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

Collapsing property of speed tablet

Technical field

The present invention relates to by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process collapsing property of the speed tablet (particularly Orally disintegrating tablet) with cellular structure.In addition, the present invention relates to by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the manufacture method of collapsing property of the speed tablet (particularly Orally disintegrating tablet) with cellular structure.

Background technology

In the time that medicine preparation is provided, in most cases require to develop contain utilize to temperature or the unsettled medicine of humidity, have bitterness medicine, need to give slow-releasing the medicine such as medicine characteristic and given the medicine preparation containing drug particle of certain function.

In medicine preparation, tablet is extensively provided in medical treatment as one of optimal dosage form in compliance aspect of taking from patient on-the-spot.

On the other hand, according to the Health and human services department carrying out the 1980s scientific research silver scientific research of improving people's living condition, carry out report (the medicine thing daily paper distribution on August 22nd, 1989 of " the most applicable novel formulation to old people's administration and the making and research of new packing container " (Tokyo woman medical university, the former positive Thailand of China fir etc.); Non-patent literature 1).For example, as novel formulation, Orally dissolving type preparation, b) paste-like preparation, c) gelatin preparation are adopted a), wherein, from easily taking, the viewpoint of stability, Orally dissolving type preparation and paste-like preparation are all regarded as the preparation that old people is easily taken.

Orally disintegrating tablet is to be suitable for patient's the dosage form that swallow reduces, widely known as the dosage form that water is taken in limited disease, the convenience that do not need water also can take before going to bed or while going out etc. is high.

As the preparation technique that relates to Orally disintegrating tablet, reported the following invention that relates to Orally disintegrating tablet, described Orally disintegrating tablet contain by using the high saccharide of formability as binding agent to the granules (patent documentation 1) that the low saccharide of formability is sprayed, coating and/or pelletize form.

In addition, report the invention of the following manufacture method that relates to instant capacity tablet, described manufacture method is characterised in that, in order to improve the poor flow quality that supplying material occurs, when pressurization, material is to the unfavorable condition in the such manufacture of the faults such as adhering on pressing element, comprise: will contain medicament, the tablet material of the drying regime of water-soluble binder and water soluble excipient is made the form of tablet and is carried out the sheeting process of press molding to be able to maintain the required minimum pressure of hardness of this form, for making the humidification operation of the tablet moisture absorption after sheeting process is shaped and making the dry drying process (patent documentation 2) of the tablet after humidification in humidification operation.

In addition, report the following invention that relates to Orally disintegrating tablet, wherein, for the compositions that contains medicine, saccharide and Polyethylene Glycol, said composition is carried out after low pressure tabletting, by heating up under the temperature conditions making described Polyethylene Glycol melting, Polyethylene Glycol is formed between particle between medicine and saccharide crosslinked, there is thus cellular structure (patent documentation 3).

In addition, report: a kind of invention (patent documentation 4) that relates to collapsing property of speed tablet in oral cavity, wherein, in order to improve tablet strength and to improve wear intensity in the situation that not extending in intraoral disintegration time, in described oral cavity, collapsing property of speed tablet contains medicine, diluent and fusing point and compares relatively low saccharide with medicine with diluent, low-melting saccharide is engaged in tablet equably, between medicine and/or diluent particle, utilize the melting and solidification thing of low-melting saccharide to be formed with crosslinked, a kind of invention (patent documentation 5) that relates to Orally disintegrating tablet, described Orally disintegrating tablet contains biological active substances and polyvinyl alcohol-polyethyleneglycol-graft copolymer, a kind of invention (patent documentation 6) of the manufacture method that relates to collapsing property of speed tablet, described manufacture method is characterised in that, there is disintegrative and fully collapsing property of the speed tablet of tablet strength rapidly in order to prepare, comprise: (1) is by effective ingredient, the operation that the additive of allowing on acrylic copolymer and at least one pharmacology mixes, (2) mixture obtaining is carried out the operation of compression molding and (3) the compression molding thing obtaining is incubated under the temperature conditions of 50～100 DEG C the operation of certain hour in the operation of (1) in the operation of (2), a kind of invention (patent documentation 7) of the manufacture method that relates to collapsing property of speed tablet, described manufacture method is characterised in that, make the composition of powder morphology contact and make its homogenization with pressurized liquefied gas or admixture of gas, reduce pressure adding to depress after importing in shaping dies, a kind of invention (patent documentation 8) that relates to fast disintegrating tablet in oral cavity, in described oral cavity, fast disintegrating tablet is by comprising the method manufacture in following stage: manufacture the stage of tablet and described tablet is contacted with supercritical fluid thereby the mixture that contains active component, additive and dissolve in the material of supercritical fluid is carried out to tabletting the stage that extracts the material that dissolves in supercritical fluid and make to form in tablet slight void, Deng.

But the breakage of collapsing property of the speed tablet (particularly Orally disintegrating tablet) in circulation operation still becomes problem, needs further improvement technology.In addition, to be enough to carry out the preparation hardness of preparation operation and to there is the tablet of disintegrative (collapsing property of speed tablet (particularly Orally disintegrating tablet)) fast in order to provide to have on the basis that maintains the function that functional particle is original had, need further improvement technology.

In addition, due to heat treated, add wet process and may make medicine decompose, therefore, for the manufacture method of collapsing property of the speed tablet (particularly Orally disintegrating tablet) that stability to medicine does not impact is provided, need further improvement technology.

Prior art document

Patent documentation

Patent documentation 1: International Publication WO95/20380 pamphlet

Patent documentation 2: No. 2919771 communique of Japan Patent

Patent documentation 3: Japanese kokai publication hei 11-33084 communique

Patent documentation 4: TOHKEMY 2004-292457 communique

Patent documentation 5: TOHKEMY 2006-76971 communique

Patent documentation 6: International Publication WO2006/070845 pamphlet

Patent documentation 7: TOHKEMY 2007-516977 communique

Patent documentation 8: Japanese Unexamined Patent Application Publication 2012-509315 communique

Non-patent literature

Non-patent literature 1: " the Fitness な new Regulations System drug of high Elderly person's To administration and the new Regulations packing container of び make research (the most applicable novel formulation to old people's administration and the making and research of new packing container) ", Tokyo woman medical university, the former positive Thailand of China fir etc., medicine thing daily paper, on August 22nd, 1989 publish

Summary of the invention

Invent problem to be solved

Problem of the present invention is to provide improved the collapsing property of speed of the breakage tablet (particularly Orally disintegrating tablet) that makes tablet.

In addition, problem of the present invention is to provide collapsing property of the speed tablet that also can be applicable to adding wet process, the unsettled medicine of heat treatment (particularly Orally disintegrating tablet).In addition, problem of the present invention is to provide a kind of collapsing property of speed tablet (particularly Orally disintegrating tablet), it is to contain the tablet containing drug particle (also brief note is functional particle sometimes below) of having given the desired function being brought by the characteristic of medicine, even (sometimes process under high-temperature or high humility from preparation design aspect through preparation chemical industry order, sometimes the function of the particle that contains functional medicine is exerted an influence), also fully show this function.

Another problem of the present invention is to provide the manufacture method that also can be applicable to the tablet of the collapsing property of speed to adding wet process, the unsettled medicine of heat treatment (particularly Orally disintegrating tablet).In addition, another problem of the present invention is to provide the manufacture method of a kind of collapsing property of speed tablet (particularly Orally disintegrating tablet), described collapsing property of speed tablet is to contain the tablet containing drug particle that has been endowed the desired function being brought by the characteristic of medicine, even (sometimes process under high-temperature or high humility from preparation design aspect through preparation chemical industry order, sometimes medicine may occur decompose or may exert an influence to the function of the particle that contains functional medicine), medicine self is also stable, or also fully shows this function of functional particle.

For the means of dealing with problems

Under this situation, inventor utilizes carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process, result is known, crosslinked by having the material of fusing point or glass transition temperature reduction and making this material construct so-called " between particle " in the space of composition and composition, can be used as binding agent and play a role.

In addition, owing to manufacturing with gentle treatment conditions, therefore, collapsing property of the speed tablet (particularly Orally disintegrating tablet) so obtaining contains temperature or the unsettled medicine of humidity or (for example contains functional particle in tablet, the solid dispersion particle being formed by insoluble drug, bitterness covers particle, slow-releasing particle etc.) situation under, can on the basis that fully maintains this stability and desired function, there is cellular structure, therefore, can provide to have is enough to carry out the tablet hardness of preparation operation and has the tablet of disintegrative (collapsing property of speed tablet (particularly Orally disintegrating tablet)) fast, thereby complete the present invention.

, the present invention relates to:

[1] a kind of collapsing property of speed tablet, it contains medicine and by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material with binding agent function, and obtains by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process.

[2] collapsing property of the speed tablet as described in [1], wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material that fusing point or glass transition temperature are reduced.

[3] collapsing property of the speed tablet as described in [1] or [2], wherein, the material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to have binding agent function is for selecting one or more the material in the group of free following substances composition:

Vinylpyrrolidone/vinyl acetate copolymer, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, polyvidone, the pre-mixed formulation of polyvidone and vinyl acetate resin, Eudragit L100D55, polyvinyl alcohol-polyethyleneglycol-graft copolymer, the pre-mixed formulation of polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxy propylidene (67) glycol, Polyethylene Glycol, polyoxyethylene castor oil hydrogenated (40), amino alkyl methacrylate copolymer E, Eudragit L100, dry Eudragit L100D55, Eudragit L100D55, Eudragit S100, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, EUDRAGIT NE 30 D EUDRAGIT NE 30D dispersion liquid, ethyl cellulose, methyl methacrylate-diethyl aminoethyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, Lac, carbomer and polyvinyl acetal lignocaine acetas.

[4] collapsing property of the speed tablet as described in any one in [1]～[3], wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is more than 0.1 % by weight and below 50 % by weight with respect to the weight of tablet.

[5] collapsing property of the speed tablet as described in any one in [1]～[4], wherein, also contains plasticizer.

[6] collapsing property of the speed tablet as described in any one in [1]～[5], wherein, also contains disintegrating agent.

[7] collapsing property of the speed tablet as described in any one in [1]～[6], wherein, tablet hardness is more than 20N.

[8] collapsing property of the speed tablet as described in any one in [1]～[7], wherein, the ratio of the damaged sheet number being obtained by shatter test is below 5%.

[9] collapsing property of the speed tablet as described in any one in [1]～[8], wherein, collapsing property of speed tablet is Orally disintegrating tablet.

[10] collapsing property of the speed tablet as described in [9], wherein, the intraoral disintegration time is in 120 seconds.

[11] collapsing property of the speed tablet as described in any one in [1]～[10], wherein, medicine forms temperature or the unsettled medicine of humidity and/or functional particle.

[12] collapsing property of the speed tablet as described in [11], wherein, functional particle is the freely particle of one or more in molecular group of following grain of choosing:

Solid dispersion particle, the bitterness being made up of insoluble drug covers particle and slow-releasing particle.

[13] manufacture method for collapsing property of speed tablet, it comprises:

The operation of (1) medicine being mixed with the material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process with binding agent function,

(2) mixture of (1) is carried out to compression molding and prepare tablet operation and

(3) operation that the carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed by the tablet utilization of (2).

