WO2017188362A1 - Comprimé contenant de la tosufloxacine tosilate, un désintégrateur et un acide aminé acide - Google Patents

Comprimé contenant de la tosufloxacine tosilate, un désintégrateur et un acide aminé acide Download PDF

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Publication number
WO2017188362A1
WO2017188362A1 PCT/JP2017/016682 JP2017016682W WO2017188362A1 WO 2017188362 A1 WO2017188362 A1 WO 2017188362A1 JP 2017016682 W JP2017016682 W JP 2017016682W WO 2017188362 A1 WO2017188362 A1 WO 2017188362A1
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Prior art keywords
tablet
powder
sieve
opening
disintegrant
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PCT/JP2017/016682
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English (en)
Japanese (ja)
Inventor
一美 田谷
侑輝 粕谷
康太郎 岡田
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富山化学工業株式会社
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Priority to JP2018514691A priority Critical patent/JP6600084B2/ja
Publication of WO2017188362A1 publication Critical patent/WO2017188362A1/fr

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to a tablet containing tosufloxacin tosylate, a disintegrant and an acidic amino acid.
  • Tosfloxacin is a new quinolone antibacterial agent having a broad antibacterial spectrum against Gram positive bacteria, Gram negative bacteria and anaerobic bacteria (Patent Document 1).
  • Patent Document 1 As a prescription and production method of a solid preparation containing tosufloxacin, it is known to prepare a preparation by mixing tosufloxacin tosylate hydrate, an organic acid having 2 to 6 carbon atoms and a general medical carrier ( Patent Document 2).
  • Patent Document 3 Also known is a granular solid preparation comprising tosufloxacin tosylate, sugar or sugar alcohol and a nonionic water-soluble cellulose derivative or polyvinyl alcohol (Patent Document 3).
  • tablets containing tosufloxacin tosylate are commercially available.
  • granular solid preparations and tablets are known.
  • a granular solid formulation is preferred.
  • the swallowing function develops like an elementary school student and the taste becomes clearer, tablets tend to be preferred.
  • the size of tablets greatly affects compliance. If it is too large, the child will not be able to swallow and compliance will be reduced. Since tablets for adults have a tablet diameter of 7.5 to 8.5 mm, which is large for children, there is a concern that the compliance of children will be reduced. Fine granules have been marketed as pediatric preparations containing tosufloxacin tosylate, but pediatric tablets have not been developed.
  • An object of the present invention is to provide a tablet containing tosufloxacin tosylate which exhibits rapid dissolution and has a stable dissolution rate even after storage.
  • a tablet comprising (1) tosufloxacin tosylate, (2) a disintegrant, and (3) an acidic amino acid, wherein the disintegrant is one or two selected from disintegrant A and disintegrant B
  • the present invention further provides the following.
  • [9] The tablet according to any one of [1] to [8], wherein the content of tosufloxacin tosylate is 20 to 70% with respect to the tablet mass.
  • the tablet according to any one of [2] to [8], wherein the content of L-aspartic acid is 15 to 25% with respect to the tablet mass.
  • the tablet of the present invention is useful as a tablet that exhibits rapid dissolution and does not deteriorate after storage.
  • the tablet of the present invention is a tablet that is easy to be taken by children and the like, is not too small, and has a reduced risk of aspiration into the trachea. Therefore, the tablet of the present invention is useful as a tablet with improved medication compliance for children.
  • the present invention is described in detail below. Unless otherwise specified,% used in the present specification means mass%.
  • the content rate of each component used in the present specification means the total content rate of a plurality of substances corresponding to each component unless there is a specific case when there are a plurality of substances corresponding to each component.
  • dissolution rate used in the present specification means the dissolution rate measured according to the 16th revised Japanese Pharmacopoeia dissolution test method 2 (paddle method) unless otherwise specified.
  • Rapid dissolution as used herein means that the dissolution rate 15 minutes after the start of the dissolution test is 85% or more unless otherwise specified.
  • the tablet of the present invention comprises tosufloxacin tosylate, a disintegrant and an acidic amino acid.
  • the tablet of the present invention means an uncoated tablet and a film-coated tablet.
