TWI612975B - Quickly disintegrating tablet - Google Patents

Abstract

The present invention provides a lozenge containing drug-containing particles that impart desired functions according to the characteristics of the drug. Even after going through a formulation step that affects its function, a rapidly disintegrating lozenge with sufficient function (especially intraoral disintegration) Ingot), and its manufacturing method.

The aforementioned fast-disintegrating lozenges treat drugs and substances having a binding agent function by processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, and processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state Got.

Description

Rapidly disintegrating lozenges

The present invention relates to a rapidly disintegrating lozenge (especially an intraoral disintegrating lozenge) with a porous structure treated with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state. Moreover, the present invention relates to a method for producing rapidly disintegrating tablets (especially intraoral disintegrating tablets) processed by supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide.

When providing pharmaceutical preparations, most companies seek to develop drugs that must be unstable to temperature or humidity, or drugs that have a bitter taste, etc., depending on the characteristics of the drug, they are given to medicinal products containing drug-containing particles with specific functions preparation.

Among pharmaceutical preparations, lozenges are widely used in the medical workplace as one of the most suitable dosage forms in terms of ease of taking by patients.

In addition, according to the silver hair scientific research conducted by the Ministry of Health, Welfare, and Health Sciences of the Ministry of Health and Welfare conducted in the 1980s, "the research on the preparation of the most suitable novel preparations and novel packaging containers for elderly people" (Tokyo Women's Medical University, Masahara Sugihara Et al.) (Pharmaceutical Daily was issued on August 22, 2011; Non-Patent Document 1). For example, a) oral dissolving preparations, b) slurry-like preparations, c) jelly-like preparations are provided as novel preparations. Among them, oral-dissolving preparations and slurry-like preparations are easy to take and stable for the elderly. Taking the preparation.

The oral disintegrating tablet is a dosage form suitable for patients with reduced swallowing ability, and it is widely known to be widely used as a patient who is restricted in intake of water, or highly convenient for drinking without water such as before bedtime or when going out Dosage form.

About oral disintegrating tablet preparation technology, report on oral disintegrating tablet containing granules formed by spraying and coating and / or granulating sugar with low formability and using high formability sugar as a binder Invention (Patent Document 1).

In addition, in order to improve the manufacturing problems such as poor fluidity of the supplied material or adhesion of the material to the pressurizing member during pressurization, the invention of a method for manufacturing a fast-dissolving lozenge is reported, which is characterized by The dried tablet material containing the medicament, water-soluble binder and water-soluble excipient is used as a tablet form, and the minimum necessary pressure to maintain the hardness of the form is the tableting step of pressure forming, in order to make the tablet The tablet formed in the step includes a humidifying step when absorbing moisture, and a drying step for drying the tablet humidified in the humidifying step (Patent Document 2).

In addition, there is a report on a composition containing medicines, sugars, and polyethylene glycol. After the composition is subjected to low-pressure beating, the temperature is raised under the temperature conditions at which the polyethylene glycol melts. Glycols form a mouth with a porous structure by forming inter-particle crosslinks between drugs and sugars Invention of collapsible ingot in cavity (Patent Document 3).

In addition, it is reported that when the strength of the lozenge is improved and the abrasion degree is improved without prolonging the disintegration time in the oral cavity, the medicines, diluents, and sugars with lower melting points than the medicines and diluents are formed. It is uniformly blended into lozenges, and is rapidly disintegrated into the oral cavity by forming a cross-linking between the drug and / or diluent particles through the molten solidified sugar with a low melting point (Patent Document 4); Invention of active material and polyvinyl alcohol-polyethylene glycol graft copolymer for oral disintegrating tablets (Patent Document 5); invention related to the manufacturing method of rapidly disintegrating tablets for the production of rapid disintegrating and For rapid disintegrating lozenges of sufficient lozenge strength, the steps of (1) mixing the active ingredient with an acrylic copolymer and at least one pharmacologically acceptable additive, (2) carrying out the mixture obtained in step (1) Compression molding step, and (3) Invention formed by the step of holding the compression molded article obtained in step (2) under a temperature condition of 50 to 100 ° C for a certain period of time (Patent Document 6); related to rapidly disintegrating ingot The invention of the manufacturing method of the agent In order to bring the components in powder form into contact with the pressurized liquefied gas or gas mixture and homogenize them, the pressure is introduced into the forming mold to reduce the pressure (Patent Document 7); the invention relates to the invention of rapid disintegrating ingot In order to make tablets by making a mixture containing an active ingredient, an additive and a supercritical fluid soluble substance, the stage of manufacturing a tablet, and contacting the aforementioned tablet with a supercritical fluid to extract the supercritical fluid soluble substance, and in the tablet The method is produced at the stage of forming fine voids (Patent Document 8).

However, there are still rapid disintegrating tablets (especially oral The problem of the shortcomings of internal disintegrants must be further improved technology. In addition, in order to maintain the original function of the functional particles, in order to provide tablets with sufficient formulation hardness and rapid disintegration during formulation treatment (rapidly disintegrating tablets (especially intraoral disintegrating tablets)) At this time, the technology must be further improved.

In addition, in the case of heat treatment or humidification treatment, due to the possibility of drug decomposition, in order to provide a manufacturing method of fast disintegrating tablets (especially intraoral disintegrating tablets) that will not affect the stability of the drug, it is necessary to go further Improvement technology.

[Conventional Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. WO95 / 20380 Manual

[Patent Document 2] Patent No. 2919771

[Patent Document 3] Japanese Patent Laid-Open No. 11-33084

[Patent Document 4] Japanese Patent Laid-Open No. 2004-292457

[Patent Document 5] Japanese Patent Laid-Open No. 2006-76971

[Patent Document 6] Manual of International Publication No. WO2006 / 070845

[Patent Document 7] Japanese Patent Laid-Open No. 2007-516977

[Patent Document 8] Japanese Patent Publication No. 2012-509315

[Non-patent literature]

[Non-Patent Document 1] "Study on the most suitable novel preparations and novel packaging containers for the elderly" Tokyo Women's Medical University, Sugihara Chint, et al., Pharmaceutical Affairs Daily, August 22, 2011

The object of the present invention is to provide a rapidly disintegrating lozenge (especially an oral disintegrating lozenge) which can improve the breaking defects of the lozenge.

Furthermore, the object of the present invention is to provide fast-disintegrating tablets (especially intraoral disintegrating tablets) that can be suitably used for drugs that are unstable with respect to humidification treatment or heating treatment. In addition, the subject of the present invention also provides a lozenge containing drug-containing particles (hereinafter referred to as "functional particles") that impart desired functions according to drug characteristics, even after going through the formulation step (in terms of formulation design, high temperature or high In the case of humidity treatment, which affects the function of functional drug-containing particles), it still has sufficient rapid disintegrating tablets (especially intraoral disintegrating tablets).

Another object of the present invention is to provide a method for producing fast-disintegrating tablets (especially intraoral disintegrating tablets) that can be suitably used for drugs that are unstable to humidification or heating. In addition, another subject of the present invention is to provide a lozenge containing drug-containing particles that impart desired functions in accordance with the characteristics of the drug, even after going through the formulation step (in terms of formulation design, it may be treated at high temperature or high humidity. Will cause the decomposition of the drug or affect the function of the particles containing functional drugs), the drug itself is still stable or has sufficient functional particles of the fast disintegrating tablets (especially intraoral disintegrating tablets).

In view of this situation, the inventors found that there is a substance that lowers the melting point or glass transition temperature when processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state. The so-called "inter-particle" cross-linking functions as a binding agent.

In addition, since it can be manufactured under stable processing conditions, the resulting rapid disintegration Lozenges (especially oral disintegrating tablets) containing drugs that are unstable to temperature or humidity, or containing functional particles (such as solid dispersion particles made of poorly soluble drugs, bitter taste masking particles) , Xufang particles, etc.), in order to maintain the stability or the desired function sufficiently, due to the porous structure, it can provide tablets with sufficient hardness for the formulation treatment and rapid disintegration Lozenges (rapidly disintegrating lozenges (particularly disintegrating lozenges in the oral cavity)) complete the present invention.

In other words, the present invention is related

[1] A rapidly disintegrating lozenge, which contains a drug and a substance that has a binder function by being treated with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, and in a supercritical or subcritical state From carbon dioxide or liquid or gaseous carbon dioxide.

[2] The fast disintegrating lozenge as described in [1], in which a substance having a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state is obtained by supercritical or subcritical Substance in which carbon dioxide or liquid or gaseous carbon dioxide is treated in a critical state to lower the melting point or glass transition temperature.

[3] The rapidly disintegrating lozenge described in [1] or [2], wherein the substance having a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state is selected from ethylene Pyrrolidone. Vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetic acid-polyethylene glycol graft copolymer, polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone / vinyl acetate resin premix preparation, methyl alcohol Based acrylic copolymer LD, polyvinyl alcohol. Polyethylene glycol graft copolymer, polyvinyl alcohol. Poly Glycol graft copolymer / polyvinyl alcohol premix preparation, polyethylene oxide (196), polypropylene oxide (67) glycol, polyethylene glycol (macrogol), polyethylene oxide hardened castor oil (40), aminoalkane Methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, Ethyl acrylate. Methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate. Diethylaminoethyl methacrylate copolymer, hydroxypropyl methyl cellulose acetate succinate, shellac, carbomer, and polyvinyl acetal diethyl One or more of the aminoacetate groups.

[4] The rapidly disintegrating lozenge as described in any one of [1] to [3], wherein the substance having a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, It is 0.1% by weight or more and 50% by weight or less relative to the weight of the tablet.

[5] The fast disintegrating lozenge described in any one of [1] to [4], which further contains a plasticizer.

[6] The fast disintegrating lozenge described in any one of [1] to [5], which further contains a disintegrating agent.

[7] The rapidly disintegrating lozenge described in any one of [1] to [6], wherein the hardness of the lozenge is 20N or more.

[8] The rapid disintegrating lozenge described in any one of [1] to [7], wherein the ratio of the number of broken ingots by the drop test is 5% or less.

〔9〕 The rapid disintegrating lozenge described in any one of [1] to [8], which The medium-speed disintegrating tablet is an oral disintegrating tablet.

[10] The fast disintegrating lozenge described in [9], wherein the disintegrating time in the oral cavity is within 120 seconds.

[11] The fast disintegrating lozenge described in any one of [1] to [10], wherein the drug constitutes a drug and / or functional particles that are unstable to temperature or humidity.

[12] The fast disintegrating lozenge as described in [11], wherein the functional particles are selected from the group consisting of solid dispersion particles made of poorly soluble drugs, bitter taste masking particles, and Xufang particles or More than 2 types of particles.

[13] A method for manufacturing rapidly disintegrating lozenges, characterized by comprising (1) a step of mixing a drug and a substance having a binder function by processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state , (2) The step of compressing the mixture of (1) to prepare a tablet, and (3) The step of treating the tablet of (2) with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state.

[14] The method for producing rapidly disintegrating lozenges as described in [13], wherein a substance having a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, by supercritical Or the subcritical state of carbon dioxide or liquid or gaseous carbon dioxide treatment to reduce the melting point or glass transition temperature of the substance.

[15] The method for producing rapidly disintegrating lozenges as described in [13] or [14], in which carbon dioxide or liquid in supercritical or subcritical state or Gaseous carbon dioxide treatment with a binding agent is selected from vinyl pyrrolidone. Vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetic acid-polyethylene glycol graft copolymer, polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone / vinyl acetate resin premix preparation, methyl alcohol Based acrylic copolymer LD, polyvinyl alcohol. Polyethylene glycol graft copolymer, polyvinyl alcohol. Polyethylene glycol graft copolymer / polyvinyl alcohol premix, polyethylene oxide (196), polypropylene oxide (67) glycol, polyethylene glycol (macrogol), polyethylene oxide hardened castor oil (40), amine Alkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate. Methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate. One or more of diethylaminoethyl methacrylate copolymer, hydroxypropyl methyl cellulose acetate succinate, shellac, and carbomer.