[14] manufacture method of collapsing property of the speed tablet as described in [13], wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material that fusing point or glass transition temperature are reduced.

[15] manufacture method of collapsing property of the speed tablet as described in [13] or [14], wherein, the material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to have binding agent function is for selecting one or more the material in the group of free following substances composition:

Vinylpyrrolidone/vinyl acetate copolymer, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, polyvidone, the pre-mixed formulation of polyvidone and vinyl acetate resin, Eudragit L100D55, polyvinyl alcohol-polyethyleneglycol-graft copolymer, the pre-mixed formulation of polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxy propylidene (67) glycol, Polyethylene Glycol, polyoxyethylene castor oil hydrogenated (40), amino alkyl methacrylate copolymer E, Eudragit L100, dry Eudragit L100D55, Eudragit L100D55, Eudragit S100, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, EUDRAGIT NE 30 D EUDRAGIT NE 30D dispersion liquid, ethyl cellulose, methyl methacrylate-diethyl aminoethyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, Lac and carbomer.

[16] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[15], wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is more than 0.1 % by weight and below 50 % by weight with respect to the weight of tablet.

[17] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[16], wherein, also contains plasticizer.

[18] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[17], wherein, also contains disintegrating agent.

[19] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[18], wherein, tablet hardness is more than 20N.

[20] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[19], wherein, collapsing property of speed tablet is Orally disintegrating tablet.

[21] manufacture method of collapsing property of the speed tablet as described in [20], wherein, the intraoral disintegration time is in 120 seconds.

[22] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[21], wherein, medicine forms temperature or the unsettled medicine of humidity and/or functional particle.

[23] manufacture method of collapsing property of the speed tablet as described in [22], wherein, functional particle is the freely particle of one or more in molecular group of following grain of choosing:

Solid dispersion particle, the bitterness being made up of insoluble drug covers particle and slow-releasing particle.

[24] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[23], wherein, comprising: utilize 0.1MPa carbon dioxide above and below 50MPa and more than-40 DEG C and below 100 DEG C to process.

[25] manufacture method of collapsing property of the speed tablet as described in any one in [13]～[24], wherein, utilizes atmospheric carbon dioxide to process.

Invention effect

According to the present invention, can provide and there is collapsing property of the speed tablet (particularly Orally disintegrating tablet) that makes damaged improved breakage resistance and there is collapsing property of speed in oral cavity.In addition, for example, owing to processing under the temperate condition of about room temperature, therefore, in the case of containing, temperature or the unsettled medicine of humidity, the solid dispersion particle, the bitterness that are made up of insoluble drug are covered particle, slow-releasing particle etc., collapsing property of speed tablet (particularly Orally disintegrating tablet) can be provided on the basis that fully maintains this stability and desired function.

Detailed description of the invention

Below, embodiments of the present invention are elaborated.

In this manual, " supercritical (state) " refers to the non-condensability dense fluids of pressure, the equal postcritical of temperature.

In addition, " subcritical (state) " refers to the state of any one postcritical in only pressure, temperature.Critical point refers to " the Particle Formation with Supercritical Fluids-A Review " that for example J.W.Tom and P.G.Debenedetti show, J.Aerosol Sci., 22 (5), the critical point of recording in detail in 555-584 page, Fig. 1 in 1991.

In addition, by all postcriticals and the state that liquefies is called " liquid " not of pressure, temperature.

In addition, by all postcriticals and the state that gasifies is called " gas " not of pressure, temperature.

Particularly, be the state that simultaneously exceedes the critical pressure of approximately 7.38 megapascal (MPa)s (MPa) and approximately 304.1 Kelvins' (K) critical temperature in supercritical carbon dioxide.It is particularly the carbon dioxide beyond solid state.For example, can enumerate liquid CO 2, atmospheric carbon dioxide, supercritical carbon dioxide.

In this manual; about " being enough to carry out the tablet hardness of preparation operation " or " good tablet hardness "; degree that can be not damaged in circulation operation as long as tablet is not particularly limited; for example; the standard of the intensity of taking out as preparation being extruded from screening glass, can enumerate longitudinal hardness of tablet.This hardness because of size, the shape of tablet different, for example, more than being defined as 20N in the time of the sheet of diameter 8.0mm and 180mg, be defined as 30N in the time of diameter 8.5mm more than, be defined as 50N in the time of diameter 10.0mm more than, be defined as 60N in the time of diameter 12.0mm more than.Preparation of the present invention all has the in the situation that of any size can fully tolerate the intensity of taking out from PTP packaging.In addition, as can be applicable to the intensity of bottle packaging (enclosing the packaging that has tablet in the container of glass, plastics etc.), can tolerate conveying move in common bottle container time between tablet or the standard of tablet and the intensity of the tablet contacting of chamber wall, more than being preferably 30N.In addition, as another way, can enumerate for example breakage rate being obtained by shatter test of the tablet of PTP packaging.For example, regulation has following intensity: by 10 1 PTP package panel inner packing have tablet state PTP package panel so that tablet incorporating section (capsule) mode upward from being highly that the eminence of 150cm is while falling, the breakage rate of above-mentioned tablet is below 5%, is below 2% as another way.Preparation of the present invention has the conveying can fully tolerate bottle packaging time or the intensity of moving into.

The tablet (collapsing property of speed tablet) in this manual, with " disintegrative fast " refers to does not need to take water in oral cavity, utilize saliva can have disintegrative enough in practicality or deliquescent tablet.At this, there is individual variation in disintegrative or dissolubility enough in practicality, but be conventionally defined in oral cavity with approximately 1 second to approximately 300 seconds, as another way with approximately 1 second to approximately 150 seconds, as another way with approximately 1 second to approximately 90 seconds, as disintegrate or dissolving in approximately 1 second to approximately 60 seconds for another way.In addition, in the time using Tricorptester disintegration tester to measure, regulation disintegration time at 1 second in 300 seconds, as another way at 1 second in 120 seconds, as another way at 1 second in 90 seconds, as another way at 1 second in 60 seconds, as another way at 1 second in 40 seconds.In addition, also there is individual variation in " Orally disintegrating tablet ", but typically refer in oral cavity with approximately 1 second to approximately 120 seconds, as approximately 1 second to approximately 90 seconds, tablet as another way with disintegrate in approximately 1 second to approximately 60 seconds or dissolving for another way.In addition, in the time using Tricorptester disintegration tester to measure, refer at 1 second in 120 seconds, as another way at 1 second in 90 seconds, as the tablet of another way disintegrate or dissolving in 1 second disintegration time in 60 seconds, as another way in 1 second to 40 seconds.

In this manual, about " cellular structure ", as long as tablet is at intraorally rapidly disintegrating, be not particularly limited, for example, regulation porosity is more than 15% and below 90%, being more than 25% and below 70% as another way, is more than 30% and below 50% as another way.

As the medicine using in the present invention, as long as effective effective active component in active component or prophylactic therapeutically, be not particularly limited.As this active constituents of medicine, for example can enumerate: sedative hypnotic, hypnotic, migraine agent, antianxiety drugs, antuepileptic, antidepressants, antiparkinsonism drug, the neural medication of spirit, central nervous system's medication, local anesthetic, skeletal muscle relaxant, autonomic drug, actasal, spasmolytic, antivertigo drug, cardiac tonic, arrhythmia medication, diuretic, hypotensor, vasoconstrictor, vasodilation, cardiovascular preparation, hyperlipemia medicine, respiratory stimulant, antitussive, the agent of reducing phlegm, relieving cough and resolving phlegm agent, bronchodilator, diarrhea, drug for controlling intestinal function, peptic ulcer medication, digestive and stomachic, antacid, cathartic, choleretic, digestive organs medication, adrenal hormone medicine, hormone drug, urinary organs medication, vitamin medicine, hemorrhage, hepatic disease medication, gout therapertics, diabetic, antihistaminic, antibiotic, antimicrobial drug, anti-malignant-tumor agent, chemotherapeutic agent, full effect coldrex, nourish strong health care medicinal, osteoporosis medicine etc.As said medicine, for example can enumerate: the overactive bladder curatives such as solifenacin, tolterodine, Mirabegron; The hypnotic such as diphenhydramine, lorazepam, zolpidem; The antiinflammatory such as indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, Phenylbutazone, oxyphenbutazone, DA-398, aspirin, ethenzamide, acetaminophen, aminophenazone, phenacetin, scopolamine butylbromide, morphine, etomidoline, pentazocine, fenoprofen calcium, naproxen, celecoxib, valdecoxib, tramadol, antipyretic, spasmolytic or analgesic; The migraine agents such as sumatriptan; The antitubercular agents such as the antirheumatics such as etodolac, isoniazid, ebutol; The cardiovascular preparations such as sorbide nitrate, nitroglycerin, nifedipine, YM-09730-5, Licardipine Hydrochloride, dipyridamole, amrinone, hydrochloric acid indenolol, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, nitric acid guanethidine, reserpine, YM-09538, lisinopril, metoprolol, pilocarpine, telmisartan; Chlorpromazine hydrochloride, amitriptyline hydrochloride, nemonapride, haloperidol, Luvatren (Cilag-Chemie)., perphenazine, diazepam, lorazepam, chlorine nitrogen the psychosis such as adinazolam, alprazolam, methylphenidate, midalcipran, paroxetine, risperidone, sodium valproate; The antidepressants such as imipramine; The Bendectins such as metoclopramide, Ramosetron HCl, Granisetron Hydrochloride, Ondansetron Hydrochloride, Azasetron hydrochloride; The antihistaminics such as chlorphenamine maleate; The vitamin medicines such as thiamine mononitrate, tocopheryl acetate, cycotiamine, pyridoxal 5-phosphate, cobamamide, ascorbic acid, nicotiamide; The gout medicines such as allopurinol, colchicine, probenecid; The parkinson disease such as levodopa, selegiline medicine; The sedative hypnotic such as amobarbital, bromisovalum, midazolam, chloral hydrate; The anti-malignant-tumor agents such as fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thio-tepa; The antiallergic agent such as pseudoephedrine, terfenadine; The Rezulins such as acetohexamide, insulin, tolbutamide, Desmopressin, glipizide, Nateglinide, metformin, sitagliptin, vildagliptin, BI 1356; The diuretic such as hydrochlorothiazide, polythiazide, triamterene; The bronchodilators such as aminophylline, formoterol fumarate, theophylline; The cough medicines such as codeine phosphate, narcotine, Dimemorfan phosphate, dextromethorphan; The antiarrhythmics such as nitric acid quinidine, Digitoxin, propafenone hydrochloride, procainamide; The topical anesthetics such as benzocaine, lignocaine, cinchocaine hydrochloride; The antuepileptics such as phenytoin, ethosuximide, primidone; The synthetic Adrenocorticosteroidses such as hydrocortisone, andrographolide, triamcinolone acetonide, betamethasone; The digestive tract medications such as famotidine, ranitidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, plaunotol, 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole; Central nervous system's medications such as indeloxazine, idebenone, Tiapride Hydrchloride, E-0687, calcium hopantenate; The remedy for hyperlipemia such as pravastatin sodium, simvastatin, lovastatin, atorvastatin; The antibiotic such as talampicillin hydrochloride, cefotetan, josamycin; The BPH therapeutic agents such as Tamsulosin, Carclura, terazosin hydrochloride; The antasthmatics such as pranlukast, zafirlukast, albuterol, ambroxol, budesonide, levosalbutamol; The peripheral circulation improving agent of the prostacyclin I2 derivants such as beraprost sodium; The agent of the osteoporosis treatment such as minodronic acid, alendronic Acid; The therapeutic agent of the various complication of diabetes; Remedies for skin ulcer; Deng.