  • the film-coated tablet means a tablet obtained by coating a base tablet with a coating agent such as a polymer compound. As the tablet, a film-coated tablet is preferable.
  • the tablet diameter is preferably 5.0 to 7.0 mm.
  • the dose and the number of doses can be appropriately selected according to the age, weight and symptoms of the patient, but the amount capable of exerting the drug effect is usually divided from once to several times a day. Can be administered. In general, 30 to 2000 mg of tosufloxacin may be administered in 1 to several divided doses a day.
  • Tosfloxacin tosylate used in the present invention can be produced, for example, by the method described in JP-B-63-020828.
  • Tosfloxacin tosylate used in the present invention includes hydrates, solvates and various forms of crystals and amorphous solids.
  • the tosufloxacin tosylate used in the present invention is preferably a hydrate.
  • the content of tosufloxacin tosylate is preferably 20 to 70%, more preferably 40 to 60%, still more preferably 45 to 55% with respect to the tablet mass.
  • disintegrant used in the present invention examples include one or more selected from disintegrant A and disintegrant B.
  • Disintegrant A is one or more selected from carmellose, carmellose calcium and croscarmellose sodium.
  • Disintegrant B is a combination of low substituted hydroxypropylcellulose and crospovidone.
  • Low-substituted hydroxypropyl cellulose is a low-substituted hydroxypropyl ether of cellulose, and the dried product contains hydroxypropoxy groups (—OC 3 H 6 OH: 75.09) 5.0 to 16.0% when quantified.
  • the tablet of the present invention only needs to contain at least disintegrant A or disintegrant B, and may contain both disintegrant A and disintegrant B.
  • disintegrant A when used, a tablet exhibiting rapid dissolution is produced by using at least one selected from carmellose, carmellose calcium and croscarmellose sodium. Can do.
  • disintegrant B even if one of low substituted hydroxypropyl cellulose or crospovidone is used, it is not possible to produce a tablet exhibiting rapid dissolution, by combining the two types, Tablets exhibiting rapid dissolution can be produced.
  • the content of the disintegrant is preferably 5 to 50%, more preferably 5 to 30%, still more preferably 8 to 15% based on the tablet mass.
  • the ratio (mass ratio) of the low-substituted hydroxypropylcellulose and crospovidone is preferably 1: 1 to 9: 1.
  • the tablet of the present invention may contain a disintegrant other than the disintegrant A and the disintegrant B.
  • the acidic amino acid used in the present invention means an amino acid having two or more carboxy groups in the molecule.
  • acidic amino acids include one or two selected from aspartic acid and glutamic acid.
  • Preferable acidic amino acids include aspartic acid, and L-aspartic acid is more preferable.
  • the content of acidic amino acids is preferably 5 to 50%, more preferably 5 to 30%, still more preferably 10 to 20% based on the tablet mass.
  • the tablet of the present invention preferably further contains an excipient.
  • the excipient include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl Cyclodextrins such as ⁇ -cyclodextrin and sulfobutyl ether ⁇ -cyclodextrin sodium; celluloses such as crystalline cellulose and microcrystalline cellulose; starches such as corn starch, potato starch and pregelatinized starch; malonic acid and fumaric acid, etc.
  • sugar alcohols such as erythritol, mannitol, xylitol and sorbitol
  • sugars such as sucrose, powdered sugar, lactose and glucose
  • dicarboxylic acids One kind selected from dicarboxylic acids; oxycarboxylic acids such as glycolic acid, gluconic acid, tartaric acid, malic acid and citric acid; and organic acids having 2 to 6 carbon atoms such as ascorbic acid Others include two or more thereof.
  • Preferred excipients include sugar alcohols, and erythritol is more preferred.
  • the amount of the excipient used is not particularly limited, and an amount corresponding to the dosage form may be used.
  • the tablet of the present invention preferably further contains a sweetener.
  • the sweetening agent include one or more selected from aspartame, sucralose, thaumatin, acesulfame potassium and saccharin sodium.
  • Preferred sweeteners include one or two selected from aspartame and sucralose.
