CN102170912A - Compression-molded preparation and method for producing the same - Google Patents
Compression-molded preparation and method for producing the same Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
Provided are a compression-molded preparation such as an oral disintegrating preparation which has a property of rapidly disintegrating in the oral cavity and also has a hardness required for production, transportation, or the like and simultaneously does not cause a problem even if the preparation is produced with high productivity; and a method for producing the same. The compression-molded preparation contains a sugar alcohol, starch or a starch-derived compound and a polymeric binder selected from the group consisting of a polyvinyl alcohol-based polymer and copolyvidone. The method for producing the compression-molded preparation comprises a step of granulating a sugar alcohol with an aqueous solution obtained by dissolving starch or a starch-derived compound and a polymeric binder selected from the group consisting of a polyvinyl alcohol-based polymer and copolyvidone to form granules, and then a step of compression-molding the resulting granules.
Description
Technical field
The present invention relates to compressed-shaping formulation and manufacture methods thereof such as Orally disintegrating tablet, more specifically, relate to a kind of compressed-shaping formulation and manufacture method thereof, described compressed-shaping formulation has the hardness in the degree of producing, can loss when carrying, and in the oral cavity, have excellent disintegrative, and then be lifted at the manufacturing on the existing equipment.
Background technology
At present, as the dosage form of medicine, from simplicity, take the aspect of easiness, oral agents such as tablet, capsule, granule, powder are the most widely-used.But there is the problem that is difficult to take in most this oral formulations for old people, child or dysphagic patient.
Therefore, though dry syrup etc. also is provided, it is in order to take easily, and can when taking, suspend in water and make syrup, but when said preparation is powder or granular form, even if be packaged as dose respectively one time, sometimes also can be in packing residual content, when Kaifeng its part may be scattered etc., have problems aspect the appropriate amount taking.
Therefore, in recent years, in order to solve the problem of taking, just at active development: there is not water also can take and at the tablet and even the lozenge of intraorally rapidly disintegrating; Even under the situation of taking that is dissolved in the water, also can be dissolved into tablet and even lozenge in the aqueous solvent fast.
For example, as the manufacture method of tablet as described above and even lozenge, known have: the manufacture method (patent documentation 1) of the mixture of the moisture that contains the moistening degree of particle surface being carried out the Orally disintegrating tablet of tabletting; With unformed saccharide as main body, carry out compression forming with low pressure after, tablet be positioned under the humidification make it moistening, carry out the manufacture method (patent documentation 2 and 3) of exsiccant Orally disintegrating tablet again.But, though these technology all can obtain roughly to keep in aqueous solvent immediately disintegrable, carry the preparation of required hardness, but need the processing of moisture in the manufacturing process, the placement under the high humility etc., the problem that may cause stability because of relation with employed physiologically active ingredient, in addition, from the aspect of manufacturing process's management, also may not necessarily be satisfactory.In addition, with the prior art for preparing preparation time, the pressure in the time of need be with compression forming is adjusted to constant, has the setting of the creating conditions complicated problems that becomes.
To this, find before the inventor etc., coat the granule that sugar obtains by using with Magnesiumaluminumsilicate (magnesium aluminometasilicate), thereby do not need the processing, the placement under the high humility of the moisture in the manufacturing process, special manufacturing process etc., can obtain Orally disintegrating tablet by common manufacture method, and carry out patent application (patent documentation 4).
Yet, when compressed-shaping formulations such as manufacturing Orally disintegrating tablet, require further to boost productivity.That is, the general manufacture method as tablet adopts following method: in order to simplify working process, and mix the method (direct compression process) of directly carrying out tabletting as raw-material additive; The uniformity of the content of the biological active substances of adding in order to guarantee, and form the method that granule carries out tabletting more for the time being.But, under the situation of direct compression process, be difficult to sometimes handle as raw-material powder body, in addition, after forming granule, carry out having following shortcoming under the situation of method of tabletting: disperse etc. owing to result from the powder of the following granule of specified particle diameter due to increasing, and cause productivity ratio to reduce.And then, under the situation of making compressed-shaping formulation, attaching in order to suppress pestle, push up and split (capping), lamination (lamination), die friction tabletting defectives such as (die friction), compression forming need spend the more time than usual.Therefore, because the tablet manufacturing number of time per unit lacks than common tablet, so there is the problem of producing rate variance.And then, under the situation of the hardness that can't manage tablet fully, can cause producing, the breakage when carrying the problem that exists yield rate to reduce.