Or, for example can enumerate: steroid anti-inflammatory agent, anti-inflammatory analgesic, antipyretic analgesic, antuepileptic, chemotherapeutic agent, synthetic antibacterial drug, antiviral agents, antifungal agent, hormone drug, angiogenesis inhibitors, immunosuppressant or treatment of ulcerative colitis agent etc.As steroid anti-inflammatory agent, for example can enumerate: cortisone acetate, betamethasone, prednisolone, fluticasone propionate, dexamethasone, budesonide, beclometasone, triamcinolone acetonide, loteprednol, fluorometholone, difluprednate, momestasone furoate, clobetasol propionate, acetic acid diflorasone, pentane acid double fluoro dragon-a/ible, fluocinonide, amcinonide, halcinonide, fluocinolone acetonide, triamcinolone acetonide, Flumetasoni Pivalate or clobetasone butyrate etc.As anti-inflammatory analgesic, for example can enumerate: alclofenac, alminoprofen, ibuprofen, indomethacin, epirizole, oxaprozin, ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam, fenbufen, flufenamic acid, flurbiprofen, floctafenine, pentazocine, metiazinic acid or mefenamic acid, mofezolac etc.As antipyretic analgesic, for example can enumerate: acetaminophen or dipyrone etc.As antuepileptic, for example can enumerate: acetazolamide, carbamazepine, clonazepam, diazepam or nitrazepam etc.As chemotherapeutic agent, for example can enumerate: sulfasalazine, sulfadimethoxine, sulfamethizole, sulfalene the sulfur agent such as azoles, sulfalene or sulfamonomethoxine; Enoxacin, ofloxacin, cinoxacin, Sparfloxacin, thiamphenicol, nalidixan, Tosufloxacin Tasylate, norfloxacin, Deblaston (Madaus), minaline, fleroxacin or levofloxacin magnitude synthetic antibacterial drug; The antiviral agents such as acyclovir, ganciclovir, didanosine, zidovudine or vidarabine; The antifungal agent such as itraconazole, ketoconazole, fluconazol, flucytosine, miconazole or pimaricin.As hormone drug, for example can enumerate: zinc insulin, Testosterone Propionate or estradiol benzoate etc.As immunosuppressant, for example can enumerate: ciclosporin, rapamycin or tacrolimus etc.As treatment of ulcerative colitis agent, can enumerate mesalazine etc.

In addition, as the another way of the medicine using in the present invention, can enumerate temperature or the unsettled medicine of humidity.About the fit system in pharmaceutical composition to temperature or the unsettled medicine of humidity, as long as normally used method in pharmacopedics, be not particularly limited.For example, medicine can be carried out together with medicated premix to pelletize and/or mixing, carry out pelletize and/or mixing after also can medicine being coated on the nuclear particles such as セ Le Off ィ ア (Asahi Chemical Industry's manufacture) together with stabilizing agent etc. together with medicated premix.

In addition, as the another way of the medicine using in the present invention, can enumerate: form functional particle medicine (have bitterness medicine, need to give the medicine of slow-releasing, the medicine of slightly solubility).As functional particle, for example can enumerate: bitterness covers particle, slow-releasing particle, solid dispersion particle etc.

In addition, can select as the medicine with bitterness, need to give the medicine of slow-releasing or the medicine of slightly solubility and to temperature or the unsettled medicine of humidity as the medicine that forms functional particle.

Medicine can use any one in permissible salt in sequestered or pharmacy.In addition, medicine also can or use two or more combinations by one.In addition, these medicines, for can be applicable to an example of the present invention, should not explained from determinate angle.

About its use level, conventionally can suitably select according to the kind of medicine or medicinal usage (indication), but as long as therapeutically effectively effectively measuring in amount or prophylactic, be not particularly limited.For example, in collapsing property of speed tablet (particularly Orally disintegrating tablet), be 0.001～80 % by weight, be 0.01～70 % by weight as another way, be 0.01～60 % by weight as another way.

Collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet) is by utilizing " processing the material with binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide " carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process, at composition (for example in tablet, make " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function ", medicine and the excipient adding according to expectation, disintegrating agent, stabilizing agent, lubricant etc.) between form crosslinked, there is thus cellular structure.

As " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function " that use in the present invention, the material working as binding agent as long as the fusing point by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to make this " material " or glass transition temperature reduction, thus, does not limit.As another way, as long as the hardness ratio by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to make the tablet that contains this " material " is containing the material of tablet increase that should " material ", do not limit.Particularly, as the pressure of processing, be about 0.1MPa～about 50MPa as a mode, be about 1MPa～about 20MPa as another way.Be about 1MPa～15MPa as another way.Be about 1MPa～about 5MPa as another way.As another way, be for example that fusing point or glass transition temperature when pressure setting is 20MPa reduces for example 5 DEG C of above materials, be to reduce by 20 DEG C of above materials as another way.As another way, can enumerate and for example in structural formula, have particularly and carbon dioxide has compound of unsaturated bond between the styrene skeleton, carbonyl, ehter bond, ester bond, carbon atom of affinity etc.

As the compound with styrene skeleton, for example, be polystyrene resin and copolymer thereof etc.

As the compound with carbonyl, for example, be aldehyde compound, ketonic compound, carboxylic acid compound, ester compounds, amide compound, ketene compound, carboxylic acid chlorination (halogenation) thing, anhydride and polymer, copolymer etc.

As the compound with ehter bond, for example, it is the polyethers taking Polyethylene Glycol, polypropylene glycol etc. as representative.

As the compound with unsaturated bond between carbon atom, for example, be alkene, ethylene, propylene, benzene, annulene or polymer, the copolymer with this structure.

Particularly, can enumerate: vinylpyrrolidone/vinyl acetate copolymer (below sometimes referred to as copolyvidone), Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), polyvidone, the pre-mixed formulation (Polyvinyl acetate and polyvinylpyrrolidone (8:2)) of polyvidone and vinyl acetate resin, Eudragit L100D55 (Methacrylic acid and ethyl acrylate copolymer), polyvinyl alcohol-polyethyleneglycol-graft copolymer (Polyvinyl alcohol and Polyethylene glycol graft copolymer (75:25)), the pre-mixed formulation (Polyvinyl alcohol and Polyethylene glycol graft copolymer (75:25) and polyvinyl alcohol (60/40)) of polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxy propylidene (67) glycol (Ethylene oxide and propylene oxide), Polyethylene Glycol, polyoxyethylene castor oil hydrogenated (40), amino alkyl methacrylate copolymer E, Eudragit L100, dry Eudragit L100D55, Eudragit L100D55, Eudragit S100, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, EUDRAGIT NE 30 D EUDRAGIT NE 30D dispersion liquid, ethyl cellulose, methyl methacrylate-diethyl aminoethyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate (below sometimes referred to as HPMCAS), Lac, carbomer, polyvinyl acetal lignocaine acetas etc.As another way, can enumerate: the pre-mixed formulation of copolyvidone, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, amino alkyl methacrylate copolymer E, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, methyl methacrylate-diethyl aminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, Lac, polyvidone and vinyl acetate resin, polyvidone, carbomer, polyoxyethylene (196) polyoxy propylidene (67) glycol.As another way, can enumerate: the pre-mixed formulation of copolyvidone, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, amino alkyl methacrylate copolymer E, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, methyl methacrylate-diethyl aminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, polyvidone and vinyl acetate resin.As another way, can enumerate: copolyvidone, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, amino alkyl methacrylate copolymer E, HPMCAS, ethyl cellulose.As another way, can enumerate: copolyvidone, amino alkyl methacrylate copolymer E.As another way, can enumerate amino alkyl methacrylate copolymer E.

These compounds for example can obtain using following trade name as commercially available product.

Copolyvidone: Kollidon VA-64 (BASF Japan), Kollidon VA-64Fine (BASF Japan), プ ラ ス De Application S-630 (ISP Japan)

Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer: Soluplus (BASF Japan)

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

The pre-mixed formulation of polyvidone and vinyl acetate resin: Kollidon SR (BASF Japan)

Eudragit L100D55: Kollicoat MAE 100P (BASF Japan)

Polyvinyl alcohol-polyethyleneglycol-graft copolymer: Kollicoat IR (BASF Japan)

The pre-mixed formulation of polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol: Kollicoat Protect (BASF Japan)

Polyoxyethylene (196) polyoxy propylidene (67) glycol: コ リ フ ォ ー Le P407 (BASF Japan)

Polyethylene Glycol: Lutrol E400 (BASF Japan)

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

Amino alkyl methacrylate copolymer E: オ イ De ラ ギ ッ ト E100 (winning wound Japan), オ イ De ラ ギ ッ ト EPO (winning wound Japan)

Eudragit L100: オ イ De ラ ギ ッ ト L100 (winning wound Japan)

Dry Eudragit L100D55: オ イ De ラ ギ ッ ト L100-55 (winning wound Japan)

Eudragit L100D55: オ イ De ラ ギ ッ ト L30D-55 (winning wound Japan)

Eudragit S100: オ イ De ラ ギ ッ ト S100 (winning wound Japan)

EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO: オ イ De ラ ギ ッ ト RL100 (win wound Japan), オ イ De ラ ギ ッ ト RLPO (winning wound Japan)), オ イ De ラ ギ ッ ト RS100 (winning wound Japan), オ イ De ラ ギ ッ ト RSPO (winning wound Japan)

EUDRAGIT NE 30 D EUDRAGIT NE 30D dispersion liquid: オ イ De ラ ギ ッ ト NE30 (winning wound Japan), Kollicoat EMM30D (BASF Japan)

Ethyl cellulose: エ ト セ Le (DOW Chemical Japan)

Methyl methacrylate-diethyl aminoethyl methacrylate copolymer: Kollicoat Smartseal 30D (BASF Japan)

HPMCAS:AQOAT AS-HF, AQOAT AS-MF, AQOAT AS-LF (SHIN-ETSU HANTOTAI's chemical industry)

Lac: by commercially available dry transparent white Lac of Japanese Lac industrial group etc.

Carbomer: by Lubrizol Corp. commercially available Carbopol 71G, 971P, 974P, 980,981,5984, ETD2020, Ultrez10,934,934P, 940,941,1342 etc. and Pemulen TR-1, TR-2 etc., by Sumitomo refine company commercially available AQUPEC HV-501, HV501E, HV-501ER, HV-504, HV-504E, HV-505, HV-505E, HV-505ED etc., by with commercially available Ha イ PVC ス ワ コ ー 103,104,105 of the pure medicine of light etc.

Polyvinyl acetal lignocaine acetas: AEA (Mitsubishi Chemical's food) etc.

In collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet), as " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function " that use in the present invention, can use one or be used in combination of two or more.

Being shaped as of " processing the material with binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide " is granular, needle-like etc., is not particularly limited.Also can pulverize rear use.In the case of being shaped as of this material is granular, as long as have the function of binding agent, mean diameter is not particularly limited, and for example, the mean diameter while mensuration as use laser diffraction formula particle size distribution device, is preferably 0.1～350 μ m.It is a kind of or by different appropriately combined uses of two or more materials such as grade, shape, mean diameters that this material can use.

Its use level, as long as performance is as the amount of the function of " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function ", does not limit.As another way, as long as improving the amount of hardness of collapsing property of speed tablet (particularly Orally disintegrating tablet), be not particularly limited.Particularly, for example, in collapsing property of speed tablet (particularly Orally disintegrating tablet), be 0.1～50 % by weight, be 1～30 % by weight as another way, be 3～20 % by weight as another way.

Collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet) can be according to expecting to contain the plasticizer that the function of " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function " is improved.

The plasticizer improving as the function that makes " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function " using in the present invention, for example can enumerate: triethyl citrate, カ リ オ Application 83, glycerol, fatty acid glyceride, Oleum sesami, dimethyl polysiloxane-silica mixture, D-Sorbitol, MCT Oil, come from the sugar alcohol liquid of corn starch, glyceryl triacetate, concentrated glycerin, Oleum Ricini, diethyl phthalate, dibutyl phthalate, butyl phthalyl glycolic butyl ester, propylene glycol, polyoxyethylene (105) polyoxy propylidene (5) glycol, polysorbate80, PEG400, Macrogol 600, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glyceryl monostearate, the saccharides such as xylitol.As another way, can enumerate: the saccharides such as triethyl citrate, glyceryl triacetate, Macrogol 4000, polyethylene glycol 6000, xylitol.As another way, can enumerate triethyl citrate.Plasticizer can use one or be used in combination of two or more.As the use level of plasticizer, as long as the amount that the function of " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function " is improved, be not particularly limited.Particularly, for example, in collapsing property of speed tablet (particularly Orally disintegrating tablet), be 0.1～20 % by weight, be 0.1～10 % by weight as another way, being 0.1～7 % by weight as another way, is 1～7 % by weight as another way, is 2～5 % by weight as another way.In addition, use level as plasticizer with respect to " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function ", it is for example 0.5～200 % by weight, be 0.5～40 % by weight as another way, be 10～40 % by weight in another way.

In collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet), can be according to expecting to contain the excipient conventionally adding as drug additive.

As the excipient using in the present invention, as long as hydroaropic substance or water-soluble substances, do not limit.As a mode, can enumerate: saccharide, cellulose derivative, phosphate, sulfate.As saccharide, for example can enumerate: mannitol, lactose, sucrose, sucrose, glucose, fructose, Sorbitol, xylitol, red tinea sugar alcohol, trehalose, white sugar, maltose alcohol.As cellulose derivative, can enumerate microcrystalline Cellulose etc.As phosphate, can enumerate: calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, dibastic sodium phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate etc.As sulfate, can enumerate calcium sulfate etc.

In collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet), excipient can use one or be used in combination of two or more.

About the use level of excipient, particularly, for example, in collapsing property of speed tablet (particularly Orally disintegrating tablet), be 0.001～99.99 % by weight, be 1～99.9 % by weight as another way, be 10～99 % by weight as another way.

In collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet), except above-mentioned excipient, can further use various medicated premixs according to expectation, and preparation.As this medicated premix, as long as allowing in pharmacy and pharmacologically acceptable medicated premix, be not particularly limited.For example can use: binding agent, disintegrating agent, acidic flavoring agent, foaming agent, artificial sweetener, spice, lubricant, coloring agent, stabilizing agent, buffer agent, antioxidant, surfactant etc.In addition, except by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material with binding agent function, can also add binding agent as follows.

As binding agent, for example can enumerate: copolyvidone, polyvidone, polyvinyl alcohol-polyethyleneglycol-graft copolymer, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methylmethacrylate copolymer, hydroxypropyl emthylcellulose, arabic gum, Icing Sugar, sodium alginate, alphalise starch, agar, vinyl acetate resin, pulullan polysaccharide, starch, hydroxypropyl cellulose etc.

As disintegrating agent, for example can enumerate: corn starch, potato starch, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, alphalise starch, part alphalysed starch, carboxymethyl cellulose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, magnesium carbonate, low-substituted hydroxypropyl cellulose, low substituted carboxymethyl starch sodium, winnofil, gelatin, aluminum magnesium hydroxide, synthetic aluminium silicate etc.As another way, can enumerate: polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low substituted hydroxy-propyl methylcellulose, carboxymethyl starch sodium, alphalise starch, part alphalysed starch, carboxymethyl cellulose, carboxymethylcellulose calcium.As another way, can enumerate: low substituted hydroxy-propyl methylcellulose, part alphalysed starch, cross-linking sodium carboxymethyl cellulose.

As acidic flavoring agent, for example can enumerate: citric acid, tartaric acid, malic acid etc.

As foaming agent, for example can enumerate: sodium bicarbonate, tartaric acid, sodium bicarbonate, Citric anhydride, sodium bicarbonate etc.

As artificial sweetener, for example can enumerate: saccharin sodium, glycyrrhizic acid dipotassium, aspartame, stevioside, Talin etc.

As spice, for example can enumerate: Fructus Citri Limoniae, Citrus aurantium Linn., Citrus, Herba Menthae etc.

As lubricant, for example can enumerate: magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, Polyethylene Glycol, Talcum, stearic acid etc.

As coloring agent, for example can enumerate: yellow iron sesquioxide, red iron sesquioxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, edible blue No. 3 etc.

As stabilizing agent, for example can enumerate: ascorbic acid, aspartic acid, sodium chloride, magnesium chloride, glycine, glycerol, light silicon anhydride, magnesium gluconate, xylitol, calcium citrate, calcium hydroxide, sodium hydroxide, magnesium hydroxide, potassium carbonate, potassium bicarbonate, sodium bicarbonate etc.

As buffer agent, can enumerate: citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its esters, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its esters, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or its esters etc.

As antioxidant, for example can enumerate: ascorbic acid, dibenzylatiooluene, propyl gallate etc.

As surfactant, for example can enumerate: polysorbate80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor wet goods.

Can suitably add in right amount one or combination add two or more as medicated premix.

The use level of above-mentioned various medicated premixs can be set arbitrarily.

Collapsing property of speed tablet of the present invention is preferably Orally disintegrating tablet.

Below, the manufacture method of collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet) is described.

" utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process " in the present invention, between composition and composition, construct processing cross-linked structure, be dissolved to " completely " dissolving as the material " part " of the function of so-called " binding agent " as long as making to have, do not limit.Particularly, the difference according to using the size, kind of container, for example, with respect to the carbon dioxide of the approximately 1mL～about 2000L in supercriticality or subcritical state or liquid or gaseous state so that the tablet (particularly Orally disintegrating tablet) after tabletting as a mode be about 0.1g～about 2000kg, being about 5g～about 100kg as another way, ratio is processed.About the time of processing, be approximately 1 minute～approximately 50 hours as a mode, be approximately 1 minute～approximately 24 hours as another way, be approximately 2 minutes～approximately 12 hours as another way, as another way approximately 5 minutes～approximately 2 hours.

Process and preferably in the container of resistance to pressure, carry out.Particularly, for example, for using pressure vessel in system formation: H series (smart device manufacture rubs more), EV series (Japanese light splitting manufacture) or VE-1 (manufacture of mitsubishi chemical industry machine), CO2 liquid-feeding pump: SCF-GET, PU-2086 (Japanese light splitting manufacture), CO2 compressor: PU-1 (manufacture of mitsubishi chemical industry machine), thermometer: platinum temperature detecting resistance body (R36S) (Japanese electrical measurement manufacture), TI-2068-01 (Japanese light splitting manufacture), heater: ribbon heater (JK) (sub-fast prosperous manufacture), baking oven CO-2060 (Japanese light splitting manufacture), thermometer instruction controller: E5CN (Omron manufacture), pressure instruction machine: WGA-710B (manufacture of consonance electric industry), piezometer: PG-500KU (manufacture of consonance electric industry), the device of automatic back pressure regulating valve: BP-2080 (Japanese light splitting manufacture) etc.Process temperature according to form collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet) composition kind and difference is approximately-40 DEG C～approximately 100 DEG C as a mode.For example, be copolyvidone in the case of " carbon dioxide by utilization in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed the material with binding agent function ", the temperature of processing is approximately 25 DEG C～approximately 70 DEG C, the in the situation that of Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, for approximately 10 DEG C～approximately 65 DEG C, the in the situation that of amino alkyl methacrylate copolymer E, for approximately 10 DEG C～approximately 65 DEG C, the in the situation that of ethyl cellulose, be approximately 10 DEG C～approximately 100 DEG C.Process pressure equally according to form collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet) composition kind and difference is about 0.1MPa～about 50MPa as a mode, as the about 1MPa of another way～about 20MPa.

When processing, can wait and in carbon dioxide, add other solvents by mixing.As other solvents, for example can use: water; Benzene, toluene, ethyl acetate, cyclohexane extraction, dimethylbenzene etc. are aromatic hydrocarbon based; Methyl ether, ether, dioxane, diethoxyethane, oxolane, 1, the ethers such as 2-dimethoxy-ethane; Dichloromethane, chloroform, carbon tetrachloride, 1, the organochlorine class organic solvents such as 2-dichloroethanes; The alkyl such as acetonitrile, propionitrile nitrile; The nitroparaffin such as Nitrocarbol., nitroethane hydro carbons; The amide-type such as DMF, N,N-dimethylacetamide; The ketones such as acetone; The fatty acids such as acetic acid, acetic anhydride, oleic acid; The alcohols such as methanol, ethanol, propanol; The sulfoxide types such as dimethyl sulfoxine etc.; Or their mixed solvent etc., wherein preferred alcohol, acetone etc.Conventionally, the use amount of other solvents in the carbon dioxide in supercritical or subcritical state or liquid or gaseous state, is approximately 0.1 volume %～approximately 99.9 volume % as a mode, is approximately 1 volume %～approximately 99 volume % as another way.

In addition, when processing, can in carbon dioxide, add other gas.As other gas, can use such as nitrogen etc.

Particularly, for example, can, after the step of following (0), manufacture collapsing property of speed tablet of the present invention (particularly Orally disintegrating tablet) according to any one step in following (1)～(4), but be not limited to following step.Below, sometimes also any one step in (1)～(4) being recited as to carbon dioxide (pressure) processes.

(0) prepare collapsing property of the speed tablet (for example, Orally disintegrating tablet) before carbon dioxide treatment.

