WO2015152190A1 - Formulation solide granulaire contenant un ester de céphalosporine, et son procédé de production - Google Patents

Formulation solide granulaire contenant un ester de céphalosporine, et son procédé de production Download PDF

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WO2015152190A1
WO2015152190A1 PCT/JP2015/060034 JP2015060034W WO2015152190A1 WO 2015152190 A1 WO2015152190 A1 WO 2015152190A1 JP 2015060034 W JP2015060034 W JP 2015060034W WO 2015152190 A1 WO2015152190 A1 WO 2015152190A1
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granular solid
solid preparation
drug
production method
fatty acid
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PCT/JP2015/060034
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English (en)
Japanese (ja)
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美咲 吉村
佳子 久保
哲規 山川
将司 金子
裕將 冨田
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富山化学工業株式会社
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Priority to JP2016511904A priority Critical patent/JP6196730B2/ja
Publication of WO2015152190A1 publication Critical patent/WO2015152190A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a granular solid preparation containing a cephalosporin ester and a method for producing the same.
  • Non-patent Document 1 The granular solid preparations such as powders, fine granules, granules and dry syrups can be freely changed in dosage. Therefore, these formulations are important in improving medication compliance for children and / or the elderly. In granular solid preparations that can be easily taken by children and / or the elderly, it is required to suppress unpleasant tastes such as astringency and bitterness of medicinal ingredients (Non-patent Document 1). In recent years, it has been reported that resistant bacteria of Streptococcus pneumoniae and Haemophilus influenzae are increasing in the pediatric field and otolaryngology field (Non-Patent Documents 2, 3, and 4).
  • Cephalosporin esters are ⁇ -lactam antibiotics, and for example, cefteram pivoxil, cefcapene pivoxil and cefditoren pivoxil are known.
  • these drugs can have an unpleasant bitter taste.
  • it is necessary to devise methods such as imparting sweetness and masking the bitter taste. So far, composite granular solid preparations in which the bitter taste of cefteram pivoxil is reduced are known (Patent Document 1).
  • the drug content of granular solid preparations such as cephalosporin ester fine granules that are easy for children to take is only 10%. Therefore, when a high dose is administered, the upper limit (1 g) of the recommended single dose in the pharmacist association guidelines may be exceeded.
  • a method for reducing the bitter taste of a drug a method is known in which a sweetener layer is coated on the surface of a drug-containing coating layer that coats a core substance using an aqueous solution of a sweetener.
  • a granular solid preparation containing a cephalosporin ester having a high drug content is produced by this method, the drug may leak and cause bitterness.
  • Development of a granular solid preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness is strongly desired.
  • a granular solid preparation containing drug granules containing The drug-containing layer includes a cephalosporin ester and a hot melt material,
  • the content of hot melt material is 10-20% with respect to the mass of drug granules,
  • the content of cephalosporin ester is 20-40% of the mass of the granular solid preparation.
  • a granular solid preparation comprising a drug granule comprising (1) a core substance and (2) a drug-containing layer covering the core substance, wherein the drug-containing layer comprises a cephalosporin ester and a hot-melt substance
  • the hot-melt material is one or more selected from hydrogenated oil, higher alcohol, higher fatty acid, wax, vegetable or animal fat, ethylene oxide polymer, and sugar or glycerin fatty acid ester.
  • Granular solid formulation [12] The granular solid preparation according to [11], wherein the sweetener is one or more selected from sucrose, aspartame and acesulfame potassium.
  • a method for producing a granular solid preparation comprising drug granules comprising (1) a core substance, and (2) a drug-containing layer covering the core substance, wherein the drug-containing layer comprises a cephalosporin ester and a hot melt
  • the content of the hot melt substance is 10-20% with respect to the mass of the drug granules
  • the content of the cephalosporin ester is 20-40% with respect to the mass of the granular solid preparation
  • a production method comprising coating a core substance with a powder containing a cephalosporin ester and a hot-melt substance, and forming a drug-containing layer on the surface of the core substance.
  • the hot melt material is one or more selected from hydrogenated oil, higher alcohol, higher fatty acid, wax, vegetable or animal fat, ethylene oxide polymer and sugar or glycerin fatty acid ester.
  • the hot-melt material is a sucrose fatty acid ester.
  • the granular solid preparation of the present invention is a preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness, and has improved compliance with children and / or the elderly.
  • the production method of the present invention is useful as a production method of a preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness.
  • the “granular solid preparation” of the present invention means “a preparation containing drug granules”.
  • Drug granule means “a granule comprising a core substance and a drug-containing layer covering the core substance”.
  • Drug-containing layer means “a layer containing a cephalosporin ester and a hot-melt material covering a core material”.