[16] The method for producing fast-disintegrating lozenges as described in any one of [13] to [15], which has a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state The substance is 0.1% by weight or more and 50% by weight or less relative to the weight of the tablet.

[17] The method for producing a fast-disintegrating tablet according to any one of [13] to [16], which further contains a plasticizer.

[18] The method for producing a fast-disintegrating tablet according to any one of [13] to [17], which further contains a disintegrating agent.

〔19〕 Fast disintegrating lozenges as described in any of [13] to [18] Manufacturing method, wherein the hardness of the tablet is 20 N or more.

[20] The method for producing a fast-disintegrating tablet according to any one of [13] to [19], wherein the fast-disintegrating tablet is an oral disintegrating tablet.

[21] The method for producing fast disintegrating lozenges as described in [20], wherein the disintegrating time in the oral cavity is within 120 seconds.

[22] The method for producing fast-disintegrating lozenges as described in any one of [13] to [21], wherein the drug constitutes a drug and / or functional particles that are unstable to temperature or humidity.

[23] The method for producing fast-disintegrating lozenges as described in [22], wherein the functional particles are selected from the group consisting of solid dispersion particles, bitter taste shielding particles, and Xufang particles made of insoluble drugs One or more particles.

[24] The method for producing a rapidly disintegrating tablet according to any one of [13] to [23], which includes treatment with carbon dioxide of 0.1 MPa or more and 50 MPa or less and -40 ° C or more and 100 ° C or less.

[25] The method for producing a rapidly disintegrating lozenge as described in any one of [13] to [24], wherein it is treated with gaseous carbon dioxide.

According to the present invention, it is possible to provide a fast-disintegrating lozenge (especially an intra-oral disintegrating tablet) having improved breakage resistance and quick disintegration in the oral cavity. Furthermore, for example, it contains solid dispersion particles, bitter taste masking particles, and exothermic particles, which can be processed under stable conditions of about room temperature, so that it can provide solid dispersion particles made of drugs that are unstable to temperature or humidity or poorly soluble drugs. At this time, in order to sufficiently maintain the stability or desired function, fast disintegrating tablets (especially intraoral disintegrating tablets) can be provided.

[Forms for carrying out the invention]

In the following, the embodiments of the present invention will be described in detail.

In this specification, "supercritical (state)" refers to a non-condensable high-density fluid whose pressure and temperature simultaneously exceed the critical point.

In addition, "subcritical (state)" refers to a state where only one of pressure and temperature exceeds the critical point. Critical point refers to "Particle Formation with Supercritical Fluids-A Review" by JWTom and PG Debenedetti, Journal of Aerosol Science (J. Aerosol Sci.), 22 (5), pages 555-584, Fig. 1 in 1991 Detailed record.

In addition, the liquefaction state where neither pressure nor temperature exceeds the critical point is called "liquid".

Moreover, the gasification state where neither the pressure nor the temperature exceeds the critical point is called "gas".

Specifically, the carbon dioxide in the supercritical state simultaneously exceeds the critical pressure of about 7.38 Megapascal (MPa) and the critical temperature of about 304.1 Kelvin (K). Specifically, except for the solid state. For example, liquid carbon dioxide, gaseous carbon dioxide, supercritical carbon dioxide.

In this specification, "adequate tablet hardness for formulation treatment" or "excellent tablet hardness" is not particularly limited as long as the tablet does not break during the circulation step, and for example, it can be roughly Self-sourcing The strength of the preparation and removal, such as the hardness of the tablet in the longitudinal direction. The hardness varies depending on the size and shape of the tablet. For example, a 180 mg tablet has a diameter of about 8.0 mm and is defined as 20 N or more, a diameter of about 8.5 mm is defined as 30 N or more, and a diameter of about 10.0 mm is defined as 50 N or more, and a diameter At 12.0mm, it is specified as 60N or more. Regardless of the size of the preparation of the present invention, it suffices to have sufficient strength to withstand removal from the PTP package. In addition, it can be applied to the strength of the bottle (the packaging of the tablets in glass, plastic, etc. containers), that is, generally in the general bottle container, resistant to the tablets between the tablets during the transportation, or the tablets and the container wall The strength of the lozenge contacted with it is preferably 30N or more. In addition, another form such as a tablet packed in PTP has a breakage rate by a drop test. For example, when a PTP packaging sheet is packed in a PTP packaging sheet in the state of a tablet, so that when the tablet storage portion (Pocket) is dropped from above from 150 cm in height of 10 sheets, the breakage rate of the tablet is less than 5%, Another form provides strength of 2% or less. The preparation of the present invention has a bottled container with sufficient strength when transported or carried in.

In this specification, lozenges with "rapid disintegration" (rapidly disintegrating lozenges) refer to tablets that have practically sufficient disintegrability or solubility through saliva without taking water in the oral cavity Agent. Here, practically sufficient disintegrability or solubility varies depending on the individual, and is generally prescribed in the oral cavity at about 1 to 300 seconds, preferably at about 1 to 150 seconds, more preferably at about 1 to 90 seconds, most The best form disintegrates or dissolves within about 1 to 60 seconds. In addition, when prescribed by Tricorp Tester, the disintegration time is within 1 to 300 seconds, the preferred form is within 1 to 120 seconds, the more preferred form is within 1 to 90 seconds, and the particularly preferred form is within 1 to 60 seconds, the best The form is within 1 to 40 seconds. another In addition, the "orally disintegrating tablet" depends on the individual, and it is usually prescribed in the oral cavity for about 1 to 120 seconds, the preferred form is about 1 to 90 seconds, and the better form is about 1 to 60 seconds to disintegrate or dissolve. In addition, when measured by Tricorp Tester, the disintegration time is within 1 to 120 seconds, the preferred form is within 1 to 90 seconds, the more preferred form is within 1 to 60 seconds, and the optimal form is within 1 to 40 seconds. Dissolved lozenges.

In this specification, the "porous structure" is not particularly limited as long as the lozenge rapidly disintegrates in the oral cavity. For example, the porosity is specified to be 15% or more and 90% or less, and the preferred form is 25% or more and 70% or less , The better form is more than 30% and less than 50%.

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. The medicinal active ingredients such as hypnotic sedatives, sleep-introducing agents, migraine agents, anti-restorative agents, antiepileptic agents, antidepressant drugs, anti-Parkinson's agents, psychoactive agents, central nervous system drugs, local anesthetics, skeletal muscles Relaxant, autonomic nerve agent, antipyretic analgesic and anti-inflammatory agent, antispasmodic agent, antihalation agent, cardiotonic agent, arrhythmia agent, diuretic agent, blood pressure lowering agent, vasoconstrictor, vasodilator, circulatory organ medicine, hyperlipidemia agent , Breath-promoting agent, antitussive agent, phlegm agent, antitussive and phlegm agent, bronchodilator, antidiarrheal agent, intestinal agent, peptic ulcer agent, stomach digestion agent, antacid, laxative, choleretic agent, Digestive organ medications, paraadrenal hormones, hormones, diuretic organs, vitamins, hemostatics, liver patients, gout treatment, diabetes, antihistamines, antibiotics, antibacterials, anti-malignant Tumor, chemotherapy, comprehensive cold, nourishing Zhuang health medicine, osteoporosis medicine, etc. This drug is used to treat bladder hyperactivity such as Solifenacin, tolterdine, Mirabegron, diphenyldramine, Lozazepam, Zo Hypnotics such as Zolpidem, indomethacin, diclofenac, diclofenac sodium, codenine, ibuprofen, phenbutyrazole Ketone (phenylbutazone), oxyphenbutazone, oxyphenbutazone, mepirizol, aspirin, ethenzamide, acetanilide, aminopyridine, acetoxy Phenacetin, scopolamine, morphine, etomidolin (transliteration), pentazocin, fenoprofen calcium, Anti-inflammatory, antipyretic, antispasmodic or analgesic, naproxen, celecoxib, valdecoxib, tramadol, etc., sumatriptan, etc. Anti-rheumatic drugs such as migraine medicine, etodolac, and isoniazid tincture (isoniazid) Anti-tuberculosis drugs such as ethidinol hydrochloride, isosorbide nitrate, nitroglycerin, nifedipine, barnidipine, nicardipine hydrochloride, Dipyridamole, amrinone, indenolol hydrochloride, pyrazine hydrochloride, methyldioxyphenylalanine (dopa), furosemide, spiro Steroid lactone (spironolactone), guanethidine, reserpine, amosulalol, amosulalol, lisinopril, metroprorol, pilocarpine ), Telmisatan (telmisatan) and other circulatory organ medications, chlorinated puromycin hydrochloride, amibutamine hydrochloride, nemonapride, dopamine antagonist (haloperidol), methylpiperidine hydrochloride Moperone, perphenazine, diazepam, lorazepam, chlordiazepoxide, adinazolam, triazoxide ( alprazolam), mrthylphenidate, milnacipran, paroxetin, risperidone, valproic acid sodium and other antipsychotics, Antidepressants such as imipramine, metoclopramide, ramosetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride Antiemetics such as azasetron and antihistamines such as chlorpheniramine maleate Vitamins such as thiamine nitrate, tocopheryl acetate, cycotiamine, pyridoxal, cobamamide, ascorbic acid, niacinamide, and isopurinol ( allopurinol), colchicine, probenecid and other gout treatments, levodopa, selegiline and other treatments for Perkins disease, isopababi Amolbarbital, bromoprovalon, midazolam Hypnotic sedatives such as midazolam, chloral hydrate, etc., fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa Anti-malignant tumor drugs, anti-allergic drugs such as pseudophedine, terfenadine, acetaminophen, insulin, tolbutamide, denitrogenation Desmopressin, Glipizide, nateglinide, metformin, sitagliptin (transliteration), vildagliptin (transliteration) , Diabetic medicines such as linagliptin (transliteration), diuretics such as hydrochlirothiazide (hydrochlirothiazide), polybenzothiazide, triamterene (triamterene), aminopyrine ( bronchodilators such as aminophylline), formoterol fumarate (formoterol), theophyllin (theophyllin), codeine phosphate, noscapine, dimethyl morphol phosphate (dimemorgfan), dextromethoxyl Antitussive drugs such as dextromethorphan, quinidine nitrate, and digitonin (di gitoxin), propafenone hydrochloride, procainacide and other anti-arrhythmic drugs, ethyl aminobenzoate, mucaine (lidocaine), dibucaine hydrochloride (dibucaine) ) And other anti-epileptic drugs such as epidermal anesthetics, phenytoin, ethosuximide, primidone, hydrocortisone, dehydrocortisol (prednisolone), Tyan Synthetic paraadrenal corticosteroids, such as triamcinolone, betamethasone, famotidine, ranitidine hydrochloride, cimetidine, and sclafi sucralfate), sulpiride, teprenone, plaunotol, 5-aminosalicylic acid, sulfasalazine, omeprazole, prazimidazole (lansoprazole) and other gastrointestinal medicines, indeloxazine, idebenone, tiapride hydrochloride, bifemelane hydrochloride, hopantennate calcium, etc. Drugs for treatment of central nervous system, pravastatin (pracastatin) sodium, simvastatin, lovastatin, atorvastatin, etc. Antibiotic substances such as cefotetan, leukomycin, tamsulosin, doxazosin mesylate, terazosin hydrochloride (terazosin), etc. Pranlukast, zalust (zafirlikast), salbutamol (salbutamol), bromocyclohexanol (ambroxol), butadiene cortisol (budesonide), anti-asthmatic agents such as labetalbutanol (transliteration), beraprot (beraprost) sodium, etc. Prostaglandin I2 derivative terminal nerve circulation improver, minodronic acid, alendronic acid and other osteoporosis treatment agents, diabetes comorbidity treatment agents, skin ulcer treatment Agent.

