US20150141517A1 - Granulated composite, rapid release tablet and method for producing same - Google Patents

Granulated composite, rapid release tablet and method for producing same Download PDF

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Publication number
US20150141517A1
US20150141517A1 US14/534,337 US201414534337A US2015141517A1 US 20150141517 A1 US20150141517 A1 US 20150141517A1 US 201414534337 A US201414534337 A US 201414534337A US 2015141517 A1 US2015141517 A1 US 2015141517A1
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Prior art keywords
weight
mannitol
granulated composite
aqueous dispersion
drug
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US14/534,337
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Inventor
Yasuyuki Hirama
Naosuke Maruyama
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Shin Etsu Chemical Co Ltd
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Shin Etsu Chemical Co Ltd
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Assigned to SHIN-ETSU CHEMICAL CO., LTD. reassignment SHIN-ETSU CHEMICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Hirama, Yasuyuki
Assigned to SHIN-ETSU CHEMICAL CO., LTD. reassignment SHIN-ETSU CHEMICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MARUYAMA, NAOSUKE
Publication of US20150141517A1 publication Critical patent/US20150141517A1/en
Priority to US16/601,270 priority Critical patent/US11723872B2/en
Abandoned legal-status Critical Current

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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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—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

Definitions

  • the present invention relates to a granulated composite and a rapid release tablet, each comprising low-substituted hydroxypropyl cellulose, which are used in the field of pharmaceuticals, food or the like; and a method for producing them.
  • orally rapidly disintegrating tablet which a patient having low swallowing ability, such as the aged or an infant, can take easily without water.
  • the orally rapidly disintegrating tablet is not limited to a patient having low swallowing ability, but is convenient and useful for any patient since it is in dosage form taken without water.
  • the orally rapidly disintegrating tablet is required to have a short disintegration time in the oral cavity and a tablet hardness enough to withstand breakage during production or transport.
  • the orally rapidly disintegrating tablet sometimes has a reduced hardness and a prolonged disintegration time owing to moisture absorbed thereby when exposed to a humidified environment after opening, it is desired in a medical site that the orally rapidly disintegrating tablet have excellent storage stability, allowing the tablet after opening to have the tablet hardness as high as and a disintegration time as short as those immediately after production.
  • Direct dry-tableting has recently attracted attentions as a method for producing an orally rapidly disintegrating tablet.
  • the direct dry-tableting is a method comprising the steps of simply mixing a drug and an additive, further mixing in addition of a lubricant, and then compression-molding the resulting mixture into tablets. This method is productive because it needs neither a special technology nor a special apparatus and further, it comprises neither a granulation step nor a drying step.
  • JP 2010-189384A discloses a granulation method using a sugar or sugar alcohol and an aqueous dispersion of low-substituted hydroxypropyl cellulose.
  • the orally rapidly disintegrating tablet obtained in the method of JP 2010-189384A is excellent in disintegrability but further improvement in moldability is desired.
  • the disintegration time sometimes increases during storage so that further improved storage stability is desired.
  • An object is to provide a granulated composite and a rapid release tablet excellent in binding capability and disintegrability and also excellent in storage stability.
  • the present inventors have studied a granulated composite comprising low-substituted hydroxypropyl cellulose and D-mannitol. As a result, it has been found unexpectedly that an orally disintegrating tablet comprising a drug and a granulated composite comprising low-substituted hydroxypropyl cellulose and D-mannitol having small D-sorbitol content is excellent in disintegrability and also excellent in storage stability, leading to the completion of the invention.
  • a granulated composite comprising low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of from 5 to 16% by weight and D-mannitol, wherein the D-mannitol contains 0.9% by weight or less of D-sorbitol.
  • a rapid release tablet comprising the granulated composite and a drug.
  • a method for producing a granulated composite comprising the steps of: mixing low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of from 5 to 16% by weight, first D-mannitol and water to obtain an aqueous dispersion, and granulating while adding the aqueous dispersion to second D-mannitol, wherein the first and the second D-mannitol contain 0.9% by weight or less of D-sorbitol.
  • a method for producing a rapid release tablet comprising each step comprised by the method for producing the granulated composite, a step of mixing the granulated composite with a drug to obtain a mixture, and a step of tableting the mixture.
