CN104168891A - Rapidly disintegrating tablet - Google Patents

Abstract

Provided are: a rapidly disintegrating tablet (in particular, an orally disintegrating tablet) containing drug-containing particles imparting a desired function based on the properties of the drug, which tablet still fully expresses the function even after a formulation step which might sometimes have an impact on the function thereof; and a method for producing the same. The rapidly disintegrating tablet is obtained by treating, with carbon dioxide in a super critical or subcritical state or with carbon dioxide liquid or gas, a drug and a material which is given the function of a binding agent by treatment with carbon dioxide in a super critical or subcritical state or with carbon dioxide liquid or gas.

Description

fast disintegrating tablet

technical field

The present invention relates to rapidly disintegrating tablets (particularly orally disintegrating tablets) having a porous structure by treatment with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide. In addition, the present invention relates to a method for producing rapidly disintegrating tablets (especially orally disintegrating tablets) having a porous structure by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide.

Background technique

When providing pharmaceutical preparations, it is often required to develop drug-containing particles that are endowed with a certain function by utilizing the characteristics of drugs such as drugs that are unstable to temperature or humidity, drugs that have a bitter taste, and drugs that require sustained release. Pharmaceutical preparations.

Among pharmaceutical preparations, tablets are widely provided at medical sites as one of the most suitable dosage forms in terms of compliance with patient administration.

On the other hand, based on the Ministry of Health, Welfare and Welfare Science Research silver scientific research conducted in the 1980s, "Research on the production of new formulations and new packaging containers most suitable for administration to the elderly" was carried out (Tokyo Women's Medical University, Masahiro Sugihara, etc. ) report (pharmaceutical daily issue on August 22, 1989; non-patent literature 1). For example, as new formulations, a) orally dissolving formulations, b) paste formulations, and c) jelly formulations have been adopted, among which, from the viewpoint of ease of administration and stability, both the orally dissolving formulations and the paste formulations have been adopted. It is regarded as a preparation that is easy to take for the elderly.

The orally disintegrating tablet is a dosage form suitable for patients with reduced swallowing ability, and is widely known as a highly convenient dosage form that can be taken without water, such as before going to bed or when going out, for diseases where water intake is restricted.

As a formulation technology related to an orally disintegrating tablet, the following invention related to an orally disintegrating tablet containing a saccharide having a low formability by using a highly formable saccharide as a binder has been reported. A granulated product obtained by spraying, coating and/or granulating sugar (Patent Document 1).

In addition, the following invention related to the production method of fast-dissolving tablets is reported. The production method is characterized in that in order to improve the occurrence of failures such as poor fluidity of the supplied material and adhesion of the material to the pressing member during pressurization, manufacturing deficiencies, including: forming tablet form from dry state tablet material containing pharmaceutical agent, water-soluble binder, and water-soluble excipients to the minimum hardness required to maintain that form A tableting step for compression molding by pressure, a humidification step for absorbing moisture to the tablet formed in the tableting step, and a drying step for drying the humidified tablet in the humidification step (Patent Document 2).

In addition, the following invention related to an orally disintegrating tablet is reported, wherein, for a composition containing a drug, sugar, and polyethylene glycol, after the composition is subjected to low-pressure compression, the polyethylene glycol By raising the temperature under the temperature conditions at which the glycol melts, the polyethylene glycol forms interparticle crosslinks between the drug and the sugar, thereby having a porous structure (Patent Document 3).

In addition, an invention related to a rapidly disintegrating tablet in the oral cavity is reported (Patent Document 4), wherein, in order to increase the tablet strength and improve the degree of abrasion without prolonging the disintegration time in the oral cavity, the Orally rapidly disintegrating tablets contain drugs, diluents, and sugars with relatively low melting points compared with drugs and diluents. During the period, cross-linking is formed by melting and solidifying sugars with a low melting point; an invention related to an orally disintegrating tablet (Patent Document 5), which contains physiologically active substances and polyvinyl alcohol-polymer Ethylene glycol graft copolymer; an invention related to a manufacturing method of a rapidly disintegrating tablet (Patent Document 6), which is characterized in that, in order to prepare a tablet having rapid disintegration and sufficient tablet strength A rapidly disintegrating tablet comprising: (1) a process of mixing an active ingredient, an acrylic acid copolymer, and at least one pharmacologically acceptable additive; (2) compression molding the mixture obtained in the process of (1) and (3) the process of keeping the compression molded product obtained in the process of (2) at a temperature of 50-100°C for a certain period of time; an invention related to a manufacturing method of a fast-disintegrating tablet (patent document 7), the production method is characterized in that the components in the form of powder are contacted with pressurized liquefied gas or gas mixture to make it homogenized, and then introduced into the forming mold under pressure and then decompressed; Invention of a disintegrating tablet (Patent Document 8) that rapidly disintegrates in an orally produced by a method comprising the stages of compressing a mixture containing an active ingredient, an additive, and a substance soluble in a supercritical fluid to produce a tablet and a stage in which the tablet is brought into contact with a supercritical fluid to extract substances soluble in the supercritical fluid to form minute voids in the tablet; and the like.

However, breakage of rapidly disintegrating tablets (especially orally disintegrating tablets) in the distribution process still poses a problem, and further improvement in technology is required. In addition, in order to provide tablets with sufficient formulation hardness for formulation manipulation and rapid disintegration (rapidly disintegrating tablets (especially orally disintegrating tablets) while maintaining the original functions of the functional particles ), the technology needs to be further improved.

In addition, since heat treatment and humidification treatment may decompose the drug, further improvement of technology is required in order to provide a method for producing a rapidly disintegrating tablet (especially an orally disintegrating tablet) that does not affect the stability of the drug.

prior art literature

patent documents

Patent Document 1: International Publication No. WO95/20380 Pamphlet

Patent Document 2: Japanese Patent No. 2919771

Patent Document 3: Japanese Patent Application 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: International Publication No. WO2006/070845 Pamphlet

Patent Document 7: Japanese Patent Laid-Open No. 2007-516977

Patent Document 8: Japanese National Publication No. 2012-509315

non-patent literature

Non-Patent Document 1: "Studies on the creation of the most suitable new regulated drugs and new regulated packaging containers for the elderly" Pharmaceutical Affairs Daily, published on August 22, 1989

Contents of the invention

The problem to be solved by the invention

An object of the present invention is to provide a rapidly disintegrating tablet (particularly an orally disintegrating tablet) in which breakage of the tablet is improved.

Another object of the present invention is to provide a rapidly disintegrating tablet (particularly an orally disintegrating tablet) that can be applied to a drug that is unstable to humidification or heating. Another object of the present invention is to provide a rapidly disintegrating tablet (particularly, an orally disintegrating tablet) containing drug-containing particles (hereinafter sometimes abbreviated as Functional particles) tablets, even after the formulation process (from the aspect of formulation design, it is sometimes processed at high temperature or high humidity, which sometimes affects the function of the particles containing functional drugs), fully exhibits this effect. Function.

Another object of the present invention is to provide a method for producing a rapidly disintegrating tablet (particularly an orally disintegrating tablet) applicable to a drug unstable to humidification or heating. In addition, another object of the present invention is to provide a method for producing a rapidly disintegrating tablet (particularly an orally disintegrating tablet) containing the desired drug due to the characteristics of the drug. Tablets containing functional drug particles may decompose the drug or may affect the function of the particles containing functional drugs ), the drug itself is also stable, or fully exhibits the function of functional particles.

means of solving problems

Under such circumstances, the inventors have conducted treatment with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide, and as a result, it has been found that by the presence of a substance having a lowered melting point or glass transition temperature and making the substance in the composition-to-component The formation of so-called "interparticle" crosslinks in the voids can function as a binder.

In addition, since it can be produced under mild processing conditions, the thus obtained rapidly disintegrating tablet (especially orally disintegrating tablet) contains a drug unstable to temperature or humidity or contains functional particles ( For example, in the case of solid dispersion particles composed of poorly soluble drugs, bitter taste-masking particles, sustained-release particles, etc.), it is possible to have a porous structure while sufficiently maintaining the stability and desired functions. Therefore, it is possible to provide The present invention has been accomplished by finding a tablet having sufficient tablet hardness and rapid disintegration properties (rapidly disintegrating tablet (especially orally disintegrating tablet)) sufficient for formulation handling.

That is, the present invention relates to:

[1] A rapidly disintegrating tablet containing a drug and a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide, and by using carbon dioxide in a supercritical or subcritical state Carbon dioxide in a critical state or liquid or gaseous carbon dioxide is obtained by processing.

[2] The rapidly disintegrating tablet as described in [1], wherein the substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide is obtained by using carbon dioxide in a supercritical state. or subcritical carbon dioxide or liquid or gaseous carbon dioxide to lower the melting point or glass transition temperature.

[3] The rapidly disintegrating tablet as described in [1] or [2], wherein a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide is selected. One or more substances in the group consisting of the following substances:

Vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone, premixed preparation of povidone and vinyl acetate resin, methacrylic acid copolymer LD, polyvinyl alcohol-polyethylene glycol graft copolymer, premixed preparation of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxypropylene (67) Diol, polyethylene glycol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, formazan Acrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate-methyl methacrylate diethylaminoethyl acrylate copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, carbomer and polyvinyl acetal diethylaminoacetate.

[4] The rapidly disintegrating tablet according to any one of [1] to [3], which has a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide The substance is 0.1 weight% or more and 50 weight% or less with respect to the weight of a tablet.

[5] The rapidly disintegrating tablet according to any one of [1] to [4], which further contains a plasticizer.

[6] The rapidly disintegrating tablet according to any one of [1] to [5], which further contains a disintegrant.

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

[8] The rapidly disintegrating tablet according to any one of [1] to [7], wherein the ratio of the number of broken tablets obtained by a drop test is 5% or less.

[9] The rapidly disintegrating tablet according to any one of [1] to [8], which is an orally disintegrating tablet.

[10] The fast-disintegrating tablet according to [9], wherein the oral disintegration time is within 120 seconds.

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

[12] The fast-disintegrating tablet according to [11], wherein the functional particles are one or more particles selected from the group consisting of:

Solid dispersion particles, bitter taste masking particles and sustained release particles composed of poorly soluble drugs.

[13] A method for producing a fast-disintegrating tablet, comprising:

(1) A process of mixing a drug with a substance that functions as a binder by treating it with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide,

(2) A step of compressing the mixture of (1) to prepare a tablet, and

(3) A step of treating the tablet of (2) with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide.

[14] The method for producing a rapidly disintegrating tablet as described in [13], wherein the substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is obtained by using Carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide, is treated to lower its melting point or glass transition temperature.

