example 3. Moreover, it was confirmed that the tablet manufactured in Example 3 has substantially the same tablet hardness as the tablet manufactured in Comparative Example 4.
  • silica porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used. Moreover, erythritol (commercially available product) was used as a drug to be kneaded with silica or an excipient other than silica. The porous silica powder and erythritol are kneaded at a weight ratio of 1: 2, using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of 120 ° C. near the melting point of erythritol. It was. Thereby, composite particles for tablets were obtained.
  • a twin-screw kneader trade name: KRC Jr., Kurimoto Seiko
  • the composite particles for tablets and other tablet components were mixed and tableted to produce tablets.
  • erythritol excipient as another tablet component
  • crospovidone disintegrant
  • magnesium stearate lubricant
  • 10% by weight of composite particles for tablets, 10% by weight of crospovidone, and 1% by weight of magnesium stearate are mixed with erythritol.
  • a tablet (orally disintegrating tablet) having a total weight of 200 mg was produced using a tablet machine.
  • erythritol excipients as other tablet components
  • crospovidone disintegrant
  • magnesium stearate lubricant
  • Erythritol is mixed with 10% by weight of silica / erythritol composite particles, 10% by weight of crospovidone and 1% by weight of magnesium stearate, using a single-punch tableting machine at a compression pressure of 150 MPa at 8 mm flat plate.
  • a tablet (orally disintegrating tablet) having a total weight of 200 mg was produced.
  • Example 4 For the orally disintegrating tablet produced in Example 4 and the orally disintegrating tablet produced in Comparative Example 5, the tablet hardness and the disintegration time in the oral cavity were measured. Tablet hardness was measured using a portable checker (Okada Seiko Co., Ltd.). In addition, the disintegration time in the mouth is the start time when the measurer takes an orally disintegrating tablet with the cooperation of four measurers (healthy adult men and women of the age of 20-30). The swallowing of the taken orally disintegrating tablet was considered to have been disintegrated when the measurer raised his hand, and the time from the start time to the time when the measurer raised his hand was taken. The measurement results are shown in Table 2. The orally disintegrating tablet produced in Example 4 showed almost the same tablet hardness and disintegration time as the orally disintegrating tablet produced in Comparative Example 5.
  • the production method of the present invention can be preferably used for production of a tablet containing a poorly water-soluble drug as an active ingredient.
  • the production method of the present invention is less dependent on the type of drug, it can be used to provide a new tablet formulation to a pharmaceutical manufacturer who is a customer in the field of contracted drug manufacturing.

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Abstract

Provided is a process for easily producing a tablet which contains silica produced at low cost. Also provided are: a silica-containing tablet produced by the process; and composite particles for producing the tablet. The process for producing a silica-containing tablet includes a step in which silica is kneaded together with a molten chemical or with an excipient other than silica and the resultant mixture is returned to ordinary temperature to thereby obtain composite particles for tablets.

Description

シリカを含む錠剤の製造方法、錠剤及び錠剤用複合粒子Manufacturing method of tablet containing silica, tablet and composite particle for tablet
　本発明は、シリカを含む錠剤の製造方法に関する。さらに、本発明は錠剤を製造するための錠剤用複合粒子、及び当該製造方法により製造されたシリカを含む錠剤にも及ぶ。 The present invention relates to a method for producing a tablet containing silica. Furthermore, the present invention extends to tablet-containing composite particles for producing tablets, and tablets containing silica produced by the production method.
　製剤技術の１つとして、錠剤の成分としてシリカを用いる技術が存在する。例えば、特許文献１には、分散剤としてシリカを配合することにより、薬剤の溶出性を改善できる旨が開示されている。但し、特許文献１の錠剤の課題として、製造される錠剤の硬度が低いことが挙げられていた。 As one of the formulation technologies, there is a technology that uses silica as a component of tablets. For example, Patent Document 1 discloses that the drug elution can be improved by blending silica as a dispersant. However, the problem of the tablet of Patent Document 1 is that the hardness of the tablet to be produced is low.
　特許文献２は、シリカと、前記シリカ以外の１または２以上の成分とを、あらかじめ複合化して複合化粒子を形成する工程を含む製造により、この特許文献１の課題を解決している。特に、賦形剤をシリカと複合化することにより、製造された錠剤の硬度が向上する技術が開示されている。特許文献１における複合化は、主として、噴霧乾燥法により行われる。 Patent Document 2 solves the problem of Patent Document 1 by manufacturing including a step of previously combining silica and one or more components other than silica to form composite particles. In particular, a technique is disclosed in which the hardness of a manufactured tablet is improved by combining an excipient with silica. The compounding in Patent Document 1 is mainly performed by a spray drying method.
　しかしながら、噴霧乾燥法は、特許文献２の場合、シリカとシリカ以外の１または２以上の成分を何らかの溶媒に溶解又は分散した液を噴霧することにより製造する方法である。つまり、シリカの複合化にあたっては、（１）シリカとシリカ以外の１または２以上の成分を何らかの溶媒に溶解又は分散した液を調製し、（２）シリカと噴霧した溶液における溶媒の乾燥をするという２工程を行う。このため、シリカの複合化にあたっての製造工程数が多く、製造コストが高いという問題がある。 However, in the case of Patent Document 2, the spray drying method is a method of producing by spraying a liquid in which silica or one or more components other than silica are dissolved or dispersed in some solvent. In other words, when compositing silica, (1) prepare a solution in which one or more components other than silica and silica are dissolved or dispersed in some solvent, and (2) dry the solvent in the solution sprayed with silica. 2 steps are performed. For this reason, there are many problems in that the number of manufacturing steps for complexing silica is high and the manufacturing cost is high.
　さらには、シリカ以外の１または２以上の成分が、例えば、インドメタシン等の難水溶性の薬剤である場合、使用する溶媒は、水ではなく、有機溶媒が使用される。しかしながら、残留した有機溶媒による毒性の問題や環境への負荷などさらなる問題が引き起こされるおそれがある。 Furthermore, when one or more components other than silica are, for example, poorly water-soluble drugs such as indomethacin, the solvent used is not water but an organic solvent. However, there is a possibility that further problems such as toxicity problems due to the remaining organic solvent and environmental load may be caused.
国際公開第９７／４０８２８号パンフレットInternational Publication No. 97/40828 Pamphlet 特開２００６－２４８９２２号公報JP 2006-248922 A
試験例１における結果を示す図である。It is a figure which shows the result in Test Example 1. 試験例２における結果を示す図である。It is a figure which shows the result in Test Example 2.