As the technology that solves the problem in the above-mentioned manufacturing, the inventor finds, by use all or part of as the crystalline mannitol of δ type as carrier components, even thereby shorten the compression forming time, the compressed-shaping formulation that also can obtain to have in intraoral immediately disintegrable and the hardness that can tolerate production, carry is an Orally disintegrating tablet, in addition, the amount of the micropowder during by the minimizing pelletize, can suppress powder disperses, and then, by improving compression forming, the damage of preparation in the time of can reducing production, conveying, and carried out patent application (patent documentation 5).Yet, even utilize this invention, compare with common tabletting, reduced the manufacturing quantity hourly of compacting shape machine, and if do not use in the common compression forming special machinery such as obsolete external lubrication device, can't compression forming.Therefore, in fact, room for improvement is arranged still as the autofrettage of the high compressed-shaping formulation of economy.
The prior art document
Patent documentation
Patent documentation 1: Japanese kokai publication hei 5-271054 communique
Patent documentation 2: Japanese kokai publication hei 11-12162 communique
Patent documentation 3: Japanese kokai publication hei 11-349475 communique
Patent documentation 4: TOHKEMY 2002-308760 communique
Patent documentation 5:WO2006/106923
Summary of the invention
The problem that invention will solve
Therefore, in the manufacturing of compressed-shaping formulation, a kind of technology need be provided, it has at intraoral immediately disintegrable, and have required hardness such as production, conveying concurrently, even simultaneously do not use special device also can guarantee high production rate, problem of the present invention promptly is the technology that provides such.
The scheme that is used to deal with problems
The inventor etc. further investigate at compressed-shaping formulation, found that, the solution that contains specific polymer system binding agent such as starch or starch source machining object and polyvinyl alcohol etc. by use carries out pelletize to sugar alcohols such as mannitols, even thereby under very high speed tabletting condition, also can obtain to have concurrently, thereby finished the present invention as the disintegrative of the excellence of Orally disintegrating tablet and the compressed-shaping formulation of hardness fully.
That is, the present invention is a kind of compressed-shaping formulation, and it contains the chemical compound of sugar alcohol, starch or starch source and is selected from polymer system binding agent in the group of being made up of vinol series polymer and copolyvidone (copolyvidone).
In addition, the present invention is a kind of manufacture method of compressed-shaping formulation, it is characterized in that, with chemical compound that is dissolved with starch or starch source and the aqueous solution that is selected from the polymer system binding agent in the group of forming by vinol series polymer and copolyvidone sugar alcohol is carried out pelletize and makes granule, then with its compression forming.
The effect of invention
According to the present invention, can obtain a kind of compressed-shaping formulation, even it uses high speed tablet press to surpass 50,000 slice/hour speed is carried out tabletting, also need not special device, can not cause pestle attach, push up split, tabletting defective such as die friction, and taken into account disintegrative and hardness.In addition, even the high speed tabletting by suitable adjustment tabletting pressure, also can be regulated the hardness of preparation or in intraoral disintegration time.
Like this, by the present invention, owing to can high speed production have compressed-shaping formulations such as Orally disintegrating tablet,, can increase substantially productivity ratio so can shorten the production time, raise the efficiency, improve yield rate etc. in the hardness of the disintegrative of intraoral appropriateness and appropriateness.
The specific embodiment
As the sugar alcohol that uses in the compressed-shaping formulation of the present invention, for example can list mannitol, xylitol, Sorbitol, erythritol etc., wherein preferred mannitol.And then when using mannitol as sugar alcohol, preferred all mannitols are the δ type, and perhaps the part mannitol is the δ type, is other crystal formations in addition.
That is, though there are α, the β that can discern, the polymorphic of δ type in the known mannitol by the result of X-ray diffraction, because δ type mannitol wherein has the effects such as friction that reduce between the pestle mortar, so expectation contains part δ type mannitol at least.
When using mannitol as sugar alcohol, the amount of δ type mannitol is not particularly limited, and more than whole 3 quality % of mannitols (below, only with " % " expression), is preferably more than 5%, more preferably more than 10%, more preferably more than 20%.
In addition, the starch that uses among the present invention or the chemical compound of starch source (hereinafter referred to as " starch based ") are utilized as being dissolve or swell in binding agent in the water (below, abbreviate " binding agent " sometimes as) at normal temperatures.