[15] The method for producing a rapidly disintegrating tablet according to [13] or [14], wherein the tablet having a binder function is treated with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide The substance is one or two or more substances selected from the group consisting of the following substances:

Vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone, premixed preparation of povidone and vinyl acetate resin, methacrylic acid copolymer LD, polyvinyl alcohol-polyethylene glycol graft copolymer, premixed preparation of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxypropylene (67) Diol, polyethylene glycol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, formazan Acrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate-methyl methacrylate Diethylaminoethyl Acrylate Copolymer, Hydroxypropyl Methyl Cellulose Acetate Succinate, Shellac and Carbomer.

[16] The method for producing a fast-disintegrating tablet as described in any one of [13] to [15], wherein a viscous The substance which functions as a mixture is 0.1 weight% or more and 50 weight% or less with respect to the weight of a tablet.

[17] The method for producing a rapidly disintegrating tablet according to any one of [13] to [16], further comprising a plasticizer.

[18] The method for producing a rapidly disintegrating tablet according to any one of [13] to [17], further comprising a disintegrant.

[19] The method for producing a fast-disintegrating tablet according to any one of [13] to [18], wherein the tablet hardness is 20N or more.

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

[21] The method for producing a fast-disintegrating tablet according to [20], wherein the oral disintegration time is within 120 seconds.

[22] The method for producing a rapidly disintegrating tablet according to any one of [13] to [21], wherein the drug constitutes a drug and/or functional particles that are unstable to temperature or humidity.

[23] The method for producing a fast-disintegrating tablet according to [22], wherein the functional particles are one or more particles selected from the group consisting of:

Solid dispersion particles, bitter taste masking particles and sustained release particles composed of poorly soluble drugs.

[24] The method for producing a fast-disintegrating tablet according to any one of [13] to [23], comprising: using carbon dioxide of 0.1 MPa to 50 MPa and -40°C to 100°C. deal with.

[25] The method for producing a rapidly disintegrating tablet according to any one of [13] to [24], wherein the treatment is performed with gaseous carbon dioxide.

Invention effect

According to the present invention, it is possible to provide a rapidly disintegrating tablet (particularly, an orally disintegrating tablet) having improved fracture resistance and rapidly disintegrating in the oral cavity. In addition, for example, since the treatment can be performed under mild conditions at about room temperature, it can be used in solid dispersion particles containing drugs that are unstable to temperature or humidity, solid dispersion particles composed of poorly soluble drugs, bitter taste masking particles, sustained-release particles, etc. In some cases, a rapidly disintegrating tablet (especially an orally disintegrating tablet) can be provided on the basis of sufficiently maintaining the stability and desired function.

Detailed ways

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

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

In addition, "subcritical (state)" means the state in which only any one of pressure and temperature exceeds a critical point. Critical point refers to the critical point detailed in, for example, Figure 1 of J.W.Tom and P.G.Debenedetti, "Particle Formation with Supercritical Fluids-A Review", J.Aerosol Sci., 22(5), pp. 555-584, 1991. point.

In addition, the state in which neither pressure nor temperature exceeds a critical point and is liquefied is called "liquid".

In addition, the gasified state in which neither the pressure nor the temperature exceeds the critical point is called "gas".

Specifically, carbon dioxide in a supercritical state is a state in which both a critical pressure of about 7.38 megapascals (MPa) and a critical temperature of about 304.1 Kelvin (K) are exceeded. Specifically, it is carbon dioxide other than solid state. For example, liquid carbon dioxide, gaseous carbon dioxide, and supercritical carbon dioxide can be cited.

In this specification, "tablet hardness sufficient for preparation handling" or "excellent tablet hardness" is not particularly limited as long as the tablet is not damaged during the distribution process. The standard of the strength of extrusion and extraction from the protective sheet includes the hardness in the longitudinal direction of the tablet. The hardness varies depending on the size and shape of the tablet. For example, for a tablet with a diameter of about 8.0 mm and 180 mg, it is set to be 20 N or higher, for a diameter of about 8.5 mm, it is set to be 30 N or higher, and for a diameter of about 10.0 mm, it is set to be 50 N or higher. When the diameter is about 12.0mm, it is specified as 60N or more. The formulations of the present invention have sufficient strength to withstand removal from PTP packaging in any size. In addition, as the strength that can be applied to bottle packaging (packaging that encloses tablets in containers such as glass and plastic), that is, it can withstand the gap between tablets or between tablets and the container wall during transportation and loading in ordinary bottle containers. The standard of the strength of the tablet in contact is preferably 30N or higher. In addition, as another aspect, for example, a breakage rate of a tablet packaged in PTP by a drop test can be mentioned. For example, it is specified that the strength is as follows: when 10 PTP packaging sheets in which tablets are packaged in one PTP packaging sheet are dropped from a height of 150 cm with the tablet storage part (bag) facing upward, The breakage rate of the above tablet is 5% or less, or 2% or less in another embodiment. The formulation of the present invention has sufficient strength to withstand transportation or loading during bottle packaging.

In this specification, a tablet having "rapid disintegration" (rapidly disintegrating tablet) refers to a tablet that has practically sufficient disintegration or solubility using saliva without taking water in the oral cavity. agent. Here, there are individual differences in the practically sufficient disintegration or solubility, but it is generally prescribed for about 1 second to about 300 seconds in the oral cavity, or about 1 second to about 150 seconds for another mode, or about 1 second for another mode. Disintegrate or dissolve in about 1 second to about 90 seconds, alternatively in about 1 second to about 60 seconds. In addition, when using a Tricorptester disintegration instrument for measurement, the prescribed disintegration time is within 1 second to 300 seconds, as another form within 1 second to 120 seconds, as another form within 1 second to 90 seconds, as another form In one aspect, it is within 1 second to 60 seconds, and in another aspect, it is within 1 second to 40 seconds. In addition, "orally disintegrating tablet" also has individual differences, but it usually means about 1 second to about 120 seconds in the oral cavity, as another embodiment, about 1 second to about 90 seconds, and as another embodiment, about 1 second to about 1 second. Seconds to about 60 seconds for disintegrating or dissolving tablets. In addition, when measured using a Tricorptester disintegration instrument, it means within 1 second to 120 seconds, as another embodiment, within 1 second to 90 seconds, as another embodiment, within 1 second to 60 seconds, as another embodiment A tablet that disintegrates or dissolves within a disintegration time of 1 second to within 40 seconds.

In this specification, the "porous structure" is not particularly limited as long as the tablet disintegrates rapidly in the oral cavity. For example, the predetermined porosity is 15% or more and 90% or less. 70% or less, or 30% or more and 50% or less as another embodiment.

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. Examples of active ingredients of the drug include: sedative-hypnotics, hypnotics, migraine drugs, anxiolytics, antiepileptic drugs, antidepressants, anti-Parkinsonian drugs, neuropsychiatric drugs, central nervous system drugs, local anesthetics , skeletal muscle relaxants, autonomic drugs, antipyretic, analgesic and anti-inflammatory drugs, antispasmodics, antivertigo drugs, cardiotonic drugs, arrhythmia drugs, diuretics, blood pressure lowering drugs, vasoconstrictors, vasodilators, circulation Organ medicine, hyperlipidemia medicine, respiratory stimulant, cough suppressant, expectorant, cough suppressant, bronchodilator, antidiarrheal medicine, intestinal medicine, peptic ulcer medicine, stomach and digestive medicine, antacid, Laxatives, choleretic drugs, digestive organ drugs, adrenaline hormone drugs, hormone drugs, urinary organ drugs, vitamin drugs, hemostatic drugs, liver disease drugs, gout drugs, diabetes drugs, antihistamines, antibiotics, antibacterial drugs, anti-malignant drugs Tumor medicine, chemotherapy medicine, full-effect cold medicine, nourishing and strong health medicine, osteoporosis medicine, etc. Examples of the above-mentioned drugs include overactive bladder therapeutic drugs such as solifenacin, tolterodine, and mirabegron; hypnotics such as diphenhydramine, lorazepam, and zolpidem; Acryl, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutazone, hydroxybuzone, pyrimiprazole, aspirin, ethyl salicylamine, acetaminophen, aminopyrine, phenacetin, butyl bromide Scopolamine, morphine, etodolin, pentazocine, fenoprofen calcium, naproxen, celecoxib, valdecoxib, tramadol and other anti-inflammatory, antipyretic, antispasmodic or analgesic drugs; sumatriptan anti-rheumatic drugs such as etodolac, anti-tuberculosis drugs such as isoniazid and ethambutol hydrochloride; isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, double Pyridamole, amrinone, indenolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, guanethidine nitrate, reserpine, amisulolol hydrochloride, lisinopril, Metoprolol, pilocarpine, telmisartan and other circulatory medicines; chlorpromazine hydrochloride, amitriptyline hydrochloride, nemopride, haloperidol, mopirone hydrochloride, perphenazine, Zepam, Lorazepam, Chlorazepam Aldizolam, alprazolam, methylphenidate, milnacipran, paroxetine, risperidone, sodium valproate and other antipsychotics; imipramine and other antidepressants; metoclopramide, hydrochloric acid Antiemetic drugs such as ramosetron, granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride; antihistamines such as chlorpheniramine maleate; vitamins such as amine, pyridoxal phosphate, adenosylcobalamin, ascorbic acid, and nicotinamide; gout drugs such as allopurinol, colchicine, and probenecid; Parkinson’s disease drugs such as levodopa and selegiline; Pentobarbital, bromivaleroyl urea, midazolam, chloral hydrate and other sedative hypnotics; fluorouracil, carmofur, arubicin hydrochloride, cyclophosphamide, thiotepa and other anti-cancer drugs; pseudoephedrine , terfenadine and other antiallergic drugs; acesulfame, insulin, tolbutamide, desmopressin, glipizide, nateglinide, metformin, sitagliptin, vildagliptin, Diabetic drugs such as linagliptin; diuretics such as hydrochlorothiazide, polythiazide, and triamterene; bronchodilators such as aminophylline, formoterol fumarate, and theophylline; codeine phosphate, narcotine Antitussives such as Dimethorphan Phosphate, Dextromethorphan, etc.; Antiarrhythmics such as Quinidine Nitrate, Digoxigenin, Propafenone Hydrochloride, Procainamide, etc.; Ethylaminobenzoate, Lidocaine Antiepileptic drugs such as phenytoin, ethosuximide, and primidone; synthetic adrenal corticosteroids such as hydrocortisone, prednisone, triamcinolone acetonide, and betamethasone; Tidine, ranitidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, praunutol, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansola azoles and other gastrointestinal drugs; indolozine, idebenone, tiapride hydrochloride, diphenmelane hydrochloride, hyperpantothenate calcium and other central nervous system drugs; pravastatin sodium, simvastatin, lovastatin, atropine Therapeutic agents for hyperlipidemia such as vastatin; antibiotics such as thalidomide hydrochloride, cefotetan, and josamycin; therapeutic agents for BPH such as tamsulosin, doxazosin mesylate, and terazosin hydrochloride; Anti-asthma drugs such as lenkast, zafirlukast, albuterol, ambroxol, budesonide, levalbuterol; peripheral circulation improving agents of prostaglandin I2 derivatives such as beraprost sodium; minodronic acid, alendronate A therapeutic agent for osteoporosis such as acid; a therapeutic agent for various complications of diabetes; a therapeutic agent for skin ulcers; etc.

