WO2013129644A1 - Comprimé à désintégration rapide - Google Patents

Comprimé à désintégration rapide Download PDF

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Publication number
WO2013129644A1
WO2013129644A1 PCT/JP2013/055634 JP2013055634W WO2013129644A1 WO 2013129644 A1 WO2013129644 A1 WO 2013129644A1 JP 2013055634 W JP2013055634 W JP 2013055634W WO 2013129644 A1 WO2013129644 A1 WO 2013129644A1
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WO
WIPO (PCT)
Prior art keywords
carbon dioxide
tablet
disintegrating tablet
rapidly disintegrating
pressure
Prior art date
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PCT/JP2013/055634
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English (en)
Japanese (ja)
Inventor
正範 小林
伊藤　佳孝
篤 真栄田
澄栄 柏原
大竹　勝人
Original Assignee
アステラス製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by アステラス製薬株式会社 filed Critical アステラス製薬株式会社
Priority to KR1020147027362A priority Critical patent/KR102092423B1/ko
Priority to JP2014502409A priority patent/JP6098634B2/ja
Priority to CN201380012176.2A priority patent/CN104168891B/zh
Publication of WO2013129644A1 publication Critical patent/WO2013129644A1/fr
Priority to PH12014501772A priority patent/PH12014501772A1/en

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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
    • A61K9/0012—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
    • A61K9/20—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 rapidly disintegrating tablet (particularly an orally disintegrating tablet) having a porous structure by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide.
  • the present invention also relates to a method for producing a rapidly disintegrating tablet (particularly an orally disintegrating tablet) having a porous structure by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide. Is.
  • Drug-containing particles that provide certain functions depending on the characteristics of the drug, such as drugs that are unstable in temperature or humidity, drugs that have a bitter taste, or drugs that require sustained release when providing pharmaceutical preparations In many cases, it is required to develop pharmaceutical preparations containing.
  • the invention relating to the orally disintegrating tablet is an invention relating to an orally disintegrating tablet comprising a granulated product obtained by spraying, coating and / or granulating a saccharide having a low moldability and a saccharide having a high moldability as a binder.
  • Patent Document 1 has been reported.
  • drugs, water-soluble binders and water-soluble excipients are used.
  • An invention relating to an orally disintegrating tablet having a porous structure has been reported by forming interparticle crosslinks between the two (Patent Document 3). Furthermore, in order to increase tablet strength and improve friability without prolonging the disintegration time in the oral cavity, it contains a drug, a diluent, and a saccharide having a melting point relatively lower than that of the drug and the diluent.
  • Patent Document 4 An invention relating to an orally rapidly disintegrating tablet in which a low-sugar saccharide is uniformly mixed in a tablet and a cross-link is formed between drug and / or diluent particles by a melt-solidified product of a low-melting saccharide (Patent Document 4) , An invention relating to an orally disintegrating tablet containing a physiologically active substance and a polyvinyl alcohol-polyethylene glycol graft copolymer (Patent Document 5); ) A step of mixing an active ingredient, an acrylic copolymer and at least one pharmacologically acceptable additive; (2) compression of the mixture obtained in the step of (1) And (3) a method for producing a rapidly disintegrating tablet, characterized by comprising the step of keeping the compression-molded product obtained in steps (3) and (2) at a temperature of 50 to 100 ° C.
  • Patent Document 6 a rapidly disintegrating tablet, wherein a component in powder form is brought into contact with a pressurized liquefied gas or a gas mixture, homogenized, introduced into a mold by pressurization, and decompressed
  • Patent Document 7 a rapidly disintegrating tablet, wherein a component in powder form is brought into contact with a pressurized liquefied gas or a gas mixture, homogenized, introduced into a mold by pressurization, and decompressed
  • Patent Document 7 relating to the production method of the above, tableting a mixture comprising an active ingredient, an additive, and a supercritical fluid soluble substance to produce a tablet; and contacting the tablet with a supercritical fluid to make a supercritical fluid
  • An invention (Patent Document 8) and the like relating to an intraoral quick disintegrating tablet produced by a method comprising a step of extracting a fluid-soluble substance and forming fine voids in the tablet has been reported.
  • the subject of this invention is providing the quick disintegrating tablet (especially orally disintegrating tablet) which improved the cracking chip of the tablet.
  • Another object of the present invention is to provide a rapidly disintegrating tablet (particularly an orally disintegrating tablet) that can be applied to a drug that is unstable in humidification or heating treatment.
  • an object of the present invention is to prepare a formulation step (formulation design) even for a tablet containing drug-containing particles imparted with a desired function based on drug characteristics (hereinafter sometimes abbreviated as functional particles). In addition, it may be processed at high temperature and high humidity, and may affect the function of the functional drug-containing particles. In disintegrating tablets).
  • Another object of the present invention is to provide a method for producing a rapidly disintegrating tablet (especially an orally disintegrating tablet) that can be applied to a drug that is unstable in humidification or heating treatment.
  • a tablet containing drug-containing particles imparted with a desired function based on the characteristics of the drug is processed at a high formulation temperature (high temperature and high humidity for formulation design).
  • the drug may decompose or may affect the function of the functional drug-containing particles), but the drug itself is stable, or the function of the functional particles is fully expressed.
  • Another object of the present invention is to provide a method for producing a functional tablet (particularly an orally disintegrating tablet).
  • the rapidly disintegrating tablet thus obtained contains a drug unstable in temperature or humidity in the tablet, or
  • functional particles for example, solid dispersion particles composed of poorly soluble drugs, bitterness masking particles, sustained-release particles, etc.
  • the present invention [1] Carbon dioxide or liquid in a supercritical or subcritical state containing a drug and a substance having a function of a binder by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state Or fast disintegrating tablets obtained by treatment with gaseous carbon dioxide, [2]
  • the substance having the function of a binder by treating with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state is carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state.
  • a substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is a vinyl pyrrolidone / vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol.
  • [1]-[3] fast disintegrating tablets [5] The rapidly disintegrating tablet according to any one of [1] to [4], further comprising a plasticizer, [6] The rapidly disintegrating tablet according to any one of [1] to [5], further comprising a disintegrant, [7] The rapidly disintegrating tablet of any one of [1] to [6], wherein the tablet hardness is 20 N or more, [8] The rapidly disintegrating tablet of any one of [1] to [7], wherein the ratio of the number of broken tablets by a drop test is 5% or less, [9] The rapidly disintegrating tablet according to any one of [1] to [8], wherein the rapidly disintegrating tablet is an orally disintegrating tablet, [10] The rapidly disintegrating tablet according to [9], wherein the oral disintegration time is within 120 seconds, [11] The rapidly disintegrating tablet according to any one of [1] to [10], wherein the drug constitutes a drug and / or functional particles unstable to temperature or humidity, [12] The speed according to [11], wherein the
  • Disintegrating tablets [13] (1) A step of mixing a drug and a substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide, (2) A step of preparing a tablet by compression molding the mixture of (1), and (3) a step of treating the tablet of (2) with carbon dioxide in a supercritical or subcritical state or with liquid or gaseous carbon dioxide.
  • a method for producing a rapidly disintegrating tablet [14]
  • the substance having the function of a binder by treating with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state is carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state.