  • the content of the sweetening agent is preferably 0.2 to 5%, more preferably 0.5 to 2%, based on the tablet mass.
  • the sweetener is preferably contained in the uncoated tablet.
  • a film-coated tablet is preferable.
  • the film coating layer may contain a sweetening agent, but preferably does not contain a sweetening agent.
  • the tablet of the present invention preferably further contains a binder.
  • the binder include one or more selected from hydroxypropylcellulose, carmellose sodium, polyvinylpyrrolidone, polyvinyl alcohol, hypromellose, methylcellulose, and the like.
  • a preferred binder is hydroxypropylcellulose.
  • the usage-amount of a binder is not specifically limited, What is necessary is just to use a required quantity.
  • additives generally used for drugs can be used as long as the effects of the present invention are not impaired.
  • the additive include a colorant, a flavoring agent, a surfactant, a fluidizing agent, a lubricant, and a coating agent.
  • the colorant include one or more selected from titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible red No. 102, edible yellow No. 4, edible yellow No. 5, and the like.
  • flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, One or two or more kinds selected from powder flavors such as peach micron, strawberry micron, and orange micron; vanillin; and ethyl vanillin.
  • the surfactant include one or more selected from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbates, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and the like.
  • Examples of the fluidizing agent include one or more selected from talc, synthetic aluminum silicate, silicon dioxide, and the like, and silicon dioxide is preferable.
  • Preferred silicon dioxide includes hydrous silicon dioxide and light anhydrous silicic acid, with hydrous silicon dioxide and light anhydrous silicic acid being more preferred.
  • Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc and sucrose fatty acid ester.
  • Examples of the coating agent include one or more selected from polymer compounds, plasticizers, colorants, lubricants, brighteners, and the like.
  • Examples of the polymer compound include one or more selected from hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer, and the like.
  • Examples of the plasticizer include one or more selected from triethyl citrate, dibutyl phthalate, macrogol (polyethylene glycol), triacetin, glycerol monocaprycaprate, lecithin, propylene glycol, and the like.
  • Examples of the lubricant used as the coating agent include talc.
  • Examples of the brightening agent include one or more selected from carnauba wax, white beeswax, beeswax and the like.
  • the amount of the polymer compound, plasticizer, colorant, lubricant and brightening agent used is not particularly limited, and a necessary amount may be appropriately blended depending on the purpose. These additives may be added either alone or in combination of two or more. The addition amount is not particularly limited, and an amount corresponding to the dosage form may be added.
  • a granulated powder is produced by a dry or wet granulation method, and if desired, an excipient, a fluidizing agent, a disintegrant and / or a lubricant are further granulated.
  • a tableting mixed powder may be used.
  • the obtained tablet may be film-coated by a conventional method.
  • a preferable granulation method in the method for producing a granulated powder of the present invention includes a wet granulation method.
  • wet granulation method examples include fluidized bed granulation method, rolling fluidized granulation method, centrifugal rolling granulation method, mixed stirring granulation method, high speed mixed stirring granulation method, rolling granulation method, wet crushing method
  • examples thereof include a granulation method and an extrusion granulation method.
  • Preferable wet granulation methods include fluidized bed granulation method, rolling fluidized granulation method, wet crushing granulation method and high-speed mixing and agitation granulation method, and rolling fluidized granulation method and fluidized bed granulation method include More preferred.
  • Aspartame Ajinomoto KK Aspartame (Ajinomoto) Acesulfame potassium: Sanet (Kirin Kyowa Foods) Pregelatinized starch: SWELSTAR PD-1 (Asahi Kasei Chemicals) L-aspartic acid: L-aspartic acid (Kyowa Hakko Bio) Erythritol: Erythritol T fine powder (Mitsubishi Chemical Foods) Carmellose: NS-300 (Gotoku Pharmaceutical) Carmellose calcium: ECG505 (Gotoku Pharmaceutical) Hydrous silicon dioxide: Carplex # 80 (DSL.