Alternatively, for example, steroidal anti-inflammatory drugs, anti-inflammatory analgesics, antipyretic analgesics, antiepileptic drugs, chemotherapeutic drugs, synthetic antibacterial drugs, antiviral drugs, antifungal drugs, hormone drugs, angiogenesis inhibitors , an immunosuppressant, or a therapeutic agent for ulcerative colitis. Examples of steroidal anti-inflammatory drugs include: cortisone acetate, betamethasone, prednisolone, fluticasone propionate, dexamethasone, budesonide, beclomethasone propionate, triamcinolone acetonide, loteprednol , fluorometholone, difluprednate, mometasone furoate, clobetasol propionate, diflurasone acetate, diflucorone valerate, fluocinonide acetate, amcinonide, halcinonide, flucinide De, triamcinolone acetonide, flumetasone pivalate or clobetasone butyrate, etc. Examples of anti-inflammatory and analgesic drugs include: aclofenac, aminoprofen, ibuprofen, indomethacin, ipirazole, oxaprozin, ketoprofen, diclofenac sodium, diflunisal, Naproxen, piroxicam, fenbufen, flufenamic acid, flurbiprofen, frofenin, pentazocine, mezonic acid or mefenamic acid, mobendazole, etc. Examples of antipyretic and analgesic agents include acetaminophen, metamizole, and the like. Examples of antiepileptic drugs include acetazolamide, carbamazepine, clonazepam, diazepam, and nitrazepam. Examples of chemotherapeutic drugs include: sulfasalazine, sulfidexoxine, sulfamethizole, sulfamethoxine Sulfur agents such as azoles, sulfamethopyrazine or sulfamethoxine; enoxacin, ofloxacin, cinoxacin, sparfloxacin, thiamphenicol, nalidixic acid, trollin tosylate Synthetic antimicrobials such as floxacin, norfloxacin, pipemidic acid trihydrate, pyrrolic acid, fleroxacin, or levofloxacin; acyclovir, ganciclovir, didanosine, zidovudine, or arabinose Antiviral medicines such as adenosine; antifungal medicines such as itraconazole, ketoconazole, fluconazole, flucytosine, miconazole, or pimarmycin. Examples of hormone drugs include zinc insulin, testosterone propionate, estradiol benzoate, and the like. Examples of immunosuppressants include cyclosporine, rapamycin, and tacrolimus. Examples of therapeutic agents for ulcerative colitis include mesalamine and the like.

In addition, as another aspect of the drug used in the present invention, a drug that is unstable to temperature or humidity can be mentioned. There are no particular limitations on how the drug that is unstable to temperature or humidity is blended into the pharmaceutical composition, as long as it is a method generally used in pharmacy. For example, the drug can be granulated and/or mixed with the drug additive, or the drug can be granulated and/or mixed with the drug additive after coating the core particles such as Silphia (manufactured by Asahi Kasei) together with the stabilizer. .

In addition, another embodiment of the drug used in the present invention includes a drug constituting functional particles (a drug having a bitter taste, a drug requiring sustained release, and a poorly soluble drug). Examples of functional particles include bitter taste masking particles, sustained-release particles, solid dispersion particles, and the like.

In addition, a drug that has a bitter taste, a drug that requires sustained release, or a drug that is poorly soluble and unstable to temperature or humidity can be selected as the drug constituting the functional particles.

Any of free forms and pharmaceutically acceptable salts can be used as the medicine. In addition, drugs may be used singly or in combination of two or more. In addition, these medicines are examples applicable to the present invention, and should not be construed from a restrictive point of view.

The compounding amount can usually be appropriately selected according to the type of drug or the use (indication) of the drug, but it is not particularly limited as long as it is a therapeutically effective amount or a preventively effective amount. For example, in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), it is 0.001 to 80% by weight, as another embodiment, it is 0.01 to 70% by weight, and as another embodiment, it is 0.01 to 60% by weight.

The fast-disintegrating tablet (especially the orally disintegrating tablet) of the present invention is obtained by using "a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide" in a supercritical or subcritical state. Carbon dioxide in a critical or subcritical state or liquid or gaseous carbon dioxide is treated, and in tablets "substances which have a binder function by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide" are included in the composition (For example, cross-links are formed between drugs and optionally added excipients, disintegrants, stabilizers, lubricants, etc.), thereby having a porous structure.

As "a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide" used in the present invention, as long as it is treated by using carbon dioxide in a supercritical or subcritical state or a liquid There is no limitation on substances that are treated with gaseous carbon dioxide to lower the melting point or glass transition temperature of the "substance", thereby functioning as a binder. Alternatively, as long as it is a substance that increases the hardness of a tablet containing the "substance" compared to a tablet not containing the "substance" by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide , there is no limit. Specifically, the processing pressure is about 0.1 MPa to about 50 MPa in one embodiment, and about 1 MPa to about 20 MPa in another embodiment. Another aspect is about 1 MPa to 15 MPa. In another embodiment, it is about 1 MPa to about 5 MPa. Another embodiment is, for example, a melting point or a glass transition temperature lowered by, for example, 5° C. or more when the pressure is set to 20 MPa, and another embodiment is a lowered material by 20° C. or more. Another embodiment includes, for example, a compound having a styrene skeleton, a carbonyl group, an ether bond, an ester bond, or an unsaturated bond between carbon atoms in the structural formula, which has an affinity with carbon dioxide.

As a compound which has a styrene skeleton, polystyrene resin, its copolymer etc. are mentioned, for example.

Examples of compounds having a carbonyl group include aldehyde compounds, ketone compounds, carboxylic acid compounds, ester compounds, amide compounds, enone compounds, carboxylic acid chlorides (halides), acid anhydrides, polymers, and copolymers thereof.

As a compound which has an ether bond, polyether represented by polyethylene glycol, polypropylene glycol, etc. is mentioned, for example.

Examples of compounds having unsaturated bonds between carbon atoms include olefins, ethylene, propylene, benzene, annulene, and polymers and copolymers having such structures.

Specifically, it can be enumerated: vinylpyrrolidone-vinyl acetate copolymer (hereinafter referred to as copovidone sometimes), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (polyvinyl caprolactam-polyvinyl acetate) -polyethylene glycol graftcopolymer), povidone, premixed preparation of povidone and vinyl acetate resin (Polyvinylacetate and polyvinylpyrrolidone (8:2)), methacrylic acid copolymer LD (Methacrylic acid and ethyl acrylate copolymer), polyethylene Alcohol-polyethylene glycol graft copolymer (Polyvinyl alcohol and Polyethylene glycol graft copolymer (75:25)), polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol premixed preparation (Polyvinyl alcohol and Polyethylene Glycol graft copolymer (75:25) and polyvinyl alcohol (60/40)), polyoxyethylene (196) polyoxypropylene (67) diol (Ethylene oxide and propylene oxide), polyethylene glycol, polyoxygen Ethylene hydrogenated 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, Hydroxyl Acetate Propyl methylcellulose succinate (hereinafter sometimes abbreviated as HPMCAS), shellac, carbomer, polyvinyl acetal diethylaminoacetate, etc. As another example, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methyl methacrylate-diethylaminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, shellac, premixed preparation of povidone and vinyl acetate resin, povidone, carbopol Mu, polyoxyethylene (196) polyoxypropylene (67) diol. As another example, copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer A premixed formulation of RS, methyl methacrylate-diethylaminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, povidone and vinyl acetate resin. Another embodiment includes copovidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, HPMCAS, and ethyl cellulose. As another aspect, copovidone and aminoalkyl methacrylate copolymer E are mentioned. As another aspect, aminoalkyl methacrylate copolymer E is mentioned.

These compounds are commercially available, for example, under the following trade names.

Copovidone: Kollidon VA-64 (BASF Japan), Kollidon VA-64Fine (BASF Japan), Platinum S-630 (ISP Japan)

· Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer: Soluplus (BASF Japan)

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

Premixed formulation of povidone and vinyl acetate resin: Kollidon SR (BASF Japan)

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

· Polyvinyl alcohol-polyethylene glycol graft copolymer: Kollicoat IR (BASF Japan)

Premixed preparation of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol: Kollicoat Protect (BASF Japan)

・Polyoxyethylene (196) polyoxypropylene (67) diol: Corifol P407 (BASF Japan)

Polyethylene glycol: Lutrol E400 (BASF Japan)

· Polyoxyethylene hydrogenated castor oil (40): Cremophor RH40 (BASF Japan)

·Aminoalkyl Methacrylate Copolymer E: Oidlagit E100 (Evonik Japan), Oidlagit EPO (Evonik Japan)

・Methacrylic acid copolymer L: オイドラギット L100 (Evonik Japan)

·Dried methacrylic acid copolymer LD: オイドラギット L100-55 (Evonik Japan)

· Methacrylic acid copolymer LD: オイドラギット L30D-55 (Evonik Japan)

·Methacrylic acid copolymer S: オイドラギット S100 (Evonik Japan)

·Aminoalkyl Methacrylate Copolymer RS: Oidlagit RL100 (Evonik Japan), Oidlagit RLPO (Evonik Japan), Oidlagit RS100 (Evonik Japan), Oidlagit RSPO (Evonik Japan)

Ethyl acrylate-methyl methacrylate copolymer dispersion: オイドラギット NE30 (Evonik Japan), Kollicoat EMM30D (BASF Japan)

Ethyl cellulose: Etocell (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 shellac commercially available from Nippon Shellac Industry Co., Ltd., etc.

Carbopol: Carbopol 71G, 971P, 974P, 980, 981, 5984, ETD2020, Ultrez10, 934, 934P, 940, 941, 1342, etc., and Pemulen TR-1, TR-2, etc., commercially available from Lubrizol , AQUPEC HV-501, HV501E, HV-501ER, HV-504, HV-504E, HV-505, HV-505E, HV-505ED commercially available from Sumitomo Seika Co., Ltd., and HIBISUWACO commercially available from Wako Pure Chemical Industries, Ltd. 103, 104, 105, etc.

· Polyvinyl acetal diethylaminoacetate: AEA (Mitsubishi Chemical Foods) and the like.

In the fast-disintegrating tablet (especially orally disintegrating tablet) of the present invention, as used in the present invention, "having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide Substances" can be used alone or in combination of two or more.