  • the granulated composite can provide a rapid release tablet having high hardness and excellent disintegrability, free of reduction in hardness and increase in disintegration time under humidified conditions, and excellent in storage stability, without using a special method or special apparatus. Accordingly, a tablet which can be taken smoothly and handled easily can be produced with respect to oral administration of the tablet comprising a various type of drug in the field of pharmaceuticals, food or the like.
  • the granulated composite is nonionic and has low hygroscopicity so that it has less interaction with a drug and is suited for production of rapid release tablet excellent in stability.
  • D-mannitol is usually produced by hydrogenating easily available fructose as a raw material. Since hydrogenation of fructose is not stereoscopic, it produces D-mannitol and sorbitol in almost equal amounts. After the hydrogenation, therefore, D-mannitol is separated and purified in another step and then provided as a product.
  • D-mannitol is now produced by a plurality of manufacturers and its purification degree varies depending on a manufacturer. Even D-mannitol produced by the same manufacturer sometimes has a different degree of purification.
  • the present inventors have carried out an intensive investigation and have focused on the content of D-sorbitol slightly present as an impurity in D-mannitol which is one of sugar alcohols.
  • the D-sorbitol content in D-mannitol comprised by the granulated composite is less than 0.9% by weight, preferably 0.3% by weight or less. When the content is more than 0.9% by weight, a disintegration time increases during storage of the rapid release tablet comprising the granulated composite and a drug.
  • the D-sorbitol content in D-mannitol can be measured using the method of liquid chromatography described in the section of D-mannitol in EUROPEAN PHARMACOPOEIA 7.5. For example, it can be measured under the conditions of a feed rate of 0.5 mL/min and a column oven temperature of 85° C. while using Rezex RCM-Monosaccharide Ca 2+ (8%) 300 ⁇ 8 mm (product of Phenomenex) as a column, RID (differential refractive index detector) as a detector, and ultrapure water as a mobile phase.
  • the granulated composition can be produced by granulation while adding an aqueous dispersion prepared by mixing low-substituted hydroxypropyl cellulose, first D-mannitol and water to second D-mannitol.
  • the D-sorbitol content in the D-mannitol contained by the granulated composite is a sum of first D-sorbitol content in the first D-mannitol contained by the aqueous dispersion and second D-sorbitol content in the second D-mannitol to which the aqueous dispersion is added.
  • the average particle size of the first D-mannitol to be dissolved in water is not particularly limited insofar as it is soluble therein. It is preferably from 5 to 500 ⁇ m, more preferably from 10 to 100 ⁇ m. D-mannitol having an average particle size of less than 5 ⁇ m is not easily available industrially. D-mannitol having an average particle size of more than 500 ⁇ m may result in lowered disintegrability and binding capability because of the presence of undissolved portion.
  • the average particle size of the second D-mannitol to which the aqueous dispersion is added is preferably from 5 to 200 ⁇ m, more preferably from 5 to 100 ⁇ m, still more preferably from 10 to 50 ⁇ m. When the average particle size is less than 5 ⁇ m, fluidity or disintegrability may be lowered. When it is more than 100 ⁇ m, binding capability may be lowered.
  • the average particle size of each of the first D-mannitol and the second D-mannitol is a volume-based particle size and can be measured by a powder size measurement method using laser diffraction. It can be measured using, for example, HELOS & RODOS (product of Japan Laser Corp.).
  • a total amount of the first D-mannitol comprised by the aqueous dispersion and the second D-mannitol to which the aqueous dispersion is added is preferably from 80 to 99% by weight, more preferably from 90 to 98% by weight, in the resulting granulated composite.
  • the total amount is less than 80% by weight, texture in the oral cavity may be lowered, or the stability of the drug formulation may be lowered owing to increased hygroscopicity caused by an increase in the amount of the other additive.
  • the total amount is more than 99% by weight, the intended binding capability or disintegrability may not be obtained.
  • the amount of the first D-mannitol comprised by the aqueous dispersion is preferably from 1 to 50% by weight, more preferably from 5 to 30% by weight in the total amount of the D-mannitol comprised by the granulated composite obtained. When the amount is less than 1% by weight, binding capability or disintegrability may be lowered. When the amount is more than 50% by weight, an undissolved portion may become large, or may precipitate or cause clogging during feeding.