  • a substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is a vinyl pyrrolidone / vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol Graft copolymer, povidone, povidone / vinyl acetate resin premix formulation, methacrylic acid copolymer LD, polyvinyl alcohol / polyethylene glycol graft copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer / polyvinyl alcohol premix formulation, polyoxyethylene (196) polyoxypropylene (67) Glycol, macrogol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, meta Rylic acid copolymer L, dry methacrylic
  • a method for producing a rapidly disintegrating tablet [17] A method for producing a rapidly disintegrating tablet according to any one of [13] to [16], further comprising a plasticizer, [18] The method for producing a rapidly disintegrating tablet according to any one of [13] to [17], further comprising a disintegrant, [19] The method for producing a rapidly disintegrating tablet of any one of [13] to [18], wherein the tablet hardness is 20 N or more, [20] The method for producing a rapidly disintegrating tablet according to any one of [13] to [19], wherein the rapidly disintegrating tablet is an orally disintegrating tablet, [21] The method for producing a rapidly disintegrating tablet according to [20], wherein the oral disintegration time is within 120 seconds, [22] The method for producing a rapidly disintegrating tablet according to any one of [13] to [21], wherein the drug constitutes a drug and / or functional particles unstable to temperature or humidity.
  • a fast disintegrating tablet (particularly an orally disintegrating tablet) having breakage resistance with improved cracking and having rapid disintegration in the oral cavity.
  • a fast disintegrating tablet having breakage resistance with improved cracking and having rapid disintegration in the oral cavity.
  • drugs that are unstable in temperature or humidity, solid dispersion particles composed of poorly soluble drugs, bitterness masking particles, sustained release particles, and the like.
  • a rapidly disintegrating tablet (particularly an orally disintegrating tablet) while sufficiently maintaining the stability and desired functions.
  • “supercritical (state)” means a non-condensable dense fluid that exceeds the critical point in both pressure and temperature.
  • “Subcritical (state)” means a state in which only one of pressure and temperature exceeds the critical point.
  • the critical point is, for example, “Particle Formation with Supercritical Fluids-A Review” by JW Tom and PG Debenedetti, Journal of Aerosol Sci., 22 (5), pp. 555-584, 1991 The one described in detail in .1.
  • the state in which the pressure and temperature are not liquefied without exceeding the critical point is referred to as “liquid”.
  • a state where both pressure and temperature are vaporized without exceeding the critical point is referred to as “gas”.
  • carbon dioxide in a supercritical state is a state in which both a critical pressure of about 7.38 megapascal (MPa) and a critical temperature of about 304.1 Kelvin (K) are exceeded. Specifically, it is something other than a solid state. Examples include liquid carbon dioxide, gaseous carbon dioxide, and supercritical carbon dioxide.
  • tablette hardness sufficient for handling the formulation or “excellent tablet hardness” is not particularly limited as long as the tablet is not damaged in the distribution process.
  • the formulation is extruded from the cover sheet and taken out.
  • the hardness in the longitudinal direction of the tablet can be mentioned.
  • the hardness varies depending on the size and shape of the tablet. For example, when the diameter is about 8.0 mm and a 180 mg tablet is 20 N or more, when the diameter is about 8.5 mm, it is 30 N or more, when the diameter is about 10.0 mm, 50 N or more, and the diameter is about 12 It is specified as 60N or more when 0.0mm.
  • the preparation of the present invention has a strength sufficient to withstand removal from the PTP package in any size. Furthermore, the strength applicable to bottle packaging (packaging in which tablets are encapsulated in glass, plastic, etc.), that is, tablets that can withstand contact between tablets or between tablets and container walls when transported in a normal bottle container. As a measure of the strength, 30N or more is preferable. Further, as another aspect, for example, a breakage rate by a drop test of a PTP-packed tablet can be mentioned.
  • the damage rate of the tablets is 5% or less, and in another embodiment, it is defined as having a strength of 2% or less.
  • the preparation of the present invention has sufficient strength to withstand transportation or carry-in in bottle packaging.
  • a tablet having “rapid disintegration” refers to a tablet having practically sufficient disintegration or solubility by saliva without taking water in the oral cavity. means.
  • practically sufficient disintegration or solubility has individual differences, but usually within the oral cavity is about 1 to 300 seconds, as another aspect about 1 to 150 seconds, as a further aspect about 1 to 90 seconds,
  • the decay time is within 1 to 300 seconds, as another embodiment within 1 to 120 seconds, as a further embodiment within 1 to 90 seconds, and as another embodiment within 1 to 60 seconds. Further, it is defined as 1 to 40 seconds or less as another aspect.
  • the “orally disintegrating tablet” varies depending on individuals, but usually disintegrates or dissolves in the oral cavity in about 1 to 120 seconds, in other embodiments in about 1 to 90 seconds, and in further embodiments in about 1 to 60 seconds. Means tablets. In addition, when measured with a tricoop tester, the decay time is within 1 to 120 seconds, as another embodiment within 1 to 90 seconds, as a further embodiment within 1 to 60 seconds, and as another embodiment within 1 to 40 seconds. Means tablets that disintegrate or dissolve.
  • the “porous structure” is not particularly limited as long as the tablet rapidly disintegrates in the oral cavity.
  • the porosity is 15% or more and 90% or less, and as another aspect, 25% or more and 70%.
  • it is specified as 30% or more and 50% or less as a further aspect.
  • the drug used in the present invention is not particularly limited as long as it is a therapeutically effective active ingredient or a prophylactically effective active ingredient.
  • pharmaceutically active ingredients include hypnotic sedatives, sleep-inducing agents, migraine agents, anti-anxiety agents, antiepileptic agents, antidepressants, anti-Parkinson agents, psychiatric agents, central nervous system agents, local anesthetics Agent, skeletal muscle relaxant, autonomic nerve agent, antipyretic analgesic / antiinflammatory agent, antispasmodic agent, antipruritic agent, cardiotonic agent, arrhythmic agent, diuretic agent, antihypertensive agent, vasoconstrictor, vasodilator, cardiovascular agent, high Dyslipidemic agent, respiratory accelerator, antitussive agent, expectorant, antitussive agent, bronchodilator, antidiarrheal agent, intestinal adjuster, peptic ulcer agent, stomach digestive agent, antacid, laxative, antibacterial agent,
  • Such drugs include, for example, overactive bladder therapeutic agents such as solifenacin, tolterodine, mirabegron, sleep-inducing drugs such as diphenhydramine, lorazepam, zolpidem, indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone , Mepyrazole, aspirin, etenzamide, acetaminophen, aminopyrine, phenacetin, butylscopolamine bromide, morphine, etmidrin, pentazocine, fenoprofen calcium, naproxen, celecoxib, valdecoxib, tramadol, etc.
  • overactive bladder therapeutic agents such as solifenacin, tolterodine, mirabegron
  • sleep-inducing drugs such as diphenhydramine, lorazepam, zolpidem, indometh
  • Migraine drugs such as sumatriptan, antirheumatic drugs such as etodolac, antituberculosis drugs such as isoniazid and ethambutol hydrochloride, isosorbide nitrate , Nitroglycerin, nifedipine, varnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indenolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, guanethidine nitrate, reserpine, amosulalol hydrochloride, lisinopril, metoprolol, pilocarpine, telmisartan, etc.
  • Antipsychotics such as chlorpromazine hydrochloride, amitriptyline hydrochloride, nemonapride, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, adinazolam, alprazolam, methylphenidate, milnacipran, peroxetine, risperidone, sodium valproate, etc.
  • chlorpromazine hydrochloride amitriptyline hydrochloride, nemonapride, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, adinazolam, alprazolam, methylphenidate, milnacipran, peroxetine, risperidone, sodium valproate, etc.