Particularly, for example can enumerate: to by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to add the method that mixture that active ingredient obtains carries out compression molding in processing the material with binding agent function; The method that active ingredient is carried out to pelletize and obtained granules carried out to compression molding with the aqueous solution containing by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material with binding agent function; By active ingredient with there is the method that the material aqueous solution of binding agent function carries out pelletize and obtained granules carried out to compression molding by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process; By active ingredient with there is the method that the material organic solvent of binding agent function carries out pelletize and obtained granules carried out to compression molding by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process; Active ingredient and the matter utilization by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to have binding agent function are there is to the method that the material of binding agent function carries out pelletize and obtained granules carried out to compression molding by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process; The method that material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to have binding agent function and other drug additive are carried out to pelletize and the mixture that obtained granules and active ingredient are obtained by mixing is carried out to compression molding; Or the method etc. that uses spray dryer to make solid dispersion and the mixture that obtained solid dispersion and other drug additive are obtained by mixing is carried out to compression molding active ingredient and the material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process with binding agent function.

(1)

In resistance to pressure container, pack collapsing property of speed tablet (for example, Orally disintegrating tablet) into.

Make more than the temperature of this resistance to pressure container is held in the critical point of carbon dioxide.

Filling arbon dioxide in this resistance to pressure container (mixing as required above-mentioned solvent or other gas).

Make more than pressure in this resistance to pressure container is held in the critical point of carbon dioxide, to carry out carbon dioxide treatment.

After utilizing carbon dioxide treatment to finish, release, takes out collapsing property of the speed tablet (for example, Orally disintegrating tablet) obtaining.

(2)

In resistance to pressure container, pack collapsing property of speed tablet (for example, Orally disintegrating tablet) into.

Make more than the temperature of this resistance to pressure container is held in the critical point of carbon dioxide.

Filling arbon dioxide in this resistance to pressure container (mixing as required above-mentioned solvent or other gas).

Make the pressure in this resistance to pressure container be held in the pressure lower than the critical point of carbon dioxide, carry out carbon dioxide treatment.

After utilizing carbon dioxide treatment to finish, release, takes out collapsing property of the speed tablet (for example, Orally disintegrating tablet) obtaining.

(3)

In resistance to pressure container, pack collapsing property of speed tablet (for example, Orally disintegrating tablet) into.

Make the temperature of this resistance to pressure container be held in the temperature lower than the critical point of carbon dioxide.

Filling arbon dioxide in this resistance to pressure container (mixing as required above-mentioned solvent or other gas).

Make pressure in this resistance to pressure container be held in the pressure more than critical point of carbon dioxide, carry out carbon dioxide treatment.

After utilizing carbon dioxide treatment to finish, release, takes out collapsing property of the speed tablet (for example, Orally disintegrating tablet) obtaining.

(4)

In resistance to pressure container, pack collapsing property of speed tablet (for example, Orally disintegrating tablet) into.

Make the temperature of resistance to pressure container be held in the temperature lower than the critical point of carbon dioxide.

Filling arbon dioxide in this resistance to pressure container (mixing as required above-mentioned solvent or other gas).

Make the pressure in this resistance to pressure container be held in the pressure lower than the critical point of carbon dioxide, carry out carbon dioxide treatment.

After utilizing carbon dioxide treatment to finish, release, takes out collapsing property of the speed tablet (for example, Orally disintegrating tablet) obtaining.

Embodiment

Below, the present invention will be described in more detail to enumerate embodiment, comparative example, reference example and test example, but the present invention is not subject to the limited interpretation of these examples.

In addition, according to the difference of medicine, also have the medicine that will coordinate denier (for example, number nanogram or number microgram etc.), therefore, following embodiment is all considered as the medicine that contains denier.

Embodiment 1

PEARLITOL 25C (Pearitol 50C, ROCKET Japan manufactures, below identical unless otherwise noted) 59.0w/w%, microcrystalline Cellulose (MCC SANAQ burst, PHARMATRANS SANAQ AG manufacture) 20.0w/w%, copolyvidone (Kollidon VA64 Fine, BASF Japan manufactures) 10.0w/w%, polyvinylpolypyrrolidone (Kollidon CL, BASF Japan manufactures) 10.0w/w% are mixed.In this mixture, coordinate magnesium stearate (Parteck LUB MST, Merck manufacture, below identical unless otherwise noted) 1.0w/w%, use single-punching tablet press (オ ー ト グ ラ Off AGS-20kNG, Shimadzu Seisakusho Ltd. to manufacture, below identical unless otherwise noted) make every tablet of tablet as 180mg (tablet diameters 8.5mm) taking the tabletting pressure of 1.0kN/ punching.Tablet hardness is 8N (n=1).Then, use resistance to pressure container (withstand voltage element) to process 30 minutes under pressure carbon dioxide 8.0MPa, the condition of 45 DEG C in this tablet, then, with the about 16kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 2

PEARLITOL 25C 54.0w/w%, microcrystalline Cellulose (MCC SANAQ burst, PHARMATRANS SANAQ AG manufacture) 20.0w/w%, copolyvidone (Kollidon VA64 Fine, BASF Japan manufactures) 15.0w/w%, polyvinylpolypyrrolidone (Kollidon CL, BASF Japan manufactures) 10.0w/w% are mixed.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make every tablet of tablet as 180mg (tablet diameters 8.5mm) taking the tabletting pressure of 1.0kN/ punching.Tablet hardness is 8N (n=1).Then, use withstand voltage element to process 30 minutes under pressure carbon dioxide 8.0MPa, the condition of 45 DEG C in this tablet, then, with the about 16kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 3

PEARLITOL 25C 97.0w/w%, copolyvidone (Kollidon VA64 Fine, BASF Japan manufactures) 3.0w/w% are mixed.Use single-punching tablet press to make every tablet of tablet as 270mg (tablet diameters 9.0mm) taking the tabletting pressure of 1.0kN/ punching in this mixture, tablet hardness is 10N (n=3).Then, use withstand voltage element to process 30 minutes under pressure carbon dioxide 6.0MPa, the condition of 40 DEG C in this tablet, then, decompression, obtains collapsing property of speed tablet of the present invention naturally.

Embodiment 4

PEARLITOL 25C 95.0w/w%, copolyvidone (Kollidon VA64 Fine, BASF Japan manufactures) 5.0w/w% are mixed.Use single-punching tablet press to make every tablet of tablet as 270mg (tablet diameters 9.0mm) taking the tabletting pressure of 1.0kN/ punching in this mixture.Tablet hardness is 10N (n=1).Then, use withstand voltage element to process 30 minutes under pressure carbon dioxide 6.0MPa, the condition of 40 DEG C in this tablet, then, decompression, obtains collapsing property of speed tablet of the present invention naturally.

Embodiment 5

PEARLITOL 25C 90.0w/w%, copolyvidone (Kollidon VA64 Fine, BASF Japan manufactures) 10.0w/w% are mixed.Use single-punching tablet press to make every tablet of tablet as 270mg (tablet diameters 9.0mm) taking the tabletting pressure of 1.0kN/ punching in this mixture.Tablet hardness is 10N (n=1).Then, use withstand voltage element to process 30 minutes under pressure carbon dioxide 6.0MPa, the condition of 40 DEG C in this tablet, then, decompression, obtains collapsing property of speed tablet of the present invention naturally.

Embodiment 6

エ Off メ Le ト (Fuji's chemistry is manufactured) 89.0w/w%, copolyvidone (Kollidon VA64Fine, BASF Japan manufactures) 10.0w/w% are mixed.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make every tablet of tablet as 180mg (tablet diameters 8.0mm) taking the tabletting pressure of 1.0kN/ punching.Tablet hardness is 17N (n=3).Intraoral disintegration time showing is 19 seconds (n=3).Then, use withstand voltage element to process 30 minutes under pressure carbon dioxide 6.0MPa, the condition of 40 DEG C in this tablet, then, decompression, obtains collapsing property of speed tablet of the present invention naturally.

Embodiment 7

エ Off メ Le ト (Fuji's chemistry is manufactured) 89.0w/w%, copolyvidone (Kollidon VA64Fine, BASF Japan manufactures) 10.0w/w% are mixed.In this mixture, coordinate 1.0w/w% magnesium stearate, use rotary tablet machine (HT-EX series, field ironworker manufacturing, below identical unless otherwise noted) to make the tablet (reference example 1) (tablet diameters 8.0mm) of every 180mg with the tabletting pressure of 1.0kN/ punching.Then, use withstand voltage element to process 5 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in this tablet, then, decompression, obtains collapsing property of speed tablet of the present invention naturally.

Embodiment 8

Use withstand voltage element to process 15 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 9

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 10

Use withstand voltage element to process 5 minutes under pressure carbon dioxide 8MPa, the condition of 25 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 11

Use withstand voltage element to process 15 minutes under pressure carbon dioxide 8MPa, the condition of 25 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 12

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 8MPa, the condition of 25 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 13

Use withstand voltage element to process 5 minutes under pressure carbon dioxide 4MPa, the condition of 35 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 14

Use withstand voltage element to process 15 minutes under pressure carbon dioxide 4MPa, the condition of 35 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 15

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 4MPa, the condition of 35 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 16

Use withstand voltage element to process 5 minutes under pressure carbon dioxide 8MPa, the condition of 35 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 17

Use withstand voltage element to process 15 minutes under pressure carbon dioxide 8MPa, the condition of 35 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 18

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 8MPa, the condition of 35 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 19

Use withstand voltage element to process 5 minutes under pressure carbon dioxide 4MPa, the condition of 45 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 20

Use withstand voltage element to process 15 minutes under pressure carbon dioxide 4MPa, the condition of 45 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 21

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 4MPa, the condition of 45 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 27kPa/ second.

Embodiment 22

Use withstand voltage element to process 5 minutes under pressure carbon dioxide 8MPa, the condition of 45 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 23

Use withstand voltage element to process 15 minutes under pressure carbon dioxide 8MPa, the condition of 45 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 24

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 8MPa, the condition of 45 DEG C with reference to the tablet of example 1, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition is carried out with about 16kPa/ second.

Embodiment 25

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 8MPa, the condition of 45 DEG C with reference to the tablet of example 1, then, with the about 800kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 26

Use withstand voltage element to process 2400 minutes under pressure carbon dioxide 8MPa, the condition of 45 DEG C with reference to the tablet of example 1, then, with the about 800kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 27

Use withstand voltage element to process 2400 minutes under pressure carbon dioxide 8MPa, the condition of 45 DEG C with reference to the tablet of example 1, then, with the about 16kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 28

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 20MPa, the condition of 45 DEG C with reference to the tablet of example 1, then, with the about 27kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 29

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 20MPa, the condition of 45 DEG C with reference to the tablet of example 1, then, with the about 2000kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 30

Use withstand voltage element to process 2400 minutes under pressure carbon dioxide 20MPa, the condition of 45 DEG C with reference to the tablet of example 1, then, with the about 2000kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 31

Use withstand voltage element to process 2400 minutes under pressure carbon dioxide 20MPa, the condition of 45 DEG C with reference to the tablet of example 1, then, with the about 27kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 32

Use withstand voltage element to process 30 minutes under pressure carbon dioxide 20MPa, the condition of 40 DEG C with reference to the tablet of example 1, then, with the about 2000kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 33

Use withstand voltage element to process 2400 minutes under pressure carbon dioxide 20MPa, the condition of 40 DEG C with reference to the tablet of example 1, then, with the about 2000kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Embodiment 34

PEARLITOL 25C 54.0w/w%, microcrystalline Cellulose (PHARMATRANS SANAQ AG manufacture) 20.0w/w%, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer (ソ Le プ ラ ス, BASF Japan manufactures) 15.0w/w%, polyvinylpolypyrrolidone (Kollidon CL, BASF Japan manufactures) 10.0w/w% are mixed.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make every tablet of tablet as 180mg (tablet diameters 8.5mm) taking the tabletting pressure of 1.0kN/ punching.Then, use withstand voltage element to process 30 minutes under pressure carbon dioxide 8.0MPa, the condition of 45 DEG C in this tablet, then, with the about 16kPa/ decompression rate decompression of second, obtain collapsing property of speed tablet of the present invention.