　本発明は、簡便で、かつ製造コストが安価であるシリカを含むシリカを含む錠剤の製造方法を提供することを課題とする。 An object of the present invention is to provide a method for producing a tablet containing silica containing silica that is simple and inexpensive to produce.
　本発明の従来技術における課題に対する解決手段は、下記の錠剤の製造方法である。 The solution to the problem in the prior art of the present invention is the following tablet manufacturing method.
　まず、本発明の製造方法は、［１］シリカと、融解した薬剤又はシリカ以外の賦形剤を混練し、常温に戻すことで錠剤用複合粒子を得る工程を含む。つまり、シリカの複合化にあたっての製造工程数は１工程で済む。 First, the production method of the present invention includes [1] a step of obtaining composite particles for tablets by kneading silica and a melted drug or an excipient other than silica and returning to normal temperature. In other words, the number of manufacturing steps for compounding silica is only one.
　シリカとは、ＩＵＰＡＣ名で二酸化ケイ素と称し、また、石英又は無水ケイ酸とも称する無機化合物をいう。本発明の製造方法に用いるシリカの形状は、粉末又は粉末よりも細かい粒子径のものが望ましい。また、シリカの品質としては、医薬品添加物規格適合グレードのものが望ましい。このようなシリカは、例えば、富士シリシア化学社製のサイリシア（登録商標）シリーズ及びデグサ社製のアエロジル（登録商標）が挙げられる。また、シリカは、複合化が容易となる観点から、多孔性のものが望ましい。市販されている多孔性のシリカとしては、富士シリシア化学社製のサイリシア（登録商標）シリーズが挙げられる。 Silica refers to an inorganic compound called silicon dioxide under the IUPAC name and also called quartz or silicic anhydride. The shape of the silica used in the production method of the present invention is preferably a powder or a particle having a particle diameter smaller than that of the powder. Further, the quality of the silica is preferably a pharmaceutical additive standard compliant grade. Examples of such silica include Cylicia (registered trademark) series manufactured by Fuji Silysia Chemical Ltd. and Aerosil (registered trademark) manufactured by Degussa. Silica is preferably porous from the viewpoint of easy compounding. Examples of the commercially available porous silica include Silicia (registered trademark) series manufactured by Fuji Silysia Chemical Ltd.
　シリカと混練する錠剤成分は、薬剤又は賦形剤である。シリカと薬剤を混練する場合は、製造された錠剤における当該薬剤の溶出性が向上する。また、シリカとシリカ以外の賦形剤を混練する場合は、製造された錠剤の硬度が向上する。つまり、当業者は、使用する薬剤や賦形剤に応じて、シリカと混練する錠剤成分を決定することができる。 The tablet component kneaded with silica is a drug or an excipient. When silica and a drug are kneaded, the dissolution property of the drug in the manufactured tablet is improved. Moreover, when knead | mixing silica and excipient | fillers other than a silica, the hardness of the manufactured tablet improves. That is, those skilled in the art can determine the tablet components to be kneaded with silica according to the drug or excipient used.
　薬剤は、錠剤への製剤化が可能な化合物であればよく、常温で個体のものであれば、特に限定されるものではない。このような薬剤としては、例えば、インドメタシン、フェノフィブラート、アセトアミノフェン、ファモチジン、シメチジン、塩酸ラニチジン、塩酸ロキサチジンアセタート、ニザチジン、ラフチジン、オメプラゾール、オメプラゾールナトリウム、ランソプラゾール、ラベプラゾールナトリウム、塩酸ピレンゼピン、プログルミド、ウガストロン、フェニトイン、フェノバルビタール、フェノバルビタールナトリウム、プリミドン、バルプロ酸ナトリウム、カルバマゼピン、トリメタジオン、ゾーミッグ、塩酸グラニセトロン、塩酸アゼセトロン、塩酸オンダセトロン、塩酸ラモセトロン、塩酸トロピセトロン、トリアゾラム、プロチゾラム、塩酸リルマザホン、ロルメタゼパム、トルブタミド、グリベンクラミド、グリミクロン、グリメピリド、グリブゾール、塩酸ブホルミン及び塩酸メトホルミン等が挙げられる。 The drug may be a compound that can be formulated into a tablet, and is not particularly limited as long as it is an individual at room temperature. Examples of such drugs include indomethacin, fenofibrate, acetaminophen, famotidine, cimetidine, ranitidine hydrochloride, roxatidine acetate, nizatidine, lafutidine, omeprazole, omeprazole sodium, lansoprazole, rabeprazole sodium, pirenzepine hydrochloride, proglumide , Ugastron, phenytoin, phenobarbital, phenobarbital sodium, primidone, sodium valproate, carbamazepine, trimethadione, Zomig, granisetron hydrochloride, azesetron hydrochloride, ondasetron hydrochloride, ramosetron hydrochloride, tropisetron hydrochloride, triazolam, protizolam, rilmazaphone hydrochloride, lorbutazem hydrochloride , Glibenclamide, Glymicron, Glime Lido, glybuzole include hydrochloric buformin and metformin hydrochloride and the like.
　シリカ以外の賦形剤とは、錠剤において、薬剤の有効量が少ない場合に、錠剤として取り扱いの適当な量となるように加えるシリカ以外の錠剤成分をいい、生理活性を持たないものをいう。シリカ以外の賦形剤も、錠剤への製剤化が可能な化合物であればよく、常温で個体のものであれば、特に限定されるものではない。このような賦形剤としては、例えば、マンニトール、エリスリトール、ソルビトール、キシリトール、トレハロース、マルチトール並びにラクチトール等の糖アルコール、及び、結晶セルロース、粉末セルロース、ヒドロキシプロピルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルメチルセルロース及びエチルセルロース等のセルロース類等が挙げられる。上述のシリカもいわゆる賦形剤に相当するものであるが、上述の通り製造される錠剤における錠剤硬度を向上させるために、これらシリカ以外の賦形剤は添加される。 Excipients other than silica refer to tablet components other than silica that are added so as to be an appropriate amount for handling as a tablet when the effective amount of the drug in the tablet is small, and refers to those having no physiological activity. Excipients other than silica may be any compound that can be formulated into tablets, and are not particularly limited as long as they are solid at room temperature. Examples of such excipients include sugar alcohols such as mannitol, erythritol, sorbitol, xylitol, trehalose, maltitol and lactitol, and crystalline cellulose, powdered cellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and ethylcellulose. And the like. The silica described above corresponds to a so-called excipient, but an excipient other than silica is added to improve tablet hardness in the tablet produced as described above.
　上述した薬剤又はシリカ以外の賦形剤は、融解又は結晶水和した状態でシリカと混練する。 The above-mentioned drugs or excipients other than silica are kneaded with silica in a melted or crystal hydrated state.