The shape of the "substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide" is granular, needle-like, etc., and is not particularly limited. It can also be used after crushing. When the shape of the substance is granular, the average particle size is not particularly limited as long as it functions as a binder. For example, the average particle size when measured using a laser diffraction particle size distribution analyzer is preferably 0.1 to 350 μm. . This substance may be used alone or in combination of two or more substances different in grade, shape, average particle diameter, and the like.

The compounding amount is not limited as long as it functions as a "substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide". As another aspect, there is no particular limitation as long as it is an amount capable of improving the hardness of a rapidly disintegrating tablet (especially an orally disintegrating tablet). Specifically, for example, in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 0.1 to 50% by weight, as another embodiment, 1 to 30% by weight, and as another embodiment, 3 to 20% by weight .

The fast-disintegrating tablet (particularly, the orally disintegrating tablet) of the present invention may contain "a substance that functions as a binder by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide" as desired. A plasticizer with improved functionality.

As the plasticizer used in the present invention to improve the function of "a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide", for example: tricitric acid Ethyl esters, Karion 83, glycerin, glycerin fatty acid esters, sesame oil, dimethyl polysiloxane-silica mixture, D-sorbitol, medium chain fatty acid triglycerides, sugar alcohol liquid from corn starch, Glyceryl Triacetate, Concentrated Glycerin, Castor Oil, Diethylphthalate, Dibutylphthalate, Butylphthalyl Butyl Glycolate, Propylene Glycol, Polyoxyethylene (105) Polyoxyethylene Propyl(5) Glycol, Polysorbate 80, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 4000, Macrogol 6000, Glyceryl Monostearate , xylitol and other sugars. As another aspect, sugars such as triethyl citrate, triacetin, polyethylene glycol 4000, polyethylene glycol 6000, and xylitol may be mentioned. Another embodiment includes triethyl citrate. Plasticizers can be used alone or in combination of two or more. The compounding amount of the plasticizer is not particularly limited as long as it is an amount that improves the function of "a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide". Specifically, for example, in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 0.1 to 20% by weight, as another embodiment, 0.1 to 10% by weight, and as another embodiment, 0.1 to 7% by weight , as another embodiment, it is 1 to 7% by weight, and as another embodiment, it is 2 to 5% by weight. In addition, the blending amount of the plasticizer relative to the "substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide" is, for example, 0.5 to 200% by weight. In one embodiment, it is 0.5 to 40% by weight, and in another embodiment, it is 10 to 40% by weight.

The fast-disintegrating tablet (particularly orally disintegrating tablet) of the present invention may contain excipients that are usually added as pharmaceutical additives as desired.

The excipient used in the present invention is not limited as long as it is a hydrophilic substance or a water-soluble substance. As one aspect, sugars, cellulose derivatives, phosphates, and sulfates are mentioned. Examples of sugars include mannitol, lactose, sucrose, sucrose, glucose, fructose, sorbitol, xylitol, erythritol, trehalose, sucrose, and maltitol. Examples of the cellulose derivative include microcrystalline cellulose and the like. Examples of the phosphate 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. Calcium sulfate etc. are mentioned as a sulfate.

In the fast-disintegrating tablet (particularly, orally disintegrating tablet) of the present invention, excipients may be used alone or in combination of two or more.

Specifically, the compounding quantity of an excipient is 0.001-99.99 weight% in a fast-disintegrating tablet (particularly an orally disintegrating tablet), for example, 1-99.9 weight% in another form, and 1-99.9 weight% in another form. One aspect is 10 to 99% by weight.

In the fast-disintegrating tablet (particularly, orally disintegrating tablet) of the present invention, in addition to the above-mentioned excipients, various pharmaceutical additives may be further used and formulated as desired. The pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, binders, disintegrants, sour agents, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants and the like can be used. In addition, in addition to substances having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide, binders shown below may be added.

Examples of binders include copovidone, povidone, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl Methyl cellulose, gum arabic, powdered sugar, sodium alginate, α-starch, agar, vinyl acetate resin, pullulan, starch, hydroxypropyl cellulose, etc.

Examples of disintegrants include corn starch, potato starch, carmellose calcium, carmellose sodium, crospovidone, α-starch, partially α-starch, carboxymethylcellulose, Microcrystalline cellulose, croscarmellose sodium, sodium carboxymethyl starch, magnesium carbonate, low-substituted hydroxypropyl cellulose, low-substituted sodium carboxymethyl starch, precipitated calcium carbonate, gelatin, aluminum magnesium hydroxide, Synthetic aluminum silicate, etc. As another embodiment, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, carboxymethyl starch sodium, α-starch, partially α-starch, carboxymethyl Base cellulose, carboxymethyl cellulose calcium. As another aspect, low-substituted hydroxypropylmethylcellulose, partially pregelatinized starch, and croscarmellose sodium are mentioned.

As a sour agent, citric acid, tartaric acid, malic acid etc. are mentioned, for example.

As a foaming agent, sodium bicarbonate, tartaric acid, sodium bicarbonate, citric anhydride, sodium bicarbonate etc. are mentioned, for example.

Examples of artificial sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevioside, and thaumatin.

Examples of flavors include lemon, lime, mandarin orange, mint and the like.

Examples of lubricants include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid and the like.

Examples of the coloring agent include yellow ferric oxide, red ferric oxide, edible yellow No. 4 and No. 5, edible red No. 3 and No. 102, edible blue No. 3, and the like.

Examples of stabilizers include ascorbic acid, aspartic acid, sodium chloride, magnesium chloride, glycine, glycerin, light silicic anhydride, magnesium gluconate, xylitol, calcium citrate, calcium hydroxide, sodium hydroxide, Magnesium hydroxide, potassium carbonate, potassium bicarbonate, sodium bicarbonate, etc.

Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof class, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or their salts, etc.

Examples of antioxidants include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.

As a surfactant, polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, etc. are mentioned, for example.

One type or two or more types may be added in an appropriate amount as a pharmaceutical additive.

The compounding quantity of the above-mentioned various pharmaceutical additives can be set arbitrarily.

The fast-disintegrating tablet of the present invention is preferably an orally disintegrating tablet.

Hereinafter, the manufacturing method of the fast-disintegrating tablet (particularly orally disintegrating tablet) of this invention is demonstrated.

"Treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide" in the present invention refers to the so-called "binder" that functions as a cross-linked structure between components. The treatment of "partially" soluble to "completely" soluble substances is not limited. Specifically, depending on the size and type of the container used, for example, with respect to about 1 mL to about 2000 L of carbon dioxide in a supercritical state or a subcritical state or in a liquid or gaseous state, the compressed tablet (especially Orally disintegrating tablet) is processed at a ratio of about 0.1 g to about 2000 kg in one embodiment, and about 5 g to about 100 kg in another embodiment. Regarding the time of treatment, it is about 1 minute to about 50 hours as one embodiment, about 1 minute to about 24 hours as another embodiment, about 2 minutes to about 12 hours as another embodiment, and about 5 minutes as another embodiment. ~ about 2 hours.

The treatment is preferably carried out in a pressure-resistant container. Specifically, for example, pressure vessels used in the system configuration: H series (manufactured by Tama Seiki), EV series (manufactured by JASCO) or VE-1 (manufactured by Mitsubishi Chemical Machinery), CO2 liquid delivery pump: SCF-GET, PU-2086 (manufactured by Nippon Spectro), CO2 compressor: PU-1 (manufactured by Mitsubishi Chemical Machinery), thermometer: platinum resistance temperature detector (R36S) (manufactured by Nippon Denso), TI-2068-01 (manufactured by Nippon Spectro) , Heater: electric heating belt (JK) (manufactured by Azowan), oven CO-2060 (manufactured by Nippon Specko), thermometer indicator controller: E5CN (manufactured by Omron), pressure indicator: WGA-710B (manufactured by Kyowa Electric Co., Ltd.) , Pressure gauge: PG-500KU (manufactured by Kyowa Electric Co., Ltd.), automatic back pressure regulating valve: BP-2080 (manufactured by JASCO), etc. The treatment temperature varies depending on the types of components constituting the rapidly disintegrating tablet (especially orally disintegrating tablet) of the present invention, and is about -40°C to about 100°C in one embodiment. For example, in the case where the "substance having a binder function by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide" is copovidone, the treatment temperature is about 25°C to about 70°C , in the case of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, it is about 10°C to about 65°C, in the case of aminoalkyl methacrylate copolymer E, it is about 10°C to about 65°C, in the case of ethyl cellulose, about 10°C to about 100°C. The processing pressure also differs depending on the type of components constituting the rapidly disintegrating tablet (especially orally disintegrating tablet) of the present invention, and is about 0.1 MPa to about 50 MPa in one embodiment, and about 1 MPa to about 20 MPa in another embodiment. .

At the time of processing, other solvents may be added to carbon dioxide by mixing or the like. As other solvents, for example, water; aromatic hydrocarbons such as benzene, toluene, ethyl acetate, cyclohexane, and xylene; methyl ether, diethyl ether, dioxane, diethoxyethane, and tetrahydrofuran can be used. , 1,2-dimethoxyethane and other ethers; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and other organic chlorine organic solvents; acetonitrile, propionitrile and other alkyl nitriles ; Nitroalkanes such as nitromethane and nitroethane; Amides such as N,N-dimethylformamide and N,N-dimethylacetamide; Ketones such as acetone; Acetic acid, acetic anhydride, oleic acid Fatty acids such as methanol, ethanol, and propanol; alcohols such as methanol, ethanol, and propanol; sulfoxides such as dimethyl sulfoxide; or their mixed solvents, among which ethanol, acetone, and the like are preferred. Usually, other solvents are used in an amount of about 0.1 volume % to about 99.9 volume % in one form, and about 1 volume % to about 99 volume % in another form in carbon dioxide in a supercritical or subcritical state or in a liquid or gaseous state. volume%.

In addition, other gases can be added to the carbon dioxide during processing. As another gas, nitrogen etc. can be used, for example.

Specifically, for example, the fast-disintegrating tablet (especially orally disintegrating tablet) of the present invention can be produced according to any one of the following steps (1) to (4) after the following step (0) , but not limited to the following steps. Hereinafter, any one of steps (1) to (4) may be described as carbon dioxide (pressure) treatment.

(0) Rapidly disintegrating tablets (for example, orally disintegrating tablets) before carbon dioxide treatment are prepared.