  • Coating A means “present on at least a part of the surface of A”.
  • Examples of the core substance used in the present invention include purified sucrose, D-mannitol, lactose, erythritol, xylitol and sorbitol. Purified sucrose and D-mannitol are preferred, and purified sucrose is more preferred.
  • the content of the core substance is preferably 30 to 60%, more preferably 35 to 55%, still more preferably 37 to 53% with respect to the mass of the granular solid preparation.
  • cephalosporin ester examples include cefteram pivoxil, cefcapene pivoxil and cefditoren pivoxil, and cefteram pivoxil is preferable.
  • Cephalosporin esters are metabolized in the body to form cephalosporin and exhibit antibacterial activity.
  • cefteram pivoxil is metabolized in the body to cefteram and exhibits antibacterial activity.
  • Cefteram pivoxil can be produced, for example, by the method described in JP-B-60-52755.
  • Cephalosporin esters include hydrates, solvates and crystals of various shapes as well as amorphous forms.
  • the content of the cephalosporin ester is preferably 20 to 40%, more preferably 22 to 38%, still more preferably 23 to 35% with respect to the mass of the granular solid preparation.
  • the hot-melt material used in the present invention melts by heating and acts as a coating agent for the granulated powder surface when a layer containing a drug is formed on the granulated powder surface.
  • the hot melt material used in the present invention include hardened oils such as hardened castor oil, hardened soybean oil and hardened rapeseed oil; higher alcohols such as stearyl alcohol and cetanol; higher fatty acids such as stearic acid and palmitic acid; carnauba wax Waxes such as cocoa butter and beef tallow; ethylene oxide polymers such as Macrogol 4000 and Macrogol 6000; and sugars such as sucrose fatty acid esters or fatty acid esters of glycerin, etc. May be used in combination.
  • Preferable hot melt materials include sucrose fatty acid esters.
  • the content of the hot melt substance is preferably 10 to 20%, more preferably 11 to 18%, based on the mass of the drug granule.
  • the drug-containing layer covers the core material and includes a cephalosporin ester and a hot melt material.
  • the drug-containing layer is present on at least a part of the surface of the core substance.
  • the drug-containing layer preferably covers 1/4 or more of the surface of the core substance, more preferably 1/2 or more, and covers the entire surface of the core substance. Further preferred.
  • the drug-containing layer preferably contains a disintegrant. Examples of the disintegrant include one or more selected from crospovidone, carmellose calcium, and croscarmellose sodium.
  • the disintegrant is preferably one or two selected from crospovidone and croscarmellose sodium, and more preferably crospovidone.
  • the content of the disintegrant is preferably 1 to 7%, more preferably 2 to 4% with respect to the mass of the granular solid preparation.
  • the granular solid preparation includes a drug granule including (1) a core substance, and (2) a drug-containing layer covering the core substance.
  • Examples of granular solid preparations include powders, fine granules, granules, and dry syrup.
  • the granular solid preparation may contain a solid substance not containing a drug in addition to the drug granule. Examples of solids that do not contain a drug include solids intended for sweetness.
  • the granular solid preparation of the present invention preferably contains a “layer containing thaumatin covering the drug-containing layer”.
  • the thaumatin used in the present invention can be extracted and purified from the fruit of Thaumatococcus daniellii of the family of Marantaceae by a known method, but is commercially available thaumatin (for example, Sun Sweet T; Saneigen EF -Eye) can also be used. Also called thaumatin.
  • the content of thaumatin is preferably 0.001 to 0.2%, more preferably 0.005 to 0.1% with respect to the mass of the granular solid preparation.
  • the layer containing thaumatin is present on at least a part of the surface of the drug-containing layer.
  • the layer containing thaumatin preferably covers 1/4 or more of the surface of the drug-containing layer, more preferably 1/2 or more, and covers the entire surface of the drug-containing layer. More preferably.
  • the layer containing thaumatin preferably further contains a sweetener.
  • the sweetener used in the present invention include sucrose, aspartame, neotame, saccharin, sodium saccharin, stevia, sucralose, trehalose, erythritol, sorbitol, xylitol and acesulfame potassium, and sucrose, aspartame and acesulfame potassium. Is preferred.
  • Sweetening agents may be used in combination. The content of the sweetening agent is preferably 1 to 10%, more preferably 2 to 7%, based on the mass of the granular solid preparation.
  • additives can be used as long as the effects of the present invention are not impaired.
  • Such additives include lubricants, colorants, flavoring agents, surfactants, disintegrants and suspending agents.
  • lubricant include magnesium stearate, talc, hydrous silicon dioxide, and light anhydrous silicic acid.