In addition, for example, steroidal anti-inflammatory agents, anti-inflammatory analgesics, antipyretic analgesics, antiepileptic agents, chemotherapeutic agents, synthetic antibacterial agents, antiviral agents, antifungal agents, hormonal agents, angiogenesis inhibitors, immunosuppressive agents and Treatment agent for ulcerative intestinal inflammation. Steroids are anti-inflammatory such as cortisone acetate, betamethasone, dehydrocortisol, fluticasone propionate, fludexasone, dexamethasone, cortisol, chlordipropionate Methasone, triamcinolone, loteprednol, fluometholone, difluprednate, momethasone furoate, propionic acid Clobecortisol, diflorasone diacetate, diflucortolone valerate, fluocinonide, amcinonide, halcinonide , Acetone, flurocortisol, triamcinolone (triamcinolone), flumetasone pivalate (flumetasone), and clofluxone butyrate, etc. Anti-inflammatory analgesics such as alclofenac, alminoprofen, ibuprofen, indomethacin, epirizol, 4,5-diphenyl-2 -Oxaprozin, ketoprofen, ketoprofen, diflunisal, naproxen, piroxican, fenbufen ( fenbufen), flufenamic acid, flurbiprofen, flotafenin, pentazocine, phenothiene Methiazinic acid, mefenamic acid, mofezolac (transliteration), etc. Antipyretic analgesics such as acetamidophenol, sulpyrine, etc. Antiepileptic agents such as acetazolamide, carbamazepine, clonazepine, diazepam, nitrazepam, etc. Chemotherapy agents such as sulfasalazine, sulfadimethoxine, sulfamethizole, sulfamethizole, sulfamethoxazole, sulfamethoxazine, and sulfamethoxazole (Sulfa drug), enoxacin, ofloxacin, cinoxacin, sparfloxacin, thiamphenicol, thiaconic acid , Synthetic antibacterial agents such as tosufloxacin tosilate, norfloxacin, pipemidic acid trihydrate, pyrrole acid, fleroxacin, and levofloxacin, aseville (acyclovir), ganciclovir, didanosine (transliteration), zidovudine, and vidarabine and other antiviral agents, itraconazole , Ketoconazole (ketoconaole), fluconazole (furconazole), flucytosine (flucytosine), miconazole (miconazole) and pimafucin (pimafucin) and other antifungal agents. Hormonal agents include insulin zinc, testosterone propionate, and estradiol benzoate. Immunosuppressive agents such as cyclosporin, rapamycin, and Tekmos (tacrolimus) etc. Examples of therapeutic agents for ulcerative colitis include mesalazine and the like.

In addition, another form of the drug used in the present invention is, for example, a drug that is unstable with respect to temperature or humidity. The form in which the drug that is unstable with respect to temperature or humidity is incorporated in the pharmaceutical composition is not particularly limited as long as it is a method generally used in pharmacy. For example, drugs can be granulated and / or mixed at the same time as pharmaceutical additives, or drugs can be used as stabilizers and coated on core particles such as CELPHERE (manufactured by Asahi Kasei Chemicals), and then granulated and / or mixed as pharmaceutical additives .

In addition, another form of the drug used in the present invention is, for example, a drug that constitutes functional particles (a drug with a bitter taste, a drug that must be imparted with a release property, and a drug that is hardly soluble). Functional particles are, for example, bitter taste masking particles, exothermic particles, solid dispersion particles, and the like.

In addition, drugs with bitter taste, drugs that must be imparted with exothermic properties or poorly soluble drugs, drugs that are unstable with respect to temperature or humidity can be further selected as drugs that constitute functional particles.

The drug may also use any of free body or pharmaceutically acceptable salts. In addition, one drug may be used alone or two or more drugs may be used in combination. In addition, these drugs are examples of the invention that can be used, and are not limited to these.

The blending amount is usually appropriately selected depending on the type of drug or medical use (indications), and it is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount. For example, in fast-disintegrating tablets (particularly intraoral disintegrating tablets), it is 0.001 to 80% by weight, the preferred form is 0.01 to 70% by weight, and the more preferred form is 0.01 to 60% by weight.

The fast-disintegrating tablet of the present invention (especially the disintegrating tablet in the oral cavity) is a "substance with supercritical or subcritical state of carbon dioxide or liquid or gaseous carbon dioxide treatment with a binder function", by supercritical Or subcritical state carbon dioxide or liquid or gaseous carbon dioxide treatment, in the tablet "substances that have a binder function by treatment with supercritical or subcritical state carbon dioxide or liquid or gaseous carbon dioxide" in the ingredients (such as drugs , Depending on the required excipients, disintegrants, stabilizers, lubricants) formed cross-linked and has a porous structure.

As used in the present invention, "a substance having a binder function by processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state" as long as it is processed by carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state It is sufficient to lower the melting point or glass transition temperature of the "substance" to have a function as a binder, and there is no particular limitation. Another form is a substance that can be increased if the hardness of the lozenge containing the "substance" is compared with that without the "substance" as long as it is treated with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state. That is, there are no special restrictions. Specifically, one form of the treatment pressure is about 0.1 MPa to about 50 MPa, and a preferred form is about 1 MPa to about 20 MPa. A more preferable form is about 1 MPa to about 15 MPa. The particularly good form is about 1 MPa to about 5 MPa. Furthermore, another form such as a substance whose melting point or glass transition temperature is reduced by, for example, 5 ° C or more when the pressure is 20 MPa, and a preferred form is a substance reduced by 20 ° C or more. In addition, another form is, for example, a compound having a styrene skeleton having an affinity for carbon dioxide, a carbonyl group, an ether bond, an ester bond, and an unsaturated bond between carbon atoms in the structural formula.

Compounds with a styrene skeleton, such as polystyrene resins and their copolymers.

Compounds having a carbonyl group, such as aldehyde compounds, ketone compounds, carboxylic acid compounds, ester compounds, amide compounds, enone compounds, carboxylic acid chlorides (halides), acid anhydrides and their polymers, copolymers, etc.

Compounds having an ether bond, such as polyethylene glycol or polypropylene glycol, are typical polyethers.

The compound having an unsaturated bond between carbon atoms, for example, a polymer or copolymer having an alkene group, vinyl group, propenyl group, benzene or annulene or its structure.

Specifically, for example, vinylpyrrolidone. Vinyl acetate copolymer (hereinafter referred to as copolypyrrolidone), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), polypyridine Ketone, polyvinylpyrrolidone / vinyl acetate resin premix (polyvinyl acetate and polyvinylpyrrolidone (8: 2)), methacrylic acid copolymer LD (Methacrylic acid and ethyl acrylate copolymer), polyvinyl alcohol. Polyethylene glycol graft copolymer (polyvinyl alcohol and Polyethylene glycol graft copolymer (75:25)), polyvinyl alcohol. Polyethylene glycol graft copolymer / polyvinyl alcohol premix preparation (polyvinyl alcohol and polyethylene glycol graft copolymer (75:25) and polyvinyl alcohol (60/40)), polyoxyethylene (196) polyoxypropylene (67) Ethylene oxide and propylene oxide, polyethylene glycol, polyethylene oxide harden Castor oil (40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkane Base methacrylate copolymer RS, ethyl acrylate. Methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate. Diethylaminoethyl methacrylate copolymer, hydroxypropyl methyl cellulose acetate succinate (hereinafter abbreviated as HPMCAS), shellac, carbomer and polyvinyl acetal diethyl Aminoacetate. Preferred forms such as copolypyrrolidone, polyvinyl caprolactam-polyvinyl acetic acid-polyethylene glycol graft copolymer, amino alkyl methacrylate copolymer E, amino alkyl methacrylic acid Ester copolymer RS, methyl methacrylate. Diethylaminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, shellac, polypyrrolidone / vinyl acetate resin premix preparation, polypyrrolidone, carbomer, polyethylene oxide (196) Polypropylene oxide (67) ethylene glycol. Better forms such as copolypyrrolidone, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylic acid Ester copolymer RS, methyl methacrylate. Diethylaminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, polyvinylpyrrolidone / vinyl acetate resin premix preparation. Particularly preferred forms include copolypyrrolidone, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, HPMCAS, ethyl cellulose. Particularly preferred forms include copolypyrrolidone and aminoalkyl methacrylate copolymer E. The best form is, for example, aminoalkyl methacrylate copolymer E.

Such compounds can be obtained from the following trade names commercially available, for example.

. Copolypyrrolidone: kollidon VA-64 (BASF Japan), Kollidon VA-64 Fine (BASF Japan), Plusdon S-630 (ISP. Japan)

. Polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer: Soluplus (BASF Japan)

. Povidone: kollidon 12PF (BASF Japan), Kollidon 17PF (BASF Japan), Kollidon 30 (BASF Japan), Kollidon 90F (BASF Japan)

. Polypyrrolidone / vinyl acetate resin premix preparation: Kollidon SR (BASF Japan)

. Methacrylic acid copolymer LD: Kollicoat MAE 100P (BASF Japan)

. Polyvinyl alcohol. Polyethylene glycol graft copolymer: Kollicoat IR (BASF Japan)

. Polyvinyl alcohol. Polyethylene glycol graft copolymer / polyvinyl alcohol premix preparation: Kollicoat Protect (BASF Japan)

. Polyoxyethylene (196) Polyoxypropylene (67) Ethylene glycol: Kolliphor P407 (BASF Japan)

. Polyethylene glycol: Lutrol E400 (BASF Japan)

. Polyoxyethylene hardened castor oil (40): Cremophor RH40 (BASF Japan)

. Aminoalkyl methacrylate copolymer E: EUDRAGIT E100 (Evonik Degussa Japan), EUDRAGIT EPO (Evonik Degussa Japan)

. Methacrylic acid copolymer L: EUDRAGIT L100 (Evonik Degussa Japan)

. Dry methacrylic acid copolymer LD: EUDRAGIT L100-55 (Evonik Degussa Japan)

. Methacrylic acid copolymer LD: EUDRAGIT L30D-55 (Evonik Degussa Japan)

. Methacrylic acid copolymer S: EUDRAGIT S100 (Evonik Degussa Japan)

. Aminoalkyl methacrylate copolymer RS: EUDRAGIT RL100 (Evonik Degussa Japan), EUDRAGIT RLPO (Evonik Degussa Japan), EUDRAGIT RS100 (Evonik Degussa Japan), EUDRAGIT RSPO (Evonik Degussa Japan)

. Ethyl acrylate. Methyl methacrylate copolymer dispersion: EUDRAGIT NE30 (Evonik Degussa Japan), Kollicoat EMM30D (BASF Japan)

. Ethyl cellulose: Ethocel (Dow Chemical Japan)

. Methyl methacrylate. Diethylaminoethyl methacrylate copolymer: Kollicoat Smartseal 30D (BASF Japan)

. HPMCAS: AQOAT AS-HF, AQOAT AS-MF, AQOAT AS-LF (Shin-Etsu Chemical Industry)

. Shellac: Dry transparent white glue sold by Japan Shellac Industries, etc.

. Carbomer: Carbopol 71G, 971P, 974P, 980, 981, 5984, ETD2020, Ultrez10, 934, 934P, 940, 941, 1342, etc., or Pemulen TR-1, TR-2, etc., commercially available from Lubrizol Corporation AQUPEC HV-501, HV-501E, HV- 501ER, HV-504, HV-504E, HV-505, HV-505E, HV-505ED, etc., and Hibiswaco 103, 104, 105, etc. commercially available from Wako Pure Chemicals

. Polyvinyl acetal diethylaminoacetate: AEA (Mitsubishi Chemical Co., Ltd.), etc.

The fast-disintegrating tablet of the present invention (especially the intra-oral disintegrating tablet) can use one kind or a combination of two or more kinds of "using the supercritical or subcritical state of carbon dioxide or liquid or gaseous carbon dioxide "Substances that have a binder function".