  • Antidepressant metoclopramide, ramosetron hydrochloride, granisetro hydrochloride , Antiemetics such as ondansetron hydrochloride and azacetron hydrochloride, antihistamines such as chlorpheniramine maleate, vitamin drugs such as thiamine nitrate, tocophenol acetate, chicotiamine, pyridoxal phosphate, cobamide, ascorbic acid, nicotinamide, Goutants such as allopurinol, colchicine, probenecid, Parkinson's disease drugs such as levodopa and selegiline, hypnotic sedatives such as amobarbital, bromvalerylurea, midazolam, chloral hydrate, fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, etc.
  • antihistamines such as chlorpheniramine maleate
  • Antineoplastic drugs, pseudoephedrine, anti-allergic drugs such as terfenadine, acetohexamide, insulin, tolbutamide, desmopressin, glipizide, nateglinide, metformin, sita Diabetic drugs such as gliptin, vildagliptin, linagliptin, diuretics such as hydrochlorothiazide, polythiazide, triamterene, bronchodilators such as aminophylline, formoterol fumarate, theophylline, antitussives such as codeine phosphate, noscapine, dimemorphan phosphate, and dextromethorphan , Antiarrhythmic drugs such as quinidine nitrate, dichitoxin, propaphenone hydrochloride, procainamide, surface anesthetics such as ethyl aminobenzoate, lidocaine, dibucaine hydrochloride, antiepileptic
  • Antihyperlipidemic agent antibiotics such as ampicillin phthalidyl hydrochloride, cefotetan, josamycin, BPH therapeutic agents such as tamsulosin, doxazosin mesylate, terazosin hydrochloride, pranlukast, zafirlukast, albuterol, ambroxol, budesonide, level Anti-asthmatic agents such as terol, peripheral circulation improving agents such as prostaglandin I2 derivatives such as beraprost sodium, osteoporosis therapeutic agents such as minodronic acid and alendronic acid, Therapeutic agent species complications, skin ulcer therapeutic agents, and the like.
  • antibiotics such as ampicillin phthalidyl hydrochloride, cefotetan, josamycin
  • BPH therapeutic agents such as tamsulosin, doxazosin mesylate, terazosin hydrochloride, pranlukast, zafirl
  • steroidal anti-inflammatory agents include anti-inflammatory analgesics, antipyretic analgesics, antiepileptic agents, chemotherapeutic agents, synthetic antibacterial agents, antiviral agents, antifungal agents, hormone agents, angiogenesis inhibitors, immunosuppressants, or Examples include ulcerative colitis therapeutic agents.
  • steroidal anti-inflammatory agents include cortisone acetate, betamethasone, prednisolone, fluticasone propionate, dexamethasone, budesonide, beclomethasone propionate, triamcinolone, rotopredonol, fluorometholone, diflupredone, mometasone furanate, clobetasol propionate, diflorazone propionate, Examples include diflucortron valerate, fluocinonide, amsinonide, harsinonide, fluocinolone acetonide, triamcinolone acetonide, flumethasone pivalate, or clobetasone butyrate.
  • Antiinflammatory analgesics include, for example, alclofenac, aluminoprofen, ibuprofen, indomethacin, epilysole, oxaprozin, ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam, fenbufen, flufenamic acid, flurbiprofen, fructaphenine, pentazocine, methazidic acid, or Examples include mefenamic acid and mofezolac. Examples of antipyretic analgesics include acetaminophen, sulpyrine, and the like.
  • antiepileptic agent examples include acetazolamide, carbamazepine, clonazepam, diazepam, and nitrazepam.
  • chemotherapeutic agents include sulfa drugs such as salazosulfapyridine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfamethopyrazine, or sulfamonomethoxine, enoxin, ofloxacin, synoxacin, sparfloxacin Synthetic antibacterial agents such as thiamphenicol, nalidixic acid, tosufloxacin tosylate, norfloxacin, pipemidic acid trihydrate, pyromido acid, fleloxacin, or levofloxacin, antiviral agents such as acyclovir, ganciclovir, didanosine, zidovudine, or vitarabine,
  • hormone agents include insulin zinc, testosterone propionate, or estradiol benzoate.
  • immunosuppressive agent include cyclosporine, rapamycin, tacrolimus and the like.
  • therapeutic agent for ulcerative colitis include mesalazine.
  • another embodiment of the drug used in the present invention is a drug that is unstable with respect to temperature or humidity.
  • the drug may be granulated and / or mixed with a pharmaceutical additive, or the drug may be coated on core particles such as SELPHYA (manufactured by Asahi Kasei) together with a stabilizer and the like, and then granulated and / or mixed with the pharmaceutical additive. You may mix.
  • drugs constituting functional particles drugs constituting functional particles (drugs with a bitter taste, drugs that need to be sustained-released, drugs with poor solubility) can be mentioned.
  • functional particles include bitterness masking particles, sustained release particles, solid dispersion particles, and the like.
  • a drug having a bitter taste, a drug that needs to be sustained-released or a poorly soluble drug, and a drug that is unstable with respect to temperature or humidity may be selected as a drug constituting the functional particles. Good.
  • the drug can be used in either a free form or a pharmaceutically acceptable salt. Moreover, a drug can also be used 1 type or in combination of 2 or more types. These drugs are examples that can be applied to the present invention, and should not be interpreted in a limited manner.
  • the compounding amount is usually selected as appropriate depending on the type of drug or pharmaceutical use (indication), but is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount. For example, it is 0.001 to 80% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 0.01 to 70% by weight as another embodiment, and 0.01 to 60% by weight as another embodiment. %.
  • the rapidly disintegrating tablet of the present invention is a supercritical or subcritical carbon dioxide or a substance having a binder function by treatment with liquid or gaseous carbon dioxide.
  • the “substance having a function” has a porous structure by forming a cross-link between components (for example, a drug, and optionally, an excipient, a disintegrant, a stabilizer, a lubricant, etc.).
  • the “substance having the function of a binder by treating with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state” used in the present invention includes carbon dioxide or liquid in a supercritical or subcritical state. Or if it is a substance which functions as a binder because the melting point or glass transition temperature of this "substance" falls by processing with gaseous carbon dioxide, it will not be restrict
  • by treating with carbon dioxide in a supercritical or subcritical state or with liquid or gaseous carbon dioxide the hardness of the tablet containing the “substance” is compared with that not containing the “substance”. Any substance that increases can be used.
  • the treatment pressure is about 0.1 MPa to about 50 MPa in one embodiment, and about 1 MPa to about 20 MPa in another embodiment. In a further embodiment, the pressure is about 1 MPa to 15 MPa. In yet another embodiment, the pressure is about 1 MPa to about 5 MPa. In another embodiment, for example, the melting point or glass transition temperature when the pressure is 20 MPa is reduced by, for example, 5 ° C. or more. Still another embodiment includes, for example, a compound having a styrene skeleton, a carbonyl group, an ether bond, an ester bond, an unsaturated bond between carbon atoms, etc., particularly having an affinity for carbon dioxide in the structural formula.
  • Examples of the compound having a styrene skeleton include a polystyrene resin and a copolymer thereof.
  • Examples of the compound having a carbonyl group include an aldehyde compound, a ketone compound, a carboxylic acid compound, an ester compound, an amide compound, an enone compound, a carboxylic acid chloride (halogen), an acid anhydride, a polymer thereof, a copolymer, and the like.