In this starch based, the chemical compound of starch source is to make the starch that is not dissolved in usually in the water be in the chemical compound of all or part of dissolved state with any means, particularly, can list αization thing, the hydrolysate of starch.
In addition, so-called αization is meant by adding the starch of heat leak in water and cuts off the hydrogen bond that is used to keep crystal structure, and makes water enter the state of crystal structure.Particularly, by making starch suspension in water and heat this suspension, can carry out αization.In addition,, also comprise at least its part through the starch of αization in the starch of αization, that is, in fact through the starch of αization.
In addition, as the chemical compound through αization, commercially available have alphalysed starch, so also can utilize this commercially available product at present.In addition, through the starch of αization, commercially available have the part alphalysed starch as in fact, so also can utilize this commercially available product.
And then starch also is " starch based " through the additive of hydrolysis, can make full use of in the present invention.As the concrete example of this glucidtemns, can list dextrin.And then pulullan polysaccharide also can be given full play to the effect of this patent, this pulullan polysaccharide be cultivate a kind of black yeast be Aureobasidium pullulans (
Aureobasidium pullulans) and obtain, be maltotriose rule and exactly with the natural polysaecharides of α-1,6 bonding.
And then, the vinol series polymer that utilizes among the present invention, copolyvidone also play a role (below, sometimes they are generically and collectively referred to as " polymer system binding agent ") as binding agent.
Wherein, so-called vinol series polymer is polyvinyl alcohol described later or vinyl alcohol and other monomeric copolymers.Wherein, as the copolymer of polyvinyl alcohol, can list the part from main chain branches out the copolymer of other polymer as graft copolymer, the formation unit of polymer is irregularly arranged as random copolymer copolymer or block copolymer etc.As the object lesson of graft copolymer, can list polyvinyl alcohol-polyethyleneglycol-graft copolymer, as the object lesson of random copolymer, can list polyvinyl alcohol-acrylic copolymer.
In the above-mentioned polymer system binding agent, as polyvinyl alcohol, its molecular weight is preferably 10,000～300, and about 000, be preferably especially about 30,000～200,000.This polyvinyl alcohol can be by making or obtain with the vinyl acetate polyisocyanate polyaddition and with its saponification.In addition, be categorized as fully saponified type and partly-hydrolysed type, no matter use which kind of polyvinyl alcohol all can give full play to effect of the present invention among the present invention according to saponified degree.
In addition, aforementioned polymer is in the binding agent, polyvinyl alcohol-polyethyleneglycol-graft copolymer be shown in following formula (I) like that main chain by Polyethylene Glycol (PEG) part constitutes, side chain is made of polyvinyl alcohol (PVA) part PEG and the graft copolymer of PVA.
(in the formula, l
1, l
2And l
3Represent natural number independently.)
As this polyvinyl alcohol-polyethyleneglycol-graft copolymer, its molecular weight is preferably 10,000～100, and about 000, be preferably especially about 30,000～70,000.In addition, in this polyvinyl alcohol-polyethyleneglycol-graft copolymer, the weight ratio of peg moiety and PVA part is preferably 1: 0.1～and 10.As this polyvinyl alcohol-polyethyleneglycol-graft copolymer, because the commercially available Kollicoat IR (trade name) that has BA SF company to make so can use this commercially available product, also can use other goods.
And then in the polymer system binding agent, polyvinyl alcohol-acrylic copolymer is the copolymer that comprises PVA, acrylic acid and (methyl) acrylic acid methyl ester. shown in following formula (II) like that.
(in the formula, R ' is essentially hydrogen atom, but its part also can be acetyl group, m
1, m
2And m
3Represent natural number independently.)
The molecular weight of this polyvinyl alcohol-acrylic copolymer is preferably 10,000～200, and about 000, be preferably especially about 30,000～100,000.In this polyvinyl alcohol copolymer, the weight ratio of PVA and acrylic acid and methyl methacrylate is preferably 1: 0.01～and 0.1: 0.1～0.5.As this polyvinyl alcohol-acrylic copolymer, there is day newly to change into the POVACOAT (trade name) that company makes owing to commercially available, so can use this commercially available product, also can use other goods.
And then in the polymer system binding agent, copolyvidone is the such copolymer of l-vinyl-2-pyrrolidone and vinylacetate shown in following formula (III).
(in the formula, n
1And n
2Represent natural number independently.)