Comparative example 1

エ Off メ Le ト (Fuji's chemistry is manufactured) 89.0w/w%, copolyvidone (Kollidon VA64Fine, BASF Japan manufactures) 10.0w/w% are mixed.In this mixture, coordinate 1.0w/w% magnesium stearate, use rotary tablet machine to make every tablet of tablet as 180mg (tablet diameters 8.0mm) taking the tabletting pressure of about 2.5kN/ punching.

Test example 1

The tablet of embodiment 1,2,34 (n=1), embodiment 3～6 (n=3), embodiment 7～33, comparative example 1 (n=5) is measured to hardness.Hardness is used tablet hardness tester (tablet hardness tester, " rope niobium lattice ", 6D type, Suo Ni lattice company manufacture) to measure.The results are shown in table 3.

Test example 2

The tablet of reference example 1, embodiment 1,2,6,34 (n=1), embodiment 7～33, comparative example 1 (n=3) is measured to the intraoral disintegration time.The intraoral disintegration time is used intraoral disintegration tester (Tricorptester, Gang Tian Seiko company manufacture) to measure.The results are shown in table 3.

Test example 3

The tablet of reference example 1, embodiment 7～33, comparative example 1 is measured to thickness (n=5).The thickness of tablet uses digital display scale (Mitutoyo Absolute, three rich companies manufacture) to measure.The results are shown in table 3.

Test example 4

The tablet of reference example 1, embodiment 7～33, comparative example 1 is measured to porosity (n=1).Porosity is used sedimentating density measuring device (ア キ ュ PVC ッ Network 1330, GeoPyc ^tM1360, Mike Mo Ruitike company manufactures) measure.The results are shown in table 3.

Test example 5

Use carbon dioxide, copolyvidone (Kollidon VA64, BASF Japan) and Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer (Soluplus, BASF Japan) are processed.Pressure carbon dioxide during by processing and the glass transition temperature of each material are shown in table 1 (copolyvidone) and table 2 (Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer).

As a result, observe the phenomenon (table 1, table 2) that fusing point or glass transition temperature reduce.This glass transition temperature is obtained by confirming the temperature undergoing phase transition with the each material in the withstand voltage element of visual judgement.Like this, by using carbon dioxide, even near room temperature, also can utilize by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the phase transformation of the material with binding agent function, can be applied to collapsing property of speed tablet (particularly Orally disintegrating tablet) by forming crosslinked cellular structure between particle.

[table 1]

[table 2]

[table 3]

Reference example 2

For direct compression, in mannitol (Parteck M100, Merck manufacture), coordinate 1.0w/w% magnesium stearate (Parteck LUB MST, Merck manufacture at 99.0w/w%, below identical unless otherwise noted), use single-punching tablet press (オ ー ト グ ラ Off AGS-20kNG, Shimadzu Seisakusho Ltd. to manufacture, below identical unless otherwise noted) carry out tabletting (tablet diameters 8.5mm), making tablet hardness is that about 20N, tablet thickness are about 3.9mm.

Use withstand voltage element to process 60 minutes under pressure carbon dioxide 10MPa, the condition of 40 DEG C in these tablets, then decompression, obtains the tablet of reference example 2.

Reference example 3～8

For direct compression, in mannitol (Parteck M100, Merck manufacture), mix the various medicated premixs shown in 20.0w/w% table 4 at 79.0w/w%.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to carry out tabletting (tablet diameters 8.5mm), making tablet hardness is that about 20N, tablet thickness are about 3.9mm.

Use withstand voltage element to process 45 minutes under pressure carbon dioxide 6MPa, the condition of 25 DEG C in these tablets, then decompression, obtains the tablet of reference example 3～8.

Reference example 9～24

For direct compression, in mannitol (Parteck M100, Merck manufacture), mix the various medicated premixs shown in 20.0w/w% table 4 at 79.0w/w%.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to carry out tabletting (tablet diameters 8.5mm), making tablet hardness is that about 20N, tablet thickness are about 3.9mm.

Use withstand voltage element to process 60 minutes under pressure carbon dioxide 10MPa, the condition of 40 DEG C in these tablets, then decompression, obtains the tablet of reference example 9～24.

Test example 6

Reference example 2～24 is measured respectively to pressure carbon dioxide and process the tablet hardness of front and back.Hardness is used tablet hardness tester (tablet hardness tester, " rope niobium lattice ", 6D type, Suo Ni lattice company manufacture) to measure.The results are shown in table 4.

[table 4]

As shown in Table 4, for reference example 2, reference example 15～24, even if also do not observe the rising of tablet hardness after pressure carbon dioxide is processed, on the other hand, in reference example 3～14, confirm hardness and rise.By this results verification, by the medicated premix with reference to containing in example 3～14 and pressure carbon dioxide treatment combination, utilize the phase transformation of material to improve tablet hardness.Therefore, reference example 3～14 also can be used as embodiments of the invention.

Reference example 25

For direct compression, in mannitol (Parteck M100, Merck manufacture), mix the copolyvidone (Kollidon VA64 Fine, BASF Japan manufactures) of 20.0w/w% mean diameter 10～20 μ m at 79.0w/w%.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to obtain the tablet (tablet diameters 8.5mm) that tablet hardness is about 3.9mm for 19N, tablet thickness.Use withstand voltage element to process 45 minutes under pressure carbon dioxide 6MPa, the condition of 25 DEG C in this tablet, then decompression, obtains the tablet of reference example 25.

Test example 7

For the tablet of reference example 25, measure respectively the hardness of tabletting product and carbon dioxide treatment product.Hardness is used tablet hardness tester (tablet hardness tester, " rope niobium lattice ", 6D type, Suo Ni lattice company manufacture) to measure.The results are shown in table 5.

[table 5]

As shown in the result of table 5, known with the result that the tablet hardness of reference example 25 compares with reference to example 8, even in the case of using same composition as processing by pressure carbon dioxide the material with binding agent function, by must be less by particle diameter control, also can in the time processing induced transformation by pressure carbon dioxide, more effectively improve tablet hardness.Think that this is because by must be less by the particle diameter control of the composition of phase transformation, surface area increases, and crosslinkedly between particle is able to carry out more efficiently.Therefore, reference example 25 also can be used as embodiments of the invention.

Reference example 26

For direct compression, in mannitol (Parteck M100, Merck manufacture), mix 20.0w/w% ethyl cellulose (Ethocel standard 7 FP Premium, DOW Chemical manufacture) at 79.0w/w%.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to carry out tabletting (tablet diameters 8.5mm), making tablet hardness is that about 20N, tablet thickness are about 3.9mm.Use withstand voltage element to process 45 minutes under pressure carbon dioxide 6MPa, the condition of 25 DEG C in these tablets, then decompression, obtains the tablet of reference example 26.

Reference example 27

Ethyl cellulose (Ethocel standard 7 FP Premium, DOW Chemical manufacture) 13.5g and triethyl citrate (Triethyl Citrate, Tokyo change into manufacture) 1.5g are dissolved in ethanol (ethanol 99.5%, Northeast chemistry are manufactured) 150g, use spray dryer (mini spray exsiccator B-290, the manufacture of step fine jade, below identical unless otherwise noted) spraying is dried, and obtains thus ethyl cellulose/triethyl citrate (9/1) spraying dry product.

For direct compression, in mannitol (Parteck M100, Merck manufacture), mix 20.0w/w% ethyl cellulose/triethyl citrate (9/1) spraying dry product at 79.0w/w%.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to obtain the tablet (tablet diameters 8.5mm) that tablet hardness is about 3.9mm for 22N, tablet thickness.Use withstand voltage element to process 45 minutes under pressure carbon dioxide 6MPa, the condition of 25 DEG C in this tablet, then decompression, obtains the tablet of reference example 27.

Reference example 28

Ethyl cellulose (Ethocel standard 7 FP Premium, DOW Chemical manufacture) 11.25g and triethyl citrate (Triethyl Citrate, Tokyo change into manufacture) 3.75g are dissolved in ethanol (ethanol 99.5%, Northeast chemistry are manufactured) 150g, use spray dryer to spray dry, obtain thus ethyl cellulose/triethyl citrate (7.5/2.5) spraying dry product.

For direct compression, in mannitol (Parteck M100, Merck manufacture), mix 20.0w/w% ethyl cellulose/triethyl citrate (7.5/2.5) spraying dry product at 79.0w/w%.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to obtain the tablet (tablet diameters 8.5mm) that tablet hardness is about 3.9mm for 20N, tablet thickness.Use withstand voltage element to process 45 minutes under pressure carbon dioxide 6MPa, the condition of 25 DEG C in this tablet, then decompression, obtains the tablet of reference example 28.

Test example 8

The tablet of reference example 26～28 is measured respectively to the hardness before and after carbon dioxide treatment.Hardness is used tablet hardness tester (tablet hardness tester, " rope niobium lattice ", 6D type, Suo Ni lattice company manufacture) to measure.The results are shown in table 6.

[table 6]

By the results verification of table 6, for using the tablet of reference example 27 and 28 of the spraying dry product that contains plasticizer in ethyl cellulose, compared with the effect that only uses ethyl cellulose to bring, tablet hardness obtains improving more significantly.Therefore, reference example 26～28 also can be used as embodiments of the invention.