  • the colorant include iron sesquioxide, yellow sesquioxide, edible red No. 102, edible yellow No. 4, and 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, Powder flavors such as peach micron, strawberry micron and orange micron; vanillin and ethyl vanillin.
  • surfactant include sodium lauryl sulfate and dioctyl sodium sulfosuccinate.
  • suspending agent include carmellose sodium, sodium alginate, methyl cellulose, polysorbate 80, tragacanth powder, carrageenan and xanthan gum.
  • the granular solid preparation of the present invention can be used as a preparation of powders, granules, fine granules, dry syrups and the like by a conventional method using pharmaceutically acceptable excipients such as excipients, carriers and diluents as appropriate. However, for example, it is preferably used as a fine granule and powder for oral use and a suspension dispersed in water or syrup.
  • the administration method, dose and number of administrations can be appropriately selected according to the age, weight and symptoms of the patient, but usually the amount that can exert the drug effect is divided into 1 to several times a day.
  • cefteram pivoxil may be orally administered in a daily dose of 9 to 18 mg (titer) / kg divided into three doses.
  • 150-600 mg (titer) daily as cefteram pivoxil should be divided into 3 doses and administered orally after meals.
  • the method for producing a granular solid preparation of the present invention is a method for producing a granular solid preparation comprising drug granules comprising (1) a core substance, and (2) a drug-containing layer covering the core substance, wherein the drug-containing layer comprises: , Cephalosporin ester and hot melt substance, the content of hot melt substance is 10-20% with respect to the mass of drug granules, and the content of cephalosporin ester is with respect to the mass of the granular solid preparation
  • the manufacturing method is characterized in that the core material is coated with a powder containing a cephalosporin ester and a hot-melt material to form a drug-containing layer on the surface of the core material.
  • the method for producing the granular solid preparation of the present invention is not particularly limited, but the core material heated to the vicinity of the melting point of the hot melt material is stirred, fluidized or fluidly stirred, the hot melt material, the cephalosporin ester and the necessary It is preferable to perform granulation near the melting point of the hot-melt material by adding a powder obtained by adding other additives according to the conditions.
  • the substance generated by melting the hot melt substance becomes a binder, and the cephalosporin ester and other additives are bound onto the core substance.
  • a layer containing a cephalosporin ester and a hot melt material covering a core material A method for producing a granular solid preparation containing a drug granule containing sucrose is preferred, a tumbling stirring granulation method and a tumbling fluid stirring granulation method are more preferred, and a rolling fluid stirring granulation method is more preferred.
  • a method of forming a “layer containing thaumatin covering a drug-containing layer” is preferable.
  • a method in which a core material is coated with a powder containing a drug and a hot-melt material, and then a layer containing thaumatin is formed without adding water is preferable.
  • other layers may be formed according to a conventional method in addition to the drug-containing layer and the layer containing thaumatin as long as the effects of the present invention are not impaired.
  • another layer may be formed between the core substance and the drug-containing layer, or another layer may be formed between the drug-containing layer and the layer containing thaumatin, and the surface of the layer containing thaumatin
  • Other layers may be formed.
  • the other layer is a layer containing an additive generally used for a drug, and may be two or more layers.
  • Cefteram pivoxil Toyama Chemical Co., Ltd.
  • Cefditoren pivoxil Purified white sugar: Sukurene SR80 / 100 Refined white sugar pulverized product: Granulated sugar (Shisui Port Sugar Co., Ltd.)
  • Sucrose fatty acid ester Ryoto sugar ester S-370F (Mitsubishi Chemical Foods)
  • Crystalline cellulose / carmellose sodium Theolas RC-A591NF (Asahi Kasei Chemicals Corporation)
  • Carmellose calcium ECG-505 (Nichirin Chemical Industry Co., Ltd.)
  • Carmellose sodium CMC Daicel 1190J (Daicel Finechem Co., Ltd.)
  • Crospovidone Polyplusdon XL-10 (IS Japan Co., Ltd.) Croscarmellose sodium: Primerose (DMV Japan) Aspartame (Ajinomoto Co., Inc.) Aces
  • Rolling fluid granulation coating equipment Multiplex MP-10 (Paurec Co., Ltd.)
  • Granulator Power mill, Model P-5S, 24 mesh screen (Showa Giken Co., Ltd.)
  • the colored sukurene used in the examples is charged with 78.0 kg of refined sucrose in a film coating apparatus (Doria Coater DRC1200; Pou Lec). A colored liquid consisting of 0.499 kg of purified water was sprayed and dried.