The shape of "a substance having a binding agent function by processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state" may be granular, needle-shaped, etc., and is not particularly limited. It can also be crushed. When the shape of the substance is granular, the average particle diameter is not particularly limited as long as it has a binder function. For example, the average particle diameter when measured by a laser diffraction particle size distribution measuring device is preferably 0.1 to 350 μm . This substance can be used alone or in combination of two or more types with different levels, shapes, average particle diameters, and the like.

The blending amount is not particularly limited as long as it can function as a "substance having a binder function by treatment with supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide." The preferred form is not particularly limited as long as it can improve the hardness of rapidly disintegrating tablets (especially intraoral disintegrating tablets). Specifically, for example, in a rapidly disintegrating tablet (particularly an oral disintegrating tablet), it is 0.1 to 50% by weight, preferably 1 to 30% by weight, and more preferably 3 to 20% by weight.

The fast-disintegrating tablet of the present invention (especially the disintegrating tablet in the oral cavity) depends on It may also contain a plasticizer that can improve the function of "a substance that has a binder function by treatment with supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide."

The plasticizer used in the present invention to improve the function of "a substance having a binder function by processing in supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide", such as triethyl citrate, calio 83, propylene Triol, glycerin fatty acid ester, flax oil, dimethyl polysiloxane. Silicon dioxide mixture, D-sorbitol, medium chain fatty acid triglyceride, sugar alcohol liquid from corn starch, glycerol triacetate, concentrated glycerin, castor oil, diethyl phthalate, phthalic acid Dibutyl ester, butylphthalobutylbutyl glycol ester, propylene glycol, polyethylene oxide (105), polypropylene oxide (5) ethylene glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, glycerol monostearate, xylulose and other sugars. Preferred forms include sugars such as triethyl citrate, triacetin, polyethylene glycol 4000, polyethylene glycol 6000, and xylulose. A more preferred form is triethylene citrate. The plasticizer can be used alone or in combination of two or more. The amount of the plasticizer blended is not particularly limited as long as it can increase the function of "a substance having a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state." Specifically, for example, in a rapidly disintegrating tablet (especially an oral disintegrating tablet), it is 0.1 to 20% by weight, preferably 0.1 to 10% by weight, and more preferably 0.1 to 7% by weight. The best one is 1 ~ 7% by weight, and the best one is 2 ~ 5% by weight. In addition, as opposed to "by supercritical or subcritical carbon dioxide or liquid or gas dioxide "Carbon-treated substances with binder function" refers to the blending amount of the plasticizer, for example, 0.5 to 200% by weight, preferably 0.5 to 40% by weight, and more preferably 10 to 40% by weight.

The fast-disintegrating tablet of the present invention (especially the intra-oral disintegrating tablet) contains, as necessary, an excipient generally added as a pharmaceutical additive.

The excipient used in the present invention is not particularly limited as long as it is a hydrophilic substance or a water-soluble substance. Preferred forms, such as sugars, cellulose inducers, phosphates, and sulfates. Sugars such as mannitol, lactose, sucrose, saccharose, glucose, fructose, sorbitol, xylulose, erythritol, trehalose, white sugar, polysaccharides. Cellulose inducers such as crystalline cellulose and the like. Examples of phosphates include calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, and the like. Sulfates such as calcium sulfate and the like.

In the fast-disintegrating tablet of the present invention (particularly, the intra-oral disintegrating tablet), one type or two or more types of excipients can be used in combination.

The blending amount of the excipient is, for example, 0.001 to 99.99% by weight in a fast disintegrating tablet (especially an intraoral disintegrating tablet), and the preferred form is 1 to 99.9% by weight, more preferably The form is 10 ~ 99% by weight.

In addition to the aforementioned excipients, various medical additives can be further formulated and formulated into the rapidly disintegrating tablets (particularly intraoral disintegrating tablets) of the present invention. The pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, binding agents, disintegrating agents, sour agents, foaming agents, artificial sweeteners, flavors, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants can be used Wait. Furthermore, in addition to substances having a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, a binder shown below may be added.

Binders such as copomidone, povidone, polyvinyl alcohol. Polyethylene glycol graft copolymer, polyvinyl alcohol, polyvinyl alcohol. acrylic acid. Methyl methacrylate copolymer, hydroxypropyl methylcellulose, gum arabic, powdered sugar, sodium alkanoate, alpha starch, cold weather, vinyl acetate resin, pullulan, starch, hydroxypropyl Cellulose, etc.

Disintegrants such as corn starch, potato starch, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, alpha starch, partially alpha starch, carboxy methyl cellulose (CMC), crystalline cellulose 、 Crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, magnesium carbonate, low substitution degree hydroxypropyl cellulose, low substitution degree sodium carboxymethyl starch, precipitated calcium carbonate, gelatin, aluminum magnesium hydroxide, synthetic silicon Acid aluminum, etc. Preferred forms such as crospovidone, croscarmellose sodium, hydroxypropyl methylcellulose with low degree of substitution, sodium carboxymethyl starch, alpha starch, partially alpha starch, carboxy methyl fiber Calcium, carboxymethyl cellulose calcium. More preferred forms are, for example, hydroxypropyl methyl cellulose with a low degree of substitution, partially alpha starch, and cross-linked sodium carboxymethyl cellulose.

Sour agents such as citric acid, tartaric acid, malic acid and the like.

Blowing agents such as baking soda, tartaric acid, sodium bicarbonate, citric anhydride, sodium bicarbonate and the like.

Artificial sweeteners such as sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.

Spices such as lemon, lime, orange, menthol, etc.

Lubricants such as magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearate fumarate, polyethylene glycol, talc, stearic acid and the like.

The coloring agent is, for example, yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, edible blue No. 3, etc.

Stabilizers such as ascorbic acid, aspartic acid, sodium chloride, magnesium chloride, glycine, glycerin, light anhydrous silicic acid, magnesium gluconate, xylulose, calcium citrate, calcium hydroxide, hydroxide Sodium, magnesium hydroxide, potassium carbonate, potassium bicarbonate, sodium bicarbonate, etc.

Buffers such as citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its salts, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its salts, Magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or its salts, etc.

Antioxidants such as ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.

Surfactants are, for example, polysorbate 80, sodium lauryl sulfate, polyethylene oxide hardened castor oil, and the like.

The pharmaceutical additives may be added in an appropriate amount in one kind or in combination of two or more kinds.

The blending amount of these various medical additives can be arbitrarily set.

The fast disintegrating tablet of the present invention is preferably a disintegrating tablet in the oral cavity.

In the following, the method for producing the fast-disintegrating tablet (particularly the intra-oral disintegrating tablet) of the present invention will be explained.

In the present invention, "by using supercritical or subcritical carbon dioxide or "Liquid or gaseous carbon dioxide treatment" is not particularly limited as long as it is a substance that has a so-called "binder" function that has a cross-linking structure between components, and "partially" or "completely" dissolves it. Specifically, it depends on the size or type of the container used. For example, for the supercritical state or subcritical state and the liquid or gas state of about 1mL to about 2000L of carbon dioxide, the tablets after the tablet (special It is suitable for disintegrating tablets in the oral cavity). It is preferably about 0.1g to about 2000kg, and the preferred form is about 5g to about 100kg. The processing time is preferably about 1 minute to about 50 hours, the preferred form is about 1 minute to about 24 hours, the better is about 2 minutes to about 12 hours, the best is about 5 minutes to about 2 hours .

The treatment can also be carried out in a pressure-resistant container. Specifically, for example, a pressure-resistant container: H series (made by Tama Seiki) or EV series (made by Japan Spectroscopy) or VE-1 (Mitsubishi Chemical Corporation), CO ₂ liquid delivery pump: SCF-GET or PU-2086 ( Japan Spectroscopy), CO ₂ air compressor: PU-1 (Mitsubishi Chemical Mechanism), thermometer: platinum temperature resistance (R36S) (made by Nippon Electric Measurement) or TI-2068-01 (Japan Spectroscopy), heater: Bow-type heater (JK) (manufactured by AS ONE) or Oven CO-2060 (manufactured by Japan Spectroscopy), thermometer indicator controller: E5CN (manufactured by OMRON), pressure indicator: WGA-710B (manufactured by Kyowa Electric), pressure gauge : PG-500KU (manufactured by Kyowa Electric), automatic back pressure adjustment valve: BP-2080 (manufactured by Japan Spectroscopy) is equal to the device used when the system is constructed. The treatment temperature differs depending on the type of ingredients constituting the fast-disintegrating tablet of the present invention (especially the intra-oral disintegrating tablet), and is preferably about -40 ° C to about 100 ° C. For example, "a substance with a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state" is about 25 ° C to about 70 ° C when it is copolypyrrolidone, which is polyvinyl caprolactam- Polyvinyl acetic acid-polyethylene glycol graft polymer is about 10 ℃ ~ about 65 ℃, when it is amino alkyl methacrylate copolymer E is about 10 ℃ ~ about 65 ℃, when it is ethyl cellulose 10 ℃ ~ about 100 ℃. The treatment pressure is similarly different depending on the types of ingredients constituting the fast-disintegrating tablet of the present invention (especially the intra-oral disintegrating tablet), and is preferably about 0.1 MPa to about 50 MPa, preferably about 1 MPa to About 20MPa.

During the treatment, other solvents and the like may be mixed with carbon dioxide and added. For other solvents, for example, water; aromatic hydrocarbons such as benzene, toluene, ethyl acetate, cyclohexane, and xylene; dimethyl ether, diethyl ether, dioxane, diethoxyethane, tetrahydrofuran, 1, Ethers such as 2-dimethoxyethane; organic chlorine-based organic solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; alkanenitriles such as acetonitrile and propionitrile; Nitroalkanes such as nitromethane and nitroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide; ketones such as acetone; acetic acid Fatty acids such as acetic anhydride, oleic acid, etc .; alcohols such as methanol, ethanol, propanol, etc .; sulfonanes such as dimethyl sulfoxide; etc .; and mixed solvents of these, etc., among which ethanol, acetone, etc. are preferred . The amount of other solvents used is usually about 0.1 to about 99.9% by volume in carbon dioxide in supercritical or subcritical state or liquid or gas state, and the preferred form is about 1 to 99% by volume.

In addition, other gases can be added to the carbon dioxide during processing. For other gases, for example, nitrogen gas or the like can be used.

Specifically, for example, after the treatment of (O) below, according to the following (1) to (4) In any order, the rapid disintegrating lozenges (especially intraoral disintegrating lozenges) of the present invention are manufactured, but are not limited to the following. The following also describes any of (1) to (4) as carbon dioxide (pressure) treatment.

(O) Preparation of rapidly disintegrating tablets before carbon dioxide treatment (for example, oral disintegrating tablets)

Specifically, for example, a method of compressing and forming a mixture of medicinal ingredients by adding a mixture of medicinal ingredients to a substance having a binder function by processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state; A method of granulating an aqueous solution of a substance having a binding agent function by processing carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, and compressing and forming the resulting granules; A method for granulating a substance in a critical or subcritical state with carbon dioxide or liquid or gaseous carbon dioxide and having the function of a binder with an aqueous solution, and compressing the resulting granules; by using supercritical or subcritical components Carbon dioxide or liquid or gaseous carbon dioxide in the state of treatment and the substance with a binder function is granulated with an organic solvent, and the resulting granulated material is compressed and shaped; the medicinal components and the carbon dioxide by supercritical or subcritical state Or liquid or gaseous carbon dioxide treatment with a binder function of the substance, use by super A method for granulating a substance with a binder function by processing carbon dioxide or liquid or gaseous carbon dioxide in a boundary or subcritical state, and compressing and forming the resulting granules; by using carbon dioxide or liquid in a supercritical or subcritical state Or gaseous carbon dioxide treatment and a substance with a binder function and other pharmaceutical additives are granulated, and the resulting The method of compressing and forming the mixture of the granulated substance and the medicinal ingredient; and the use of the spray dryer for the medicinal ingredient and the substance that has the function of a binder by treatment with carbon dioxide or liquid or gaseous carbon dioxide in supercritical or subcritical state A method of preparing a solid dispersion and compressing a mixture of the obtained solid dispersion and other medical additives, and the like.