Embodiment 35

Using copolyvidone (Kollidon VA64, BASF Japan manufacture) aqueous solution (10.0w/w%) 100g as in conjunction with liquid; use fluidized bed pelletizer (seed-coating machine (フ ロ ー コ ー タ ー flows) FLO-1, the former making manufacturing in FREUND industry/great river; below identical unless otherwise noted) to PEARLITOL 25C (Pearitol 50C, ROCKET Japan manufactures, below identical unless otherwise noted), 410g carries out pelletize.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E (Eudragit EPO, win wound Japan manufacture, identical unless otherwise noted below), 5.0w/w% polyvinylpolypyrrolidone (manufacture of Kollidon CL-F, BASF Japan).In this mixture, coordinate 1.0w/w% magnesium stearate, use rotary tablet machine (HT-EX series, field ironworker manufacturing, below identical unless otherwise noted) to make every tablet of tablet as about 170mg (tablet diameters 8.5mm) taking the tabletting pressure of about 1kN/ punching.Tablet hardness is 11N (n=10).Use withstand voltage element to process after 5 minutes under pressure carbon dioxide 5MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 36

Use withstand voltage element to process 60 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in the tablet of embodiment 35, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 37

Use withstand voltage element to process 840 minutes under pressure carbon dioxide 3MPa, the condition of 25 DEG C in the tablet of embodiment 35, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 38

Use withstand voltage element to process 45 minutes under pressure carbon dioxide 4MPa, the condition of 15 DEG C in the tablet of embodiment 35, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 39

Use withstand voltage element to process 45 minutes under pressure carbon dioxide 4MPa, the condition of 45 DEG C in the tablet of embodiment 35, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 40

Use withstand voltage element to process 45 minutes under pressure carbon dioxide 3MPa, the condition of 60 DEG C in the tablet of embodiment 35, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 41

エ Off メ Le ト (Fuji's chemistry is manufactured) 89.0w/w%, amino alkyl methacrylate copolymer E 1.0w/w%, copolyvidone (Kollidon VA64, BASF Japan manufactures) 9.0w/w% are mixed.In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make every tablet of tablet as 170mg (tablet diameters 8.5mm) taking the tabletting pressure of about 1.5kN/ punching.Tablet hardness is 12N (n=3).Use withstand voltage element to process 120 minutes under pressure carbon dioxide 3MPa, the condition of 45 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 42

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 7.5w/w% amino alkyl methacrylate copolymer E, 10.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 190mg with the tabletting pressure of about 2.5kN/ punching.Tablet hardness is 27N (n=2).Use withstand voltage element to process 120 minutes under pressure carbon dioxide 3MPa, the condition of 45 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 43

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 20.0w/w% amino alkyl methacrylate copolymer E, 10.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 176mg with the tabletting pressure of about 2.0kN/ punching.Tablet hardness is 37N (n=2).Use withstand voltage element to process 840 minutes under pressure carbon dioxide 1MPa, the condition of 35 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 44

Using the mixed liquor of copolyvidone (Kollidon VA64, BASF Japan manufacture) aqueous solution (5.0w/w%) 50g and polyvidone (Kollidon K30, BASF Japan manufactures) aqueous solution (5.0w/w%) 50g as in conjunction with liquid, use fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 5.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use rotary tablet machine to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 171mg with the tabletting pressure of 1.0kN/ punching.Tablet hardness is 12N (n=10).Use withstand voltage element to apply after the nitrogen pressure of 10MPa in tablet, further under pressure carbon dioxide 5.0MPa, the condition of 25 DEG C, process 45 minutes, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 45

Use withstand voltage element to apply after the pressure carbon dioxide of 5.0MPa in the tablet of embodiment 44, further apply the nitrogen pressure of 5.0MPa, process 45 minutes under the condition of 25 DEG C, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 46

Using polyvidone (Kollidon K30, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 5.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use rotary tablet machine to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 170mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 13N (n=10).Use withstand voltage element to process 30 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 47

Using polyvinyl alcohol-acrylic acid-methylmethacrylate copolymer (POVACOAT Type F, Datong District change into industry manufacture) aqueous solution (5.0w/w%) 80g as in conjunction with liquid, use fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 320g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 8.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 16N (n=2).Use withstand voltage element to process 35 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 48

Using hydroxypropyl cellulose (HPC-SSL, Japanese Cao Da manufacture) aqueous solution (5.0w/w%) 80g as in conjunction with liquid, use fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 320g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 8.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 12N (n=2).Use withstand voltage element to process 45 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 49

Using hydroxypropyl emthylcellulose (TC-5E, SHIN-ETSU HANTOTAI's chemical industry are manufactured), aqueous solution (5.0w/w%) 80g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 320g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 8.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 12N (n=2).Use withstand voltage element to process 45 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 50

Using polyvinyl alcohol-polyethyleneglycol-graft copolymer (Kollicoat IR, BASF Japan manufactures), aqueous solution (5.0w/w%) 80g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 320g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 8.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 12N (n=2).Use withstand voltage element to process 45 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 51

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 9.0w/w% amino alkyl methacrylate copolymer E, 9.0w/w% low-substituted hydroxypropyl cellulose (L-HPC NBD-022, SHIN-ETSU HANTOTAI's chemical industry are manufactured).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 185mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 13N (n=3).Use withstand voltage element to process 35 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 52

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 5.0w/w% cross-linking sodium carboxymethyl cellulose (Kiccolate ND-2HS, Asahi Chemical Industry's chemistry are manufactured).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 12N (n=3).Use withstand voltage element to process 10 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 53

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 9.0w/w% amino alkyl methacrylate copolymer E, 9.0w/w% part alphalysed starch (PCS, Asahi Chemical Industry's chemistry are manufactured).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 9N (n=3).Use withstand voltage element to process 35 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 54

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 9.0w/w% amino alkyl methacrylate copolymer E, 9.0w/w% carboxymethyl starch sodium (Primojel, DMV-Fonterra Excipients manufacture).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 185mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 8N (n=3).Use withstand voltage element to process 10 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 55

Using copolyvidone (Kolidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 5.0w/w% carboxymethylcellulose calcium (ECG-505, five DS medicines are manufactured).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 181mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 10N (n=3).Use withstand voltage element to process 10 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 56

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 9.0w/w% amino alkyl methacrylate copolymer E, 9.0w/w% alphalysed starch (SWELSTAR PD-1, Asahi Chemical Industry's chemistry are manufactured).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 184mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 8N (n=3).Use withstand voltage element to process 35 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 57

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 9.0w/w% amino alkyl methacrylate copolymer E, 9.0w/w% carboxymethyl cellulose (NS-300, five DS medicines are manufactured).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 181mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 11N (n=3).Use withstand voltage element to process 10 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 58

Using polyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In this granules 7.59g, mix acetaminophen (manufacture of Yamamoto chemical industry) 0.56g, amino alkyl methacrylate copolymer E 1.0g, polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures) 0.75g.In this mixture, coordinate magnesium stearate 0.10g, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 12N (n=3).Use withstand voltage element to process 25 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 59

Using polyvidone (Kollidon K30, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In this granules 7.04g, mix famotidine (Astellas pharmacy manufacture) 1.11g, amino alkyl methacrylate copolymer E 1.0g, polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures) 0.75g.In this mixture, coordinate magnesium stearate 0.10g, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 16N (n=3).Use withstand voltage element to process 25 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 60

Using polyvidone (Kollidon K30, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In this granules 8.09g, mix tamsulosin hydrochlorate (Astellas pharmacy manufacture) 0.056g, amino alkyl methacrylate copolymer E 1.0g, polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures) 0.75g.In this mixture, coordinate magnesium stearate 0.10g, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 180mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 17N (n=3).Use withstand voltage element to process 25 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 61

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 20.0w/w%HPMCAS (AQOAT AS-HF, SHIN-ETSU HANTOTAI's chemical industry are manufactured), 8.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 176mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 25N (n=3).Use withstand voltage element to process 45 minutes under pressure carbon dioxide 5MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 62

Using copolyvidone (Kollidon VA64, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 15.0w/w%HPMCAS (AQOATAS-HF, SHIN-ETSU HANTOTAI's chemical industry are manufactured), 8.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 176mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 25N (n=3).Use withstand voltage element to process 840 minutes under pressure carbon dioxide 5MPa, the condition of 45 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 63

Use withstand voltage element to process 45 minutes under pressure carbon dioxide 5MPa, the condition of 60 DEG C in the tablet of embodiment 62, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 64

Using polyvidone (Kollidon K30, BASF Japan manufactures), aqueous solution (10.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 410g.In a part for this granules, mix 15.0w/w% ethyl cellulose (Ethocel standard 7 FP Premium, DOW Chemical manufacture), 8.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures), 1.0w/w%l-menthol (Northeast chemistry is manufactured).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 171mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 21N (n=3).Use withstand voltage element to process 45 minutes under pressure carbon dioxide 5MPa, the condition of 60 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 65

Use withstand voltage element to process 120 minutes under pressure carbon dioxide 3.5MPa, the condition of 25 DEG C in the tablet of embodiment 35, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 66

Use withstand voltage element to process 120 minutes under pressure carbon dioxide 3.5MPa, the condition of 25 DEG C in the tablet of embodiment 46, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 67

Use withstand voltage element to process 120 minutes under pressure carbon dioxide 3.5MPa, the condition of 25 DEG C in the tablet of embodiment 44, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 68

Using polyvidone (Kollidon K30, BASF Japan manufactures), aqueous solution (5.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 415g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 5.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use rotary tablet machine to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 171mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 10N (n=10).Use withstand voltage element to process 40 minutes under pressure carbon dioxide 4MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Embodiment 69

Using polyvidone (Kollidon K30, BASF Japan manufactures), aqueous solution (5.0w/w%) 100g, as in conjunction with liquid, uses fluidized bed pelletizer to carry out pelletize to PEARLITOL 25C 415g.In a part for this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 5.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use rotary tablet machine to make the tablet (tablet diameters 8.5mm) of every agreement that contracts a film or TV play to an actor or actress 186mg with the tabletting pressure of about 1.8kN/ punching.Tablet hardness is 19N (n=10).Use withstand voltage element to process 90 minutes under pressure carbon dioxide 3.5MPa, the condition of 25 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Comparative example 2

By the tablet of embodiment 35 in atmosphere, carry out at 60 DEG C, after the processing of 45 minutes, obtaining the tablet of comparative example 2.

Comparative example 3

By the tablet of embodiment 69 in atmosphere, carry out at 70 DEG C, after the processing of 840 minutes, obtaining the tablet of comparative example 3.

Comparative example 4

By the tablet of embodiment 70 in atmosphere, carry out at 70 DEG C, after the processing of 840 minutes, obtaining the tablet of comparative example 4.

Test example 9

Tablet to embodiment 35～69, comparative example 2～4 is measured respectively hardness.Hardness is used tablet hardness tester (tablet hardness tester, " rope niobium lattice ", 6D type, Suo Ni lattice company manufacture) to measure.The results are shown in table 7.

Test example 10

The tablet of embodiment 35～69, comparative example 2～4 is measured to the intraoral disintegration time.The intraoral disintegration time is used intraoral disintegration tester (Tricorptester, Gang Tian Seiko company manufacture) to measure.The results are shown in table 7.

Test example 11

The tablet of embodiment 35～69, comparative example 2～4 is measured to thickness (n=5).The thickness of tablet uses digital display scale (Mitutoyo Absolute, three rich companies manufacture) to measure.The results are shown in table 7.

Test example 12

Collapsing property of the speed tablet of embodiment 65～69, comparative example 3～4 is packaged in PTP sheet (34 × 111mm, 7 × 2 row/sheet), carries out shatter test with following condition.

Height of fall: 150cm

Fall number of repetition: 10 times

The PTP sheet number of testing: 10

PTP sheet towards: make medicine containing portion (capsule) upward

Breakage rate: (breaking and/or damaged collapsing property of speed number of tablets)/140 × 100

The results are shown in table 7.

[table 7]

As shown in Table 7, it is crosslinked that amino alkyl methacrylate copolymer E, the HPMCAS being caused by pressure carbon dioxide processing by utilization and the phase transformation of ethyl cellulose produce, and can obtain collapsing property of the speed tablet of the present invention that tablet hardness is improved.