  • Examples of the compound having an ether bond include polyethers typified by polyethylene glycol and polypropylene glycol.
  • Examples of the compound having an unsaturated bond between carbon atoms include alkenes, ethylene, propylene, benzene, annulene, and polymers and copolymers having the structure.
  • vinylpyrrolidone / vinyl acetate copolymer hereinafter sometimes abbreviated as copolyvidone
  • polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer polyvinyl caprolactam-polyvinyl glycyline graft copolymer, bipolymer.
  • copolyvidone polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer
  • aminoalkyl methacrylate copolymer E aminoalkyl methacrylate copolymer RS, methyl methacrylate / diethylaminoethyl methacrylate copolymer
  • HPMCAS ethyl cellulose
  • shellac povidone / vinyl acetate Resin premix preparation, povidone, carbomer, polyoxyethylene (196) polyoxypropylene (67) glycol.
  • Further embodiments include copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methyl methacrylate / diethylaminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, povidone / vinyl acetate resin pre A mixed preparation is mentioned.
  • Still other embodiments include copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, HPMCAS, and ethyl cellulose.
  • Another embodiment includes copolyvidone and aminoalkyl methacrylate copolymer E.
  • Yet another embodiment includes aminoalkyl methacrylate copolymer E.
  • Pemulen TR-1, TR-2, etc. such as AQUPEC HV-501, HV501E, HV-501ER, HV-504, commercially available from Sumitomo Seika. HV-504E, HV-505, HV-505E, HV-505ED, etc. Hibiswako 103, 104, 105, etc. commercially available from Wako Pure Chemical Industries, Ltd. Polyvinyl acetal diethylaminoacetate: AEA (Mitsubishi Chemical Foods), etc.
  • AEA Mitsubishi Chemical Foods
  • the function of the binder can be achieved by treating with “supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide used in the present invention.
  • “substance having” one kind or a combination of two or more kinds can be used.
  • the shape of the “substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” is not particularly limited, such as granular or needle-like. It can also be used after pulverization.
  • the shape of the substance is granular, the average particle size is not particularly limited as long as it has a function of a binder.
  • the average particle size when measured with a laser diffraction particle size distribution analyzer is 0.1 to 350 ⁇ m. Is preferred. These substances can be used singly or in combination of two or more kinds having different grades, shapes, average particle diameters, and the like.
  • the blending amount thereof is not limited as long as the amount exhibits the function as “substance having the function of a binder by being treated with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide”.
  • the amount is not particularly limited as long as the hardness of the fast disintegrating tablet (particularly the orally disintegrating tablet) is improved. Specifically, for example, it is 0.1 to 50% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 1 to 30% by weight as another embodiment, and 3 to 20 as another embodiment. % By weight.
  • the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention is optionally “a substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide”.
  • the plasticizer which improves the function of can be contained.
  • plasticizer can be used 1 type or in combination of 2 or more types.
  • the blending amount of the plasticizer is not particularly limited as long as it is an amount that enhances the function of “substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide”. Specifically, for example, it is 0.1 to 20% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 0.1 to 10% by weight as another embodiment, and 0 as another embodiment.
  • the blending amount of the plasticizer with respect to “substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” is, for example, 0.5 to 200% by weight. In another embodiment, it is 0.5 to 40% by weight, and in yet another embodiment, 10 to 40% by weight.
  • the fast disintegrating tablet (especially orally disintegrating tablet) of the present invention can contain an excipient usually added as a pharmaceutical additive, if desired.
  • the excipient used in the present invention is not limited as long as it is a hydrophilic substance or a water-soluble substance.
  • saccharides, a cellulose derivative, phosphate, and a sulfate are mentioned.
  • saccharide include mannitol, lactose, sucrose, sucrose, glucose, fructose, sorbitol, xylitol, erythritol, trehalose, sucrose, and multirole.
  • a cellulose derivative etc. are mentioned as a cellulose derivative.
  • Examples of the phosphate include calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granule, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate and the like. It is done.
  • Examples of the sulfate include calcium sulfate.
  • the excipient can be used alone or in combination of two or more.
  • the blending amount of the excipient is, for example, 0.001 to 99.99% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), and in another aspect, 1 to 99.9.
  • the weight percentage is 10 to 99 weight% in still another embodiment.
  • various pharmaceutical additives are appropriately used as needed in the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention to be formulated.
  • a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable.
  • binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, and the like are used.
  • the following binders can also be added.
  • binder examples include copolyvidone, povidone, polyvinyl alcohol / polyethylene glycol graft copolymer, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, hydroxypropyl methylcellulose, gum arabic, candy powder, sodium alginate, pregelatinized starch , Agar, vinyl acetate resin, pullulan, starch, hydroxypropyl cellulose, and the like.
  • disintegrant examples include corn starch, potato starch, carmellose calcium, carmellose sodium, crospovidone, pregelatinized starch, partially pregelatinized starch, carmellose, crystalline cellulose, croscarmellose sodium, sodium carboxymethyl starch, magnesium carbonate, Examples include low-substituted hydroxypropyl cellulose, low-substituted sodium carboxymethyl starch, precipitated calcium carbonate, gelatin, magnesium alumina hydroxide, and synthetic aluminum silicate.
  • crospovidone croscarmellose sodium
  • low-substituted hydroxypropyl methylcellulose sodium carboxymethyl starch, pregelatinized starch, partially pregelatinized starch, carmellose, and carmellose calcium.
  • Still other embodiments include low substituted hydroxypropyl methylcellulose, partially pregelatinized starch, croscarmellose sodium.
  • the sour agent include citric acid, tartaric acid, malic acid and the like.
  • the foaming agent include sodium bicarbonate, tartaric acid, sodium hydrogen carbonate, anhydrous citric acid, sodium hydrogen carbonate and the like.
  • Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
  • Examples of the fragrances include lemon, lemon lime, orange and menthol.
  • Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid and the like.
  • Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
  • the stabilizer examples include ascorbic acid, aspartic acid, sodium chloride, magnesium chloride, glycine, glycerin, light anhydrous silicic acid, magnesium gluconate, xylitol, calcium citrate, calcium hydroxide, sodium hydroxide, magnesium hydroxide, Examples thereof include potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like.
  • Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
  • antioxidant examples include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
  • surfactant examples include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
  • a pharmaceutical additive one or a combination of two or more can be appropriately added. The compounding quantity of these various pharmaceutical additives can be arbitrarily set.
  • the rapidly disintegrating tablet of the present invention is preferably an orally disintegrating tablet.
  • the production method of the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention will be described below.
  • “treated with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” has a function as a so-called “binder” that builds a crosslinked structure between components.
  • Biner that builds a crosslinked structure between components.
  • a tablet after compression (about 1 mL to about 2000 L of carbon dioxide in a supercritical state, a subcritical state, or a liquid or gaseous state (In particular, orally disintegrating tablets) are treated at a rate of about 0.1 g to about 2000 kg in one embodiment and about 5 g to about 100 kg in another embodiment.
  • the treatment time is from about 1 minute to about 50 hours in one embodiment, from about 1 minute to about 24 hours in another embodiment, from about 2 minutes to about 12 hours in another embodiment, and from about 5 minutes in another embodiment. About 2 hours.
  • the treatment is preferably performed in a pressure-resistant container.