As this copolyvidone, its molecular weight is preferably 10,000～100, and about 000, be preferably especially about 45,000～70,000.In this copolyvidone, the weight ratio of l-vinyl-2-pyrrolidone and vinylacetate is not particularly limited, be preferably 1: 5～and 0.1, more preferably 1: 1～0.5.As this copolyvidone, because the commercially available kollidon VA64 (trade name) that has BASF AG to make so can use this commercially available product, also can use other goods.
In the compressed-shaping formulation of the present invention, the use level of sugar alcohol is about 30～98% in preparation, is preferably 50～95%.In addition, the use level of starch based is about 0.01～10% in preparation, is preferably about 0.05～5%, and the use level of polymer system binding agent is about 0.01～10% in preparation, is preferably about 0.05～2%.In addition, about the cooperation ratio of starch based, be 0.1～5 preferably with respect to sugar alcohol 100 with respect to sugar alcohol, about the cooperation ratio of polymer system binding agent, be 0.5～10 preferably with respect to sugar alcohol 100 with respect to sugar alcohol.
As using the above-mentioned example that respectively becomes to assign to prepare the method for optimizing of compressed-shaping formulation of the present invention, can list following method: at first, make starch based and polymer system binding agent the dissolving or be suspended in the purified water equal solvent, use this dissolving or suspension that sugar alcohols such as mannitol are carried out pelletize.
As the prilling granulator that uses this moment,, then be not particularly limited so long as can form comminutor with the state that does not almost have micropowder as the shot-like particle of common tabletting with granule.But if consider productivity ratio etc., the comminutor that then preferably lists fluidized bed pelletizer, stirring granulating machine, extruding granulator, rotary pelleting machine, Wurster comminutor or they are combined as the comminutor of the best, can list fluidized bed pelletizer.
The pelletize thing that forms of pelletize then is compressed molding and preparationization like this.This compression forming so long as the method for general compression forming then can be not particularly limited to be used.For example, by the powder preparing granule that will mix as mannitol of sugar alcohol etc., starch based, polymer system binding agent and biological active substances and the inorganic salts that cooperates as required or other any compositions, with this granule with common tablet machine for example rotary tablet machine, single punch tablet machine etc. carry out compression forming, thereby can prepare compressed-shaping formulation.
In addition, if consider actual production, then preferred compacting shape machine is a rotary tablet machine.At this moment, if be accompanied by actual production, then the productivity ratio hourly for compression molding is not particularly limited, but is preferably per 1 hour more than 50,000, more preferably more than 100,000.Because rotary tablet machine changes the compression forming time by the rotating speed of rotating disk, so can bring very big influence to tabletting characteristics.In addition, same with the rotating speed of rotating disk, the size of known rotating disk also can be brought influence to tabletting characteristics.
Therefore, by adjusting these factors, production capacity also difference can occur.Usually, lower or its radius of the rotating speed of rotating disk more can not produce the tabletting defective, can stably produce.On the other hand, if rotating speed lower or/and the radius of rotating disk shorter, then since productivity ratio hourly reduce, so do not meet actual production.Therefore, with the rotating speed hourly (rpm) of rotating disk square with the product representation of the radius (radius of this moment is the distance (m) at the center from the center to the mortar) of rotating disk the time, with more than 50, be preferably more than 80, situation that more preferably condition more than 150 is carried out tabletting is suitable for actual production.
In addition, pressure when carrying out compression forming, as long as intraoral disintegration time, quality suitably and during fabrication, do not break during carrying damagedly etc., then be not particularly limited, preferably with 100～2000kgf, more preferably carry out compression forming with 300～1500kgf.
And then compressed-shaping formulation of the present invention also can be made Orally disintegrating tablet.So-called Orally disintegrating tablet of the present invention, so long as when being contained in compressed-shaping formulation in the oral cavity fast disintegrate get final product, as concrete disintegration time,, be preferably in 1 minute, more preferably in 30 seconds for being contained in the oral cavity in back 3 minutes.And this Orally disintegrating tablet of being finished of invention is the preparation that is increased to for breaking of carrying etc., for damaged more than the present level, has given the durability same with common compressed-shaping formulation.As the index of verifying these, utilize the wear intensity test method(s) of the tablet of putting down in writing in the 15th edition Pharmacopeia of Japan to estimate.
Particularly, in the wear intensity testing machine of in the 15th edition Pharmacopeia of Japan, putting down in writing, put into the tablet of 100 compressed molding, make device running 30 minutes.Then, the tablet weight before and after the determination test is obtained the slip of tablet weight by following formula.Consequently, the slip of tablet weight is that 5.0% following person is a preferred compressed-shaping formulation of the present invention, more preferably below 2.0%, and the preferred especially compressed-shaping formulation below 1.0%.