Specifically, for example, a method of compression-molding a mixture obtained by adding a medicinal ingredient to a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide ; granulate the medicinal ingredient with an aqueous solution containing a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide, and compression-molding the obtained granulate A method of granulating a medicinal ingredient and a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide with an aqueous solution, and compressing the obtained granules A molding method; granulating a medicinal ingredient and a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide with an organic solvent, and granulating the obtained granulated product A method of performing compression molding; using a medicinal ingredient and a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide by using carbon dioxide in a supercritical or subcritical state or A method of granulating a substance having a binder function by treating liquid or gaseous carbon dioxide, and compressing the obtained granulate; it will be carried out by using carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide A method of granulating a substance having a binder function and other pharmaceutical additives after processing, and compressing the mixture obtained by mixing the obtained granules with the medicinal ingredients; or combining the medicinal ingredients with the Supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide is processed to form a solid dispersion using a spray dryer, and the mixture obtained by mixing the obtained solid dispersion with other pharmaceutical additives A method of performing compression molding, etc.

(1)

· A rapidly disintegrating tablet (for example, an orally disintegrating tablet) is placed in 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 (if necessary, mix the above-mentioned solvent or other gas).

- Carbon dioxide treatment is performed by maintaining the pressure in the pressure-resistant container at or above the critical point of carbon dioxide.

· After the treatment with carbon dioxide is completed, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.

(2)

· A rapidly disintegrating tablet (for example, an orally disintegrating tablet) is placed in 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 (if necessary, mix the above-mentioned solvent or other gas).

- Carbon dioxide treatment is performed by keeping the pressure in the pressure-resistant container at a pressure lower than the critical point of carbon dioxide.

· After the treatment with carbon dioxide is completed, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.

(3)

· A rapidly disintegrating tablet (for example, an orally disintegrating tablet) is placed in a pressure-resistant container.

• Keep the temperature of the pressure-resistant container at a temperature lower than the critical point of carbon dioxide.

- Fill the pressure-resistant container with carbon dioxide (if necessary, mix the above-mentioned solvent or other gas).

- Carbon dioxide treatment is performed by maintaining the pressure in the pressure-resistant container at a pressure equal to or higher than the critical point of carbon dioxide.

· After the treatment with carbon dioxide is completed, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.

(4)

· A rapidly disintegrating tablet (for example, an orally disintegrating tablet) is placed in a pressure-resistant container.

• Keep the temperature of the pressure-resistant container at a temperature lower than the critical point of carbon dioxide.

- Fill the pressure-resistant container with carbon dioxide (if necessary, mix the above-mentioned solvent or other gas).

- Carbon dioxide treatment is performed by keeping the pressure in the pressure-resistant container at a pressure lower than the critical point of carbon dioxide.

· After the treatment with carbon dioxide is completed, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.

Example

Hereinafter, although an Example, a comparative example, a reference example, and a test example are given and this invention is demonstrated in more detail, this invention is not limited and interpreted by these examples.

In addition, depending on the drug, there may be a very small amount (for example, a few nanograms or several micrograms) of the drug to be blended. Therefore, the following examples are all considered to contain a very small amount of the drug.

Example 1

D-mannitol (Pearitol 50C, manufactured by ROCKET Japan, the same unless otherwise specified below) 59.0w/w%, microcrystalline cellulose (MCC SANAQ burst, PHARMATRANS SANAQ AG) 20.0w/w%, copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) 10.0w/w%, and crospovidone (Kollidon CL, manufactured by BASF Japan) 10.0w/w% were mixed. Magnesium stearate (manufactured by Parteck LUB MST, manufactured by Merck, unless otherwise specified) 1.0w/w% was blended with this mixture, and a single-punch tablet press (Autograph AGS-20kNG, manufactured by Shimadzu Corporation) was used. , the same unless otherwise specified below) were made into 180 mg tablets (tablet diameter 8.5 mm) at a compression pressure of 1.0 kN/punch. The tablet hardness was 8N (n=1). Next, the tablet was treated with a pressure-resistant container (pressure-resistant element) at a carbon dioxide pressure of 8.0 MPa and 45° C. for 30 minutes, and then decompressed at a decompression rate of about 16 kPa/sec to obtain the instant tablet of the present invention. Disintegrating tablet.

Example 2

D-mannitol 54.0w/w%, microcrystalline cellulose (MCC SANAQ burst, manufactured by PHARMATRANS SANAQ AG) 20.0w/w%, copovidone (KollidonVA64 Fine, manufactured by BASF Japan) 15.0w/w%, cross-linked Povidone (Kollidon CL, manufactured by BASF Japan) was mixed at 10.0 w/w%. 1.0 w/w% magnesium stearate was blended into the mixture, and a single-punch tablet press was used to form 180 mg tablets (tablet diameter 8.5 mm) at a compression pressure of 1.0 kN/punch. The tablet hardness was 8N (n=1). Next, the tablet was treated for 30 minutes at a carbon dioxide pressure of 8.0 MPa and 45° C. using a pressure-resistant device, and then decompressed at a decompression rate of about 16 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 3

97.0w/w% of D-mannitol and 3.0w/w% of copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) were mixed. The mixture was made into 270 mg tablets (tablet diameter: 9.0 mm) using a single-punch tablet press with a compression pressure of 1.0 kN/punch, and the tablet hardness was 10 N (n=3). Next, the tablet was treated under the conditions of carbon dioxide pressure of 6.0 MPa and 40° C. for 30 minutes using a pressure-resistant device, and then naturally decompressed to obtain the fast-disintegrating tablet of the present invention.

Example 4

95.0w/w% of D-mannitol and 5.0w/w% of copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) were mixed. The mixture was made into 270 mg tablets (tablet diameter 9.0 mm) using a single-punch tablet press with a compression pressure of 1.0 kN/punch. Tablet hardness was 10N (n=1). Next, the tablet was treated under the conditions of carbon dioxide pressure of 6.0 MPa and 40° C. for 30 minutes using a pressure-resistant device, and then naturally decompressed to obtain the fast-disintegrating tablet of the present invention.

Example 5

90.0w/w% of D-mannitol and 10.0w/w% of copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) were mixed. The mixture was made into 270 mg tablets (tablet diameter 9.0 mm) using a single-punch tablet press with a compression pressure of 1.0 kN/punch. Tablet hardness was 10N (n=1). Next, the tablet was treated under the conditions of carbon dioxide pressure of 6.0 MPa and 40° C. for 30 minutes using a pressure-resistant device, and then naturally decompressed to obtain the fast-disintegrating tablet of the present invention.

Example 6

89.0 w/w % of Effelto (manufactured by Fuji Chemical) and 10.0 w/w % of copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) were mixed. 1.0 w/w% magnesium stearate was blended into the mixture, and a single-punch tablet press was used to form 180 mg tablets (tablet diameter 8.0 mm) at a compression pressure of 1.0 kN/punch. Tablet hardness was 17N (n=3). Oral disintegration time was shown to be 19 seconds (n=3). Next, the tablet was treated under the conditions of carbon dioxide pressure of 6.0 MPa and 40° C. for 30 minutes using a pressure-resistant device, and then naturally decompressed to obtain the fast-disintegrating tablet of the present invention.

Example 7

89.0 w/w % of Effelto (manufactured by Fuji Chemical) and 10.0 w/w % of copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) were mixed. 1.0w/w% magnesium stearate was blended into this mixture, and it was made by using a rotary tablet press (HT-EX series, manufactured by Hata Tekko, the same unless otherwise specified below) with a tableting pressure of 1.0kN/punch. into tablets of 180 mg per tablet (reference example 1) (tablet diameter 8.0 mm). Next, the tablet was treated under the conditions of carbon dioxide pressure of 4 MPa and 25° C. for 5 minutes using a pressure-resistant device, and then naturally decompressed to obtain the fast-disintegrating tablet of the present invention.

Example 8

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 25° C. for 15 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 9

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 25° C. for 30 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 10

The tablet of Reference Example 1 was treated with a pressure-resistant element under the conditions of a carbon dioxide pressure of 8 MPa and 25° C. for 5 minutes, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 11

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 25° C. for 15 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 12

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 25° C. for 30 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 13

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 35° C. for 5 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 14

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 35° C. for 15 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 15

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 35° C. for 30 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 16

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 35° C. for 5 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 17

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 35° C. for 15 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 18

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 35° C. for 30 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 19

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 45° C. for 5 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 20

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 45° C. for 15 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 21

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 4 MPa and 45° C. for 30 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 27 kPa/sec.

Example 22

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 45° C. for 5 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 23

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 45° C. for 15 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 24

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure of 8 MPa and 45° C. for 30 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 16 kPa/sec.

Example 25

The tablet of Reference Example 1 was treated for 30 minutes at a carbon dioxide pressure of 8 MPa and 45° C. using a pressure-resistant element, and then decompressed at a decompression rate of about 800 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 26

The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 8 MPa and 45° C. using a pressure-resistant element, and then decompressed at a decompression rate of about 800 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 27

The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 8 MPa and 45° C. using a pressure-resistant element, and then decompressed at a decompression rate of about 16 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 28

The tablet of Reference Example 1 was treated with a pressure-resistant element under the conditions of carbon dioxide pressure of 20 MPa and 45° C. for 30 minutes, and then decompressed at a decompression rate of about 27 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 29

The tablet of Reference Example 1 was treated with a pressure-resistant element under the conditions of carbon dioxide pressure 20 MPa and 45°C for 30 minutes, and then decompressed at a decompression rate of about 2000 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 30

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure 20MPa and 45°C for 2400 minutes using a pressure-resistant element, and then decompressed at a decompression rate of about 2000kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 31

The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 45° C. using a pressure-resistant element, and then decompressed at a decompression rate of about 27 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 32

The tablet of Reference Example 1 was treated under the conditions of carbon dioxide pressure 20MPa and 40°C for 30 minutes using a pressure-resistant element, and then decompressed at a decompression rate of about 2000kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 33

The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 40° C. using a pressure-resistant element, and then decompressed at a decompression rate of about 2000 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Example 34

54.0w/w% of D-mannitol, 20.0w/w% of microcrystalline cellulose (manufactured by PHARMATRANS SANAQAG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (manufactured by Solplus, BASF Japan) ) 15.0w/w%, and crospovidone (Kollidon CL, manufactured by BASF Japan) 10.0w/w% were mixed. 1.0 w/w% magnesium stearate was blended into the mixture, and a single-punch tablet press was used to form 180 mg tablets (tablet diameter 8.5 mm) at a compression pressure of 1.0 kN/punch. Next, the tablet was treated for 30 minutes at a carbon dioxide pressure of 8.0 MPa and 45° C. using a pressure-resistant device, and then decompressed at a decompression rate of about 16 kPa/sec to obtain the fast-disintegrating tablet of the present invention.

Comparative example 1

89.0 w/w % of Effelto (manufactured by Fuji Chemical) and 10.0 w/w % of copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) were mixed. 1.0 w/w% of magnesium stearate was blended into the mixture, and tablets of 180 mg per tablet (tablet diameter 8.0 mm) were prepared using a rotary tablet press at a compression pressure of about 2.5 kN/punch.