  • pressure vessel H series (manufactured by Tama Seiki), EV series (manufactured by JASCO) or VE-1 (manufactured by Mitsubishi Chemical Corporation)
  • CO 2 liquid feed pump SCF-GET or PU-2086 ( (Manufactured by JASCO)
  • CO 2 compressor PU-1 (manufactured by Mitsubishi Chemical Corporation)
  • thermometer platinum resistance thermometer (R36S) (manufactured by Nippon Denshoku) and TI-2068-01 (manufactured by JASCO)
  • heater ribbon Heater (JK) (manufactured by ASONE), oven CO-2060 (manufactured by JASCO)
  • thermometer instruction controller E5CN (manufactured by OMRON)
  • pressure indicator WGA-710B (manufactured by Kyowa Denki)
  • pressure gauge PG- 500 KU (manufactured by Kyowa Denki Co.,
  • the treatment temperature varies depending on the kinds of components constituting the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention, but in one embodiment, it is about ⁇ 40 ° C. to about 100 ° C.
  • a substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is copolyvidone, about 25 ° C.
  • the treatment pressure varies depending on the types of components constituting the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention, but in one embodiment is about 0.1 MPa to about 50 MPa, and in another embodiment about 1 MPa to about 20 MPa.
  • carbon dioxide can be added by mixing other solvents.
  • solvents include water; aromatic hydrocarbons such as benzene, toluene, ethyl acetate, cyclohexane, and xylene; ethers such as dimethyl ether, diethyl ether, dioxane, diethoxyethane, tetrahydrofuran, and 1,2-dimethoxyethane.
  • Organochlorine organic solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; alkyl nitriles such as acetonitrile and propionitrile; nitroalkanes such as nitromethane and nitroethane; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide; Ketones such as acetone; Fatty acids such as acetic acid, acetic anhydride and oleic acid; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide Etc.; or and mixtures of these solvents are used, inter alia ethanol, acetone is preferred.
  • the amount of other solvents used is usually from about 0.1 to about 99.9% by volume, in some embodiments from about 1 to about 99.9% by volume in carbon dioxide in the supercritical or subcritical or liquid or gaseous state. 99% by volume.
  • other gases can be added to the carbon dioxide during the treatment. For example, nitrogen can be used as the other gas.
  • the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention is produced according to any one of the following procedures (1) to (4).
  • any of the procedures (1) to (4) may be referred to as carbon dioxide (pressure) treatment.
  • a rapidly disintegrating tablet (for example, orally disintegrating tablet) before carbon dioxide treatment is prepared.
  • a method of granulating a substance having a function of a binder by treatment with a medicinal component and carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide with an aqueous solution, and compression-molding the obtained granulated product Has the function of a binder by treating with medicinal ingredients and carbon dioxide in supercritical or subcritical state or liquid or gaseous carbon dioxide
  • a method of granulating a substance having a binder function by treating the substance having carbon dioxide in a supercritical or subcritical state with liquid or gaseous carbon dioxide, and compression-molding the resulting granulated product ,
  • compression molding the treated mixture or by treatment with medicinal ingredients and carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state
  • a rapidly disintegrating tablet for example, orally disintegrating tablet
  • a pressure-resistant container -Keep the temperature of the pressure-resistant container above the critical point of carbon dioxide. Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary). -The pressure in the pressure-resistant container is kept at a carbon dioxide critical point or higher to perform carbon dioxide treatment. -After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
  • a rapidly disintegrating tablet for example, orally disintegrating tablet
  • a pressure-resistant container (2) -Put a rapidly disintegrating tablet (for example, orally disintegrating tablet) into a pressure-resistant container. -Keep the temperature of the pressure-resistant container above the critical point of carbon dioxide. Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary). -The pressure in the pressure-resistant container is kept below the critical point of carbon dioxide, and carbon dioxide treatment is performed. -After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
  • a rapidly disintegrating tablet for example, orally disintegrating tablet
  • a pressure-resistant container -Keep the temperature of the pressure vessel below the critical point of carbon dioxide. Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary). -The pressure in the pressure-resistant container is kept at a carbon dioxide critical point or higher to perform carbon dioxide treatment. -After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
  • a rapidly disintegrating tablet for example, orally disintegrating tablet
  • a pressure-resistant container -Keep the pressure vessel temperature below the critical point of carbon dioxide. Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary). -The pressure in the pressure-resistant container is kept below the critical point of carbon dioxide, and carbon dioxide treatment is performed. -After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
  • Example 1 D-mannitol (Pearitol 50C, manufactured by Rocket Japan, unless otherwise noted) 59.0 w / w%, crystalline cellulose (MCC SANAQ burst, PHARMATRANS SANAQAG) 20.0 w / w%, copolyvidone (Kollidon VA64 Fine) , Manufactured by BASF Japan) 10.0 w / w% and crospovidone (Kollidon CL, manufactured by BASF Japan) 10.0 w / w% were mixed.
  • this tablet was treated in a pressure-resistant container (pressure cell) at a carbon dioxide pressure of 8.0 MPa and 45 ° C. for 30 minutes and then decompressed at a decompression rate of about 16 kPa / second to obtain the fast disintegrating tablet of the present invention. It was.
  • this tablet was treated at a carbon dioxide pressure of 8.0 MPa at 45 ° C. for 30 minutes using a pressure cell, and then decompressed at a decompression rate of about 16 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 7 Fmelt (Fuji Chemical) 89.0 w / w% and copolyvidone (Kollidon VA64 Fine, BASF Japan) 10.0 w / w% were mixed. This mixture is mixed with magnesium stearate 1.0 w / w%, and the tableting pressure is about 1.0 kN using a rotary tableting machine (HT-EX series, manufactured by Hata Seiko Co., Ltd., unless otherwise noted). / Tablets (reference example 1) of 180 mg per tablet were produced with a koji (tablet diameter 8.0 mm). Next, this tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 5 minutes using a pressure cell, and then reduced in pressure to obtain a rapidly disintegrating tablet of the present invention.
  • a koji tablet diameter 8.0 mm
  • Example 8 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 9 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 10 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 25 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 11 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 25 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 12 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 25 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 13 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 35 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 14 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 35 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 15 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 35 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 16 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 35 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 17 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 35 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 18 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 35 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 19 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 20 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 21 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 27 kPa / sec.
  • Example 22 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 45 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 23 The tablet of Reference Example 1 was treated using a pressure cell at a carbon dioxide pressure of 8 MPa at 45 ° C. for 15 minutes and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 24 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 45 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 16 kPa / sec.
  • Example 25 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 45 ° C. for 30 minutes using a pressure cell, and then depressurized at a depressurization rate of about 800 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 26 The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 8 MPa and 45 ° C. using a pressure cell, and then decompressed at a decompression rate of about 800 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 27 The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 8 MPa and 45 ° C. using a pressure cell, and then decompressed at a decompression rate of about 16 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 28 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 20 MPa and 45 ° C. for 30 minutes using a pressure cell, and then depressurized at a depressurization rate of about 27 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 29 The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 20 MPa and 45 ° C. for 30 minutes using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 30 The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 45 ° C. using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 31 The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 45 ° C. using a pressure cell, and then the pressure was reduced at a pressure reduction rate of about 27 kPa / second to obtain a rapidly disintegrating tablet of the present invention.
  • Example 32 The tablet of Reference Example 1 was treated for 30 minutes at a carbon dioxide pressure of 20 MPa and 40 ° C. using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Example 33 The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 40 ° C. using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / second to obtain a rapidly disintegrating tablet of the present invention.