　融解における温度条件としては、融点付近であることが望ましい。例えば、薬剤がインドメタシンである場合は、１５５度付近、薬剤がフェノフィブラートである場合は、８０度付近であればよい。また、賦形剤がマンニトールである場合は、１６６度付近、賦形剤がエリスリトールである場合は、１２１．５度付近、賦形剤がトレハロースである場合は、９７度付近であればよい。 As the temperature condition for melting, it is desirable to be near the melting point. For example, when the drug is indomethacin, it may be around 155 degrees, and when the drug is fenofibrate, it may be around 80 degrees. When the excipient is mannitol, it may be around 166 degrees, when the excipient is erythritol, around 121.5 degrees, and when the excipient is trehalose, it may be around 97 degrees.
　尚、上述の通り、薬剤又はシリカ以外の賦形剤の全てが融解していることが望ましいが、部分的に融解している状態も本発明における融解に含まれるものとする。したがって、混練における温度条件は、薬剤又はシリカ以外の賦形剤の融点よりも若干低くても構わない。この温度条件を定性的に表現するならば、薬剤又はシリカ以外の賦形剤の示差走査熱量測定（ＤＳＣ）における融点に帰属される吸熱が始まる温度以上の条件をいう。 As described above, it is desirable that all excipients other than the drug or silica are melted, but a partially melted state is also included in the melting in the present invention. Therefore, the temperature condition in the kneading may be slightly lower than the melting point of the excipient other than the drug or silica. If this temperature condition is expressed qualitatively, it means a condition equal to or higher than the temperature at which the endotherm attributed to the melting point in differential scanning calorimetry (DSC) of excipients other than drugs or silica begins.
　一方、結晶水和とは、薬剤又はシリカ以外の賦形剤が結晶水を有している場合であって、温度の上昇により、薬剤又はシリカ以外の賦形剤が結晶水に溶解することをいう。結晶水和は、薬剤又はシリカ以外の賦形剤の全てが結晶水により溶解している状態が望ましいが、部分的に溶解している状態も本発明における結晶水和に含まれるものとする。結晶水和における温度条件を定性的に表現するならば、示差走査熱量測定（ＤＳＣ）における結晶水の融点に帰属される吸熱が始まる温度以上の条件をいう。 On the other hand, crystal hydration is a case where excipients other than the drug or silica have water of crystallization, and the excipient other than drug or silica dissolves in the crystal water as the temperature rises. Say. Crystal hydration is preferably in a state where all of the excipients other than the drug or silica are dissolved in water of crystallization, but a partially dissolved state is also included in the crystal hydration in the present invention. If the temperature condition in crystal hydration is expressed qualitatively, it means a condition equal to or higher than the temperature at which the endotherm attributed to the melting point of crystal water in differential scanning calorimetry (DSC) starts.
　混練は、例えば、撹拌造粒法、転動造粒法及び押出造粒法に準ずる方法により行われる。薬剤又はシリカ以外の賦形剤を融解又は結晶水和して混練する。撹拌造粒法、転動造粒法及び押出造粒法に準ずる方法とは、これらの造粒法を可能とする造粒装置に、装置を加熱可能な機構を備えたものであれば、特に限定されるものではない。 Kneading is performed, for example, by a method according to the stirring granulation method, rolling granulation method, and extrusion granulation method. An excipient other than the drug or silica is melted or crystal hydrated and kneaded. The method according to the stirring granulation method, the rolling granulation method and the extrusion granulation method is a granulation apparatus that enables these granulation methods, as long as it has a mechanism capable of heating the apparatus. It is not limited.
　そして、混練後、常温に戻すことによりシリカと薬剤又はシリカ以外の賦形剤は造粒される。このようにして造粒されたシリカと薬剤又はシリカ以外の賦形剤は、シリカを基剤として、当該シリカの周囲に薬剤又はシリカ以外の賦形剤が吸着した状態で複合化される。本発明では、この造粒された粒子を「錠剤用複合粒子」と称する。 Then, after kneading, the silica and the drug or excipients other than silica are granulated by returning to normal temperature. The granulated silica and drug or excipient other than silica are combined with silica as a base material with the drug or excipient other than silica adsorbed around the silica. In the present invention, the granulated particles are referred to as “composite particles for tablets”.
　［２］上記薬剤の中でも、難水溶性の薬剤が望ましい。難水溶性の薬剤としては、例えば、インドメタシン及びフェノフィブラートが挙げられる。ここで、本発明でいう難水溶性とは、水に対する溶解度が１ｍｇ／ｍＬ以下の薬剤をいう。本発明の製造方法における第１の工程では、有機溶媒を用いないので、錠剤中における当該有機溶媒の残存が問題にならないというのが、望ましい薬剤として、難水溶性の薬剤が挙げられる理由である。 [2] Among the above drugs, a poorly water-soluble drug is desirable. Examples of poorly water-soluble drugs include indomethacin and fenofibrate. Here, poorly water-soluble in the present invention refers to a drug having a solubility in water of 1 mg / mL or less. In the first step of the production method of the present invention, since an organic solvent is not used, the remaining of the organic solvent in the tablet does not become a problem, which is why a poorly water-soluble drug is mentioned as a desirable drug. .
　［３］上記賦形剤の中でも、低成型性の賦形剤でかつ口腔内崩壊錠への応用できる観点から、糖アルコールが好ましく、さらには、マンニトール、エリスリトール及びトレハロースがさらに好ましい。 [3] Among the above-mentioned excipients, sugar alcohol is preferable from the viewpoint of being a low-molding excipient and applicable to orally disintegrating tablets, and mannitol, erythritol, and trehalose are more preferable.
　［４］上述の装置の中でも、装置が小型である観点から、撹拌造粒法用の装置が好ましい。撹拌造粒法用の装置は、主にミキサータイプのものと、スクリュータイプのものが存在する。前者の装置としては、例えば、パグミルミキサー、ヘンシェルミキサー及びアイリッヒ（登録商標）ミキサー等が挙げられる。後者の装置としては、一軸によるもの及び二軸によるものが挙げられる。 [4] Among the above-mentioned apparatuses, the apparatus for the agitation granulation method is preferable from the viewpoint that the apparatus is small. There are mainly mixer-type devices and screw-type devices for the stirring granulation method. Examples of the former apparatus include a Pugmill mixer, a Henschel mixer, and an Eirich (registered trademark) mixer. Examples of the latter device include a uniaxial device and a biaxial device.