Weight * 100 before slip (%)=(weight after the weight-test before the test)/test
When the manufacturing of compressed-shaping formulation of the present invention, except aforementioned starch based and polymer system binding agent, can also use known other binding agents.As the preference of such binding agent, can list: the chemical compound by a cellulosic part is replaced by hydrophilic substituent group in the water soluble; By starch based hydrolysis, αization being dissolvable in water the chemical compound in the water; Or cellulose, starch etc. are taken place by microorganism etc. material of chemical change etc.Particularly, can list hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, dextrin, pulullan polysaccharide, soluble poly vinyl pyrrolidone etc.
And then, also be not particularly limited about the adding method of inorganic compound, for example have: the method for adding when the pelletize with sugar alcohols such as mannitols, add method in the binding agent liquid (granulation liquid) to, the method in the granule after adding pelletize to etc.In addition, also can adopt the method that inorganic compound is coated on the pelletize thing of sugar alcohol and starch based and polymer system binding agent.Wherein, preferable methods is: the method for adding method in the binding agent liquid to, the granule after the pelletize being coated, add the method in the granule after the pelletize to, best method is: to mannitol and method that the pelletize thing of dissolving or swollen binding agent coats in water at normal temperatures or the method for adding after pelletize.
Compressed-shaping formulation of the present invention contains biological active substances basically as effective ingredient.The cooperation of biological active substances in compressed-shaping formulation, can carry out in arbitrary stage of making compressed-shaping formulation, for example can list: the method that physiologically active ingredient is cooperated when the pelletize with sugar alcohol, the method in the binding agent liquid of adding to, the method that cooperates simultaneously with granule etc. through pelletize.
And then, the physiologically active ingredient that cooperates as can be used as effective ingredient, also be not particularly limited, for example can utilize sleeping pill, antianxiety drug, Anti-epileptics, the antipyretic-antalgic agent, antiparkinsonism drug, the neural medication of spirit, the autonomic nerve medicine, tranquilizer, cardiac tonic, the arrhythmia medication, diuretic, depressor, vasoconstrictor, vasodilation, the hyperlipemia medication, anti-tussive agents, expectorant, bronchodilator, diarrhea, the peptic ulcer medication, digestive pharmaceutical is good for the stomach, antacid, cathartic, the hormone agent, vitamin, nourish analeptic, enzyme preparation, the diabetes agent, hydryllin, anti-allergic agent, antibiotic formulations, synthetic antibacterial agents, the effective ingredient of antiblooming agent etc. is a physiologically active ingredient.
Wherein, as the physiologically active ingredient of sleeping pill, antianxiety drug, for example can list alprazolam, estazolam, quazepam, triazolam, brotizolam, amobarbital, tandospirone etc.; As the physiologically active ingredient of Anti-epileptics, for example can list phenytoin, carbamazepine, clonazepam, phenytoin etc.; As the physiologically active ingredient of antipyretic-antalgic agent, for example can list acetaminophen, Phenacetin, mefenamic acid, aspirin, ethenzamide, isopropylantipyrine, sodium salicylate, indomethacin, diclofenac, tiaramide, actarit, ampiroxicam, ibuprofen, etodolac, ketoprofen, Zaltoprofen, piroxicam, pranoprofen, loxoprofen etc.; As the physiologically active ingredient of anti-parkinson agent, for example can list amantadine, biperiden, selegiline, benzhexol, cabergoline, pergolide etc.; As the neural physiologically active ingredient of spirit, for example can list chlorpromazine, perphenazine, trifluoperazine, imipramine, etizolam, olanzapine, quazepam, sulpiride, haloperidol, risperidone etc. with agent; As the physiologically active ingredient of autonomic nerve agent, for example can list the Kapp ammonium, this bright, tolazoline etc.; As ataractic physiologically active ingredient, can list N-butylscopolammonium bromide, papaverine, eperisone, tizanidine, baclofen etc.