  • Example 1a 356 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 82 ° C., and a mixture of 309 g of cefteram pivoxil, 139 g of sucrose fatty acid ester and 29.0 g of carmellose calcium was stirred while rotating at 300 rpm. Added over a minute. After stirring for 3 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 2a 371 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 82 ° C., and a mixture of 310 g of cefteram pivoxil, 124 g of sucrose fatty acid ester and 29.2 g of carmellose calcium was stirred while rotating at 350 rpm. Added over a minute. After stirring for 6 minutes, it was passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 3a 362 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 82 ° C., and a mixture of 309 g of cefteram pivoxil, 133 g of sucrose fatty acid ester and 29.1 g of carmellose calcium was stirred while rotating at 300 rpm. Added over a minute. After stirring for 6 minutes, it was passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 4a 299 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 85 ° C., and a mixture of 266 g of cefteram pivoxil, 127 g of sucrose fatty acid ester and 25.0 g of carmellose calcium was stirred with a rotation speed of 250 rpm. Added over a minute. Further, a mixture of 3.1 g of sucrose fatty acid ester, 40.1 g of purified sucrose pulverized product and 15.0 g of crystalline cellulose / carmellose sodium was added over 1 minute and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation. It was.
  • Example 5a In the same manner as in Example 4a, a granular granulated powder was produced using 299 g of colored skrane, 266 g of cefteram pivoxil, 127 g of sucrose fatty acid ester and 25.1 g of crospovidone. Further, 3.0 g of sucrose fatty acid ester, 40.0 g of purified white sugar pulverized product and 15.0 g of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 6a In the same manner as in Example 4a, a granular granulated powder was produced using 299 g of colored skrane, 266 g of cefteram pivoxil, 127 g of sucrose fatty acid ester and 25.2 g of croscarmellose sodium. Further, 3.1 g of sucrose fatty acid ester, 40.1 g of purified sucrose pulverized product and 15.0 g of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 7a 30.9 kg of colored skelenium was charged into a tumbling fluidized granulation coating device (multiplex MP-200; Powrec Co., Ltd.) set at a jacket temperature of 80 ° C., while stirring at 110 rpm, 16.0 kg of cefteram pivoxil, sucrose A mixture of 6.86 kg fatty acid ester and 1.50 kg crospovidone was added over 20 minutes. After stirring for 17 minutes, 0.18 kg of sucrose fatty acid ester was added over 1 minute.
  • a tumbling fluidized granulation coating device multiplex MP-200; Powrec Co., Ltd.
  • Example 8a 30.8 kg of refined white sugar was charged into a rolling fluidized granulation coating device (multiplex MP-200; POWREC Co., Ltd.) set at a jacket temperature of 80 ° C. Cefteram pivoxil 16.0 kg, sucrose fatty acid ester with stirring at 110 rpm A mixture of 7.02 kg, crospovidone 1.50 kg and colorant 0.0048 kg was added over 20 minutes. After stirring for 4 minutes, 0.18 kg of sucrose fatty acid ester was added over 1 minute.
  • a rolling fluidized granulation coating device multiplex MP-200; POWREC Co., Ltd.
  • Example 9a Charge 31.1kg of refined sucrose to a rolling fluidized granulation coating device (multiplex MP-200; Pauleck Co., Ltd.) set at a jacket temperature of 79 ° C, and 16.0 kg of cefteram pivoxil, sucrose fatty acid ester with stirring at 110 rpm A mixture of 7.02 kg, crospovidone 1.50 kg and colorant 0.009 kg was added over 26 minutes. After stirring for 5 minutes, a mixture of 1.80 kg of purified sucrose ground product, 0.60 kg of carmellose sodium, 1.05 kg of aspartame, 0.60 kg of acesulfame potassium and 0.003 kg of iron sesquioxide was added over 1 minute.
  • a rolling fluidized granulation coating device multiplex MP-200; Pauleck Co., Ltd.
  • Example 10a 388 g of purified white sugar was charged into a tumbling fluidized granulation coating device set at a jacket temperature of 80 ° C, and a mixture of 174 g of cefteram pivoxil, 130 g of sucrose fatty acid ester and 24.8 g of sucrose fatty acid was applied for 8 minutes while stirring at a rotation speed of 250 rpm. Added. Further, a mixture of 3.1 g of sucrose fatty acid ester, 40.3 g of purified white sugar pulverized product and 14.7 g of carmellose sodium was added over 1 minute, stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 11a Add 10.7g of purified sucrose to a mortar set at a temperature of 90-105 ° C, add a mixture of cefditoren pivoxil 5.3g, sucrose fatty acid ester 3.4g and crospovidone 0.7g while stirring with a pestle, 20 mesh A granular solid preparation was obtained by passing through a sieve.