  • Example 34 D-mannitol 54.0 w / w%, crystalline cellulose (manufactured by PHARMATRANS SANAQ AG) 20.0 w / w%, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer (Solplus, BASF Japan) 15.0 w / w%, cross Povidone (Kollidon CL, manufactured by BASF Japan) 10.0 w / w% was mixed. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of 180 mg per tablet were produced at a tableting pressure of about 1.0 kN / kg using a single tableting machine (tablet diameter 8.5 mm).
  • this tablet was treated at a carbon dioxide pressure of 8.0 MPa at 45 ° C. for 30 minutes using a pressure cell, and then decompressed at a decompression rate of about 16 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
  • Comparative Example 1 Fmelt (Fuji Chemical) 89.0 w / w% and copolyvidone (Kollidon VA64 Fine, BASF Japan) 10.0 w / w% were mixed. This mixture was mixed with magnesium stearate 1.0 w / w%, and 180 mg tablets per tablet were prepared at a tableting pressure of about 2.5 kN / ⁇ using a rotary tableting machine (tablet diameter 8.0 mm).
  • Test Example 5 Copolyvidone (Kollidon VA64, BASF Japan) and polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer (Soluplus, BASF Japan) were treated with carbon dioxide.
  • the carbon dioxide pressure during the treatment and the glass transition point of each substance are shown in Table 1 (copolyvidone) and Table 2 (polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer).
  • Tables 1 and 2 polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer
  • Reference example 2 Single shot mannitol (Parteck M100, Merck) 99.0 w / w% and magnesium stearate (Parteck LUB MST, Merck, unless otherwise noted) 1.0 w / w% Tableting was performed using a tablet machine (Autograph AGS-20kNG, manufactured by Shimadzu Corporation, unless otherwise specified) so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm). ). These tablets were treated for 60 minutes at a carbon dioxide pressure of 10 MPa and 40 ° C. using a pressure cell, and then the pressure was reduced to obtain tablets of Reference Example 2.
  • a tablet machine Autograph AGS-20kNG, manufactured by Shimadzu Corporation, unless otherwise specified
  • Reference examples 3-8 Various pharmaceutical additives 20.0 w / w% shown in Table 4 were mixed with 79.0 w / w% for direct hitting mannitol (Parteck M100, manufactured by Merck). This mixture was mixed with 1.0 w / w% magnesium stearate, and tableted using a single tableting machine so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm). These tablets were treated using a pressure cell at a carbon dioxide pressure of 6 MPa at 25 ° C. for 45 minutes and then decompressed to obtain tablets of Reference Examples 3 to 8.
  • Reference Examples 9-24 Various pharmaceutical additives 20.0 w / w% shown in Table 4 were mixed with 79.0 w / w% for direct hitting mannitol (Parteck M100, manufactured by Merck). This mixture was mixed with 1.0 w / w% magnesium stearate, and tableted using a single tableting machine so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm). These tablets were treated for 60 minutes at a carbon dioxide pressure of 10 MPa and 40 ° C. using a pressure cell, and then decompressed to obtain tablets of Reference Examples 9 to 24.
  • Test Example 6 For Reference Examples 2 to 24, the tablet hardness before and after the carbon dioxide pressure treatment was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 4.
  • Reference Examples 3 to 14 can be examples of the present invention.
  • Reference Example 25 Copolyvidone (Kollidon VA64 Fine, manufactured by BASF Japan) 20.0 w / w% having an average particle size of 10 to 20 ⁇ m was mixed with 79.0 w / w% for direct hitting mannitol (Parteck M100, manufactured by Merck). Magnesium stearate 1.0 w / w% was blended with this mixture, and a tablet with a tablet hardness of 19 N and a tablet thickness of about 3.9 mm was obtained using a single tableting machine (tablet diameter 8.5 mm). Using a pressure cell, the tablets were treated at a carbon dioxide pressure of 6 MPa at 25 ° C. for 45 minutes and then decompressed to obtain tablets of Reference Example 25.
  • Test Example 7 About the tablet of Reference Example 25, the hardness of the tableted product and that treated with carbon dioxide were measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 5.
  • Ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) 20.0 w / w% was mixed with 79.0 w / w% of mannitol for direct hitting (Parteck M100, manufactured by Merck). This mixture was mixed with 1.0 w / w% magnesium stearate, and tableted using a single tableting machine so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm). These tablets were treated for 45 minutes at a carbon dioxide pressure of 6 MPa and 25 ° C. using a pressure cell, and then the pressure was reduced to obtain tablets of Reference Example 26.
  • Reference Example 27 13.5 g of ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) and 1.5 g of triethyl citrate (Triethyl Citrate, manufactured by Tokyo Chemical Industry) are dissolved in 150 g of ethanol (ethanol 99.5%, manufactured by Kanto Chemical) and spray dryer. By spray-drying (Mini Spray Dryer B-290, manufactured by Büch, hereinafter the same unless otherwise specified), an ethylcellulose / triethyl citrate (9/1) spray-dried product was obtained.
  • Ethyl cellulose / triethyl citrate (9/1) spray-dried product 20.0 w / w% was mixed with mannitol for direct hitting (Parteck M100, manufactured by Merck) 79.0 w / w%.
  • This mixture was mixed with magnesium stearate 1.0 w / w%, and a tablet with a tablet hardness of 22 N and a tablet thickness of about 3.9 mm was obtained using a single tableting machine (tablet diameter 8.5 mm).
  • This tablet was treated at a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a tablet of Reference Example 27.
  • Reference Example 28 11.25 g of ethylcellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) and 3.75 g of triethyl citrate (manufactured by Tokyo Chemical) are dissolved in 150 g of ethanol (ethanol 99.5%, manufactured by Kanto Chemical) and spray dryer Spray dried product of ethyl cellulose / triethyl citrate (7.5 / 2.5) was obtained. Ethyl cellulose / triethyl citrate (7.5 / 2.5) spray-dried product 20.0 w / w% was mixed with mannitol for direct hitting (Parteck M100, manufactured by Merck) 79.0 w / w%.
  • Parteck M100 manufactured by Merck
  • This mixture was mixed with magnesium stearate 1.0 w / w%, and a tablet with a tablet hardness of 20 N and a tablet thickness of about 3.9 mm was obtained using a single tableting machine (tablet diameter 8.5 mm).
  • This tablet was treated at a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes using a pressure cell, and then the pressure was reduced to obtain a tablet of Reference Example 28.
  • Test Example 8 For the tablets of Reference Examples 26 to 28, the hardness before and after the carbon dioxide treatment was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 6.
  • Reference Examples 26 to 28 can be examples of the present invention.
  • Example 35 Fluidized bed granulator using 410 g of D-mannitol (Pearitol 50C, manufactured by Rocket Japan, hereinafter the same unless otherwise specified) as an aqueous solution (10.0 w / w%) of copolyvidone (Kollidon VA64, manufactured by BASF Japan). (Flow coater FLO-1, manufactured by Freund Sangyo / Okawara Seisakusho, the same applies unless otherwise specified).
  • a part of this granulated product was aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Evonik Degussa Japan, unless otherwise noted) 10.0 w / w%, crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5 0.0 w / w% was mixed.
  • This mixture is blended with 1.0 w / w% magnesium stearate and compressed using a rotary tableting machine (HT-EX series, manufactured by Hata Seiko Co., Ltd., unless otherwise specified) with a tableting pressure of about 1 kN / kg.
  • Produced tablets of about 170 mg per tablet (tablet diameter 8.5 mm). Tablet hardness was 11N (n 10).