  • Croscarmellose sodium Kikkolate (Asahi Kasei Chemicals)
  • Crospovidone Polyplusdon XL-10 (ISP)
  • Crystalline cellulose Theolas PH101 (Asahi Kasei Chemicals) Saccharin sodium: Saccharin sodium hydrate (Daiwa Kasei)
  • Sucralose Sucralose (San-Eigen FFI)
  • Magnesium stearate Magnesium stearate vegetable (Taihei Chemical Industry)
  • Somachin Sun Sweet (San-Ei Gen F.F.I.)
  • Low-substituted hydroxypropyl cellulose L-HPC LH-21 (Shin-Etsu Chemical)
  • Sodium starch glycolate Primojel (DMV)
  • Corn starch Corn starch (Nippon Food Chemicals) Hydroxypropyl cellulose: HPC-SL (Nippon Soda)
  • Coating agent B OPADRY 03F440011 PINK (hypromellose 2910 71.9%, Macrogol 6000 14.0%, talc 7.0%, titanium oxide 7.0%, iron sesquioxide 0.1%) dispersed in water was used.
  • Tableting machine Tabflex TAB10 (Okada Seiko)
  • Rolling fluid granulation dryer Multiplex MP-01 (Paurec)
  • Rotary tableting machine HT-P18A (Hatabeko)
  • Test Example 1 Dissolution test (1) The uncoated tablets of Examples 1 to 3 and Comparative Examples 1 to 5 were used as test preparations. The test preparation was stored for 7 days under the conditions of a temperature of 60 ° C. and a relative humidity of 75%, and the dissolution rate of tosufloxacin tosylate hydrate 15 minutes before and after storage was determined.
  • Test Method According to the 16th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), 1 tablet of each test preparation was added to 900 mL of water and stirred at 50 rpm. The eluate was collected by an automatic sampling device 15 minutes after the start of the elution test and filtered with a filter having a pore size of 35 ⁇ m. The concentration of tosufloxacin tosylate was measured according to UV-Vis absorbance measurement method ⁇ Japanese Pharmacopoeia General Test Method 2.24>. The results are shown below.
  • the tablets of Examples 1 to 3 are tablets containing disintegrant A.
  • the tablets of Comparative Examples 1 to 5 are tablets containing no disintegrant A or disintegrant B. Tablets containing carmellose, carmellose calcium or croscarmellose sodium showed rapid dissolution after storage for 7 days at a temperature of 60 ° C. and a relative humidity of 75% (Examples 1 to 3).
  • tablets containing low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, pregelatinized starch or partially pregelatinized starch did not show rapid dissolution after storage for 7 days under the same conditions (Comparative Example 1). ⁇ 5).
  • the tablet of the present invention showed better dissolution than the tablet of the comparative example.
  • Test Example 2 Dissolution test (2) The uncoated tablets of Examples 4 to 6 and Comparative Examples 6 to 14 were used as test preparations. The test preparation was stored for 7 days under the conditions of a temperature of 60 ° C. and a relative humidity of 75%, and the dissolution rate of tosufloxacin tosylate hydrate 15 minutes before and after storage was determined. The test was performed in the same manner as in Test Example 1. The results are shown below.
  • the tablets of Examples 4 to 6 are tablets containing disintegrant B.
  • the tablets of Comparative Examples 6 to 11 are tablets containing only one kind selected from disintegrant B, low-substituted hydroxypropylcellulose and crospovidone.
  • the tablets of Comparative Examples 12 to 14 are tablets containing no disintegrant A or disintegrant B. Tablets containing low-substituted hydroxypropylcellulose and crospovidone did not show rapid dissolution (Test Example 1, Comparative Examples 1 and 2). On the other hand, tablets containing a combination of low-substituted hydroxypropylcellulose and crospovidone showed rapid dissolution (Examples 4 to 6).
  • tablets combining low-substituted hydroxypropylcellulose or crospovidone and sodium starch glycolate, pregelatinized starch or partially pregelatinized starch did not show rapid dissolution (Comparative Examples 6 to 11).
  • tablets containing two kinds selected from sodium starch glycolate, pregelatinized starch and partially pregelatinized starch did not show rapid dissolution (Comparative Examples 12 to 14). It was revealed that a tablet exhibiting rapid dissolution can be produced by using a combination of low-substituted hydroxypropylcellulose and crospovidone.