  • the low-substituted hydroxypropyl cellulose is a water-insoluble polymer and swells by water absorption. It has a basic cellulose skeleton and contains a small amount of hydroxypropoxy groups introduced therein. It has the degree of hydroxypropoxy substitution of from 5 to 16% by weight, more preferably from 5 to 9% by weight. When the degree of hydroxypropoxy substitution is less than 5% by weight, the swelling property by water absorption is low so that the intended disintegrability is not obtained, and the binding capability is also lowered.
  • the degree of hydroxypropoxy substitution is more than 16% by weight, water solubility increases, the intended disintegrability is not obtained, and the disintegration time of tablets obtained by molding prolongs, in spite of increase in swelling property and improvement in binding capability.
  • the degree of hydroxypropoxy substitution is measured using a method described in “low-substituted hydroxypropyl cellulose” of The Japanese Pharmacopoeia, Sixteenth Edition.
  • the average particle size of the low-substituted hydroxypropyl cellulose is preferably from 5 to 100 ⁇ m, more preferably from 10 to 80 ⁇ m, still more preferably from 20 to 60 ⁇ m.
  • the average particle size is less than 5 ⁇ m, swelling by water absorption may be lowered so that disintegrability may be lowered.
  • the average particle size is more than 100 ⁇ m, binding capability may be lowered owing to reduction in specific surface area.
  • the average particle size is a volume-based average particle size and can be measured by a powder size measuring method using laser diffraction. It can be measured using, for example, HELOS & RODOS (product of Japan Laser Corp).
  • the amount of the low-substituted hydroxypropyl cellulose is preferably from 1 to 20% by weight, more preferably from 2 to 10% by weight in the granulated composite obtained. When the amount is less than 1% by weight, a tablet having the intended disintegrability may not be obtained. When the amount is more than 20% by weight, an increase in the amount of water-insoluble substance may deteriorate the texture in the oral cavity, and enhanced hygroscopicity may lower the stability of the drug formulation thus obtained.
  • the aqueous dispersion preferably further comprises polyvinyl alcohol from the standpoint of the binding capability.
  • the amount of the polyvinyl alcohol is preferably from 0.05 to 0.4% by weight, more preferably from 0.1 to 0.3% by weight in the granulated composite thus obtained. When the amount is less than 0.05% by weight, the binding capability may not reach an intended level. When the amount is more than 0.4% by weight, the disintegrability may be lowered although the binding capability is excellent.
  • Polyvinyl alcohol is a water-soluble polymer and is used as a binder. It can be prepared by polymerization of vinyl acetate monomer and then saponification with an alkali. The polyvinyl alcohol is classified depending on the saponification degree. Polyvinyl alcohol having a saponification degree of from 80 to 90 mol %, polyvinyl alcohol having a saponification degree of more than 90 mol % but less than 98 mol %, and polyvinyl alcohol having a saponification degree of 98 mol % or greater are classified as “partially saponified type”, “intermediately saponified type” and “fully saponified type”, respectively. The partially saponified type polyvinyl alcohol dissolves in water of room temperature; the fully saponified type does not dissolve in water of room temperature but dissolves in water as hot as 90° C. or greater; and the intermediately saponified type shows a property between them.
  • the polyvinyl alcohol to be comprised by the aqueous dispersion is preferably a fully saponified type.
  • the fully saponified type polyvinyl alcohol is rich in hydroxyl groups so that it improves the binding capability further due to many hydrogen bonds formed.
  • the polyvinyl alcohol has the polymerization degree of preferably from about 500 to 2000, which is commercially available.
  • the polymerization degree and saponification degree can each be measured based on JIS K6726.
  • An aqueous dispersion comprising the low-substituted hydroxypropyl cellulose, D-mannitol and preferable optional polyvinyl alcohol may be prepared by dissolving the D-mannitol and the polyvinyl alcohol in a predetermined amount of water and then adding the low-substituted hydroxypropyl cellulose to the resulting solution, or inversely, adding the resulting solution to the low-substituted hydroxypropyl cellulose.