　［５］上述の撹拌造粒法用の装置の中でも、混練の効率がよい観点から、スクリュータイプの二軸によるもの（二軸混練機）であることが好ましい。二軸混練機は、例えば、栗本鐵工所社製のＫＲＣ（登録商標）シリーズが挙げられる。この二軸混練機を用いて混練する場合における、混練の時間は、装置の大きさに依存するため特に限定されるものではないが、１～１０分程度である。 [5] Among the above-mentioned devices for the agitation granulation method, from the viewpoint of good kneading efficiency, a screw type biaxial one (biaxial kneader) is preferable. Examples of the biaxial kneader include the KRC (registered trademark) series manufactured by Kurimoto Steel Works. In the case of kneading using this biaxial kneader, the kneading time is not particularly limited because it depends on the size of the apparatus, but it is about 1 to 10 minutes.
　本発明は、［６］シリカと、融解又は結晶水和した薬剤又はシリカ以外の賦形剤を混練し、常温に戻すことにより製造された錠剤用複合粒子にも及ぶ。錠剤用複合粒子を得るまでの工程に関しては上述の通りである。この錠剤用複合粒子は、錠剤を製造するための錠剤成分として用いることができる。 The present invention also extends to composite particles for tablets produced by kneading [6] silica with a melted or crystal hydrated drug or an excipient other than silica and returning to normal temperature. The steps up to obtaining composite particles for tablets are as described above. This composite particle for tablets can be used as a tablet component for producing a tablet.
　最後に、本発明は、［７］シリカと、融解又は結晶水和した薬剤又はシリカ以外の賦形剤を混練し、錠剤用複合粒子を得、前記錠剤用複合粒子と、他の錠剤成分を混合し、打錠することにより製造された錠剤にも及ぶ。錠剤用複合粒子を得るまでの工程に関しては上述の通りである。 Finally, the present invention provides [7] silica, a melted or crystal hydrated drug, or an excipient other than silica to knead to obtain composite particles for tablets, and the composite particles for tablets and other tablet components It extends to tablets produced by mixing and tableting. The steps up to obtaining composite particles for tablets are as described above.
　一方で、上述の錠剤用複合粒子を用いた錠剤の製造は、錠剤用複合粒子と他の錠剤成分を混合し、打錠することにより容易に行われる。 On the other hand, the manufacture of a tablet using the above-described composite particle for tablets is easily performed by mixing the composite particles for tablet and other tablet components, and tableting.
　他の錠剤成分としては、例えば、賦形剤、崩壊剤、結合剤、溶解補助剤、滑沢剤、香料、発泡剤、界面活性剤、ｐＨ調整剤、防腐剤及び着色剤等が挙げられるが、本発明はこれら添加剤の種類等により限定されるものではない。このような他の錠剤成分は、主薬の薬効に影響を及ぼさない限りにおいて、当業者により適宜選択される。特に、錠剤を口腔内崩壊錠とする場合は、崩壊剤は好適に使用される。 Examples of other tablet components include excipients, disintegrants, binders, solubilizers, lubricants, fragrances, foaming agents, surfactants, pH adjusters, preservatives, and coloring agents. The present invention is not limited by the types of these additives. Such other tablet components are appropriately selected by those skilled in the art as long as they do not affect the drug efficacy of the active ingredient. In particular, when the tablet is an orally disintegrating tablet, the disintegrant is preferably used.
　賦形剤の例は上述したシリカと複合したものと相違はない。尚、ここでいう他の錠剤成分としての賦形剤を挙げているのは、上述のシリカに複合化するものとして賦形剤を使用した場合であっても、追加して賦形剤を使用してもよいことを意味する。他の錠剤成分としての賦形剤は、上述のシリカに複合化する賦形剤と同種又は異種のいずれのものを選択してもよい。 ∙ Examples of excipients are no different from those combined with silica described above. It should be noted that the excipients as other tablet components mentioned here are used even when the excipient is used as a composite with the above-mentioned silica. It means you may do it. The excipient as the other tablet component may be the same or different from the excipient complexed with the silica described above.
　崩壊剤としては、例えば、クロスポビドン、カルボキシスターチナトリウム、カルボキシメチルスターチナトリウム、でんぷん、部分α化澱粉、コーンスターチ、乳糖、炭酸カルシウム、沈降炭酸カルシウム、クエン酸カルシウム、合成ケイ酸アルミニウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロース、クロスカルメロースナトリウム、カルボキシメチルセルロースカルシウム、カルメロース及びヒドロキシプロピルスターチ等が挙げられる。本発明は、これらの崩壊剤の種類に限定されるものではない。 Disintegrants include, for example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium carbonate, precipitated calcium carbonate, calcium citrate, synthetic aluminum silicate, low substituted hydroxy Examples include propylcellulose, croscarmellose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose and hydroxypropyl starch. The present invention is not limited to the types of these disintegrants.
　結合剤としては、例えば、ゼラチン、寒天、アルギン酸、アルギン酸ナトリウム、デキストリン、キタンサンガム、アラビアゴム末、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、部分けん化ポリビニルアルコール、メチルセルロース、プルラン、部分α化澱粉及び糖類等が挙げられる。本発明は、これらの結合剤の種類に限定されるものではない。 Examples of binders include gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, pullulan, and partially pregelatinized. Examples include starch and saccharides. The present invention is not limited to these binder types.
　溶解補助剤としては、例えば、酸化マグネシウム、酸化カルシウム、クエン酸ナトリウム、塩化マグネシウム、炭酸ナトリウム及び炭酸水素ナトリウムが挙げられる。本発明は、これらの溶解補助剤の種類に限定されるものではない。 Examples of the solubilizer include magnesium oxide, calcium oxide, sodium citrate, magnesium chloride, sodium carbonate, and sodium hydrogen carbonate. The present invention is not limited to these types of solubilizers.
　滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、ショ糖脂肪酸エステル、ポリエチレングリコール、ステアリン酸、軽質無水ケイ酸、硬化ナタネ油、硬化ひまし油、グリセリン脂肪酸エステル、フマル酸ステアリルナトリウム、安息香酸ナトリウム、Ｌ-ロイシン及びＬ-バリン等が挙げられる。本発明は、これらの滑沢剤の種類に限定されるものではない。 Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, polyethylene glycol, stearic acid, light anhydrous silicic acid, hydrogenated rapeseed oil, hydrogenated castor oil, glycerin fatty acid ester, sodium stearyl fumarate, benzoic acid Examples include sodium acid, L-leucine and L-valine. The present invention is not limited to these types of lubricants.
　香料としては、例えば、ミント、レモン及びオレンジ等が挙げられる。本発明は、これらの香料の種類に限定されるものではない。 Examples of fragrances include mint, lemon and orange. The present invention is not limited to these types of fragrances.