Test example 1

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

Test example 2

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

Test example 3

The thickness of the tablets of Reference Example 1, Examples 7 to 33, and Comparative Example 1 was measured (n=5). The thickness of the tablet was measured using a digital display gauge (Mitutoyo Absolute, manufactured by Mitutoyo Corporation). The results are shown in Table 3.

Test example 4

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

Test example 5

Copovidone (Kollidon VA64, BASF Japan) and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus, BASF Japan) were treated with carbon dioxide. The carbon dioxide pressure during the treatment and the glass transition temperature of each substance are shown in Table 1 (copovidone) and Table 2 (polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer).

As a result, a decrease in melting point or glass transition temperature was observed (Table 1, Table 2). The glass transition temperature was determined by confirming the temperature at which each substance in the voltage-resistant element undergoes a phase transition by visual judgment. In this way, by using carbon dioxide, even at around room temperature, it is possible to utilize the phase transition of a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide, enabling the formation of interparticle interactions. The linked porous structure is applied to fast-disintegrating tablets (especially orally disintegrating tablets).

[Table 1]

[Table 2]

[table 3]

Reference example 2

99.0w/w% mannitol for direct compression (Parteck M100, manufactured by Merck) was blended with 1.0w/w% magnesium stearate (Parteck LUB MST, manufactured by Merck, the same unless otherwise specified below), and used A single-punch tablet press (autograph AGS-20kNG, manufactured by Shimadzu Corporation, hereinafter the same unless otherwise specified) performs tablet compression (tablet diameter 8.5 mm) so that the tablet hardness is about 20N and the tablet thickness is About 3.9mm.

These tablets were treated under the conditions of carbon dioxide pressure of 10 MPa and 40° C. for 60 minutes using a pressure-resistant device, and then decompressed to obtain the tablet of Reference Example 2.

Reference example 3-8

20.0 w/w % of various pharmaceutical additives shown in Table 4 were mixed with 79.0 w/w % mannitol for direct compression (Parteck M100, manufactured by Merck). 1.0 w/w% magnesium stearate was blended in this mixture, and it compressed into tablets (tablet diameter 8.5mm) using a single-punch tablet machine so that the tablet hardness was about 20N, and the tablet thickness was about 3.9mm.

These tablets were treated under the conditions of a carbon dioxide pressure of 6 MPa and 25° C. for 45 minutes using a pressure-resistant device, and then depressurized to obtain tablets of Reference Examples 3 to 8.

Reference examples 9-24

20.0 w/w % of various pharmaceutical additives shown in Table 4 were mixed with 79.0 w/w % mannitol for direct compression (Parteck M100, manufactured by Merck). 1.0 w/w% magnesium stearate was blended in this mixture, and it compressed into tablets (tablet diameter 8.5mm) using a single-punch tablet machine so that the tablet hardness was about 20N, and the tablet thickness was about 3.9mm.

These tablets were treated under the conditions of a carbon dioxide pressure of 10 MPa and 40° C. for 60 minutes using a pressure-resistant device, and then depressurized to obtain tablets of Reference Examples 9 to 24.

Test example 6

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

[Table 4]

As can be seen from the results in Table 4, for Reference Example 2 and Reference Examples 15 to 24, no increase in tablet hardness was observed even after the carbon dioxide pressure treatment, whereas hardness was confirmed in Reference Examples 3 to 14. rise. From these results, it was confirmed that the combination of the pharmaceutical additives contained in Reference Examples 3 to 14 and the carbon dioxide pressure treatment improved the tablet hardness by utilizing the phase transition of substances. Therefore, Reference Examples 3 to 14 can also be used as examples of the present invention.

Reference example 25

79.0w/w% of mannitol for direct compression (Parteck M100, manufactured by Merck) was mixed with 20.0w/w% of copovidone (Kollidon VA64 Fine, manufactured by BASF Japan) with an average particle diameter of 10-20 μm. 1.0 w/w% of magnesium stearate was blended into this mixture, and tablets having a tablet hardness of 19N and a tablet thickness of about 3.9 mm (tablet diameter 8.5 mm) were obtained using a single-punch tablet press. The tablet was treated under the conditions of carbon dioxide pressure 6 MPa and 25° C. for 45 minutes using a pressure-resistant device, and then decompressed to obtain the tablet of Reference Example 25.

Test example 7

For the tablet of Reference Example 25, the hardness of the compressed product and the carbon dioxide-treated product were respectively measured. The hardness was measured using a tablet hardness tester (tablet hardness tester, "Schleuniger", type 6D, manufactured by Schleuniger AG). The results are shown in Table 5.

[table 5]

As shown in the results of Table 5, as a result of comparing the tablet hardness of Reference Example 8 and Reference Example 25, it can be seen that even when the same component is used as a substance having a binder function by carbon dioxide pressure treatment, by adding Smaller particle size control also enables a more effective increase in tablet hardness when phase transition is induced by carbon dioxide pressure treatment. This is considered to be because, by controlling the particle size of the phase-transformation component to be small, the surface area is increased, and inter-particle crosslinking is performed more efficiently. Therefore, Reference Example 25 can also be used as an example of the present invention.

Reference example 26

20.0w/w% ethylcellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) was mixed with 79.0w/w% mannitol for direct compression (Parteck M100, manufactured by Merck). 1.0 w/w% magnesium stearate was blended in this mixture, and it compressed into tablets (tablet diameter 8.5mm) using a single-punch tablet machine so that the tablet hardness was about 20N, and the tablet thickness was about 3.9mm. These tablets were treated under the conditions of carbon dioxide pressure of 6 MPa and 25° C. for 45 minutes using a pressure-resistant device, and then depressurized to obtain the tablet of Reference Example 26.

Reference example 27

13.5 g of ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) and 1.5 g of triethyl citrate (Triethyl Citrate, manufactured by Tokyo Chemical Industry) were dissolved in 150 g of ethanol (99.5% of ethyl alcohol, manufactured by Kanto Chemical), Ethylcellulose/triethyl citrate (9/1) spray-dried product was obtained by spray drying using a spray dryer (Micro Spray Dryer B-290, manufactured by Buchi, the same applies hereinafter unless otherwise specified) .

A 20.0 w/w % ethylcellulose/triethyl citrate (9/1) spray-dried product was mixed with 79.0 w/w % mannitol for direct compression (Parteck M100, manufactured by Merck). 1.0 w/w% of magnesium stearate was blended into this mixture, and tablets having a tablet hardness of 22N and a tablet thickness of about 3.9 mm (tablet diameter 8.5 mm) were obtained using a single-punch tablet press. The tablet was treated under the conditions of carbon dioxide pressure 6 MPa and 25° C. for 45 minutes using a pressure-resistant device, and then the tablet was decompressed to obtain the tablet of Reference Example 27.

Reference example 28

11.25 g of ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) and 3.75 g of triethyl citrate (Triethyl Citrate, manufactured by Tokyo Chemical Industry) were dissolved in 150 g of ethanol (99.5% of ethyl alcohol, manufactured by Kanto Chemical), Spray-drying was carried out using a spray dryer to obtain an ethylcellulose/triethyl citrate (7.5/2.5) spray-dried product.

A 20.0 w/w % ethylcellulose/triethyl citrate (7.5/2.5) spray-dried product was mixed with 79.0 w/w % mannitol for direct compression (Parteck M100, manufactured by Merck). 1.0 w/w% of magnesium stearate was blended into this mixture, and tablets having a tablet hardness of 20N and a tablet thickness of about 3.9 mm (tablet diameter 8.5 mm) were obtained using a single-punch tablet press. The tablet was treated under the conditions of carbon dioxide pressure of 6 MPa and 25° C. for 45 minutes using a pressure-resistant device, and then the tablet was decompressed to obtain the tablet of Reference Example 28.

Test example 8

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

[Table 6]

From the results in Table 6, it was confirmed that the tablets of Reference Examples 27 and 28, which used spray-dried products containing a plasticizer in ethyl cellulose, compared with the effect of using only ethyl cellulose, Tablet hardness was more significantly improved. Therefore, Reference Examples 26 to 28 can also be used as Examples of the present invention.

Example 35

Copovidone (Kollidon VA64, manufactured in Japan by BASF) 100 g of an aqueous solution (10.0w/w%) was used as a binding liquid, and a fluidized bed granulator (flow coating machine (フローコーター) FLO-1, produced by FREUND Industry/Ogawara 410 g of D-mannitol (Pearitol 50C, manufactured in ROCKET Japan, unless otherwise specified, the same below) was granulated. 10.0w/w% of aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Evonik Japan, the same unless otherwise specified), 5.0w/w% of cross-linked poly Vitamin ketone (Kollidon CL-F, made in Japan by BASF). 1.0w/w% magnesium stearate was blended into this mixture, and it was prepared by using a rotary tablet press (HT-EX series, manufactured by Hata Tekko, the same unless otherwise specified below) with a tableting pressure of about 1kN/punch. Tablets of about 170 mg each (tablet diameter 8.5 mm). Tablet hardness was 11N (n=10). The tablet is treated under the conditions of carbon dioxide pressure 5 MPa and 25° C. for 5 minutes using a pressure-resistant element, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 36

The tablet of Example 35 was treated for 60 minutes under the conditions of carbon dioxide pressure of 4 MPa and 25° C. using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 37

The tablet of Example 35 was treated for 840 minutes under the conditions of a carbon dioxide pressure of 3 MPa and 25° C. using a pressure-resistant element, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 38

The tablet of Example 35 was treated under the conditions of carbon dioxide pressure 4MPa and 15°C for 45 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 39

The tablet of Example 35 was treated under the conditions of carbon dioxide pressure 4 MPa and 45° C. for 45 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 40

The tablet of Example 35 was treated under the conditions of carbon dioxide pressure of 3 MPa and 60° C. for 45 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 41

89.0w/w% of Efmelto (manufactured by Fuji Chemical), 1.0w/w% of aminoalkyl methacrylate copolymer E, and 9.0w/w% of copovidone (Kollidon VA64, manufactured by BASF Japan) were mixed. 1.0 w/w% magnesium stearate was blended into the mixture, and a single-punch tablet press was used to form 170 mg tablets (tablet diameter 8.5 mm) at a compression pressure of about 1.5 kN/punch. Tablet hardness was 12N (n=3). The tablet is treated under the conditions of carbon dioxide pressure 3 MPa and 45° C. for 120 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 42

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 7.5w/w% of aminoalkyl methacrylate copolymer E and 10.0w/w% of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) of about 190 mg were prepared using a single-punch tablet press at a compression pressure of about 2.5 kN/punch. Tablet hardness was 27N (n=2). The tablet is treated under the conditions of carbon dioxide pressure 3 MPa and 45° C. for 120 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 43

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 20.0w/w% of aminoalkyl methacrylate copolymer E and 10.0w/w% of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) of about 176 mg were prepared using a single-punch tablet press with a compression pressure of about 2.0 kN/punch. Tablet hardness was 37N (n=2). The tablet was treated for 840 minutes under the conditions of carbon dioxide pressure of 1 MPa and 35° C. using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 44