(1)

. Add fast-disintegrating lozenges (e.g., disintegrating tablets in the mouth) to 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 above solvents or other gases as required)

. Keep the pressure in the pressure-resistant container above the critical point of carbon dioxide and carry out carbon dioxide treatment

. After the treatment with carbon dioxide is completed, the pressure is removed and the resulting rapidly disintegrating lozenges (for example, oral disintegrating lozenges)

(2)

. Add fast-disintegrating lozenges (e.g., disintegrating tablets in the mouth) to 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 above solvents or other gases as required)

. Keep the pressure-resistant container at the critical point of carbon dioxide and carry out carbon dioxide treatment

. After the treatment with carbon dioxide is completed, the pressure is removed and the resulting rapidly disintegrating ingot is removed Agents (e.g. oral disintegrating tablets)

(3)

. Add fast-disintegrating lozenges (e.g., disintegrating tablets in the mouth) to a pressure-resistant container

. Keep the temperature of the pressure-resistant container below the critical point of carbon dioxide

. Fill the pressure-resistant container with carbon dioxide (mix the above solvents or other gases as required)

. Hold the pressure-resistant container above the critical point of carbon dioxide and perform carbon dioxide treatment

. After the treatment with carbon dioxide is completed, the pressure is removed and the resulting rapidly disintegrating lozenges (for example, oral disintegrating lozenges)

(4)

. Add fast-disintegrating lozenges (e.g., disintegrating tablets in the mouth) to a pressure-resistant container

. Keep the temperature of the pressure-resistant container below the critical point of carbon dioxide

. Fill the pressure-resistant container with carbon dioxide (mix the above solvents or other gases as required)

. Keep the pressure-resistant container at the critical point of carbon dioxide and carry out carbon dioxide treatment

. After the treatment with carbon dioxide is completed, the pressure is removed and the resulting rapidly disintegrating lozenges (for example, oral disintegrating lozenges)

[Example]

In the following, the present invention will be described in more detail by taking examples, comparative examples, reference examples, and test examples, but the present invention is not limited by these.

Moreover, depending on the drug, due to the incorporation of extremely small amounts (for example, several ng or several μg, etc.), the following examples all contain extremely small amounts of drugs.

Example 1

Mixed D-mannitol (Pearitol 50C, manufactured by Rocket Japan, the same is not particularly limited below) 59.0w / w%, crystalline cellulose (MCC SANAQ burst, PHARMATRANS SANAQAG) 20.0w / w%, co-pyrrolidone ( Kollidon VA64 Fine, manufactured by BASF Japan) 10.0w / w%, cross-linked polypyrrolidone (Kollidon CL, manufactured by BASF Japan) 10.0w / w%. Magnesium stearate (Parteck LUB MST, made by Merck, the following is also the same unless otherwise specified) is mixed with 1.0w / w% of this mixture, and a single-shot spindle machine (Autograph AGS-20kNG, manufactured by Shimadzu Corporation, below) is used It is the same when there is no particular limitation), and a tablet having a tableting pressure of about 1.0 kN / shovel is used to prepare a tablet of 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 8N (n = 1). Next, the tablet was treated with a pressure-resistant container (pressure-resistant chamber) at a carbon dioxide pressure of 8.0 MPa and 45 ° C for 30 minutes, and then depressurized at a decompression rate of about 16 kPa / sec to produce the rapid disintegration of the present invention. Lozenges.

Example 2

Mixed D-mannitol 54.0w / w%, crystalline cellulose (MCC SANAQ burst, PHARMATRANSSANAQ AG) 20.0w / w%, copolypyrrolidone (Kollidon VA64 Fine, manufactured by BASF Japan) 15.0w / w%, cross-linked polypyrrolidone (Kollidon CL, manufactured by BASF Japan) 10.0w / w%. Magnesium stearate 1.0w / w% was blended into this mixture, and a single-shot tableting machine was used to make tablets with a tableting pressure of about 1.0kN / tamper to make 180mg per tablet (tablet diameter 8.5mm) . The tablet hardness is 8N (n = 1). Next, this lozenge was treated with a pressure-resistant chamber and treated at a carbon dioxide pressure of 8.0 MPa and 45 ° C for 30 minutes, and then depressurized at a depressurization rate of about 16 kPa / sec to prepare the rapidly disintegrating lozenge of the present invention.

Example 3

D-mannitol 97.0 w / w% and copolypyrrolidone (Kollidon VA64 Fine, manufactured by BASF Japan) 3.0 w / w% were mixed. A single-shot tableting machine was used for this mixture, and a tablet having a tabletting pressure of about 1.0 kN / trotter was used to prepare tablets of 270 mg per tablet (tablet diameter 9.0 mm). Tablet hardness is 10N (n = 3). Next, this lozenge was treated with a pressure-resistant chamber and treated with a carbon dioxide pressure of 6.0 MPa and 40 ° C. for 30 minutes, and then the pressure was gradually reduced to obtain the rapidly disintegrating lozenge of the present invention.

Example 4

D-mannitol 95.0w / w% and copolypyrrolidone (Kollidon VA64 Fine, manufactured by BASF Japan) 5.0w / w% were mixed. A single-shot tableting machine was used for this mixture, and a tablet having a tabletting pressure of about 1.0 kN / trotter was used to prepare tablets of 270 mg per tablet (tablet diameter 9.0 mm). The tablet hardness is 10N (n = 1). Secondly, use the pressure-resistant chamber of the lozenge with carbon dioxide pressure After treatment at 6.0 MPa and 40 ° C for 30 minutes, the pressure was slowly reduced to obtain the rapidly disintegrating tablet of the present invention.

Example 5

D-mannitol 90.0w / w% and copolypyrrolidone (Kollidon VA64 Fine, manufactured by BASF Japan) 10.0w / w% were mixed. A single-shot tableting machine was used for this mixture, and a tablet having a tabletting pressure of about 1.0 kN / trotter was used to prepare tablets of 270 mg per tablet (tablet diameter 9.0 mm). The tablet hardness is 10N (n = 1). Next, this lozenge was treated with a pressure-resistant chamber and treated with a carbon dioxide pressure of 6.0 MPa and 40 ° C. for 30 minutes, and then the pressure was gradually reduced to obtain the rapidly disintegrating lozenge of the present invention.

Example 6

F-Melt (manufactured by Fuji Chemicals) 89.0 w / w% and copolypyrrolone (Kollidon VA64 Fine, manufactured by BASF Japan) 10.0 w / w% were mixed. Magnesium stearate 1.0w / w% was blended into this mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1.0 kN / tamper to make 180 tablets per tablet (tablet diameter 8.0 mm) . The tablet hardness is 17N (n = 3). The disintegration time in the oral cavity was 19 seconds (n = 3). Next, this lozenge was treated with a pressure-resistant chamber and treated with a carbon dioxide pressure of 6.0 MPa and 40 ° C. for 30 minutes, and then the pressure was gradually reduced to obtain the rapidly disintegrating lozenge of the present invention.

Example 7

Mixed F-Melt (manufactured by Fuji Chemical) 89.0w / w%, copolypyrrolidone (Kollidon VA64 Fine, manufactured by BASF Japan) 10.0w / w%. Magnesium stearate is mixed with 1.0w / w% of this mixture, and a rotary ingot machine (HT-EX series, manufactured by CK Iron Works, the same is not the same as below) is used, and the ingot pressure is about 1.0kN / A pestle produces a lozenge (reference example 1) of 180 mg per lozenge (lozenge diameter 8.0 mm). Next, this lozenge was treated with a pressure-resistant chamber and treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 5 minutes, and then the pressure was gradually reduced to obtain the rapidly disintegrating lozenge of the present invention.

Example 8

The lozenges of Reference Example 1 were treated with a pressure-resistant chamber and treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 15 minutes, followed by depressurization to prepare the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 9

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 30 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 10

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 8 MPa and 25 ° C. for 5 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 11

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 8 MPa and 25 ° C. for 15 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 12

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 8 MPa and 25 ° C. for 30 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 13

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 35 ° C. for 5 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 14

The lozenges of Reference Example 1 were treated with a pressure-resistant chamber and treated with carbon dioxide pressure of 4 MPa and 35 ° C. for 15 minutes, followed by depressurization to prepare the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 15

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 35 ° C. for 30 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 16

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 8 MPa and 35 ° C. for 5 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 17

The tablets of Reference Example 1 were used in a pressure-resistant chamber, treated with carbon dioxide pressure of 8 MPa and 35 ° C. for 15 minutes, and then depressurized to obtain the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 18

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with carbon dioxide pressure of 8 MPa and 35 ° C. for 30 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 19

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 45 ° C. for 5 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 20

The lozenges of Reference Example 1 were treated with a pressure-resistant chamber, treated with carbon dioxide at 4 MPa and 45 ° C for 15 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 21

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 45 ° C for 30 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 27 kPa / sec.

Example 22

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 8 MPa and 45 ° C. for 5 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 23

The tablet of Reference Example 1 was used in a pressure-resistant chamber, treated with carbon dioxide at 8 MPa and 45 ° C for 15 minutes, and then depressurized to produce the present invention. The fast disintegrating lozenges. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 24

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 8 MPa and 45 ° C. for 30 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. In addition, the decompression speed condition is performed at about 16 kPa / sec.

Example 25

The tablets of Reference Example 1 were used in a pressure-resistant chamber, treated with carbon dioxide pressure of 8 MPa and 45 ° C. for 30 minutes, and then depressurized at a decompression rate of about 800 kPa / sec to prepare the rapidly disintegrating tablets of the present invention.

Example 26

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 8 MPa and 45 ° C. for 2400 minutes, and then depressurized at a decompression rate of about 800 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 27

The lozenges of Reference Example 1 were treated with a pressure-resistant chamber, treated with carbon dioxide at 8 MPa and 45 ° C. for 2400 minutes, and then depressurized at a depressurization rate of about 16 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 28

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 20 MPa and 45 ° C for 30 minutes, and then depressurized at a depressurization rate of about 27 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 29

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 20 MPa and 45 ° C for 30 minutes, and then depressurized at a depressurization rate of about 2000 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 30

The lozenges of Reference Example 1 were treated with a pressure-resistant chamber and treated at a carbon dioxide pressure of 20 MPa and 45 ° C for 2400 minutes, followed by depressurization at a depressurization rate of about 2000 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 31

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 20 MPa and 45 ° C. for 2400 minutes, and then depressurized at a depressurization rate of about 27 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 32

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 20 MPa and 40 ° C for 30 minutes, and then depressurized at a decompression rate of about 2000 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 33

The lozenges of Reference Example 1 were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 20 MPa and 40 ° C. for 2400 minutes, and then depressurized at a decompression rate of about 2000 kPa / sec to prepare the rapidly disintegrating lozenges of the present invention.

Example 34

Mixed D-mannitol 54.0w / w%, crystalline cellulose (made by PHARMATRANS SANAQ AG) 20.0w / w%, polyvinyl caprolactam-polyvinyl acetic acid-polyethylene glycol graft copolymer (Soluplus , Manufactured by BASF Japan) 15.0 w / w%, cross-linked polypyrrolidone (Kollidon CL, manufactured by BASF Japan) 10.0 w / w%. Magnesium stearate 1.0w / w% was blended into this mixture, and a single-shot tableting machine was used to make tablets with a tableting pressure of about 1.0kN / tamper to make 180mg per tablet (tablet diameter 8.5mm) . Next, this lozenge was treated with a pressure-resistant chamber and treated at a carbon dioxide pressure of 8.0 MPa and 45 ° C for 30 minutes, and then depressurized at a depressurization rate of about 16 kPa / sec to prepare the rapidly disintegrating lozenge of the present invention.