  • Test Example 3 Dissolution test (3) The uncoated tablets of Comparative Examples 15 to 18 were used as test preparations. The dissolution rate after 15 minutes of tosufloxacin tosylate hydrate of the test preparation was determined. The test was performed in the same manner as in Test Example 1. The results are shown below.
  • the tablets of Comparative Examples 15 to 17 are tablets containing disintegrant A and no acidic amino acid.
  • the tablet of Comparative Example 18 is a tablet containing an acidic amino acid and no disintegrant A or disintegrant B. Tablets containing carmellose, carmellose calcium or croscarmellose sodium as a disintegrant and not containing L-aspartic acid did not show rapid dissolution (Comparative Examples 15 to 17). In addition, tablets containing L-aspartic acid as an acidic amino acid and not disintegrating agent A or B did not show rapid dissolution (Comparative Example 18). It became clear that acidic amino acids and disintegrant A or disintegrant B are essential components of the tablet of the present invention.
  • Test Example 4 Dissolution test (4) As test preparations, the film-coated tablets of Examples 7 and 8 and the plain tablets of Examples 9 to 12 were used. The test preparation was stored under conditions of a temperature of 40 ° C. and a relative humidity of 75%, and the dissolution rate of tosufloxacin tosylate hydrate 15 minutes before and after storage was determined. Examples 7 and 8 were stored for 0.5, 1 and 3 months and Examples 9-12 were stored for 1 month. The test was performed in the same manner as in Test Example 1. The results are shown below.
  • the tablet of Example 7 is a film-coated tablet containing an acidic amino acid and a disintegrant B.
  • the tablet of Example 8 is a film-coated tablet containing an acidic amino acid, a disintegrant B, and a sweetener.
  • the tablets of Examples 7 and 8 showed rapid dissolution even after storage for 3 months.
  • the tablets of Examples 9 to 12 are uncoated tablets containing an acidic amino acid, a disintegrant B, and a sweetener.
  • the tablets of Examples 9 to 12 showed rapid dissolution even after storage for 1 month.
  • Example 1 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 4.5 g, erythritol 4.35 g, hydrous silicon dioxide 1.5 g, carmellose 3.0 g and hydroxypropylcellulose 0.9 g are weighed and mixed with a sieve having an opening of 500 ⁇ m and mixed. did. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Example 2 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 4.5 g, erythritol 4.35 g, hydrous silicon dioxide 1.5 g, carmellose calcium 3.0 g and hydroxypropylcellulose 0.9 g were weighed and sieved with a sieve having an opening of 500 ⁇ m. , Mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Example 3 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 4.5 g, erythritol 4.35 g, hydrous silicon dioxide 1.5 g, croscarmellose sodium 3.0 g and hydroxypropylcellulose 0.9 g are weighed and sieved with a sieve having an opening of 500 ⁇ m After that, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Example 4 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 4.5 g, erythritol 4.35 g, hydrous silicon dioxide 1.5 g, low-substituted hydroxypropylcellulose 2.7 g, crospovidone 0.3 g and hydroxypropylcellulose 0.9 g were weighed, The mixture was sieved with a sieve having an opening of 500 ⁇ m and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Example 5 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 4.5 g, erythritol 4.35 g, hydrous silicon dioxide 1.5 g, low-substituted hydroxypropylcellulose 2.1 g, crospovidone 0.9 g and hydroxypropylcellulose 0.9 g were weighed, The mixture was sieved with a sieve having an opening of 500 ⁇ m and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Example 6 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 4.5 g, erythritol 4.35 g, hydrous silicon dioxide 1.5 g, low-substituted hydroxypropylcellulose 1.5 g, crospovidone 1.5 g and hydroxypropylcellulose 0.9 g were weighed, The mixture was sieved with a sieve having an opening of 500 ⁇ m and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Example 7 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 33.3 g, erythritol 22.7 g, hydrous silicon dioxide 10.0 g, low-substituted hydroxypropylcellulose 20.0 g and crospovidone 6.0 g were weighed and sieved with an opening of 850 ⁇ m After sieving, it was charged into a rolling fluidized granulator and mixed. Thereafter, 300 g of a 2% hydroxypropylcellulose aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder.