  • Comparative Example 1a A mixture of 8.3 g of cefteram pivoxil, 5.3 g of sucrose fatty acid ester and 0.8 g of carmellose calcium was added to a mortar heated to 80 ° C. with 10.1 g of purified white sugar and stirred with a pestle. Further, a mixture of 0.1 g of sucrose fatty acid ester and 0.5 g of crystalline cellulose / carmellose sodium was added and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Comparative Example 2a A mixture of 2.7 g of cefteram pivoxil, 0.7 g of sucrose fatty acid ester and 0.3 g of carmellose calcium was added while stirring 3.6 g of purified white sugar in a mortar heated to 80 ° C. The resulting mixture was a mixture of granulated powder consisting of cefteram pivoxil, sucrose fatty acid ester and carmellose calcium, and purified white sugar with almost no coating layer.
  • Comparative Example 3a 389g of refined sucrose was charged into a tumbling fluidized granulation coating device set at a jacket temperature of 80 ° C, and a mixture of 288g cefteram pivoxil, 71g sucrose fatty acid ester and 27.1g carmellose calcium was stirred for 12 minutes while stirring at 250rpm. Added over time. After stirring for 11 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Comparative Example 4a 298 g of refined sucrose was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C., and 8 g of a mixture of 287 g of cefteram pivoxil, 164 g of sucrose fatty acid ester and 27.1 g of carmellose calcium was stirred with a rotation speed of 350 rpm. Added over a minute. After stirring for 4 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Tables 1 to 3 show a list of prescriptions for Examples and Comparative Examples.
  • Table 4 shows the content (%) of the hot-melt substance with respect to the mass of the drug granules and the content (%) of the cephalosporin ester with respect to the mass of the granular solid preparation.
  • Example 1b Add 40.2 parts of colored sukurene to a mortar set to 90-98 ° C and add a mixture of 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of crospovidone while stirring with a pestle. Manufactured. Further, a mixture of 0.4 part of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium was added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 2b In the same manner as in Example 1b, a granular granulated powder was produced using 40.2 parts of colored skraine, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of carmellose calcium. Furthermore, 0.4 part of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 3b In the same manner as in Example 1b, a granular granulated powder was produced using 40.2 parts of colored skrane, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of croscarmellose sodium. Furthermore, 0.4 part of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 4b 38.6 parts of colored skrene is charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 85 ° C, and granulated using 34.3 parts of cefteram pivoxil, 16.4 parts of sucrose fatty acid ester and 3.2 parts of carmellose calcium while stirring at 250 rpm. Granules were produced. Further, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 1.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 5b In the same manner as in Example 4b, a granular granulated powder was produced using 38.6 parts of colored skraine, 34.3 parts of cefteram pivoxil, 16.4 parts of sucrose fatty acid ester and 3.2 parts of crospovidone. Further, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 1.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 6b In the same manner as in Example 4b, a granular granulated powder was produced using 38.6 parts of colored skraine, 34.3 parts of cefteram pivoxil, 16.4 parts of sucrose fatty acid ester and 3.2 parts of croscarmellose sodium. Further, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 1.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 7b 48.8 parts of colored skrene is charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C., and stirred with 350 rpm, granulated using 26 parts of cefteram pivoxil, 11.2 parts of sucrose fatty acid ester and 2.4 parts of carmellose calcium A granulated powder was produced. Further, 0.3 part of sucrose fatty acid ester, 3.9 parts of purified white sugar pulverized product and 2.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition.
  • Example 8b In the same manner as in Example 7b, a granular granulated powder was produced using 48.8 parts of colored skraine, 26 parts of cefteram pivoxil, 11.2 parts of sucrose fatty acid ester and 2.4 parts of crospovidone. Further, 0.3 part of sucrose fatty acid ester, 3.9 parts of purified white sugar pulverized product and 2.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition.
  • Example 9b Charge 51.8 parts of refined sucrose to a tumbling fluidized granulation coating device (multiplex MP-200; Pauleck Co., Ltd.) set at a jacket temperature of 79 ° C. While stirring at 110 rpm, 26.6 parts of cefteram pivoxil and sucrose fatty acid ester 11.7 Particulate, 2.5 parts of crospovidone and 0.015 part of colorant were used to produce a granular granulated powder. Further, 3.0 parts of purified sucrose pulverized product, 1 part of carmellose sodium, 1.75 parts of aspartame, 1 part of acesulfame potassium and 0.005 part of coloring agent were added and stirred, and passed through a 20 mesh sieve. Further, 0.25 part of aspartame, 0.01 part of thaumatin, 0.25 part of hydrous silicon dioxide and 0.1 part of flavoring agent were mixed to obtain a granular solid preparation.