Comparative example 1

F-Melt (manufactured by Fuji Chemicals) 89.0 w / w% and copolypyrrolone (Kollidon VA64 Fine, manufactured by BASF Japan) 10.0 w / w% were mixed. Magnesium stearate 1.0 w / w% was blended into the mixture, and a rotary tableting machine was used to produce tablets with a tableting pressure of about 2.5 kN / ram and 180 mg per tablet (tablet diameter 8.0 mm).

Test Example 1

For the tablets of Examples 1, 2, 34 (n = 1), Examples 3 to 6 (n = 3), Examples 7 to 33, and Comparative Example 1 (n = 5), the hardness was measured. The hardness was measured using a tablet hardness tester (Tablet Hardness Tester, "Schleuniger", Model 6D, manufactured by Schleuniger). The results are shown in Table 3.

Test Example 2

For the lozenges of Reference Example 1, Examples 1, 2, 6, and 34 (n = 1), Examples 7 to 33, and Comparative Example 1 (n = 3), the disintegration time in the oral cavity was measured. The intraoral disintegration time was measured using an intraoral disintegration tester (Tricorptester, manufactured by Okada Seiko Co., Ltd.). The results are shown in Table 3.

Test Example 3

For the tablets of Reference Example 1, Examples 7 to 33, and Comparative Example 1, the thickness (n = 5) was measured. The thickness of the lozenge was measured using a digimatic indicator (Mitutoyo Absolute, manufactured by Mitutoyo). The results are shown in Table 3.

Test Example 4

For the tablets of Reference Example 1, Examples 7 to 33, and Comparative Example 1, the porosity (n = 1) was measured. The porosity was measured using a bulk density measuring device (Akivic 1330, GeoPyc ^™ 1360, manufactured by Micromeritics). The results are shown in Table 3.

Test Example 5

Using carbon dioxide, copolypyrrolidone (Kollidon VA64, BASF Japan) and polyvinyl caprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer (Soluplus, BASF Japan) were treated. The carbon dioxide pressure during treatment and the glass transition point of each substance are shown in Table 1 (co-polypyrrolidone) and Table 2 (polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer).

As a result, there is a phenomenon that the melting point or glass transition temperature decreases (Table 1, Table 2). The glass transition temperature is determined by visually judging each substance in the pressure chamber and confirming the temperature at which phase transition occurs. In this way, by using carbon dioxide, the phase change of the substance having a binder function can be processed by using supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide near room temperature, and the porous structure that forms cross-links between particles can be applied. For rapid disintegrating lozenges (especially oral disintegrating tablets).

Reference example 2

Magnesium stearate (Parteck LUB MST, Merck, the following is not particularly limited) 1.0w / w% is blended with 99.0w / w% of mannitol (Parteck M100, manufactured by Merck) for direct hitting, and Use list The tableting machine (Autograph AGS-20kNG, manufactured by Shimadzu Corporation, and the same when not specifically limited below) performs tabletting (tablet diameter 8.5mm) so that the tablet hardness is 20N and the tablet thickness is about 3.9mm.

These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 10 MPa and 40 ° C. for 60 minutes, and then depressurized to obtain a lozenge of Reference Example 2.

Reference example 3 ~ 8

Various medical additives 20.0w / w% described in Table 4 were mixed with mannitol (Parteck M100, manufactured by Merck) 79.0w / w% for direct hitting. Magnesium stearate 1.0w / w% was blended into the mixture, and a single-shot tableting machine was used to perform tabletting (tablet diameter 8.5mm) with a tablet hardness of 20N and a tablet thickness of about 3.9mm. .

These tablets were treated with a pressure-resistant chamber and treated with carbon dioxide at 6 MPa and 25 ° C. for 45 minutes, and then depressurized to prepare tablets of Reference Examples 3 to 8.

Reference example 9 ~ 24

Various medical additives 20.0w / w% described in Table 4 were mixed with mannitol (Parteck M100, manufactured by Merck) 79.0w / w% for direct hitting. Magnesium stearate 1.0w / w% was blended into the mixture, and a single-shot tableting machine was used to perform tabletting (tablet diameter 8.5mm) with a tablet hardness of 20N and a tablet thickness of about 3.9mm. .

Make these tablets use pressure chamber, with carbon dioxide pressure 10MPa, After treatment at 40 ° C for 60 minutes, the pressure was reduced to obtain tablets of Reference Examples 9 to 24.

Test Example 6

For Reference Examples 2 to 24, the hardness of tablets before and after carbon dioxide pressure treatment was measured. The hardness was measured using a tablet hardness tester (Tablet Hardness Tester, "Schleuniger", Model 6D, manufactured by Schleuniger). The results are shown in Table 4.

From the results in Table 4, it can be seen that in Reference Example 2 and Reference Examples 15 to 24, after the carbon dioxide pressure treatment, it can be confirmed that there is no increase in the hardness of the tablets. In contrast, Reference Examples 3 to 14 confirm the increase in hardness. From this result, it can be confirmed that, in Reference Examples 3 to 14, by combining the medical additives and carbon dioxide pressure treatment contained, it is confirmed that the hardness of the lozenge is improved by using the phase change of the substance. Therefore, Reference Examples 3 to 14 are examples of the present invention.

Reference Example 25

Co-polypyrrolidone (Kollidon VA64 Fine, BASF Japan) 20.0 w / w% with an average particle diameter of 10-20 μm was mixed with 79.0 w / w% of mannitol for direct hits (Parteck M100, manufactured by Merck). Magnesium stearate 1.0w / w% was blended into this mixture, and a single-shot tableting machine was used to make tablets with a tablet hardness of 19N and a tablet thickness of about 3.9mm (tablet diameter 8.5mm) . These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes, and then depressurized to obtain a lozenge of Reference Example 25.

Test Example 7

Regarding Reference Example 25, the hardness of ingot products and those treated with carbon dioxide pressure were measured. The hardness was measured using a tablet hardness tester (Tablet Hardness Tester, "Schleuniger", Model 6D, manufactured by Schleuniger). The results are shown in Table 5.

It can be seen from the results in Table 5 that the results of the comparison of the hardness of the tablets of Reference Example 8 and Reference Example 25 are related to the substance that has the function of a binder by carbon dioxide pressure treatment. Even if the same component is used, by controlling the particle size, When treated with carbon dioxide pressure to induce a phase change, the tablet hardness can be more effectively increased. This is achieved by controlling the particle diameter of the phase change component to a small value to increase the surface area and more effectively perform cross-linking between particles. Therefore, Reference Example 25 is also an embodiment of the present invention.

Reference example 26

Ethylcellulose (Ethocel stardard 7 FP Premium, Dow Chemical) 20.0w / w% was mixed with mannitol (Parteck M100, manufactured by Merck) 79.0w / w% for direct hitting. Magnesium stearate 1.0w / w% was blended into the mixture, and a single-shot tableting machine was used to perform tabletting (tablet diameter 8.5mm) with a tablet hardness of 20N and a tablet thickness of about 3.9mm. . These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes, and then depressurized to obtain a lozenge of Reference Example 26.

Reference Example 27

Dissolve B in 150g of ethanol (ethanol 99.5%, manufactured by Kanto Chemical) Cellulose (Ethocel stardard 7 FP Premium, manufactured by Dow Chemical) 13.5g and triethyl citrate (Triethyl Citrate, manufactured by Tokyo Chemical Industry) 1.5g, with a spray dryer (Mini Spray Dryer B-290, manufactured by Buchi, the following is not available It is the same when it is particularly restricted). Spray drying is performed to obtain an ethyl cellulose / triethyl citrate (9/1) spray dried product.

Ethylcellulose / triethyl citrate (9/1) dry spray product 20.0w / w% was mixed with 79.0w / w% of mannitol (Parteck M100, manufactured by Merck) for direct hit. Magnesium stearate 1.0w / w% was blended into this mixture, and a single-shot tableting machine was used to make tablets with a tablet hardness of 22N and a tablet thickness of about 3.9mm (tablet diameter 8.5mm) . These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes, and then depressurized to obtain a lozenge of Reference Example 27.

Reference Example 28

Dissolve 11.25 g of ethyl cellulose (Ethocel stardard 7 FP Premium, manufactured by Dow Chemical) and 3.75 g of triethyl citrate (Triethyl Citrate, manufactured by Tokyo Chemical Industry Co., Ltd.) in 150 g of ethanol (ethanol 99.5%, manufactured by Kanto Chemical Co., Ltd.) by spraying The dryer was spray-dried to obtain an ethyl cellulose / triethyl citrate (7.5 / 2.5) spray-dried product.

Ethylcellulose / triethyl citrate (7.5 / 2.5) dry spray 20.0w / w% was mixed with mannitol (Parteck M100, manufactured by Merck) 79.0w / w% for direct hit. Magnesium stearate 1.0w / w% was blended into the mixture, and a single-shot tableting machine was used to perform tabletting (tablet diameter 8.5mm) with a tablet hardness of 20N and a tablet thickness of about 3.9mm. . These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 6 MPa and 25 ° C for 45 minutes, and then depressurized to obtain a lozenge of Reference Example 28.

Test Example 8

For the tablets of Reference Examples 26 to 28, the hardness before and after the carbon dioxide pressure treatment was measured. The hardness was measured using a tablet hardness tester (Tablet Hardness Tester, "Schleuniger", Model 6D, manufactured by Schleuniger). The results are shown in Table 6.

It can be seen from the results in Table 6 that in the tablets of Reference Examples 27 and 28 using spray-dried products containing plasticizer in ethyl cellulose, it was confirmed that tablets having a more remarkable effect than ethyl cellulose alone can be obtained. The hardness of the agent increases. Therefore, Reference Examples 26 to 28 are also examples of the present invention.

Example 35

410 g of D-mannitol (Pearitol 50C, manufactured by Rocket Japan, and the same is not particularly limited below) 410 g and 100 g of copolypyrrolidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding solution were used Layer granulator (Flo-Coater FLO-1, (FREUND Industries / Ogawara Manufacturing Co., Ltd., the same is true if there is no specific limitation below) In some of these granules, an aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Evonik Degussa Japan, and the following is not particularly limited) 10.0w / w%, cross-linked polypyrrolidone (Kollidon CL -F, manufactured by BASF Japan) 5.0w / w%. Magnesium stearate is mixed with 1.0w / w% of this mixture, and a rotary ingot machine (HT-EX series, manufactured by CK Iron Works, the same is not the same as below) is used, and the ingot pressure is about 1kN / Using a pestle, a lozenge of about 170 mg per lozenge (lozenge diameter 8.5 mm) is prepared. Tablet hardness is 11N (n = 10). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 5 MPa and 25 ° C. for 5 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 36

The tablets of Example 35 were treated with a pressure-resistant chamber, treated with carbon dioxide at 4 MPa and 25 ° C for 60 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 37

The tablets of Example 35 were treated with a pressure-resistant chamber and treated with a carbon dioxide pressure of 3 MPa and 25 ° C for 840 minutes, followed by depressurization to prepare the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 38

The tablets of Example 35 were treated with a pressure-resistant chamber and treated with carbon dioxide at 4 MPa and 15 ° C. for 45 minutes, and then the pressure was reduced to obtain the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 39

The tablets of Example 35 were treated with a pressure-resistant chamber, treated with carbon dioxide at 4 MPa and 45 ° C for 45 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 40

The tablets of Example 35 were treated with a pressure-resistant chamber and treated with a carbon dioxide pressure of 3 MPa and 60 ° C for 45 minutes, and then the pressure was reduced to prepare the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 41

F-Melt (manufactured by Fuji Chemical) 89.0 w / w%, aminoalkyl methacrylate copolymer E 1.0 w / w%, copolypyrrolidone (Kollidon VA64, manufactured by BASF Japan) 9.0 w / w% were mixed. Magnesium stearate 1.0w / w% is blended into this mixture, and a single-shot spindle machine is used to reduce the pressure Approximately 1.5kN / ramming pestle is used to make a lozenge of 170mg per lozenge (lozenge diameter 8.5mm). Tablet hardness is 12N (n = 3). The tablets were used in a pressure-resistant chamber, and treated with a carbon dioxide pressure of 3 MPa and 45 ° C. for 120 minutes to prepare the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 42