  • Example 8 Tosfloxacin tosylate hydrate 100.0 g, L-aspartic acid 33.3 g, erythritol 20.7 g, hydrous silicon dioxide 10.0 g, low-substituted hydroxypropylcellulose 20.0 g, crospovidone 6.0 g and aspartame 2.0 g are weighed and opened After sieving with an 850 ⁇ m sieve, the mixture was charged into a tumbling fluidized granulator and mixed. Thereafter, 300 g of a 2% hydroxypropylcellulose aqueous solution was sprayed to granulate, dried and sized to obtain a granulated powder.
  • Example 9 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 5.0 g, erythritol 3.1 g, hydrous silicon dioxide 1.5 g, low-substituted hydroxypropylcellulose 3.0 g, crospovidone 0.9 g, sucralose 0.3 g and hydroxypropylcellulose 0.9 g The sample was weighed, sieved with a sieve having an opening of 500 ⁇ m, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • a 1% equivalent amount of magnesium stearate was added to the granulated powder through a sieve having an opening of 500 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a tablet surface, and 120 mg round uncoated tablets were obtained per tablet.
  • Example 10 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 5.0 g, erythritol 3.1 g, hydrous silicon dioxide 1.5 g, low-substituted hydroxypropylcellulose 3.0 g, crospovidone 0.9 g, thaumatin 0.3 g and hydroxypropylcellulose 0.9 g The sample was weighed, sieved with a sieve having an opening of 500 ⁇ m, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • a 1% equivalent amount of magnesium stearate was added to the granulated powder through a sieve having an opening of 500 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a tablet surface, and 120 mg round uncoated tablets were obtained per tablet.
  • Example 11 Tosufloxacin tosylate hydrate 15.0 g, L-aspartic acid 5.0 g, erythritol 3.1 g, hydrous silicon dioxide 1.5 g, low substituted hydroxypropylcellulose 3.0 g, crospovidone 0.9 g, acesulfame potassium 0.3 g and hydroxypropylcellulose 0.9 g Were weighed, sieved with a sieve having an opening of 500 ⁇ m, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • a 1% equivalent amount of magnesium stearate was added to the granulated powder through a sieve having an opening of 500 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a tablet surface, and 120 mg round uncoated tablets were obtained per tablet.
  • Example 12 Tosfloxacin tosylate hydrate 15.0 g, L-aspartic acid 5.0 g, erythritol 3.1 g, hydrous silicon dioxide 1.5 g, low-substituted hydroxypropylcellulose 3.0 g, crospovidone 0.9 g, saccharin sodium 0.3 g and hydroxypropylcellulose 0.9 g The sample was weighed, sieved with a sieve having an opening of 500 ⁇ m, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • a 1% equivalent amount of magnesium stearate was added to the granulated powder through a sieve having an opening of 500 ⁇ m and mixed to obtain a tableted powder.
  • This tableting powder was compression-molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a tablet surface, and 120 mg round uncoated tablets were obtained per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Comparative Example 5 Weigh 15.0 g of tosufloxacin tosylate hydrate, 4.5 g of L-aspartic acid, 4.35 g of erythritol, 1.5 g of hydrous silicon dioxide, 3.0 g of partially pregelatinized starch and 0.9 g of hydroxypropyl cellulose, and sieve with a sieve having an opening of 500 ⁇ m. After that, they were mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • This tableting powder was compression molded with a tableting machine using a tablet with a tablet diameter of 6.5 mm and a round uncoated tablet of 119 mg per tablet.
  • Comparative Example 16 6.0 g of tosufloxacin tosylate hydrate, 1.92 g of crystalline cellulose, 0.9 g of carmellose calcium, and 0.09 g of hydroxypropylcellulose were weighed, sieved with a sieve having an opening of 500 ⁇ m, and mixed. The powder was put in a mortar, granulated while adding water, sized with a sieve having an opening of 850 ⁇ m, dried, and further sized with a sieve having an opening of 500 ⁇ m to obtain a granulated powder. A 1% equivalent amount of magnesium stearate was added to the granulated powder through a sieve having an opening of 500 ⁇ m and mixed to obtain a tableted powder. The tableting powder was compression-molded with a rotary tableting machine using a tablet with a tablet diameter of 6.0 mm and a tablet surface, and 90 mg round uncoated tablets were obtained per tablet.