  • the low-substituted hydroxypropyl cellulose is insoluble in water, and can be rapidly dispersed in water so that mixing for several minutes with a typical stirrer is sufficient.
  • the aqueous dispersion is preferably stirred in order to prevent precipitation.
  • the solid content in the aqueous dispersion is preferably from 1 to 30% by weight, more preferably from 5 to 25% by weight, still more preferably from 10 to 25% by weight.
  • productivity may be lowered because it takes long hours to complete the addition of a predetermined amount.
  • the solid content in the aqueous dispersion may have excessively high viscosity and make feeding difficult.
  • the solid content in the aqueous dispersion means a concentration of solids which can be obtained by drying the aqueous dispersion and which constitute a granulated composite.
  • an apparatus to be used in granulating operation includes a fluidized bed granulator, a stirring granulator, a tumbling fluidized bed granulator, and a spray drying granulator. It is preferably a fluidized bed granulator since it can perform spraying and drying simultaneously and easily forms a uniform coating layer on the powder surface.
  • Second D-mannitol is placed in a fluidized bed, and granulation is carried out while spraying, as a binder liquid, an aqueous dispersion which, for example, comprises low-substituted hydroxypropyl cellulose and first D-mannitol, to the second D-mannitol, thereby producing a granulated composite.
  • an aqueous dispersion which, for example, comprises low-substituted hydroxypropyl cellulose and first D-mannitol
  • the average particle size of the granulated composite differs depending on the granulation conditions. It is preferably from 50 to 300 ⁇ m, more preferably from 50 to 250 ⁇ m, still more preferably from 50 to 200 ⁇ m. When the average particle size is less than 50 ⁇ m, the granulated composite may adhere to a tableting machine owing to low fluidity. When the average particle size is more than 300 ⁇ m, filling ability of the granulated composite into a mortar may be lowered so that the table weight variation may increase.
  • the average particle size of the granulated composite can be measured using the sieving method described in the General Tests of the Japanese Pharmacopoeia, Sixteenth Edition.
  • the dried granulated composite is obtained through a fluidized bed granulator capable of spraying and drying simultaneously, further drying is not necessary. If the granulated composite is obtained without drying or obtained using a granulator incapable of drying, then drying can be carried out in a known manner. For example, it can be dried at from 40 to 80° C. with a fluidized bed dryer or a shelf dryer.
  • the water content of the granulated composite thus obtained is preferably 5% by weight or less, more preferably 1% by weight or less. When the water content is more than 5% by weight, the stability of a drug formulation may be adversely affected.
  • a rapid release tablet comprising the granulated composite thus obtained and a drug
  • the rapid release tablet means a tablet having a short disintegration time not only in the oral cavity but also in the stomach.
  • the production of a tablet by using the granulated composite will next be described, taking an example of the direct dry-tableting method.
  • the granulated composite thus obtained are mixed with a drug to form a mixture, and then the mixture can be tableted through compression under a predetermined pressure with a typical continuous rotary press.
  • the size of the tablet can be selected freely.
  • the tablet preferably has a diameter of from about 6 to 12 mm and a weight of from 70 to 700 mg per tablet. When the tablet has a diameter of less than 6 mm, handling may not be easy. When the tablet has a diameter of more than 12 mm, swallowing the tablet may not be easy.
  • the tableting pressure is preferably from 10 to 300 MPa. When the tableting pressure is less than 10 MPa, the resulting tablet may not have an intended hardness. When the tableting pressure is more than 300 MPa, tableting troubles such as capping may happen.
  • a drug usable for a tablet comprising the granulated composite is not particularly limited insofar as it is orally administrable.
  • the drug include a drug for the central nervous system, a drug for the circulatory system, a drug for the respiratory system, a drug for the digestive system, an antibiotic, an antitussive/expectorant, an antihistamine, an analgesic, antipyretic and anti-inflammatory drug, a diuretic, an autonomic drug, an antimalarial drug, an antidiarrheal agent, a psychotropic drug, and vitamins and derivatives thereof.
  • Examples of the drug for the central nervous system include diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, dichlofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, ketoprofen and chlordiazepoxide.