410 g of D-mannitol was granulated using 100 g of copolypyrrolidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 7.5 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 10.0 w / w%. Magnesium stearate 1.0w / w% was blended into this mixture, and a single-shot tableting machine was used to make tablets with a tableting pressure of about 2.5kN / tamper to make about 190mg per tablet (tablet diameter 8.5mm) . Tablet hardness is 27N (n = 2). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 3 MPa and 45 ° C. for 120 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 43

410 g of D-mannitol was granulated using 100 g of copolypyrrolidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, using a fluidized bed granulator. In some of the granules, an aminoalkyl methacrylate copolymer E 20.0 w / w%, cross-linked polypyrrolidone is mixed (Kollidon CL-F, manufactured by BASF Japan) 10.0w / w%. Magnesium stearate 1.0w / w% was blended into this mixture, and a single-shot tableting machine was used to make tablets with a tableting pressure of about 2.0kN / tamper to make about 176mg per tablet (tablet diameter 8.5mm) . The tablet hardness is 37N (n = 2). These tablets were treated with a pressure-resistant chamber, treated with carbon dioxide at 1 MPa and 35 ° C. for 840 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 44

410g of D-mannitol was prepared by copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (5.0w / w%) 50g and polypyrrolidone (Kollidon K30, BASF Japan) aqueous solution (5.0w / w%) 50g The mixed liquid is used as a binding liquid and granulated using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. To this mixture, 1.0 w / w% of magnesium stearate was blended, and a rotary tableting machine was used to produce tablets with a tableting pressure of about 1.0 kN / ram and about 171 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 12N (n = 10). These lozenges were used in a pressure-resistant chamber, and after adding a nitrogen pressure of 10 MPa, and then treated with a carbon dioxide pressure of 5.0 MPa and 25 ° C. for 45 minutes, the pressure was reduced to obtain the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 45

The lozenge of Example 44 was used in a pressure-resistant chamber. After adding carbon dioxide pressure of 5.0 MPa, and then adding nitrogen pressure of 5.0 MPa, after processing at 25 ° C. for 45 minutes, the pressure was reduced to obtain the rapidly disintegrating ingot of the present invention. Agent. In addition, the decompression speed condition is about 1 MPa / min.

Example 46

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of polypyrrolidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. Magnesium stearate 1.0 w / w% was blended into the mixture, and a rotary tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 170 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 13N (n = 10). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C for 30 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 47

Make 320g of D-mannitol with polyvinyl alcohol. acrylic acid. 80 g of an aqueous solution (5.0 w / w%) of methyl methacrylate copolymer (POVACOAT Type F, manufactured by Datong Chemical Industry Co., Ltd.) was used as a binding liquid, and granulated using a fluidized bed granulator. In some of the granules, an aminoalkyl methacrylate copolymer E 10.0w / w%, cross-linked polypyrrolidone (Kollidon CL-F, BASF Made in Japan) 8.0w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 16N (n = 2). These tablets were treated with a pressure-resistant chamber, treated with carbon dioxide at 4 MPa and 25 ° C. for 35 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 48

320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda) aqueous solution (5.0 w / w%) as a binding liquid. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 12N (n = 2). These tablets were treated with a pressure-resistant chamber, treated with carbon dioxide at 4 MPa and 25 ° C. for 45 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 49

320 g of D-mannitol was used as an aqueous solution of hydroxymethylpropyl cellulose (hypromellose) (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) (5.0w / w%) 80g was used as a binding liquid and granulated using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 12N (n = 2). These tablets were treated with a pressure-resistant chamber, treated with carbon dioxide at 4 MPa and 25 ° C. for 45 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 50

Make 320g of D-mannitol with polyvinyl alcohol. 80 g of an aqueous solution (5.0 w / w%) of polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF Japan) was used as a binding liquid, and granulated using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 12N (n = 2). These tablets were treated with a pressure-resistant chamber, treated with carbon dioxide at 4 MPa and 25 ° C. for 45 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 51

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. In some of the granules, an aminoalkyl methacrylate copolymer E 9.0w / w%, a low-substituted hydroxypropyl cellulose (L-HPC NBD-022, manufactured by Shin-Etsu Chemical Industry) 9.0w / w %. Magnesium stearate 1.0 w / w% was blended into the mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 185 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 13N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes, and then reduced in pressure to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 52

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and cross-linked CMC-Na (Kiccolate ND-2HS, manufactured by Asahi Kasei Corporation) 5.0 w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 12N (n = 3). These tablets are processed in a pressure-resistant chamber at a carbon dioxide pressure of 4 MPa and 25 ° C for 10 minutes Thereafter, the pressure was reduced to prepare the instant disintegrating lozenge of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 53

410 g of D-mannitol was granulated using 100 g of copolypyrrolidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, using a fluidized bed granulator. A part of this granulated material was mixed with aminoalkyl methacrylate copolymer E 9.0 w / w%, and partially alpha starch (PCS, manufactured by Asahi Kasei Corporation) 9.0 w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 9N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes, and then reduced in pressure to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 54

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 9.0 w / w% and carboxymethyl starch sodium (Primojel, manufactured by DMV-Fonterra Excipients) 9.0 w / w%. Magnesium stearate 1.0w / w% is blended into the mixture, and a single-shot ingot machine is used to make an ingot of about 185mg per ingot with an ingot pressure of about 1kN / tamper. (Diabetes diameter 8.5mm). Tablet hardness is 8N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 10 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 55

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kolidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, it was granulated using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 10.0 w / w% and CMC-Ca (ECG-505, manufactured by Wude Pharmaceutical) 5.0 w / w%. Magnesium stearate 1.0 w / w% was blended into the mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 181 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 10N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 10 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 56

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 9.0 w / w% and alpha starch (SWELSTAR PD-1, manufactured by Asahi Kasei Chemicals Co., Ltd.) 9.0 w / w%. In that Magnesium stearate 1.0w / w% was blended into the mixture, and a single-shot tableting machine was used to make tablets of about 184 mg per tablet (tablet diameter 8.5 mm) with a tableting pressure of about 1 kN / ram. Tablet hardness is 8N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes, and then reduced in pressure to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 57

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. Part of the granulated product was mixed with aminoalkyl methacrylate copolymer E 9.0 w / w% and CMC (NS-300, manufactured by Wude Pharmaceutical) 9.0 w / w%. Magnesium stearate 1.0 w / w% was blended into the mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 181 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 11N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 10 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 58

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. Acetic acid is mixed with 7.59 g of the granulated material 0.56 g of aminoaminophenol (manufactured by Yamamoto Chemical Industry), 1.0 g of aminoalkyl methacrylate copolymer E, and 0.75 g of cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan). To this mixture, 0.10 g of magnesium stearate was blended, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 12N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes, and then depressurized to obtain the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 59

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of polypyrrolidone (Kollidon K30, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. To 7.04g of the granulated material, 1.11g of famotidine (manufactured by Astellas Pharmaceuticals), 1.0g of aminoalkyl methacrylate copolymer E, and cross-linked polypyrrolidone (Kollidon CL-F, BASF) Japan) 0.75g. To this mixture, 0.10 g of magnesium stearate was blended, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 16N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 60

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of polypyrrolidone (Kollidon K30, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. Tamsulosin (Astellas Pharmaceuticals) 0.056g, aminoalkyl methacrylate copolymer E 1.0g, cross-linked polypyrrolidone (Kollidon CL-F, BASF) were mixed with 8.09g of the granules Japan) 0.75g. To this mixture, 0.10 g of magnesium stearate was blended, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 180 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 17N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 61

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. HPMCAS (AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.) 20.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w% were mixed with some of the granules. Magnesium stearate 1.0 w / w% was blended into the mixture, and a single-shot tableting machine was used to make tablets with a tableting pressure of about 1 kN / ram and about 176 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 25N (n = 3). Make these tablets use pressure chamber, with carbon dioxide pressure After treatment at 5 MPa and 25 ° C for 45 minutes, the pressure was reduced to obtain the rapid disintegrating tablet of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 62

Using 410 g of D-mannitol and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid, the granulation was carried out using a fluidized bed granulator. HPMCAS (AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.) 15.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w% were mixed with part of the granulated material. Magnesium stearate 1.0 w / w% was blended into the mixture, and a single-shot tableting machine was used to make tablets with a tableting pressure of about 1 kN / ram and about 176 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 25N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 5 MPa and 45 ° C. for 840 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 63

The tablets of Example 62 were treated with a pressure-resistant chamber at a carbon dioxide pressure of 5 MPa and 60 ° C for 45 minutes, and then depressurized to prepare the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 64

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of polypyrrolidone (Kollidon K30, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. Ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) 15.0w / w%, cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 8.0w / w%, 1-Mentol (made by Kanto Chemical) 1.0w / w%. Magnesium stearate 1.0 w / w% was blended into the mixture, and a single-shot tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 171 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 21N (n = 3). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 5 MPa and 60 ° C. for 45 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 65

The tablets of Example 35 were treated with a pressure-resistant chamber at a carbon dioxide pressure of 3.5 MPa and 25 ° C for 120 minutes, and the pressure was reduced to obtain the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 66

The tablets of Example 46 were treated with a pressure-resistant chamber at a carbon dioxide pressure of 3.5 MPa and 25 ° C for 120 minutes, and the pressure was reduced to obtain the rapidly disintegrating tablets of the present invention. Moreover, at a decompression speed condition of about 1MPa / min get on.

Example 67

The tablets of Example 44 were treated with a pressure-resistant chamber at a carbon dioxide pressure of 3.5 MPa and 25 ° C. for 120 minutes, and the pressure was reduced to obtain the rapidly disintegrating tablets of the present invention. In addition, the decompression speed condition is about 1 MPa / min.

Example 68

Using 415 g of D-mannitol and 100 g of polypyrrolidone (Kollidon K30, BASF Japan) aqueous solution (5.0 w / w%) as a binding liquid, it was granulated using a fluidized bed granulator. Part of this granulated material was mixed with aminoalkyl methacrylate copolymer E 10 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a rotary tableting machine was used to produce tablets with a tableting pressure of about 1 kN / ram and about 171 mg per tablet (tablet diameter 8.5 mm). Tablet hardness is 10N (n = 10). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 4 MPa and 25 ° C. for 40 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Example 69

Using 415g of D-mannitol and 100g of aqueous solution (5.0w / w%) of polypyrrolidone (Kollidon K30, BASF Japan) as a binding liquid, a fluidized bed was used. Granulator for granulation. Part of the granulated product was mixed with aminoalkyl methacrylate E 10.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. Magnesium stearate 1.0 w / w% was blended into this mixture, and a rotary tableting machine was used to produce tablets with a tableting pressure of about 1.8 kN / ram and about 186 mg per tablet (tablet diameter 8.5 mm). The tablet hardness is 19N (n = 10). These lozenges were used in a pressure-resistant chamber, treated with a carbon dioxide pressure of 3.5 MPa and 25 ° C. for 90 minutes, and then depressurized to prepare the rapidly disintegrating lozenges of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Comparative example 2

After the tablets of Example 35 were treated in the atmosphere at 60 ° C for 45 minutes, the tablets of Comparative Example 2 were prepared.

Comparative Example 3

After the lozenges of Example 69 were treated in the atmosphere at 70 ° C for 840 minutes, the lozenges of Comparative Example 3 were prepared.

Comparative Example 4

After the tablets of Example 70 were treated in the atmosphere at 70 ° C for 840 minutes, the tablets of Comparative Example 4 were prepared.

Test Example 9

For the tablets of Examples 35 to 69 and Comparative Examples 2 to 4, the hardness was measured for each. Hardness uses Tablet Hardness Tester (Tablet Hardness Tester, "Schleuniger", Model 6D, manufactured by Schleuniger)). The results are shown in Table 7.