　発泡剤としては、例えば、酒石酸塩、クエン酸塩及び重炭酸塩等が挙げられる。本発明は、これらの発泡剤の種類に限定されるものではない。 Examples of the foaming agent include tartrate, citrate and bicarbonate. The present invention is not limited to these types of foaming agents.
　界面活性剤としては、例えば、アルキル硫酸ナトリウム等のアニオン系界面活性剤、ショ糖脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル及びポリオキシエチレンヒマシ油誘導体等の非イオン系界面活性剤等が挙げられる。本発明は、これらの界面活性剤の種類に限定されるものではない。 Examples of the surfactant include anionic surfactants such as sodium alkyl sulfate, nonionic surfactants such as sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, and polyoxyethylene castor oil derivative. Agents and the like. The present invention is not limited to these surfactant types.
　ｐＨ調整剤としては、例えば、炭酸水素ナトリウム、リン酸水素カルシウム、リン酸水素ナトリウム等の無機塩類、グリシン、酢酸、コハク酸、酒石酸、フマル酸並びにクエン酸等の有機酸又はこれら有機酸の塩類等が挙げられる。本発明は、これらのｐＨ調整剤の種類に限定されるものではない。 Examples of the pH adjuster include inorganic salts such as sodium hydrogen carbonate, calcium hydrogen phosphate and sodium hydrogen phosphate, organic acids such as glycine, acetic acid, succinic acid, tartaric acid, fumaric acid and citric acid, or salts of these organic acids. Etc. The present invention is not limited to these types of pH adjusters.
　防腐剤としては、例えば、安息香酸並びにパラオキシ安息香酸及びそれらの塩等が挙げられる。本発明は、これらの防腐剤の種類に限定されるものではない。 Examples of the preservative include benzoic acid, paraoxybenzoic acid and salts thereof. The present invention is not limited to these types of preservatives.
　着色剤としては、例えば、黄酸化鉄、黄色三二酸化鉄、三二酸化鉄（赤色）、オレンジエッセンス、褐色酸化鉄、カラメル、軽質無水ケイ酸、食用青色５号、食用黄色４号、食用黄色４号アルミニウムレーキ、食用黄色５号、食用赤色２号、食用赤色３号、食用赤色１０２号、タルク、フルオレセインナトリウム、緑茶末及びビタミンＣ等が挙げられる。本発明は、これらの着色剤の種類に限定されるものではない。 Examples of the colorant include yellow iron oxide, yellow ferric oxide, ferric oxide (red), orange essence, brown iron oxide, caramel, light anhydrous silicic acid, edible blue No. 5, edible yellow No. 4, and edible yellow 4 No. aluminum lake, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, talc, sodium fluorescein, green tea powder, vitamin C and the like. The present invention is not limited to these types of colorants.
　錠剤用複合粒子と他の錠剤成分との混合は、例えば、Ｖ型混合機、コンテナブレンダー等の装置を用いることにより行うことができる。これにより、錠剤用複合粒子と他の錠剤成分との混合物を得る。本発明は、これらの混合技術により限定されるものではない。 The mixing of the composite particles for tablets and other tablet components can be performed, for example, by using an apparatus such as a V-type mixer or a container blender. Thereby, the mixture of the composite particle for tablets and other tablet components is obtained. The present invention is not limited by these mixing techniques.
　次いで、得られた混合物を打錠する。打錠する装置としては、例えば、錠剤の成形に使用する打錠用臼、打錠用上杵及び下杵を用い、油圧式ハンドプレス機、単発式打錠機又はロータリー式打錠機等を利用することができる。本発明は、これらの打錠技術により限定されるものではない。 Next, the obtained mixture is tableted. As a tableting device, for example, a tableting mortar used for tablet molding, an upper punch and a lower punch for tableting, a hydraulic hand press machine, a single-shot tableting machine, a rotary tableting machine, etc. Can be used. The present invention is not limited by these tableting techniques.
　錠剤の形状は、当業者により適宜設計される事項であるため、特に限定されるものではない。例えば、その形状としては円盤状、ドーナツ状、多角形板状、球状、楕円状又はキャプレット状等とすることができる。特に、錠剤が崩壊剤を含む口腔内崩壊錠である場合は、その形状は、通常の錠剤の形状である円盤状であるものが好ましい。口腔内崩壊錠の大きさもまた、当業者により適宜設計される事項であるため、特に限定されるものではない。但し、直接嚥下されないように若干大きめであることが適しており、例えば、直径が３～３０ｍｍ程度、厚みが１～１０ｍｍ程度であることが好ましい。 The shape of the tablet is not particularly limited because it is a matter appropriately designed by those skilled in the art. For example, the shape may be a disk shape, a donut shape, a polygonal plate shape, a spherical shape, an elliptical shape, a caplet shape, or the like. In particular, when the tablet is an orally disintegrating tablet containing a disintegrant, the shape is preferably a disc shape which is a normal tablet shape. The size of the orally disintegrating tablet is not particularly limited because it is a matter appropriately designed by those skilled in the art. However, it is suitable to be slightly larger so as not to be swallowed directly, and for example, it is preferable that the diameter is about 3 to 30 mm and the thickness is about 1 to 10 mm.
　本発明の製造方法は、従来の製造方法と比較してシリカの複合化における工程数が減ることにより、簡便で、かつ製造コストが安価である。これにより、安価な錠剤用複合粒子及び当該錠剤用複合粒子を使用した錠剤を提供することができる。特に、本発明の最良の形態を実施した場合は、シリカ以外の少なくとも１の錠剤成分が、難水溶性の薬剤である場合は、有機溶媒を使用することがなくなるので、環境にやさしい製造方法を提供することも可能とする。これにより、より安全性の高い錠剤用複合粒子及び当該錠剤用複合粒子を提供することができる。 The production method of the present invention is simpler and less expensive to manufacture because the number of steps in the composite of silica is reduced as compared with the conventional production method. Thereby, an inexpensive tablet composite particle and a tablet using the tablet composite particle can be provided. In particular, when the best mode of the present invention is implemented, when at least one tablet component other than silica is a poorly water-soluble drug, an organic solvent is not used. It can also be provided. Thereby, the safer composite particle for tablets and the composite particle for tablets can be provided.
　以下、本発明を実施するための最良の形態を実施例により具体的に説明する。但し、本発明はこれらの実施例に限定して解釈してはならない。 Hereinafter, the best mode for carrying out the present invention will be specifically described by way of examples. However, the present invention should not be interpreted as being limited to these examples.