  • the tablet was treated for 5 minutes at a carbon dioxide pressure of 5 MPa and 25 ° C. using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1
  • Example 36 The tablet of Example 35 was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 60 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 37 The tablet of Example 35 was treated using a pressure cell at a carbon dioxide pressure of 3 MPa and 25 ° C. for 840 minutes, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 38 The tablet of Example 35 was treated at a carbon dioxide pressure of 4 MPa and 15 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 39 The tablet of Example 35 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 40 The tablet of Example 35 was treated at a carbon dioxide pressure of 3 MPa and 60 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 42 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E7.5 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 10.0 w / w%.
  • copolyvidone Kerdon VA64, manufactured by BASF Japan
  • the tablet was treated at a carbon dioxide pressure of 3 MPa and 45 ° C. for 120 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 43 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E20.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 10.0 w / w%.
  • copolyvidone Kerdon VA64, manufactured by BASF Japan
  • the tablets were treated using a pressure-resistant cell at a carbon dioxide pressure of 1 MPa and 35 ° C. for 840 minutes, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 44 A mixed solution of 410 g of D-mannitol and 50 g of copolyvidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (5.0 w / w%) and 50 g of povidone (Kollidon K30, manufactured by BASF Japan) (5.0 w / w%) Granulated using a fluid bed granulator. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%.
  • the tablet was subjected to a nitrogen pressure of 10 MPa using a pressure cell, further treated with carbon dioxide pressure of 5.0 MPa and 25 ° C. for 45 minutes, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 45 The tablet of Example 44 was added with a carbon dioxide pressure of 5.0 MPa using a pressure cell, further added with a nitrogen pressure of 5.0 MPa, treated at 25 ° C. for 45 minutes, and then decompressed to quickly disintegrate the tablet of the present invention. Got. The decompression speed condition was about 1 MPa / min.
  • Example 46 410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%.
  • povidone Kerdon K30, manufactured by BASF Japan
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 30 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 47 Using a fluidized bed granulator, 320 g of D-mannitol was combined with 80 g of an aqueous solution (5.0 w / w%) of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT Type F, manufactured by Daido Kasei Kogyo Co., Ltd.). Grained. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%.
  • POVACOAT Type F polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 48 320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) aqueous solution (5.0 w / w%) as a binder. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%.
  • HPC-SSL hydroxypropylcellulose
  • aqueous solution 5.0 w / w%
  • the tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 45 minutes using a pressure cell and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 49 320 g of D-mannitol was granulated using a fluidized bed granulator with 80 g of an aqueous solution of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) (5.0 w / w%) as a binding solution. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%.
  • the tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 45 minutes using a pressure cell and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 50 320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of an aqueous solution (5.0 w / w%) of polyvinyl alcohol / polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF Japan) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%.
  • the tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 45 minutes using a pressure cell and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 51 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid.
  • copolyvidone Kollidon VA64, manufactured by BASF Japan
  • Aminoalkyl methacrylate copolymer E 9.0 w / w% and low-substituted hydroxypropyl cellulose (L-HPC NBD-022, manufactured by Shin-Etsu Chemical Co., Ltd.) 9.0 w / w% were mixed with a part of this granulated product.
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 52 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and croscarmellose sodium (Kiccolate ND-2HS, manufactured by Asahi Kasei Chemicals) 5.0 w / w%.
  • copolyvidone Kerdon VA64, manufactured by BASF Japan
  • the tablet was treated with a pressure cell using a carbon dioxide pressure of 4 MPa at 25 ° C. for 10 minutes and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 53 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid.
  • copolyvidone Kollidon VA64, manufactured by BASF Japan
  • PCS partially pregelatinized starch
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 54 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid.
  • copolyvidone Kollidon VA64, manufactured by BASF Japan
  • Aminoalkyl methacrylate copolymer E9.0 w / w% and sodium carboxymethyl starch (Primojel, manufactured by DMV-Fonterra Experts) 9.0 w / w% were mixed with a part of the granulated product.
  • the tablet was treated with a pressure cell using a carbon dioxide pressure of 4 MPa at 25 ° C. for 10 minutes and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 55 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kolidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and carmellose calcium (ECG-505, manufactured by Gotoku Pharmaceutical) 5.0 w / w%.
  • copolyvidone Kolidon VA64, manufactured by BASF Japan
  • the tablet was treated with a pressure cell using a carbon dioxide pressure of 4 MPa at 25 ° C. for 10 minutes and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 56 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid.
  • copolyvidone Kollidon VA64, manufactured by BASF Japan
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 57 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid.
  • copolyvidone Kollidon VA64, manufactured by BASF Japan
  • the tablet was treated with a pressure cell using a carbon dioxide pressure of 4 MPa at 25 ° C. for 10 minutes and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 58 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of povidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid.
  • Acetaminophen manufactured by Yamamoto Chemical Co., Ltd.
  • aminoalkyl methacrylate copolymer E 1.0 g
  • crospovidone Karl-Open-F
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 59 410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. 7.01 g of this granulated product was mixed with 1.11 g of famotidine (manufactured by Astellas Pharma), 1.0 g of aminoalkyl methacrylate copolymer E, and 0.75 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan).
  • povidone Kerdon K30, manufactured by BASF Japan
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 60 410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid.
  • povidone Kerdon K30, manufactured by BASF Japan
  • aqueous solution (10.0 w / w%) as a binding liquid.
  • the tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 61 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid.
  • HPMCAS AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.
  • crospovidone Karl Fischer w / w%
  • 8.0 w / w% were mixed with a part of this granulated product.
  • the tablet was treated at a carbon dioxide pressure of 5 MPa and 25 ° C. for 45 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 62 410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid.
  • HPMCAS AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.
  • crospovidone Karl Fischer F, manufactured by BASF Japan
  • the tablet was treated using a pressure cell at a carbon dioxide pressure of 5 MPa at 45 ° C. for 840 minutes and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 63 The tablet of Example 62 was treated at a carbon dioxide pressure of 5 MPa and 60 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 64 410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid.
  • Part of this granulated product was ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) 15.0 w / w%, crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%, l-menthol ( Manufactured by Kanto Chemical Co., Ltd.) 1.0 w / w% was mixed.
  • This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 171 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm).
  • the tablet was treated at a carbon dioxide pressure of 5 MPa and 60 ° C. for 45 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 65 The tablet of Example 35 was treated for 120 minutes at a carbon dioxide pressure of 3.5 MPa and 25 ° C. using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 66 The tablet of Example 46 was treated for 120 minutes at a carbon dioxide pressure of 3.5 MPa and 25 ° C. using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 67 The tablet of Example 44 was treated for 120 minutes at a carbon dioxide pressure of 3.5 MPa and 25 ° C. using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Example 68 415 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (5.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%.
  • povidone Kerdon K30, manufactured by BASF Japan
  • aqueous solution 5.0 w / w%
  • Example 69 415 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (5.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%.
  • povidone Kerdon K30, manufactured by BASF Japan
  • aqueous solution 5.0 w / w%
  • the tablet was treated for 90 minutes at a carbon dioxide pressure of 3.5 MPa and 25 ° C. using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Comparative Example 2 After treating the tablet of Example 35 under atmospheric pressure at 60 ° C. for 45 minutes, the tablet of Comparative Example 2 was obtained.
  • Test Example 9 The hardness of each of the tablets of Examples 35 to 69 and Comparative Examples 2 to 4 was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 7.