  • a tumbling fluidized granulation coating device multiplex MP-200;
  • Example 10b A mixture of 20.0 parts of cefteram pivoxil, 16.8 parts of sucrose fatty acid ester, and 3.2 parts of crospovidone is charged into a rolling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C. with stirring at a rotational speed of 250 rpm. Was added over 8 minutes. Further, a mixture of 0.4 part of sucrose fatty acid ester, 5.2 parts of purified sucrose pulverized product and 1.9 parts of carmellose sodium was added over 1 minute and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 11b 40.5 parts of refined sucrose is charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C., and a mixture of 37.1 parts cefteram pivoxil, 11.7 parts sucrose fatty acid ester and 3.2 parts crospovidone while stirring at a rotation speed of 300 rpm. Was added over 10 minutes. Further, a mixture of 0.4 part of sucrose fatty acid ester, 5.2 parts of purified sucrose pulverized product and 1.9 parts of carmellose sodium was added over 1 minute and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Comparative Example 1b In the same manner as in Example 1b, a granulated product was prepared using 40.2 parts of colored skrane, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of low-substituted hydroxypropylcellulose (L-HPC LH-11; Shin-Etsu Chemical Co., Ltd.). Granules were produced. Furthermore, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Example 2b In the same manner as in Example 1b, a granular granulated powder was produced using 40.2 parts of colored sukurene, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of sodium carboxymethyl starch (Primogell; DMV Japan). Furthermore, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.
  • Tables 5 and 6 show a list of prescriptions for Examples and Comparative Examples.
  • Examples 1b-11b are formulations containing a disintegrant selected from crospovidone, carmellose calcium and croscarmellose sodium.
  • Comparative Examples 1b and 2b are preparations containing a disintegrant selected from low-substituted hydroxypropylcellulose and sodium carboxymethyl starch.
  • Examples 7b to 9b are preparations containing a disintegrant selected from crospovidone and carmellose calcium and further added with various sweeteners.
  • Example 1c 777 g of refined white sugar was charged into a tumbling fluidized granulation coating device set at a jacket temperature of 80 ° C, and a mixture of 399 g of cefteram pivoxil, 176 g of sucrose fatty acid ester, 37.5 g of crospovidone and 0.22 g of colorant was stirred at 300 rpm. This was added to produce a granular granulated powder. Further, a mixture of purified sucrose pulverized product 45.0 g, carmellose sodium 15.0 g and colorant 0.08 g was added and stirred, and passed through a 20 mesh sieve to obtain a granular composition. 96.6 g of the obtained granular composition was mixed with 0.25 g of hydrous silicon dioxide, 0.1 g of a flavoring agent and 0.1 g of thaumatin to obtain a granular solid preparation.
  • Example 2c In the same manner as in Example 1c, granular granulated powder was produced using purified white sugar 777 g, cefteram pivoxil 399 g, sucrose fatty acid ester 176 g, crospovidone 37.5 g and colorant 0.22 g. Further, 45.0 g of purified sucrose pulverized product, 15.0 g of carmellose sodium and 0.08 g of colorant were added and stirred, and passed through a 20 mesh sieve to obtain a 20 mesh sieve to obtain a granular composition. 96.6 g of the obtained granular composition was mixed with 0.25 g of hydrous silicon dioxide, 0.1 g of flavoring agent, and 0.01 g of thaumatin to obtain a mixed powder. 48.5 g of the obtained mixed powder, 0.5 g of acesulfame potassium, 0.5 g of aspartame and 0.0285 g of thaumatin were mixed to obtain a granular solid preparation.
  • Comparative Example 1c In the same manner as in Example 1c, granular granulated powder was produced using purified white sugar 777 g, cefteram pivoxil 399 g, sucrose fatty acid ester 176 g, crospovidone 37.5 g and colorant 0.22 g. Further, 45.0 g of purified sucrose pulverized product, 15.0 g of carmellose sodium and 0.08 g of colorant were added and stirred, and passed through a 20 mesh sieve to obtain a 20 mesh sieve to obtain a granular composition. 96.6 g of the obtained granular composition was mixed with 0.25 g of hydrous silicon dioxide and 0.1 g of a flavoring agent to obtain a granular solid preparation.
  • Comparative Example 2c In the same manner as in Example 1c, granular granulated powder was produced using purified white sugar 777 g, cefteram pivoxil 399 g, sucrose fatty acid ester 176 g, crospovidone 37.5 g and colorant 0.22 g. Further, 45.0 g of purified sucrose pulverized product, 15.0 g of carmellose sodium and 0.08 g of colorant were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition.