［実施例１］
　シリカとして、多孔性シリカ粉末（商品名：サイリシア３５０、富士シリシア株式会社性）を用いた。また、シリカと混練する薬剤又はシリカ以外の賦形剤としては、難水溶性の薬剤であるインドメタシン（市販品）を用いた。多孔性シリカ粉末とインドメタシンとの混練は、重量比１：１で、二軸混練機（商品名：ＫＲＣ　Ｊｒ．、栗本鐵工）を用いて、インドメタシンの融点付近である温度１６０℃にて行った。これにより、錠剤用複合粒子を得た。 [Example 1]
As silica, porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used. In addition, indomethacin (commercially available product), which is a poorly water-soluble drug, was used as a drug kneaded with silica or an excipient other than silica. The porous silica powder and indomethacin are kneaded at a weight ratio of 1: 1 using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of 160 ° C. near the melting point of indomethacin. It was. Thereby, composite particles for tablets were obtained.
［比較例１］
　市販品であるインドメタシン原末をそのまま用いた。 [Comparative Example 1]
Commercially available indomethacin bulk powder was used as it was.
［試験例１］
　実施例１で得た錠剤用複合粒子と、比較例１のインドメタシン原末について、日本薬局方　一般試験法　溶出試験法（パドル法、５０ｒｐｍ）に従い溶出試験を行った。試験液としては、日本薬局方　一般試験法　崩壊試験法　第２液（ｐＨ６．８）を用い、紫外可視吸光度測定法（測定波長：３２０ｎｍ）で測定した。その試験結果を図１に示す。錠剤用複合粒子からのインドメタシンの溶出性は、インドメタシン原末に比べ、大きく改善された。 [Test Example 1]
The composite particles for tablets obtained in Example 1 and the indomethacin bulk powder of Comparative Example 1 were subjected to a dissolution test according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method (Paddle Method, 50 rpm). As the test solution, the Japanese Pharmacopoeia General Test Method Disintegration Test Method Second Solution (pH 6.8) was used, and the measurement was performed by the ultraviolet-visible absorbance measurement method (measurement wavelength: 320 nm). The test results are shown in FIG. The dissolution properties of indomethacin from tablet composite particles were greatly improved compared to the indomethacin bulk powder.
［実施例２］
　シリカとして、多孔性シリカ粉末（商品名：サイリシア３５０、富士シリシア株式会社性）を用いた。また、シリカと混練する薬剤又はシリカ以外の賦形剤としては、難水溶性の薬剤であるフェノフィブラート（市販品）を用いた。多孔性シリカ粉末とフェノフィブラートとの混練は、重量比１：１で、二軸混練機（商品名：ＫＲＣ　Ｊｒ．、栗本鐵工）を用いて、フェノフィブラートの融点付近である温度８０℃にて行った。これにより、錠剤用複合粒子を得た。 [Example 2]
As silica, porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used. Moreover, fenofibrate (commercially available product), which is a poorly water-soluble drug, was used as a drug kneaded with silica or an excipient other than silica. The porous silica powder and fenofibrate are kneaded at a weight ratio of 1: 1 using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of about 80 ° C. near the melting point of fenofibrate. I went. Thereby, composite particles for tablets were obtained.
［比較例２］
　市販品であるフェノフィブラート原末をそのまま用いた。 [Comparative Example 2]
A commercially available fenofibrate powder was used as it was.
［試験例２］
　実施例２で得た錠剤用複合粒子と、比較例２のフェノフィブラート原末について、日本薬局方　一般試験法　溶出試験法（パドル法、５０ｒｐｍ）に従い溶出試験を行った。試験液としては０．１Ｍ　ラウリル硫酸ナトリウム溶液を用い、紫外可視吸光度測定法（測定波長：２９０ｎｍ）で測定した。その試験結果を図２に示す。錠剤用複合粒子からのフェノフィブラートの溶出性は、フェノフィブラート原末に比べ、大きく改善された。 [Test Example 2]
The composite particles for tablets obtained in Example 2 and the fenofibrate bulk powder of Comparative Example 2 were subjected to a dissolution test according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method (Paddle Method, 50 rpm). A 0.1M sodium lauryl sulfate solution was used as a test solution, and measurement was performed by an ultraviolet-visible absorbance measurement method (measurement wavelength: 290 nm). The test results are shown in FIG. The dissolution properties of fenofibrate from the tablet composite particles were greatly improved compared to the fenofibrate bulk powder.
［実施例３］
　シリカとして、多孔性シリカ粉末（商品名：サイリシア３５０、富士シリシア株式会社性）を用いた。また、シリカと混練する薬剤又はシリカ以外の賦形剤としては、エリスリトール（市販品）を用いた。多孔性シリカ粉末とエリスリトールとの混練は、重量比１：２で、二軸混練機（商品名：ＫＲＣ　Ｊｒ．、栗本鐵工）を用いて、エリスリトールの融点付近である温度１２０℃にて行った。これにより、錠剤用複合粒子を得た。 [Example 3]
As silica, porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used. Moreover, erythritol (commercially available product) was used as a drug to be kneaded with silica or an excipient other than silica. The porous silica powder and erythritol are kneaded at a weight ratio of 1: 2, using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of 120 ° C. near the melting point of erythritol. It was. Thereby, composite particles for tablets were obtained.
　次にこの錠剤用複合粒子と他の錠剤成分を混合し、打錠することにより錠剤を製造した。他の錠剤成分としては、エリスリトール（他の錠剤成分としての賦形剤）及びステアリン酸マグネシウム（滑沢剤）を用いた。エリスリトールに対し、１０重量％の錠剤用複合粒子及び１重量％のステアリン酸マグネシウムを混合し、８ｍｍ平杵において、打錠圧１５０ＭＰａの条件で単発打錠機を用いて総重量２００ｍｇの錠剤を製造した。 Next, the composite particles for tablets and other tablet components were mixed and tableted to produce tablets. As other tablet components, erythritol (excipient as another tablet component) and magnesium stearate (lubricant) were used. Erythritol is mixed with 10% by weight of tablet composite particles and 1% by weight of magnesium stearate, and a tablet with a total weight of 200 mg is produced using a single-punch tableting machine at a compression pressure of 150 MPa at 8 mm flat plate. did.
［比較例３］
　多孔性シリカ粉末とエリスリトールを、バイアル瓶中で重量比１：２にて混合し、シリカ／エリスリトール混合物を得た。 [Comparative Example 3]
Porous silica powder and erythritol were mixed at a weight ratio of 1: 2 in a vial to obtain a silica / erythritol mixture.