  • Test Example 10 Oral disintegration time was measured for the tablets of Examples 35 to 69 and Comparative Examples 2 to 4. The oral disintegration time was measured using an oral disintegration tester (Trichop Tester, Okada Seiko Co., Ltd.). The results are shown in Table 7.
  • Test Example 12 The rapidly disintegrating tablets of Examples 65 to 69 and Comparative Examples 3 to 4 were packaged in PTP sheets (34 ⁇ 111 mm, 7 tablets ⁇ 2 rows / sheet), and a drop test was performed under the following conditions.
  • -Drop height 150cm
  • -Number of repeated drops 10 times-Number of PTP sheets to be tested: 10 sheets-Orientation of PTP sheets: drug storage part (pocket) on top-Breakage rate: (Fast disintegrating tablets with cracks and / or chips) Number) / 140 ⁇ 100
  • Table 7 The results are shown in Table 7.
  • Example 35 a significant increase in tablet hardness was confirmed by treatment at 25 ° C. for 5 minutes under a carbon dioxide pressure of 5 MPa. Therefore, the tablet hardness increased even in a mild temperature environment near room temperature. It was confirmed that it was achieved.
  • Examples 44 to 45 it was confirmed that an increase in tablet hardness could be similarly induced by using carbon dioxide in combination with nitrogen. From this result, it was shown that the present invention may use other gases in addition to carbon dioxide.
  • various general-purpose binders such as povidone and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer can be used as the binder used in the granulation step.
  • the rapidly disintegrating tablet of the present invention can be obtained by using various general-purpose disintegrating agents such as low-substituted hydroxylpropycellulose, croscarmellose sodium and partially pregelatinized starch as disintegrating agents. It was done.
  • Examples 58 to 60 it was confirmed that a rapidly disintegrating tablet having the same performance can be obtained even in a preparation containing a model drug.
  • Examples 61 to 64 it was shown that tablet hardness can be increased similarly to aminoalkyl methacrylate copolymer E by combining HPMCAS or ethyl cellulose with carbon dioxide pressure treatment, and the fast disintegrating tablet of the present invention can be obtained. .
  • the rapidly disintegrating tablet of the present invention can be obtained by appropriately designing the additive group represented by the component having the function of increasing the tablet hardness by the carbon dioxide pressure in the reference example. It has been shown.
  • the failure rate in the drop test was evaluated, but all confirmed a very low failure rate of 0 to 0.7%.
  • Comparative Examples 3 and 4 in which fast disintegrating tablets of the same formulation as in Examples 68 and 69 were increased to the same degree of tablet hardness by heat treatment instead of carbon dioxide, relative to 2.1 to 5% Showed a high damage rate. It was revealed that the fast disintegrating tablet of the present invention is excellent in breakage resistance.
  • Example 70 Fluidized bed granulator using solifenacin succinate (manufactured by Astellas Pharma Inc.) and fine particle having bitterness masking function 80.7g as copolyvidone (Kollidon VA64, manufactured by BASF Japan) 100g aqueous solution (10.0w / w%) as binding liquid.
  • copolyvidone Kollidon VA64, manufactured by BASF Japan
  • Aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w% were mixed with this granulated product.
  • the tablet was treated at a carbon dioxide pressure of 5 MPa and 35 ° C. for 30 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention.
  • the decompression speed condition was about 1 MPa / min.
  • Comparative Example 5 The tablet of Example 70 was heat-treated at 70 ° C. for 840 minutes in the air to obtain the tablet of Comparative Example 5.
  • Test Example 13 The hardness of each of the rapidly disintegrating tablet of Example 70 and the tablet of Comparative Example 5 was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 8.
  • Test Example 14 The dissolution test was performed on the bitter masking particles used in Example 70, the fast disintegrating tablet of Example 70, and the tablet of Comparative Example 5.
  • Dissolution tester NTR-6100A manufactured by Toyama Chemical
  • the dissolution rate of solifenacin succinate was measured using liquid chromatography (manufactured by Shimadzu Corporation). Test conditions are shown below.
  • ⁇ Paddle method 50rpm Test liquid JP disintegration test second liquid (pH 6.8) 900 mL ⁇ Test solution temperature: 37 °C ⁇ 0.5 °C Sampling time: 2 minutes and 30 minutes are shown in Table 8.
  • Test Example 15 About the bitterness masking particle used in Example 70, the fast disintegrating tablet of Example 70, and the tablet of Comparative Example 5, the production amount of the most decomposed product (hereinafter referred to as the total amount of solifenacin succinate and its decomposed product)
  • the amount of main decomposition product may be abbreviated), and the total amount of decomposition product relative to the total amount of solifenacin succinate and its decomposition product (hereinafter, may be abbreviated as total decomposition product).
  • the results are shown in Table 8.
  • Example 70 had the same amount of main degradation products as the bitterness masking particles and the total amount of degradation products, whereas the tablet of Comparative Example 5 showed a significant increase. Admitted.
  • the present invention improves the breakage of tablets generated in the distribution process, and is characterized by drugs that are unstable in temperature or humidity, solid dispersion particles composed of poorly soluble drugs, bitterness masking particles, sustained release particles, etc. It is possible to provide a rapidly disintegrating tablet (particularly an orally disintegrating tablet) while sufficiently maintaining various functions imparted to the functional particles imparted with a desired function based on the above. As mentioned above, although this invention was demonstrated along the specific aspect, the deformation

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Abstract

L'invention concerne un comprimé à désintégration rapide (en particulier, un comprimé à désintégration par voie orale) contenant des particules contenant un médicament conférant une fonction souhaitée basée sur les propriétés du médicament, le comprimé exprimant encore entièrement la fonction, même après une étape de formulation qui peut parfois avoir un impact sur sa fonction ; et un procédé de production du comprimé. Le comprimé à désintégration rapide est obtenu par traitement, avec du dioxyde de carbone dans un état supercritique ou sous-critique ou avec un liquide ou un gaz de dioxyde de carbone, d'un médicament et d'une matière qui possède la fonction d'un agent liant par traitement avec du dioxyde de carbone dans un état supercritique ou sous-critique ou avec un liquide ou un gaz de dioxyde de carbone.
PCT/JP2013/055634 2012-03-02 2013-03-01 Comprimé à désintégration rapide WO2013129644A1 (fr)

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EP2848241A1 (fr) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations effervescentes de linagliptin
EP2848242A1 (fr) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations orodispersibles de Linagliptin
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CN112979964B (zh) * 2021-02-22 2022-05-31 烟台大学 一种高韧性虫胶及其制备方法

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EP2848242A1 (fr) * 2013-09-12 2015-03-18 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations orodispersibles de Linagliptin
US11344562B2 (en) 2017-08-15 2022-05-31 Nephron Pharmaceuticals Corporation Aqueous nebulization composition
WO2020213589A1 (fr) * 2019-04-15 2020-10-22 三生医薬株式会社 Comprimé et procédé de production de comprimé
JP7555333B2 (ja) 2019-04-15 2024-09-24 三生医薬株式会社 錠剤及び錠剤の製造方法

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JPWO2013129644A1 (ja) 2015-07-30
JP6098634B2 (ja) 2017-03-22
CN104168891A (zh) 2014-11-26
PH12014501772B1 (en) 2014-11-10
KR20140130736A (ko) 2014-11-11
TWI612975B (zh) 2018-02-01
TW201350141A (zh) 2013-12-16
PH12014501772A1 (en) 2014-11-10
KR102092423B1 (ko) 2020-03-23

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