  • Table 7 shows a list of prescriptions for Examples and Comparative Examples.
  • Example 2c and Comparative Example 2c the amount of the sweetening agent was set so that the sum of the products of the mass percentage and the sweetness degree of each sweetening agent was equal.
  • the sweetness degree is an index of the sweetness of the sweetener and is a value obtained by comparing the sweetness of the sweetener based on the sweetness of sucrose.
  • Test Example 1a (1) Initial solubility The preparations obtained in Examples 1a to 10a and Comparative Example 3a were used as test preparations. A test preparation containing 50 mg of cefteram pivoxil was accurately weighed, placed in a 10 mL Spitz tube, added with 10 mL of distilled water, and stirred with a vortex mixer for 20 seconds. 1 mL of the resulting suspension was collected and filtered through a filter (Millex-LH, hydrophilic polytetrafluoroethylene (PTFE), pore diameter 0.45 ⁇ m, diameter 25 mm; Merck Millipore). The concentration of cefteram pivoxil in the obtained filtrate was measured under the following conditions.
  • PTFE hydrophilic polytetrafluoroethylene
  • Measurement condition detector UV absorption photometer Measurement wavelength: 254nm
  • Precolumn Develosil ODS-UG-5 4.0 ⁇ 10mm (Nomura Chemical)
  • Column temperature 25 ° C
  • Mobile phase water / acetonitrile / pH 5.0 acetic acid / sodium acetate buffer (Japanese Pharmacopoeia) (525: 375: 100)
  • Test Example 1a (2) Initial solubility The preparation obtained in Example 11a was used as a test preparation. A test preparation containing 50 mg of cefditoren pivoxil was accurately weighed, placed in a 10 mL Spitz tube, added with 10 mL of distilled water, and stirred with a vortex mixer for 20 seconds. 1 mL of the resulting suspension was collected and filtered through a filter (Millex-LH, hydrophilic polytetrafluoroethylene (PTFE), pore diameter 0.45 ⁇ m, diameter 25 mm; Merck Millipore). The cefditoren pivoxil concentration in the obtained filtrate was measured under the following conditions.
  • PTFE hydrophilic polytetrafluoroethylene
  • Measurement condition detector UV absorption photometer Measurement wavelength: 231nm
  • Example 1a to 11a had sufficiently low initial solubility, which is an index for feeling bitterness when taken, and showed excellent takeability.
  • the granular solid preparation of Comparative Example 3a in which the content of the hot-melt substance in the drug granules is 10% or less, has a high initial solubility and is easy to feel a bitter taste when taken.
  • Test Example 1b Initial solubility The preparations obtained in Examples 1b to 11b were used as test preparations. The test was performed in the same manner as in Test Example 1a (1). The results are shown in Table 9.
  • the preparations obtained in Examples 1b to 11b had sufficiently low initial solubility as an index for feeling bitterness at the time of taking, and showed excellent takeability.
  • Test Example 2a Dissolution Test The preparations obtained in Examples 4a to 10a, Comparative Example 1a and Comparative Example 4a were used as test preparations.
  • the dissolution test was carried out at 37 ° C. and 50 rpm according to the dissolution test method 2 (paddle method).
  • Test Example 2b Dissolution Test The preparations obtained in Examples 1b to 11b and Comparative Example 2b were used as test preparations. The test was performed in the same manner as in Test Example 2a. The results are shown in Table 11.
  • Test Example 3 Stability Test The preparations obtained in Examples 1b to 3b and Comparative Examples 1b and 2b were used as test preparations. 10 g of the test preparation was placed in a glass bottle and stored at 40 ° C. Three months after the start of the test, the residual rate of cefteram pivoxil of each test preparation was measured. Further, the initial solubility and dissolution rate of each preparation were measured in the same manner as in Test Example 1a (1) and Test Example 2a.
  • Residual rate (%) (content rate of cefteram pivoxil 3% after the start of the test (%) / content rate of cefteram pivoxil at the start of the test (%)) ⁇ 100 The results are shown in Table 12.
  • the preparations of Examples 1b to 3b had a residual rate of 95% or more, sufficiently low initial solubility, and an elution rate of 96% or more, which was excellent in storage stability.
  • the preparations of Comparative Examples 1b and 2b had a residual rate of less than 95% and did not show sufficient stability.
  • Test Example 4a Stability test The preparations obtained in Examples 4a to 6a, 8a and 9a were used as test preparations. 100 g of the preparations of Examples 4a to 6a and 7.5 g of desiccant (made of zeolite) were placed in a plastic bottle (body: HDPE; cap: PP) and stored at 40 ° C. and 75% RH. 100 g of the preparations of Examples 8a and 9a and 15 g of desiccant (made of zeolite) were placed in a plastic bottle and stored at 40 ° C. and 75% RH. The initial solubility of each test preparation 3 months after the start of the test and the residual rate 3 months after the start of the test were measured. Further, the initial solubility and dissolution rate of each preparation were measured in the same manner as in Test Example 1a (1) and Test Example 2a.