  • Examples of the drug for the circulatory system include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide nitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, propranolol hydrochloride and alprenolol hydrochloride.
  • Examples of the drug for the respiratory system include amlexanox, dextromethorphan, theophilline, pseudo-ephedrine, salbutamol and guaiphenesin.
  • Examples of the drug for the digestive system include benzimidazole-based drugs having anti-ulcer action such as 2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole; cimetidine; ranitidine; pirenzepine hydrochloride; pancreatin; bisacodyl and 5-aminosalicylic acid.
  • benzimidazole-based drugs having anti-ulcer action such as 2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole;
  • antibiotics examples include talampicillin hydrochloride, bacampicillin hydrochloride, cephaclor and erythromycin.
  • antitussive/expectorant examples include noscapine hydrochloride, carbetapentane citrate, dextromethorphan hydrobromide, isoaminile citrate and dimemorfan phosphate.
  • antihistamine examples include chlorpheniramine maleate, diphenhydramine hydrochloride and promethazine hydrochloride.
  • analgesic, antipyretic and anti-inflammatory drug examples include ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin and ketoprofen.
  • diuretic examples include caffeine.
  • autonomic drug examples include dihydrocodeine phosphate, methylephedrine dl-hydrochloride, atropine sulfate, acetylcholine chloride and neostigmine.
  • antimalarial drug examples include quinine hydrochloride.
  • antidiarrheal agent examples include loperamide hydrochloride.
  • Examples of the psychotropic drug include chlorpromazine.
  • vitamins and derivatives thereof include Vitamin A, Vitamin B1, fursultiamine, Vitamin B2, Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, Vitamin K, calcium pantothenate and tranexamic acid.
  • the tablet may comprise, besides the granulated composite, an optional additive typically used in a solid preparation, together with a drug, wherein the additive may be in a typically used amount.
  • an additive include a disintegrant, a binder, a bulking agent, a lubricant, a taste corrigent and a flavor.
  • disintegrant examples include low-substituted hydroxypropyl cellulose, corn starch, potato starch, partly pregelatinized starch, carboxymethyl starch sodium, carmellose, croscarmellose sodium, crystalline cellulose and crospovidone.
  • binder examples include hydroxypropyl cellulose, polyvinylpyrrolidone and hydroxypropylmethyl cellulose.
  • Examples of the bulking agent include erythritol, D-mannitol, lactose, sucrose, calcium phosphate and calcium sulfate.
  • taste corrigent examples include citric acid, tartaric acid and malic acid.
  • Examples of the flavor include menthol, peppermint oil and vanillin.
  • Examples of the lubricant include magnesium stearate and sucrose fatty acid ester.
  • the hardness of the tablet is preferably 40N or greater, more preferably 50N or greater immediately after production as well as after storage under humidified conditions. When the tablet hardness is less than 40N, breakage or cracks may be caused during transport or during packaging with an automatic packaging machine.
  • maximum breaking strength at the time when the tablet is broken as a result of application of load at a rate of 1 mm/sec in a direction of the diameter of the tablet is measured. It can be measured using, for example, a tablet hardness tester (“TBH-30” product of ERWEKA).
  • the disintegration time of the tablet in the oral cavity is preferably within 30 seconds, more preferably within 20 seconds immediately after production as well as after storage under humidified conditions. When the disintegration time in the oral cavity is longer than 30 seconds, ease in taking the tablet may worsen.
  • the disintegration time in the oral cavity can be measured by administering the tablet to a human subject and allowing the tablet to disintegrate in her or his oral cavity in practice, but the disintegration time may vary largely depending on the subject. It is therefore measured using a disintegration tester for orally disintegrating tablets capable of measuring the oral disintegration time objectively. It can be measured using, for example, an orally rapid disintegrating tablet disintegration tester (“TRICORPTESTER”, product of Okada Seiko Co., Ltd.).
  • the granulated composite is not a mixture in which D-mannitol and low-substituted hydroxypropyl cellulose are physically mixed, but particles, each particle comprising the low-substituted hydroxypropyl cellulose on the surface of the D-mannitol.