With copovidone (Kollidon VA64, BASF Japan manufacture) aqueous solution (5.0w/w%) 50g and povidone (Kollidon K30, BASF Japan manufacture) aqueous solution (5.0w/w%) 50g mixed solution as binding liquid, use The fluidized bed granulator granulated 410 g of D-mannitol. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 5.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into this mixture, and tablets (tablet diameter: 8.5 mm) each of about 171 mg were prepared using a rotary tablet press at a compression pressure of 1.0 kN/punch. Tablet hardness was 12N (n=10). After applying a nitrogen pressure of 10 MPa to the tablet using a pressure-resistant element, it was further treated under the conditions of a carbon dioxide pressure of 5.0 MPa and 25° C. for 45 minutes, and then reduced pressure to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 45

After applying a carbon dioxide pressure of 5.0 MPa to the tablet of Example 44 using a pressure-resistant element, a nitrogen pressure of 5.0 MPa was further applied, and the tablet was treated at 25° C. for 45 minutes, and then decompressed to obtain the fast-disintegrating tablet of the present invention . In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 46

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of povidone (Kollidon K30, manufactured by BASF Japan) as a binding solution. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 5.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into this mixture, and tablets (tablet diameter 8.5 mm) each of about 170 mg were prepared using a rotary tablet press at a tableting pressure of about 1 kN/punch. Tablet hardness was 13N (n=10). The tablet is treated with a pressure-resistant element under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 30 minutes, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 47

Using 80 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT Type F, manufactured by Daido Chemical Industries) aqueous solution (5.0w/w%) as a binding solution, D-mannitol 320g was granulated using a fluidized bed granulator. Perform granulation. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 8.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) each of about 180 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 16N (n=2). The tablet was treated with a pressure-resistant element under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 35 minutes, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 48

320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of a hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) aqueous solution (5.0 w/w %) as a binding solution. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 8.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) each of about 180 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 12N (n=2). The tablet was treated with a pressure-resistant device under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 45 minutes, and then the pressure was reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 49

320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of an aqueous solution (5.0 w/w %) of hydroxypropylmethylcellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) as a binding solution. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 8.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) each of about 180 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 12N (n=2). The tablet was treated with a pressure-resistant device under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 45 minutes, and then the pressure was reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 50

Using 80 g of polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR, manufactured in Japan by BASF Japan) aqueous solution (5.0 w/w%) as a binding solution, 320 g of D-mannitol was granulated using a fluidized bed granulator . 10.0 w/w % of aminoalkyl methacrylate copolymer E and 8.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) each of about 180 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 12N (n=2). The tablet was treated with a pressure-resistant device under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 45 minutes, and then the pressure was reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 51

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 9.0w/w% aminoalkyl methacrylate copolymer E, 9.0w/w% low-substituted hydroxypropyl cellulose (L-HPC NBD-022, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed with a part of the granulated material . 1.0 w/w% magnesium stearate was blended in the mixture, and tablets (tablet diameter 8.5 mm) each of about 185 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 13N (n=3). The tablet was treated with a pressure-resistant element under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 35 minutes, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 52

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 10.0w/w% of aminoalkyl methacrylate copolymer E and 5.0w/w% of croscarmellose sodium (Kiccolate ND-2HS, manufactured by Asahi Kasei Chemicals) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) each of about 180 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 12N (n=3). The tablet is treated under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 10 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 53

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 9.0 w/w % of aminoalkyl methacrylate copolymer E and 9.0 w/w % of partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals) were mixed with a part of this granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) each of about 180 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 9N (n=3). The tablet was treated with a pressure-resistant element under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 35 minutes, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 54

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 9.0 w/w % of aminoalkyl methacrylate copolymer E and 9.0 w/w % of sodium carboxymethyl starch (Primojel, manufactured by DMV-Fonterra Excipients) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended in the mixture, and tablets (tablet diameter 8.5 mm) each of about 185 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. The tablet hardness was 8N (n=3). The tablet is treated under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 10 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 55

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kolidon VA64, manufactured by BASF Japan) as a binding solution. 10.0w/w% of aminoalkyl methacrylate copolymer E and 5.0w/w% of carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended in this mixture, and tablets (tablet diameter 8.5 mm) each of about 181 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 10N (n=3). The tablet is treated under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 10 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 56

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 9.0 w/w % of aminoalkyl methacrylate copolymer E and 9.0 w/w % of pregelatinized starch (SWELSTAR PD-1, manufactured by Asahi Kasei Chemicals) were mixed with a part of this granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) each of about 184 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. The tablet hardness was 8N (n=3). The tablet was treated with a pressure-resistant element under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 35 minutes, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 57

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 9.0 w/w % of aminoalkyl methacrylate copolymer E and 9.0 w/w % of carboxymethylcellulose (NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd.) were mixed with a part of this granulated material. 1.0 w/w% magnesium stearate was blended in this mixture, and tablets (tablet diameter 8.5 mm) each of about 181 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 11N (n=3). The tablet is treated under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 10 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 58

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of povidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 0.56 g of acetaminophen (manufactured by Yamamoto Chemical Industry), 1.0 g of aminoalkyl methacrylate copolymer E, and crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with 7.59 g of the granulated matter. 0.75g. 0.10 g of magnesium stearate was blended into the mixture, and tablets of about 180 mg per tablet (tablet diameter 8.5 mm) were prepared using a single-punch tablet press with a tableting pressure of about 1 kN/punch. Tablet hardness was 12N (n=3). The tablet was treated with a pressure-resistant device under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 25 minutes, and then the pressure was reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 59

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of povidone (Kollidon K30, manufactured by BASF Japan) as a binding solution. 1.11 g of famotidine (manufactured by Astellas Pharmaceuticals), 1.0 g of aminoalkyl methacrylate copolymer E, crospovidone (Kollidon CL-F, BASF Japan Manufacturing) 0.75g. 0.10 g of magnesium stearate was blended into the mixture, and tablets of about 180 mg per tablet (tablet diameter 8.5 mm) were prepared using a single-punch tablet press with a tableting pressure of about 1 kN/punch. Tablet hardness was 16N (n=3). The tablet was treated with a pressure-resistant device under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 25 minutes, and then the pressure was reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 60

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of povidone (Kollidon K30, manufactured by BASF Japan) as a binding solution. 0.056 g of tamsulosin hydrochloride (manufactured by Astellas Pharmaceuticals), 1.0 g of aminoalkyl methacrylate copolymer E, crospovidone (Kollidon CL-F, Made in BASF Japan) 0.75g. 0.10 g of magnesium stearate was blended into the mixture, and tablets of about 180 mg per tablet (tablet diameter 8.5 mm) were prepared using a single-punch tablet press with a tableting pressure of about 1 kN/punch. Tablet hardness was 17N (n=3). The tablet was treated with a pressure-resistant device under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 25 minutes, and then the pressure was reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 61

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 20.0 w/w% of HPMCAS (AQOATAS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.) and 8.0 w/w% of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) of about 176 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 25N (n=3). The tablet is treated with a pressure-resistant element under the conditions of carbon dioxide pressure 5 MPa and 25° C. for 45 minutes, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 62

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of copovidone (Kollidon VA64, manufactured by BASF Japan) as a binding solution. 15.0 w/w% of HPMCAS (AQOATAS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.) and 8.0 w/w% of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) of about 176 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 25N (n=3). The tablet was treated under the conditions of carbon dioxide pressure 5 MPa and 45° C. for 840 minutes using a pressure-resistant device, and then the pressure was reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 63

The tablet of Example 62 was treated under the conditions of carbon dioxide pressure of 5 MPa and 60° C. for 45 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 64

410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (10.0 w/w %) of povidone (Kollidon K30, manufactured by BASF Japan) as a binding solution. 15.0w/w% of ethyl cellulose (Ethocel standard 7 FPPremium, manufactured by Dow Chemical), 8.0w/w% of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. , 1.0w/w% l-menthol (manufactured by Kanto Chemical). 1.0 w/w% magnesium stearate was blended into the mixture, and tablets (tablet diameter 8.5 mm) of about 171 mg were prepared using a single-punch tablet press at a compression pressure of about 1 kN/punch. Tablet hardness was 21N (n=3). The tablet was treated under the conditions of carbon dioxide pressure 5 MPa and 60° C. for 45 minutes using a pressure-resistant element, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 65

The tablet of Example 35 was treated under the conditions of carbon dioxide pressure of 3.5 MPa and 25° C. for 120 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 66

The tablet of Example 46 was treated with a pressure-resistant device under the conditions of carbon dioxide pressure of 3.5 MPa and 25°C for 120 minutes, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 67

The tablet of Example 44 was treated under the conditions of carbon dioxide pressure of 3.5 MPa and 25° C. for 120 minutes using a pressure-resistant device, and then decompressed to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 68

415 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (5.0 w/w %) of povidone (Kollidon K30, manufactured by BASF Japan) as a binding solution. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 5.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into this mixture, and tablets (tablet diameter: 8.5 mm) each of about 171 mg were prepared using a rotary tablet press at a tableting pressure of about 1 kN/punch. Tablet hardness was 10N (n=10). The tablet is treated with a pressure-resistant element under the conditions of carbon dioxide pressure 4 MPa and 25° C. for 40 minutes, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Example 69

415 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution (5.0 w/w %) of povidone (Kollidon K30, manufactured by BASF Japan) as a binding solution. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 5.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with a part of the granulated material. 1.0 w/w% magnesium stearate was blended into this mixture, and tablets (tablet diameter 8.5 mm) each of about 186 mg were prepared using a rotary tablet press at a compression force of about 1.8 kN/punch. Tablet hardness was 19N (n=10). The tablet is treated under the conditions of carbon dioxide pressure 3.5 MPa and 25° C. for 90 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Comparative example 2

The tablet of Comparative Example 2 was obtained by treating the tablet of Example 35 in the air at 60° C. for 45 minutes.

Comparative example 3

The tablet of Comparative Example 3 was obtained by treating the tablet of Example 69 in the air at 70° C. for 840 minutes.

Comparative example 4

The tablet of Comparative Example 4 was obtained by treating the tablet of Example 70 in the air at 70° C. for 840 minutes.

Test example 9

The hardness of the tablets of Examples 35-69 and Comparative Examples 2-4 was respectively measured. The hardness was measured using a tablet hardness tester (tablet hardness tester, "Schleuniger", type 6D, manufactured by Schleuniger AG). The results are shown in Table 7.

Test Example 10

The disintegration time in the oral cavity was measured for the tablets of Examples 35 to 69 and Comparative Examples 2 to 4. The oral disintegration time was measured using an oral disintegration tester (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 tablet was measured using a digital display gauge (Mitutoyo Absolute, manufactured by Mitutoyo Corporation). The results are shown in Table 7.