Test Example 10

With regard to the tablets of Examples 35 to 69 and Comparative Examples 2 to 4, the time of oral cavity collapse was measured. The intraoral disintegration time was measured using an intraoral disintegration tester (Tricorptester, manufactured by Okada Seiko Co., Ltd.). The results are shown in Table 7.

Test Example 11

The thickness of the tablets of Examples 35 to 69 and Comparative Examples 2 to 4 was measured (n = 5). The thickness of the lozenge was measured using a digimatic indicator (Mitutoyo Absolute, manufactured by Mitutoyo). The results are shown in Table 7.

Test Example 12

The fast disintegrating tablets of Examples 65 to 69 and Comparative Examples 3 to 4 were packaged in PTP tablets (34 x 111 mm, 7 tablets x 2 rows / tablet), and the drop test was performed under the following conditions.

. Drop height: 150cm

. The number of repeated drops: 10 times

. Number of PTP tablets tested: 10 tablets

. The direction of PTP tablets: make the medicine storage part (pocket) face upward

. Breakage rate: (number of rapidly disintegrating lozenges that break and / or break) / 140 × 100

The results are shown in Table 7.

It can be seen from the results in Table 7 that the present invention with an improved tablet hardness can be obtained by the cross-linking of the phase change of aminoalkyl methacrylate copolymer E or HPMCAS and ethyl cellulose treated by carbon dioxide pressure The fast disintegrating lozenges.

Specifically, in Examples 35 to 43, it can be confirmed that the rapid disintegration of the present invention can be obtained by appropriately combining the addition amount of aminoalkyl methacrylate copolymer E, carbon dioxide treatment pressure, treatment temperature, and treatment time Lozenges. In Comparative Example 2, although the heat treatment was performed in the atmosphere at 60 ° C for 45 minutes, it was not possible to confirm that the hardness of the tablets had increased. In addition, in Example 35, treatment at a carbon dioxide pressure of 5 MPa and 25 ° C for 5 minutes confirmed a significant increase in tablet hardness. Even in a mild temperature environment near room temperature, it was confirmed that the tablet hardness increased. situation.

In Examples 44 to 45, it was confirmed that by using carbon dioxide and nitrogen together, the tablet hardness can be induced to increase in the same manner. From this result, it can be seen that the present invention has the possibility of using other gases in addition to carbon dioxide.

In Examples 46 to 50, polypyrrolidone or polyvinyl alcohol may be used as a binding agent in the granulation step. acrylic acid. Various common binders for methyl methacrylate copolymers.

In Examples 51-57, the rapid disintegration of the present invention can be obtained by using various general-purpose disintegrating agents as a dispersing agent, such as low-substituted hydroxypropyl cellulose, cross-CMC-Na, or partially alpha starch. Lozenges.

In Examples 58 to 60, it can be confirmed that rapid disintegrating lozenges with the same properties are prepared in the preparations containing typical drugs.

In Examples 61 to 64, by combining HPMCAS or ethyl fiber The pressure treatment of the element and carbon dioxide, like the aminoalkyl methacrylate copolymer, can increase the hardness of the lozenge, and the fast disintegrating lozenge of the present invention can be prepared. From this, it can be seen that the rapid disintegrating lozenges of the present invention can be produced by adding a typical additive group having a component that improves the hardness of a tablet by carbon dioxide pressure in the reference example, and by appropriate prescription design.

Regarding Examples 65 to 69, the breakage rate of the drop test was evaluated, and it was confirmed that they were all extremely low breakage rates of 0 to 0.7%. In addition, for the rapidly disintegrating lozenges of the same formulation as in Examples 68 and 69, the heat treatment was performed without carbon dioxide, and the hardness of the lozenges was increased to the same degree, showing 2.1 to 5%. Relatively high breakage rate. It can be seen that the fast-disintegrating tablet of the present invention is also excellent in breakage resistance.

Example 70

80.7 g of microparticles containing solifenacin succinate (manufactured by Astellas Pharmaceuticals) with a bitter taste masking function, and 100 g of copolypyrrolidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as binding liquid , Granulate with a fluidized bed granulator. Aminoalkyl methacrylate E 10.0 w / w% and cross-linked polypyrrolidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w% were mixed in the granulated material. Magnesium stearate 1.0w / w% was blended into the mixture, and a single-shot ingot machine was used to make an ingot of about 150 mg per ingot (sofenacin succinate) with an ingot pressure of about 1 kN / tamper Content 5mg) (tablet diameter 7.5mm). Tablet hardness is 10N (n = 3). After using these pressure-resistant tablets in a pressure-resistant chamber, after processing at a carbon dioxide pressure of 5 MPa and 35 ° C for 30 minutes, The pressure was reduced to prepare the rapidly disintegrating tablet of the present invention. Furthermore, it is performed at a reduced pressure rate condition of about 1 MPa / minute.

Comparative Example 5

After the tablets of Example 70 were treated in the atmosphere at 70 ° C for 840 minutes, the tablets of Comparative Example 5 were prepared.

Test Example 13

Regarding the fast disintegrating tablet of Example 70 and the tablet of Comparative Example 5, the hardness was measured. The hardness was measured using a tablet hardness tester (Tablet 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 taste masking particles used in Example 70, the fast-disintegrating tablets of Example 70, and the tablets of Comparative Example 5. The dissolution test apparatus used Dissolution tester NTR-6100A (manufactured by Toyama Chemical), and the dissolution rate of solifenacin succinate was measured using a liquid chromatography analyzer (manufactured by Shimadzu Corporation). The test conditions are as follows.

. Foaming method 50rpm

. Test liquid: the second liquid (pH6.8) 900mL

. Test liquid temperature: 37 ℃ ± 0.5 ℃

. Test time: 2 minutes, 30 minutes

The results are shown in Table 8.

Test Example 15

The bitter taste masking particles used in Example 70, the rapidly disintegrating tablets of Example 70, and the tablets of Comparative Example 5 were measured relative to the total amount of solifenacin succinate and its decomposed products The largest amount of decomposition products (hereinafter referred to as the main decomposition products) and the total decomposition products relative to the total amount of solifenacin succinate and its decomposition products (hereinafter referred to as the total decomposition products) ). The results are shown in Table 8.

From the results in Table 8, it can be seen that the tablets of Comparative Example 5 were confirmed to be significant relative to the amount of the main decomposition product and the total amount of decomposition products of the rapidly disintegrating tablets of Example 70 and the bitter taste masking particles. increase.

[Industrial use value]

The present invention improves the breakage of tablets produced during the circulation process, and fully maintains the solid dispersion particles, bitter masking particles, and Xu Fang that are given to drugs that are unstable according to temperature or humidity, or are made of insoluble drugs. Drug particles and other medicinal properties can provide fast-disintegrating lozenges (especially intraoral disintegrating tablets) for various functions based on which functional particles are required to function.

In the above, the description is described according to a specific form, but the modifications or improvements made by the manufacturer are included in the scope of the present invention.

Claims (21)

A rapidly disintegrating lozenge, which contains a drug and a substance that has a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, and carbon dioxide or liquid in a supercritical or subcritical state Or rapidly disintegrating lozenges obtained by treatment with gaseous carbon dioxide, the aforementioned substances having a binding agent function by treatment with supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide are selected from vinylpyrrolidone and vinyl acetate Copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl pyrrolidone / vinyl acetate resin premix preparation, methacrylic acid copolymer LD, polyvinyl alcohol‧poly Ethylene glycol graft copolymer, polyvinyl alcohol‧polyethylene glycol graft copolymer / polyvinyl alcohol premix preparation, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene hardened castor oil ( 40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid S, aminoalkyl methacrylate copolymer RS, ethyl acrylate‧methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate‧diethylaminoethyl methacrylic acid Ester copolymers, hydroxypropyl methylcellulose acetate succinate, shellac, carbomer, and polyvinyl acetal diethylaminoacetate 1 or 2 or more, and the substance having a binder function by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state is 3 wt% or more and 20 wt% relative to the weight of the tablet the following. The fast disintegrating lozenge as claimed in claim 1, wherein the substance having a binder function by treatment with supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide is obtained by supercritical or subcritical carbon dioxide Or liquid or gaseous carbon dioxide treatment to reduce the melting point or glass transition temperature of the substance. The fast disintegrating lozenge as claimed in claim 1 or 2, which further contains a plasticizer. The fast disintegrating lozenge as claimed in claim 1 or 2, which further contains a disintegrating agent. The fast disintegrating lozenge as claimed in claim 1 or 2, wherein the hardness of the lozenge is above 20N. The fast disintegrating lozenges as claimed in item 1 or 2, wherein the ratio of the number of broken tablets by the drop test is 5% or less. The fast disintegrating lozenges according to claim 1 or 2, wherein the fast disintegrating lozenges are oral disintegrating tablets. The fast disintegrating lozenge as claimed in claim 7, wherein the disintegration time in the oral cavity is within 120 seconds. A fast disintegrating lozenge as claimed in claim 1 or 2, wherein the drug constitutes a drug and / or functional particles that are unstable to temperature or humidity. The fast disintegrating lozenge as claimed in claim 9, wherein the functional particles are one or more selected from the group consisting of solid dispersion particles, bitter taste shielding particles, and Xufang particles made of insoluble drugs particle. A manufacturing method of rapidly disintegrating lozenges, which includes (1) mixed medicine and dioxygen in supercritical or subcritical state The step of carbonization or liquid or gaseous carbon dioxide treatment with a substance with a binder function, (2) the step of compressing the mixture of (1) to prepare a tablet, and (3) the tablet of (2) by A method for manufacturing fast-disintegrating lozenges in the process of supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide treatment, which has a binding agent function by the treatment of supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide The substance is selected from vinylpyrrolidone-vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl pyrrolidone / vinyl acetate resin premix preparation , Methacrylic acid copolymer LD, polyvinyl alcohol‧polyethylene glycol graft copolymer, polyvinyl alcohol‧polyethylene glycol graft copolymer / polyvinyl alcohol premix preparation, polyethylene oxide (196) polypropylene oxide (67) Glycol, polyethylene oxide hardened castor oil (40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, Methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate‧methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate‧diethylaminoethyl Methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, shellac and carbomer in one or more than two groups, and by supercritical or subcritical state The carbon dioxide or liquid or gaseous carbon dioxide treatment has a binder function of the substance, relative to the tablet The weight is 3% by weight or more and 20% by weight or less. The manufacturing method of fast disintegrating lozenges as claimed in claim 11, wherein a substance having a binder function by treatment with supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide is obtained by supercritical or subcritical Substances in which carbon dioxide or liquid or gaseous carbon dioxide is treated to lower the melting point or glass transition temperature. The method for producing a fast-disintegrating tablet according to claim 11 or 12, which further contains a plasticizer. The method for producing a fast-disintegrating tablet according to claim 11 or 12, which further contains a disintegrating agent. The manufacturing method of fast disintegrating lozenges according to claim 11 or 12, wherein the hardness of the lozenges is 20N or more. The method for manufacturing a rapidly disintegrating lozenge according to claim 11 or 12, wherein the rapidly disintegrating lozenge is an oral disintegrating lozenge. The method for manufacturing a rapidly disintegrating tablet according to claim 16, wherein the disintegration time in the oral cavity is within 120 seconds. A method for manufacturing a fast-disintegrating lozenge according to claim 11 or 12, wherein the drug constitutes a drug and / or functional particles that are unstable to temperature or humidity. The method for producing fast-disintegrating lozenges as claimed in claim 18, wherein the functional particles are selected from the group consisting of solid dispersion particles made of insoluble drugs, bitter taste masking particles and Xufang particles or 2 More than one kind of particles. For example, the manufacturing method of fast disintegrating lozenges according to claim 11 or 12, This includes treatment with carbon dioxide of 0.1 MPa or more and 50 MPa or less and -40 ° C or more and 100 ° C or less. The manufacturing method of the fast disintegrating lozenge as claimed in claim 11 or 12, wherein it is processed by gaseous carbon dioxide.