Specifically, in embodiment 35～43, confirmed, appropriately combined by the addition of amino alkyl methacrylate copolymer E, carbon dioxide treatment pressure, treatment temperature, processing time are carried out, can obtain collapsing property of speed tablet of the present invention.In comparative example 2, in atmosphere, at 60 DEG C, implement the heat treated of 45 minutes, but do not observed the rising of tablet hardness.On the other hand, in embodiment 35, at 25 DEG C, carry out the processing of 5 minutes by the pressure carbon dioxide with 5MPa, confirm the remarkable rising of tablet hardness, can confirm thus, even under the gentle temperature environment of near room temperature, also can realize the rising of tablet hardness.

In embodiment 44～45, confirm, by carbon dioxide and nitrogen are used in combination, can induce equally the rising of tablet hardness.Demonstrated the probability that can utilize in the present invention other gases on the basis of carbon dioxide by this result.

In embodiment 46～50, show, as the binding agent using, can use the various general binding agents such as polyvidone, polyvinyl alcohol-acrylic acid-methylmethacrylate copolymer in granulating working procedure.

In embodiment 51～57, show, by utilizing the various general disintegrating agents such as low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose or part alphalysed starch as disintegrating agent, can obtain collapsing property of speed tablet of the present invention.

In embodiment 58～60, confirm, for containing the preparation of model drug, also can obtain having collapsing property of the speed tablet of same performance.

In embodiment 61～64, show, by by HPMCAS or ethyl cellulose and pressure carbon dioxide treatment combination, also can similarly improve tablet hardness with amino alkyl methacrylate copolymer E, can obtain collapsing property of speed tablet of the present invention.Demonstrate thus following probability: in reference example, the additive group for the composition to have the function of utilizing pressure carbon dioxide to make tablet hardness raising as representative, by suitable recipe design, also can obtain collapsing property of speed tablet of the present invention.

Embodiment 65～69 is evaluated to the breakage rate in shatter test, all confirmed 0～0.7% low-down breakage rate.On the other hand, for utilizing heat treated with collapsing property of the speed tablet of embodiment 68,69 same formulas but not carbon dioxide is increased to for the comparative example 3,4 of equal extent tablet hardness, demonstrate 2.1～5% relatively high breakage rate.Show thus, the breakage resistance of collapsing property of speed tablet of the present invention is also good.

Embodiment 70

Using copolyvidone (Kollidon VA64, BASF Japan manufacture) aqueous solution (10.0w/w%) 100g as in conjunction with liquid, use fluidized bed pelletizer to carry out pelletize to the microgranule 80.7g that contains YM 905 (Astellas pharmacy manufacture) and there is bitterness shielding function.In this granules, mix 10.0w/w% amino alkyl methacrylate copolymer E, 5.0w/w% polyvinylpolypyrrolidone (Kollidon CL-F, BASF Japan manufactures).In this mixture, coordinate 1.0w/w% magnesium stearate, use single-punching tablet press to make the tablet (YM 905 content 5mg) (tablet diameters 7.5mm) of every agreement that contracts a film or TV play to an actor or actress 150mg with the tabletting pressure of about 1kN/ punching.Tablet hardness is 10N (n=3).Use withstand voltage element to process 30 minutes under pressure carbon dioxide 5MPa, the condition of 35 DEG C in tablet, then decompression, obtains collapsing property of speed tablet of the present invention.In addition, decompression rate condition was carried out with about 1MPa/ minute.

Comparative example 5

By the tablet of embodiment 70 in atmosphere, at 70 DEG C, implement the heat treated of 840 minutes, obtain the tablet of comparative example 5.

Test example 13

Collapsing property of speed tablet to embodiment 70 and the tablet of comparative example 5 are measured respectively hardness.Hardness is used tablet hardness tester (tablet hardness tester, " rope niobium lattice ", 6D type, Suo Ni lattice company manufacture) to measure.The results are shown in table 8.

Test example 14

The bitterness using in embodiment 70 is covered to collapsing property of the speed tablet of particle, embodiment 70 and the tablet of comparative example 5 carries out dissolution test.Dissolution test device uses dissolving-out tester NTR-6100A (Fushan Mountain chemistry is manufactured), for the dissolution rate of YM 905, uses chromatograph of liquid (Shimadzu Seisakusho Ltd.'s manufacture) to measure.Experimental condition is as follows.

Oar method 50rpm

Experimental liquid: Japanese Pharmacopoeia slaking test the second liquid (pH6.8) 900mL

Experimental liquid temperature: 37 DEG C ± 0.5 DEG C

Sample injection time: 2 minutes, 30 minutes

The results are shown in table 8.

Test example 15

The bitterness using in embodiment 70 is covered to collapsing property of the speed tablet of particle, embodiment 70 and the tablet of comparative example 5, measure with respect to growing amount total amount, that measure maximum analytes of YM 905 and analyte thereof (below sometimes referred to as the growing amount of main analyte) with respect to total analyte amount (being designated hereinafter simply as analyte total amount) of the total amount of YM 905 and analyte thereof.The results are shown in table 8.

[table 8]

As shown in Table 8, collapsing property of the speed tablet of embodiment 70 has growing amount and the analyte total amount of covering the main analyte of particle equal extent with bitterness, and on the other hand, the tablet of comparative example 5 is observed significant increase.

Utilizability in industry

The present invention can improve the breakage of the tablet occurring in circulation operation, can fully maintain the various functions of giving for temperature or the unsettled medicine of humidity or the solid dispersion particle, the bitterness that are made up of insoluble drug being covered to functional particle that particle, slow-releasing particle etc. be endowed the desired function being brought by the characteristic of medicine, and collapsing property of speed tablet (particularly Orally disintegrating tablet) can be provided.

Above, describe the present invention according to specific mode, but to those skilled in the art apparent distortion and improvement within the scope of the present invention.

Claims (25)

1. collapsing property of a speed tablet, it contains medicine and by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material with binding agent function, and obtains by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process.

2. collapsing property of speed tablet as claimed in claim 1, wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material that fusing point or glass transition temperature are reduced.

3. collapsing property of speed tablet as claimed in claim 1 or 2, wherein, the material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to have binding agent function is for selecting one or more the material in the group of free following substances composition:

Vinylpyrrolidone/vinyl acetate copolymer, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, polyvidone, the pre-mixed formulation of polyvidone and vinyl acetate resin, Eudragit L100D55, polyvinyl alcohol-polyethyleneglycol-graft copolymer, the pre-mixed formulation of polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxy propylidene (67) glycol, Polyethylene Glycol, polyoxyethylene castor oil hydrogenated (40), amino alkyl methacrylate copolymer E, Eudragit L100, dry Eudragit L100D55, Eudragit L100D55, Eudragit S100, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, EUDRAGIT NE 30 D EUDRAGIT NE 30D dispersion liquid, ethyl cellulose, methyl methacrylate-diethyl aminoethyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, Lac, carbomer and polyvinyl acetal lignocaine acetas.

4. collapsing property of the speed tablet as described in any one in claim 1～3, wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is more than 0.1 % by weight and below 50 % by weight with respect to the weight of tablet.

5. collapsing property of the speed tablet as described in any one in claim 1～4, wherein, also contains plasticizer.

6. collapsing property of the speed tablet as described in any one in claim 1～5, wherein, also contains disintegrating agent.

7. collapsing property of the speed tablet as described in any one in claim 1～6, wherein, tablet hardness is more than 20N.

8. collapsing property of the speed tablet as described in any one in claim 1～7, wherein, the ratio of the damaged sheet number being obtained by shatter test is below 5%.

9. collapsing property of the speed tablet as described in any one in claim 1～8, wherein, collapsing property of speed tablet is Orally disintegrating tablet.

10. collapsing property of speed tablet as claimed in claim 9, wherein, the intraoral disintegration time is in 120 seconds.

11. collapsing property of speed tablets as described in any one in claim 1～10, wherein, medicine forms temperature or the unsettled medicine of humidity and/or functional particle.

12. collapsing property of speed tablets as claimed in claim 11, wherein, functional particle is the freely particle of one or more in molecular group of following grain of choosing:

Solid dispersion particle, the bitterness being made up of insoluble drug covers particle and slow-releasing particle.

The manufacture method of 13. 1 kinds of collapsing property of speed tablets, it comprises:

The operation of (1) medicine being mixed with the material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process with binding agent function,

(2) mixture of (1) is carried out to compression molding and prepare tablet operation and

(3) operation that the carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide are processed by the tablet utilization of (2).

The manufacture method of 14. collapsing property of speed tablets as claimed in claim 13, wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process the material that fusing point or glass transition temperature are reduced.

The manufacture method of 15. collapsing property of speed tablets as described in claim 13 or 14, wherein, the material by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process to have binding agent function is for selecting one or more the material in the group of free following substances composition:

Vinylpyrrolidone/vinyl acetate copolymer, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, polyvidone, the pre-mixed formulation of polyvidone and vinyl acetate resin, Eudragit L100D55, polyvinyl alcohol-polyethyleneglycol-graft copolymer, the pre-mixed formulation of polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol, polyoxyethylene (196) polyoxy propylidene (67) glycol, Polyethylene Glycol, polyoxyethylene castor oil hydrogenated (40), amino alkyl methacrylate copolymer E, Eudragit L100, dry Eudragit L100D55, Eudragit L100D55, Eudragit S100, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, EUDRAGIT NE 30 D EUDRAGIT NE 30D dispersion liquid, ethyl cellulose, methyl methacrylate-diethyl aminoethyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, Lac and carbomer.

The manufacture method of 16. collapsing property of speed tablets as described in any one in claim 13～15, wherein, the material that has a binding agent function by utilizing carbon dioxide in supercritical or subcritical state or liquid or atmospheric carbon dioxide to process is more than 0.1 % by weight and below 50 % by weight with respect to the weight of tablet.

The manufacture method of 17. collapsing property of speed tablets as described in any one in claim 13～16, wherein, also contains plasticizer.

The manufacture method of 18. collapsing property of speed tablets as described in any one in claim 13～17, wherein, also contains disintegrating agent.

The manufacture method of 19. collapsing property of speed tablets as described in any one in claim 13～18, wherein, tablet hardness is more than 20N.

The manufacture method of 20. collapsing property of speed tablets as described in any one in claim 13～19, wherein, collapsing property of speed tablet is Orally disintegrating tablet.

The manufacture method of 21. collapsing property of speed tablets as claimed in claim 20, wherein, the intraoral disintegration time is in 120 seconds.

The manufacture method of 22. collapsing property of speed tablets as described in any one in claim 13～21, wherein, medicine forms temperature or the unsettled medicine of humidity and/or functional particle.

The manufacture method of 23. collapsing property of speed tablets as claimed in claim 22, wherein, functional particle is the freely particle of one or more in molecular group of following grain of choosing:

Solid dispersion particle, the bitterness being made up of insoluble drug covers particle and slow-releasing particle.

The manufacture method of 24. collapsing property of speed tablets as described in any one in claim 13～23, wherein, comprising: utilize that 0.1MPa is above and 50MPa is following and-40 DEG C of above and 100 DEG C of following carbon dioxide are processed.

The manufacture method of 25. collapsing property of speed tablets as described in any one in claim 13～24, wherein, utilizes atmospheric carbon dioxide to process.