  • a tableting powder 5.0 g of hydrous silicon dioxide, 17.5 g of corn starch, 7.5 g of crystalline cellulose and 1.2 g of magnesium stearate were added through a sieve having an opening of 500 ⁇ m and mixed to obtain a tableting powder.
  • This tableting powder was compression-molded with a rotary tableting machine using a tablet with a tablet diameter of 6.5 mm and a round tablet surface to obtain 120 mg round uncoated tablets per tablet.
  • the tablet of the present invention is useful as a tablet containing tosufloxacin tosylate that exhibits rapid dissolution and improved compliance with children.

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Abstract

Ce comprimé contenant (1) de la tosufloxacine tosilate, (2) un désintégrateur et (3) un acide aminé acide est utile en tant que comprimé contenant de la tosufloxacine tosilate qui se dissout rapidement, améliore l'observance médicamenteuse chez les enfants, et a une excellente stabilité au stockage.
PCT/JP2017/016682 2016-04-27 2017-04-27 Comprimé contenant de la tosufloxacine tosilate, un désintégrateur et un acide aminé acide WO2017188362A1 (fr)

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Citations (7)

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JPS6272616A (ja) * 1985-09-27 1987-04-03 Toyama Chem Co Ltd 抗菌剤
JPH092953A (ja) * 1995-06-16 1997-01-07 Chugai Pharmaceut Co Ltd バルフロキサシン製剤
JP2007510001A (ja) * 2003-11-04 2007-04-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト 薬剤特性が改善された矯味物質を含有する薬剤製剤
WO2013081044A1 (fr) * 2011-11-30 2013-06-06 富山化学工業株式会社 Pilule comprenant un hydrate de méthanesulfonate de 1-cyclopropyle-8-(difluorométhoxy)-7-[(1r)-1-méthyle-2,3-dihydro-1h-isoindol-5-yle]-4-oxo-1,4-dihydroquinoléine-3-acide carboxylique
JP2013147470A (ja) * 2012-01-20 2013-08-01 Nipro Corp 口腔内崩壊錠
CN106176646A (zh) * 2016-08-19 2016-12-07 珠海同源药业有限公司 一种甲苯磺酸妥舒沙星分散片及其制备方法
CN106310286A (zh) * 2016-08-19 2017-01-11 珠海同源药业有限公司 一种甲苯磺酸妥舒沙星组合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015129005A1 (fr) 2014-02-27 2015-09-03 株式会社小松製作所 Camion-benne

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6272616A (ja) * 1985-09-27 1987-04-03 Toyama Chem Co Ltd 抗菌剤
JPH092953A (ja) * 1995-06-16 1997-01-07 Chugai Pharmaceut Co Ltd バルフロキサシン製剤
JP2007510001A (ja) * 2003-11-04 2007-04-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト 薬剤特性が改善された矯味物質を含有する薬剤製剤
WO2013081044A1 (fr) * 2011-11-30 2013-06-06 富山化学工業株式会社 Pilule comprenant un hydrate de méthanesulfonate de 1-cyclopropyle-8-(difluorométhoxy)-7-[(1r)-1-méthyle-2,3-dihydro-1h-isoindol-5-yle]-4-oxo-1,4-dihydroquinoléine-3-acide carboxylique
JP2013147470A (ja) * 2012-01-20 2013-08-01 Nipro Corp 口腔内崩壊錠
CN106176646A (zh) * 2016-08-19 2016-12-07 珠海同源药业有限公司 一种甲苯磺酸妥舒沙星分散片及其制备方法
CN106310286A (zh) * 2016-08-19 2017-01-11 珠海同源药业有限公司 一种甲苯磺酸妥舒沙星组合物

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