  • both high binding capability and rapid disintegrability can be achieved by adding (preferably spraying) an aqueous dispersion comprising low-substituted hydroxypropyl cellulose, first D-mannitol and preferably optional polyvinyl alcohol to second D-mannitol so as to cover the surface of the second D-mannitol with the aqueous dispersion for surface modification.
  • an aqueous dispersion comprising low-substituted hydroxypropyl cellulose, first D-mannitol and preferably optional polyvinyl alcohol
  • the surface of the granulated composite is covered with the low-substituted hydroxypropyl cellulose and preferably optional polyvinyl alcohol, and the low-substituted hydroxypropyl cellulose and polyvinyl alcohol, both being rich in hydroxyl groups, can make firm hydrogen bonds during compression molding, thereby enhancing the binding capability.
  • the low-substituted hydroxypropyl cellulose rapidly absorbs water and swells therewith so that the compression molded product disintegrates rapidly.
  • the rapid release tablet comprising the granulated composite and the drug is excellent in storage stability under humidified conditions.
  • the reason why the reduction in tablet hardness hardly occurs is presumably because the low-substituted hydroxypropyl cellulose has low hygroscopicity in comparison with the other disintegrants and does not easily cause swelling due to moisture absorption even under humidified conditions.
  • the reason why prolongation of disintegration time hardly occurs is presumably because the D-sorbitol content in the D-mannitol comprised by the granulated composite is small.
  • D-mannitol is a sugar alcohol having low hygroscopicity
  • D-sorbitol is a sugar alcohol having high hygroscopicity
  • D-sorbitol absorbs moisture under humidified conditions so that D-mannitol present in the vicinity of the D-sorbitol partially dissolves and consolidates to reduce the void area in the tablet. Consequently, water invasiveness is obstructed and prolongs the disintegration time. It is presumed that the lower the D-sorbitol content in D-mannitol is, the more the prolongation of the disintegration time can be suppressed.
  • the 60.0 g of first D-mannitol having D-sorbitol content of 0.1% by weight was added to 322.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted at a tableting pressure of 7.5 kN with a rotary tableting machine into tablets, each tablet having a diameter of 8 mm, a radius of curvature of 12 mm and a tablet weight of 200 mg. Consequently, orally rapidly disintegrating tablets were produced.
  • the hardness and oral disintegration time of the tablets immediately after the production were measured by using a tablet hardness tester (TBH-30 produced by ERWEKA) and a disintegration testing apparatus for oral fast-disintegrating tablets (TRICORPTESTER produced by Okada Seiko Co., Ltd.), respectively. Further, the hardness and oral disintegration time of the tablets after storage for one week under the conditions of 40° C. and 75% RH (Relative Humidity) were measured again. The results are shown in Table 2.
  • the 60.0 g of first D-mannitol having D-sorbitol content of 0.8% by weight was added to 322.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • 222.0 g of second D-mannitol having D-sorbitol content of 0.8% by weight was placed in a fluidized bed granulator, and granulation was carried out by spraying the aqueous dispersion thereto in the same manner as in Example 1.
  • the composition of the aqueous dispersion and the composition of the granulated composite are shown in Table 1.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 1.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • aqueous solution of polyvinyl alcohol having a saponification degree of 98.5% and a polymerization degree of 1700 and 60.0 g of first D-mannitol having D-sorbitol content of 0.1% by weight were added to 316.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted at a tableting pressure of 5.0 kN with a rotary tableting machine into tablets, each tablet having a diameter of 8 mm, a radius of curvature of 12 mm and a tablet weight of 200 mg. Consequently, orally rapidly disintegrating tablets were produced.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • aqueous solution of polyvinyl alcohol having a saponification degree of 98.5 mol % and a polymerization degree of 1700 and 60.0 g of first D-mannitol having D-sorbitol content of 1.0% by weight were added to 316.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 3.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • aqueous solution of polyvinyl alcohol having a saponification degree of 98.5 mol % and a polymerization degree of 1700 and 60.0 g of first D-mannitol having D-sorbitol content of 0.3% by weight were added to 316.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 3.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • the 6.0 g of 10% by weight aqueous solution of polyvinyl alcohol having a saponification degree of 98.5 mol % and a polymerization degree of 1700 and 60.0 g of first D-mannitol having D-sorbitol content of 0.1% by weight was added to 316.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 3.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • aqueous solution of polyvinyl alcohol having a saponification degree of 98.5 mol % and a polymerization degree of 1700 and 60.0 g of first D-mannitol having D-sorbitol content of 0.8% by weight were added to 316.0 g of purified water, and then dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 3.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • the 60.0 g of first D-mannitol having D-sorbitol content of 2.0% by weight was added to 322.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 1.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • aqueous solution of polyvinyl alcohol having a saponification degree of 98.5 mol % and a polymerization degree of 1700 and 60.0 g of first D-mannitol having D-sorbitol content of 1.0% by weight were added to 316.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 3.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • aqueous solution of polyvinyl alcohol having a saponification degree of 98.5 mol % and a polymerization degree of 1700 and 60.0 g of first D-mannitol having D-sorbitol content of 2.0% by weight were added to 316.0 g of purified water, and dissolved by mixing with a stirring blade. Then 18.0 g of low-substituted hydroxypropyl cellulose having a degree of hydroxypropoxy substitution of 8% by weight was added to the resulting aqueous solution and mixed to produce an aqueous dispersion.