Test example 12

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

·Fall height: 150cm

· Drop repetitions: 10 times

·Number of PTP pieces to be tested: 10 pieces

・Orientation of the PTP sheet: so that the drug storage part (capsule) faces upward

Breakage rate: (Number of rapidly disintegrating tablets with cracks and/or defects)/140×100

The results are shown in Table 7.

[Table 7]

As can be seen from the results in Table 7, by utilizing the cross-linking produced by the phase transition of aminoalkyl methacrylate copolymer E, HPMCAS and ethyl cellulose caused by carbon dioxide pressure treatment, the tablet hardness can be improved. Invented fast-disintegrating tablet.

Specifically, in Examples 35 to 43, it was 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. Sex Tablets. In Comparative Example 2, heat treatment was performed at 60° C. for 45 minutes in the air, but no increase in tablet hardness was observed. On the other hand, in Example 35, by treating at 25° C. for 5 minutes with a carbon dioxide pressure of 5 MPa, a significant increase in tablet hardness was confirmed, thereby confirming that even in a mild temperature environment around room temperature , It is also possible to achieve an increase in tablet hardness.

In Examples 44 to 45, it was confirmed that an increase in tablet hardness can be induced similarly by using carbon dioxide and nitrogen in combination. This result shows the possibility that other gases can be used in addition to carbon dioxide in the present invention.

As shown in Examples 46 to 50, various general-purpose binders such as povidone and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer can be used as the binder used in the granulation step.

In Examples 51 to 57, it was shown that the present invention can be obtained by using various general-purpose disintegrants such as low-substituted hydroxypropyl cellulose, croscarmellose sodium, or partially pregelatinized starch as disintegrants. fast-disintegrating tablets.

In Examples 58 to 60, it was confirmed that rapidly disintegrating tablets having the same performance can be obtained also in preparations containing a model drug.

In Examples 61 to 64, it was shown that by combining HPMCAS or ethyl cellulose with carbon dioxide pressure treatment, the tablet hardness can be improved similarly to the aminoalkyl methacrylate copolymer E, and the instant drug of the present invention can be obtained. Disintegrating tablet. This shows the possibility that, in the reference example, the rapid disintegration of the present invention can also be obtained by appropriate formulation design for the additive group represented by the components having the function of increasing the tablet hardness by utilizing carbon dioxide pressure. Sex Tablets.

In Examples 65 to 69, the breakage rate in the drop test was evaluated, and a very low breakage rate of 0 to 0.7% was confirmed in all of them. On the other hand, Comparative Examples 3 and 4, in which the hardness of the rapidly disintegrating tablet of the same formulation as that of Examples 68 and 69 was increased to the same degree by heat treatment instead of carbon dioxide, showed a 2.1 to 5% Relatively high breakage rate. This shows that the rapidly disintegrating tablet of the present invention is also excellent in breakage resistance.

Example 70

With copovidone (Kollidon VA64, BASF Japan manufacture) aqueous solution (10.0w/w%) 100g as binding solution, use fluidized bed granulator to contain solifenacin succinate (manufactured by Astellas Pharmaceuticals) and have 80.7 g of fine particles with a bitter taste masking function were granulated. 10.0 w/w % of aminoalkyl methacrylate copolymer E and 5.0 w/w % of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed with this granulated product. Cooperate 1.0w/w% magnesium stearate in this mixture, use single-punch tablet press to make every tablet about 150mg tablet (sofenacin succinate content 5mg) ( Tablet diameter 7.5mm). Tablet hardness was 10N (n=3). The tablet is treated under the conditions of carbon dioxide pressure 5 MPa and 35° C. for 30 minutes using a pressure-resistant device, and then the pressure is reduced to obtain the fast-disintegrating tablet of the present invention. In addition, the depressurization speed condition was performed at about 1 MPa/min.

Comparative Example 5

The tablet of Example 70 was heat-processed at 70 degreeC for 840 minutes in air|atmosphere, and the tablet of Comparative Example 5 was obtained.

Test Example 13

The hardness of the rapidly disintegrating tablet of Example 70 and the tablet of Comparative Example 5 was respectively measured. The hardness was measured using a tablet hardness tester (tablet hardness tester, "Schleuniger", type 6D, manufactured by Schleuniger AG). The results are shown in Table 8.

Test Example 14

A dissolution test was performed on the bitter taste masking particles used in Example 70, the rapidly disintegrating tablet of Example 70, and the tablet of Comparative Example 5. The dissolution test apparatus used a dissolution tester NTR-6100A (manufactured by Toyama Chemical Co., Ltd.), and the dissolution rate of solifenacin succinate was measured using a liquid chromatograph (manufactured by Shimadzu Corporation). The test conditions are as follows.

·Paddle method 50rpm

Test solution: Japanese Pharmacopoeia Disintegration Test Second Solution (pH6.8) 900mL

·Test liquid temperature: 37℃±0.5℃

Injection time: 2 minutes, 30 minutes

The results are shown in Table 8.

Test Example 15

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

[Table 8]

As can be seen from Table 8, the fast-disintegrating tablet of Example 70 had the generation amount of major decomposition products and the total amount of decomposition products on the same level as the bitter taste masking particles, whereas a significant increase was observed in the tablet of Comparative Example 5.

Industrial availability

The present invention can improve the breakage of the tablet that occurs in the distribution process, and can fully maintain the drug that is unstable to temperature or humidity or solid dispersion particles composed of poorly soluble drugs, bitter taste masking particles, sustained-release particles, etc. Various functions can be imparted by functional particles with desired functions brought about by the characteristics of drugs, and fast disintegrating tablets (especially orally disintegrating tablets) can be provided.

As mentioned above, although this invention was demonstrated based on the specific aspect, the deformation|transformation and improvement which are obvious to those skilled in the art are included in the scope of the present invention.

Claims (25)

1. A rapidly disintegrating tablet containing a drug and a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide, and by using carbon dioxide in a supercritical or subcritical state State of carbon dioxide or liquid or gaseous carbon dioxide obtained by processing. 2. The fast-disintegrating tablet according to claim 1, wherein the substance having a binder function by using carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is processed by using carbon dioxide in a supercritical or subcritical state. Subcritical carbon dioxide or liquid or gaseous carbon dioxide is treated to lower the melting point or glass transition temperature. 3. The rapidly disintegrating tablet according to claim 1 or 2, wherein the substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is selected from the group consisting of One or more substances of a group consisting of: Vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone, premixed preparation of povidone and vinyl acetate resin, methacrylic acid copolymer LD, polyvinyl alcohol-polyethylene glycol graft copolymer, premixed preparation of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxypropylene (67) Diol, polyethylene glycol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, formazan Acrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate-methyl methacrylate diethylaminoethyl acrylate copolymer, hydroxypropylmethylcellulose acetate succinate, shellac, carbomer and polyvinyl acetal diethylaminoacetate. 4. The fast-disintegrating tablet according to any one of claims 1 to 3, wherein the substance having a binder function is relatively The weight of the tablet is not less than 0.1% by weight and not more than 50% by weight. 5. The rapidly disintegrating tablet according to any one of claims 1 to 4, further comprising a plasticizer. 6. The rapidly disintegrating tablet according to any one of claims 1 to 5, further comprising a disintegrant. 7. The rapidly disintegrating tablet according to any one of claims 1 to 6, wherein the tablet hardness is 20N or more. 8. The rapidly disintegrating tablet according to any one of claims 1 to 7, wherein the ratio of the number of broken tablets obtained by a drop test is 5% or less. 9. The rapidly disintegrating tablet according to any one of claims 1 to 8, wherein the rapidly disintegrating tablet is an orally disintegrating tablet. 10. The fast-disintegrating tablet according to claim 9, wherein the oral disintegration time is within 120 seconds. 11. The rapidly disintegrating tablet according to any one of claims 1 to 10, wherein the drug constitutes a drug and/or functional particles that are unstable to temperature or humidity. 12. The fast-disintegrating tablet as claimed in claim 11, wherein the functional particle is one or more particles selected from the group consisting of the following particles: Solid dispersion particles, bitter taste masking particles and sustained release particles composed of poorly soluble drugs. 13. A method for manufacturing a fast-disintegrating tablet, comprising: (1) A process of mixing a drug with a substance that functions as a binder by treating it with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide, (2) A step of compressing the mixture of (1) to prepare a tablet, and (3) A step of treating the tablet of (2) with carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide. 14. The method for manufacturing a fast-disintegrating tablet as claimed in claim 13, wherein the substance having a binder function by utilizing carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is processed by utilizing carbon dioxide in a supercritical or subcritical state. Carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide, is treated to lower its melting point or glass transition temperature. 15. The method for producing a fast-disintegrating tablet as claimed in claim 13 or 14, wherein the substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is selected One or more substances in the group consisting of the following substances: Vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone, premixed preparation of povidone and vinyl acetate resin, methacrylic acid copolymer LD, polyvinyl alcohol-polyethylene glycol graft copolymer, premixed preparation of polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxypropylene (67) Diol, polyethylene glycol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, formazan Acrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate-methyl methacrylate Diethylaminoethyl Acrylate Copolymer, Hydroxypropyl Methyl Cellulose Acetate Succinate, Shellac and Carbomer. 16. The method for producing a fast-disintegrating tablet according to any one of claims 13 to 15, wherein it has a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide The substance is 0.1 weight% or more and 50 weight% or less with respect to the weight of a tablet. 17. The method for producing a rapidly disintegrating tablet according to any one of claims 13 to 16, further comprising a plasticizer. 18. The method for producing a rapidly disintegrating tablet according to any one of claims 13 to 17, further comprising a disintegrant. 19. The method for producing a rapidly disintegrating tablet according to any one of claims 13 to 18, wherein the tablet hardness is 20N or more. 20. The method for producing a rapidly disintegrating tablet according to any one of claims 13 to 19, wherein the rapidly disintegrating tablet is an orally disintegrating tablet. 21. The method for producing a fast-disintegrating tablet according to claim 20, wherein the oral disintegration time is within 120 seconds. 22. The method for producing a rapidly disintegrating tablet according to any one of claims 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 a fast-disintegrating tablet as claimed in claim 22, wherein the functional particles are one or more particles selected from the group consisting of the following particles: Solid dispersion particles, bitter taste masking particles and sustained release particles composed of poorly soluble drugs. 24. The method for producing a rapidly disintegrating tablet according to any one of claims 13 to 23, comprising: treating with carbon dioxide of 0.1 MPa to 50 MPa, and -40°C to 100°C. 25. The method for producing a rapidly disintegrating tablet according to any one of claims 13 to 24, wherein the treatment is performed with gaseous carbon dioxide.