  • Example 4a to 6a, 8a, and 9a had a residual rate of 97% or more, sufficiently low initial solubility, and an elution rate of 84% or more, and were excellent in storage stability.
  • Test Example 4b Stability Test The preparations obtained in Examples 4b to 9b were used as test preparations. In the same manner as in Test Example 4a, the residual rate, initial solubility and dissolution rate of cefteram pivoxil of each preparation were measured. The results are shown in Table 14.
  • Example 4b to 9b had a residual ratio of 95% or more and were excellent in storage stability. Further, the initial solubility was sufficiently low, the elution rate was 85% or more, and the storage stability was excellent.
  • Test Example 5a Stability test The preparations obtained in Examples 8a and 9a were used as test preparations. 100 g of the test preparation and 15 g of a desiccant (made of zeolite) were placed in a plastic bottle (body: HDPE; cap: PP) and stored at 40 ° C. and 75% RH for 6 months. Six months after the start of the test, the residual rate, dissolution rate, and initial solubility of cefteram pivoxil of each preparation were measured. The results are shown in Table 15.
  • Example 8a and 9a had a residual rate of 97% or more, sufficiently low initial solubility, and an elution rate of 95% or more, which was excellent in storage stability.
  • Test Example 5b Stability test The preparations obtained in Examples 8b and 9b were used as test preparations. In the same manner as in Test Example 5a, the residual rate, initial solubility and dissolution rate of cefteram pivoxil of each preparation were measured. The results are shown in Table 16.
  • Example 8b and 9b had a residual rate of 97% or more, sufficiently low initial solubility, and an elution rate of 95% or more, which was excellent in storage stability.
  • Test Example 6c Taste sensory test for bitterness (1) A taste sensory test was conducted on five panelists. As the test preparation, the preparation of Example 1c and the preparation of Comparative Example 1c were used. The panelist contained 0.5 g of the first test preparation in the mouth for 30 seconds, and evaluated the bitterness at the time of taking and after taking it using the following scores. 15 minutes after taking the first preparation, and after the taste in the mouth disappeared, the second preparation was taken and evaluated in the same manner.
  • Example 1c Both the preparations of Example 1c and Comparative Example 1c had the same score when taken.
  • the score after taking was lowered and the bitterness remaining in the mouth was strong, whereas in the preparation of Example 1c, the score after taking was not lowered and the bitterness was reduced significantly. .
  • Test Example 7c Taste sensory test for bitterness (2) A taste sensory test was conducted on 15 panelists in the same manner as in Test Example 6c. As the test preparation, the preparation of Example 2c and the preparation of Comparative Example 2c were used.
  • Example 2c containing assulfame potassium and aspartame as sweeteners, a significant decrease in the score after taking was observed from the time of taking, and the bitter taste remaining in the mouth after taking the preparation could not be reduced.
  • Example 2c blended with thaumatin although the sweetness level of the whole granular solid preparation was the same as in Comparative Example 2c, the score after taking from the time of taking did not decrease, and the mouth after taking the preparation Residual bitterness was significantly reduced.
  • the granular solid preparation of the present invention is a preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness, and has improved compliance with children and / or the elderly. Useful as a formulation.

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Abstract

La présente invention concerne une formulation solide granulaire contenant des granules de médicament qui contiennent (1) une substance de noyau et (2) une couche contenant un médicament recouvrant la substance de noyau, une formulation solide granulaire dans laquelle la couche contenant le médicament contenant un ester de céphalosporine et une substance thermofusible, le rapport de teneur de substance thermofusible est situé dans la plage allant de 10 à 20 % par rapport à la masse des granules de médicament, et le rapport de teneur en ester de céphalosporine étant situé dans la plage allant de 20 à 40 % par rapport à la masse de la formulation solide granulaire, ladite formulation présentant une teneur élevée en médicament, une stabilité et une capacité d'élution exceptionnelles, et une amertume réduite, et est utile en tant que formulation améliorant l'observance chez les enfants et/ou les personnes âgées.
PCT/JP2015/060034 2014-03-31 2015-03-31 Formulation solide granulaire contenant un ester de céphalosporine, et son procédé de production WO2015152190A1 (fr)

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CN114983964A (zh) * 2022-06-24 2022-09-02 广东恒健制药有限公司 一种头孢地尼颗粒剂及其制备方法
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