  • the 90 parts by weight of the granulated composite was mixed with 10 parts by weight of ethenzamide as a drug, and then 1.0 part by weight of magnesium stearate as a lubricant was added thereto and mixed.
  • the resulting mixture was tableted in the same manner as in Example 3.
  • the tablets thus obtained were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 1 where the D-mannitol comprised by the granulated composite had D-sorbitol content of greater than 0.9% by weight, the tablets immediately after the production showed an excellent disintegrability, but the disintegration time of the tablets after storage under humidified conditions increased.
  • Examples 1 and 2 where the D-sorbitol content in the D-mannitol comprised by the granulated composite was 0.9% by weight or less, the tablets immediately after the production as well as after storage under humidified conditions showed excellent binding capability and disintegrability, and were excellent in storage stability.
  • Example 3 where the granulated composite further comprised polyvinyl alcohol differing from that in Example 1, the binding capability was increased so that the tablets having sufficient hardness were obtained even at a low tableting pressure.
  • the tablets immediately after the production as well as after storage under humidified conditions showed excellent disintegrability and were excellent in storage stability.
  • Comparative Examples 2 and 3 the tablets immediately after production showed excellent disintegrability, but the disintegration time became longer after storage of the tablets under humidified conditions.
  • Example 4 where the first D-sorbitol content in the D-mannitol comprised by the aqueous dispersion was 0.9% by weight or greater
  • Example 6 where the D-sorbitol content in the second D-mannitol to which the aqueous dispersion was added was 0.9% by weight or greater
  • both tablets immediately after the production as well as after storage under humidified conditions showed an excellent binding capability and disintegrability and were excellent in storage stability, similarly to the tablets obtained in Examples 5 and 7 in which the D-sorbitol contents in the D-mannitol comprised by granulated composites are similar to respective D-sorbitol contents in Examples 4 and 6.
  • the D-sorbitol content in the first D-mannitol comprised by the aqueous dispersion or the D-sorbitol content in the second D-mannitol to which the aqueous dispersion is added is more than 0.9% by weight, it is only necessary to make the D-sorbitol content in the D-mannitol comprised by the granulated composite 0.9% by weight or less.
  • orally disintegrating tablets excellent in binding capability and disintegrability and further excellent in storage stability under humidified conditions can be obtained by mixing the granulated composite with a drug and then tableting the resulting mixture.

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CN116510026A (zh) * 2023-07-04 2023-08-01 山东天力药业有限公司 一种甘露醇复合药用辅料及其制备方法
EP4134102A4 (en) * 2020-04-10 2024-06-26 Japan Vam & Poval Co., Ltd. SUSTAINED RELEASE BASE
RU2831451C2 (ru) * 2019-04-03 2024-12-09 Астеллас Фарма Инк. Фармацевтическая композиция
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US12178814B2 (en) 2019-04-03 2024-12-31 Astellas Pharma Inc. Pharmaceutical composition
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CN116510026A (zh) * 2023-07-04 2023-08-01 山东天力药业有限公司 一种甘露醇复合药用辅料及其制备方法

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