　錠剤（口腔内崩壊錠）の製造においては、上述のシリカ／エリスリトール混合物の他、エリスリトール（他の錠剤成分としての賦形剤）及びステアリン酸マグネシウム（滑沢剤）を用いた。具体的には、エリスリトールに対し、１０重量％のシリカ／エリスリトール混合物及び１重量％のステアリン酸マグネシウムを混合し、８ｍｍ平杵において、打錠圧１５０ＭＰａの条件で単発打錠機を用いて総重量２００ｍｇの錠剤を製造した。 In the manufacture of tablets (orally disintegrating tablets), erythritol (excipients as other tablet components) and magnesium stearate (lubricant) were used in addition to the silica / erythritol mixture described above. Specifically, 10% by weight of silica / erythritol mixture and 1% by weight of magnesium stearate are mixed with erythritol, and the total weight is obtained using a single tableting machine under a tabletting pressure of 150 MPa in an 8 mm flat plate. 200 mg tablets were produced.
［比較例４］
　多孔性シリカ粉末とエリスリトールを、バイアル瓶中で重量比１：２にて、蒸留水に分散させることにより、シリカ／エリスリトール分散液を得た。このシリカ／エリスリトール分散液を、スプレードライヤー（ヤマト科学社製、ＧＳ－３１）を用いて噴霧・乾燥することにより、シリカ／エリスリトール複合粒子を得た。次いで、エリスリトールに対し、１０重量％のシリカ／エリスリトール複合粒子及び１重量％のステアリン酸マグネシウムを混合し、８ｍｍ平杵において、打錠圧１５０ＭＰａの条件で単発打錠機を用いて総重量２００ｍｇの錠剤を製造した。 [Comparative Example 4]
Porous silica powder and erythritol were dispersed in distilled water at a weight ratio of 1: 2 in a vial to obtain a silica / erythritol dispersion. This silica / erythritol dispersion was sprayed and dried using a spray dryer (manufactured by Yamato Kagaku Co., Ltd., GS-31) to obtain silica / erythritol composite particles. Next, 10% by weight of silica / erythritol composite particles and 1% by weight of magnesium stearate were mixed with erythritol, and a total weight of 200 mg was obtained using a single tableting machine at a compression pressure of 150 MPa in an 8 mm flat plate. Tablets were manufactured.
［試験例３］
　実施例３で製造した錠剤と、比較例３及び４で製造した錠剤の錠剤硬度を測定した。錠剤硬度は、ポータブルチェッカー（岡田精工社製）を用いて測定した。その測定結果を表１に示す。実施例３で製造した錠剤は、比較例３で製造した錠剤に比べ、著しく錠剤硬度が向上した。また、実施例３で製造した錠剤は、比較例４で製造した錠剤と、ほぼ同等の錠剤硬度であることが確認された。 [Test Example 3]
The tablet hardness of the tablets produced in Example 3 and the tablets produced in Comparative Examples 3 and 4 were measured. Tablet hardness was measured using a portable checker (Okada Seiko Co., Ltd.). The measurement results are shown in Table 1. The tablet produced in Example 3 was significantly improved in tablet hardness as compared with the tablet produced in Comparative Example 3. Moreover, it was confirmed that the tablet manufactured in Example 3 has substantially the same tablet hardness as the tablet manufactured in Comparative Example 4.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
［実施例４］
　シリカとして、多孔性シリカ粉末（商品名：サイリシア３５０、富士シリシア株式会社性）を用いた。また、シリカと混練する薬剤又はシリカ以外の賦形剤としては、エリスリトール（市販品）を用いた。多孔性シリカ粉末とエリスリトールとの混練は、重量比１：２で、二軸混練機（商品名：ＫＲＣ　Ｊｒ．、栗本鐵工）を用いて、エリスリトールの融点付近である温度１２０℃にて行った。これにより、錠剤用複合粒子を得た。 [Example 4]
As silica, porous silica powder (trade name: Silicia 350, Fuji Silysia Ltd.) was used. Moreover, erythritol (commercially available product) was used as a drug to be kneaded with silica or an excipient other than silica. The porous silica powder and erythritol are kneaded at a weight ratio of 1: 2, using a twin-screw kneader (trade name: KRC Jr., Kurimoto Seiko) at a temperature of 120 ° C. near the melting point of erythritol. It was. Thereby, composite particles for tablets were obtained.
　次にこの錠剤用複合粒子と他の錠剤成分を混合し、打錠することにより錠剤を製造した。他の錠剤成分としては、エリスリトール（他の錠剤成分としての賦形剤）、クロスポビドン（崩壊剤）及びステアリン酸マグネシウム（滑沢剤）を用いた。具体的には、エリスリトールに対し、１０重量％の錠剤用複合粒子、１０重量％のクロスポビドン及び１重量％のステアリン酸マグネシウムを混合し、８ｍｍ平杵において、打錠圧１５０ＭＰａの条件で単発打錠機を用いて総重量２００ｍｇの錠剤（口腔内崩壊錠）を製造した。 Next, the composite particles for tablets and other tablet components were mixed and tableted to produce tablets. As other tablet components, erythritol (excipient as another tablet component), crospovidone (disintegrant) and magnesium stearate (lubricant) were used. Specifically, 10% by weight of composite particles for tablets, 10% by weight of crospovidone, and 1% by weight of magnesium stearate are mixed with erythritol. A tablet (orally disintegrating tablet) having a total weight of 200 mg was produced using a tablet machine.
［比較例５］
　多孔性シリカ粉末とエリスリトールを、バイアル瓶中で重量比１：２にて、蒸留水に分散させることにより、シリカ／エリスリトール分散液を得た。このシリカ／エリスリトール分散液を、ポータブルチェッカー（岡田精工社製）を用いて噴霧・乾燥することにより、シリカ／エリスリトール複合粒子を得た。 [Comparative Example 5]
Porous silica powder and erythritol were dispersed in distilled water at a weight ratio of 1: 2 in a vial to obtain a silica / erythritol dispersion. This silica / erythritol dispersion was sprayed and dried using a portable checker (Okada Seiko Co., Ltd.) to obtain silica / erythritol composite particles.
　錠剤（口腔内崩壊錠）の製造においては、上述のシリカ／エリスリトール複合粒子の他、エリスリトール（他の錠剤成分としての賦形剤）、クロスポビドン（崩壊剤）及びステアリン酸マグネシウム（滑沢剤）を用いた。エリスリトールに対し、１０重量％のシリカ／エリスリトール複合粒子、１０重量％のクロスポビドン及び１重量％のステアリン酸マグネシウムを混合し、８ｍｍ平杵において、打錠圧１５０ＭＰａの条件で単発打錠機を用いて総重量２００ｍｇの錠剤（口腔内崩壊錠）を製造した。 In the manufacture of tablets (orally disintegrating tablets), in addition to the silica / erythritol composite particles described above, erythritol (excipients as other tablet components), crospovidone (disintegrant), and magnesium stearate (lubricant) Was used. Erythritol is mixed with 10% by weight of silica / erythritol composite particles, 10% by weight of crospovidone and 1% by weight of magnesium stearate, using a single-punch tableting machine at a compression pressure of 150 MPa at 8 mm flat plate. Thus, a tablet (orally disintegrating tablet) having a total weight of 200 mg was produced.
［試験例４］
　実施例４で製造した口腔内崩壊錠と、比較例５で製造した口腔内崩壊錠について、錠剤硬度及び口腔内での崩壊時間を測定した。錠剤硬度は、ポータブルチェッカー（岡田精工社製）を用いて測定した。また、口腔内での崩壊時間は、測定者４名（年齢２０～３０歳の健常な成年男性及び女性）の協力を得て、測定者が口腔内崩壊錠を服用した時を開始時間とし、当該服用した口腔内崩壊錠を嚥下した時に測定者が挙手することにより崩壊したものとみなし、開始時間から測定者が挙手した時間までの時間とした。その測定結果を表２に示す。実施例４で製造した口腔内崩壊錠は、比較例５で製造した口腔内崩壊錠と、ほぼ同等の錠剤硬度および崩壊時間を示した。 [Test Example 4]
For the orally disintegrating tablet produced in Example 4 and the orally disintegrating tablet produced in Comparative Example 5, the tablet hardness and the disintegration time in the oral cavity were measured. Tablet hardness was measured using a portable checker (Okada Seiko Co., Ltd.). In addition, the disintegration time in the mouth is the start time when the measurer takes an orally disintegrating tablet with the cooperation of four measurers (healthy adult men and women of the age of 20-30). The swallowing of the taken orally disintegrating tablet was considered to have been disintegrated when the measurer raised his hand, and the time from the start time to the time when the measurer raised his hand was taken. The measurement results are shown in Table 2. The orally disintegrating tablet produced in Example 4 showed almost the same tablet hardness and disintegration time as the orally disintegrating tablet produced in Comparative Example 5.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　本発明の製造方法は、好適には難水溶性の薬剤を有効成分とする錠剤の製造に利用できる。また、本発明の製造方法は、薬剤の種類に依存度が低いため、医薬品の受託製造分野において、顧客である医薬品メーカーに新規な錠剤処方の提供することにも利用できる。 The production method of the present invention can be preferably used for production of a tablet containing a poorly water-soluble drug as an active ingredient. In addition, since the production method of the present invention is less dependent on the type of drug, it can be used to provide a new tablet formulation to a pharmaceutical manufacturer who is a customer in the field of contracted drug manufacturing.

Claims (7)

  1. 　シリカを含む錠剤の製造方法であって、
    シリカと、融解又は結晶水和した薬剤又はシリカ以外の賦形剤を混練し、常温に戻すことで錠剤用複合粒子を得る工程
    を含む錠剤の製造方法。     A method for producing a tablet comprising silica, comprising:
    A method for producing a tablet comprising a step of kneading a silica and a drug that has been melted or crystal hydrated or an excipient other than silica and returning to normal temperature to obtain composite particles for tablets.
  2. 　薬剤が、難水溶性の薬剤である請求項１に記載の錠剤の製造方法。 The method for producing a tablet according to claim 1, wherein the drug is a poorly water-soluble drug.
  3. 　シリカ以外の賦形剤が、糖アルコールである請求項１に記載の錠剤の製造方法。 The method for producing a tablet according to claim 1, wherein the excipient other than silica is a sugar alcohol.
  4. 　混練が、加熱可能な機構を備えた撹拌造粒法用の装置によるものである請求項１に記載の錠剤の製造方法。 2. The method for producing a tablet according to claim 1, wherein the kneading is performed by an apparatus for stirring granulation equipped with a heatable mechanism.
  5. 　撹拌造粒用装置が、二軸混練によるものである請求項４に記載の錠剤の製造方法。 The tablet production method according to claim 4, wherein the stirring granulation apparatus is based on biaxial kneading.
  6. 　シリカと、融解又は結晶水和した薬剤又はシリカ以外の賦形剤を混練し、常温に戻すことにより製造された錠剤用複合粒子。 Compound particles for tablets produced by kneading silica and a melted or crystal hydrated drug or an excipient other than silica and returning to normal temperature.
  7. 　シリカを含む錠剤であって、
    シリカと、融解又は結晶水和した薬剤又はシリカ以外の賦形剤を混練し、錠剤用複合粒子を得、
    前記錠剤用複合粒子と、他の錠剤成分を混合し、打錠する
    ことにより製造された錠剤。     A tablet comprising silica,
    Kneading silica and a melted or crystal hydrated drug or an excipient other than silica to obtain composite particles for tablets,
    A tablet produced by mixing the tablet composite particles and other tablet components and compressing them.
PCT/JP2009/057792 2008-04-17 2009-04-17 Process for producing silica-containing tablet, tablet, and composite particle for tablet WO2009128543A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021063150A (en) * 2019-10-10 2021-04-22 明彦 浪岡 Method for producing antifreeze agent

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6399012A (en) * 1986-01-21 1988-04-30 Chugai Pharmaceut Co Ltd Stable solid agent of thiol ester derivative
JPH07267850A (en) * 1994-03-28 1995-10-17 Eisai Co Ltd Medicine composition prevented in unpleasant taste and method for producing the same
WO2007034135A1 (en) * 2005-09-22 2007-03-29 Reckitt Benckiser Healthcare (Uk) Limited Composition comprising a nsaid and paracetamol
JP2008509206A (en) * 2004-08-12 2008-03-27 レキット ベンキーザー ヘルスケア （ユーケイ） リミテッド Granules containing NSAID and sugar alcohol produced by melt extrusion

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6399012A (en) * 1986-01-21 1988-04-30 Chugai Pharmaceut Co Ltd Stable solid agent of thiol ester derivative
JPH07267850A (en) * 1994-03-28 1995-10-17 Eisai Co Ltd Medicine composition prevented in unpleasant taste and method for producing the same
JP2008509206A (en) * 2004-08-12 2008-03-27 レキット ベンキーザー ヘルスケア （ユーケイ） リミテッド Granules containing NSAID and sugar alcohol produced by melt extrusion
WO2007034135A1 (en) * 2005-09-22 2007-03-29 Reckitt Benckiser Healthcare (Uk) Limited Composition comprising a nsaid and paracetamol

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021063150A (en) * 2019-10-10 2021-04-22 明彦 浪岡 Method for producing antifreeze agent

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