In addition, as cardiac tonic, for example can list Digitoxin, hot high, methyl ground suffering height, aminophylline, caffeine, etilefrine, ubidecarenone etc.; As the arrhythmia agent, for example can list procainamide, atenolol, oxprenolol, carteolol, Propranolol, nadolol, pindolol, bisoprolol, ajmaline, pilsicainide, Propafenone, methicillin, disopyramide etc.; As diuretic, for example can list hydrochlorothiazide, spironolactone, acetazolamide, isosorbide, torasemide, furosemide etc.; As depressor, for example can list hydralazine, reserpine, alacepril, imidapril, quinapril, captopril, cilazapril, enalapril, lisinopril, methyldopa, efonidipine, celiprolol, nicardipine, prazosin, betaxolol, Manidipine, carvedilol, metoprolol, cilnidipine, felodipine, doxazosin etc.; As vasoconstrictor, for example can list midodrine, dihydroergotamine etc., as vasodilation, for example can list isosorbide mononitrate, etafenone, diltiazem, benidipine, dipyridamole, sorbide nitrate, nicorandil, nisoldipine, nitroglycerine, nifedipine etc.; As the hyperlipemia agent, for example can list chlorine Bei Te, fenofibrate, bezafibrate, atorvastatin, elastoser, nicomol, pravastatin, fluvastatin, probucol, simvastatin etc.
And then, as anti-tussive agents, for example can list ephedrine, methylephedrine, oscapine, benproperine etc.; As expectorant, for example can list carbocisteine, bromhexine, ambroxol, bark of cherry, codeine, paracodin, tipepidine etc.; As bronchodilator, for example can list theophylline, fenoterol, albuterol, clenbuterol, tulobuterol, special U.S. quino, procaterol, formoterol etc.; As the diarrhea medicines for relieving intestinal disorders, for example can list berberine, albumin, lactobacillus bifidus, lactasinum, simethicone, loperamide etc.; As the peptic ulcer agent, for example can list glutamine, azulene, ranitidine, cimetidine, famotidine, nizatidine, roxatidine, aldioxa, pirenzepine, omeprazole, gefarnate, sucralfate, sulpiride, sofalcone, teprenone, troxipide, irsogladine, rabeprazole, lansoprazole etc.; As the digestive pharmaceutical that is good for the stomach, for example can list amylase, diastase (diastase), pancreatin, nux vomica tincture, carnitine, tilactase etc.; As antacid, for example can list magnesium silicate, magnesium oxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate etc.; As cathartic, for example can list Folium Sennae extract, sennoside, magnesium sulfate, sodium picosulfate etc.
And then, as the hormone agent, for example can list levothyrocine, liothyronine, thiamazole, propylthiouracil, cortisone, paramethasone, dexamethasone, betamethasone, prednisolone, testosterone, fostestrol, estriol, chlormadinone, allylestrenol, Chloramiphene, danazol, Tamsulosin, flavoxate, midodrine, gamma oryzanol etc.; As vitamin, for example can list vitamin A, calcitriol, thiamine, fursultiamine, riboflavin, pantethine, pantothenic acid, pyridoxin, folic acid, cobamamide, mecobalamin, ascorbic acid, tocopherol, phytonadione, menatetrenone, biotin etc.; As enzyme preparation, for example can list lysozyme, Serrapeptase etc.; As the diabetes agent, for example can list gliclazide, glibenclamide, glimepiride, tolbutamide, metformin, acarbose, voglibose etc.; As hydryllin, for example can list diphenhydramine, promethazine, mequitazine, chlorphenamine, clemastine etc.; As the antiallergic agent, for example can list ibudilast, azelastine, epinastine, cetirizine, suplatast tosilate, tranilast, ketotifen, pranlukast, pemirolast, loratadine etc.
And then, as antibiotic, for example can list clindamycin, lincomycin, vancomycin, kanamycin, amoxicillin, aminobenzylpenicillin, cefaclor, cefalexin, cefixime, cefpodoxime, cefdinir, cefteram, cefpodoxime, fosfomycin, faropenem, erythromycin, azithromycin, clarithromycin, Roxithromycin, chloromycetin, tetracycline, minocycline, sulfasalazine, ciprofloxacin, Gatifloxacin, norfloxacin, acyclovir, itraconazole, terbinafine, fluconazol, miconazole etc.
In the Orally disintegrating tablet of the present invention, except mentioned component, in the scope of not damaging effect of the present invention, can suitably use known in the past any composition, for example various lubricants, solubilizing agent, buffer agent, adsorbent, suspending agent, antioxidant, filler, pH regulator agent, excipient, dispersant, disintegrating agent, disintegrate auxiliary agent, damp proof compound, antiseptic, solvent, dissolution aids, fluidizing reagent etc.
Wherein, as excipient, for example can list lactose, castor sugar, crystalline cellulose, glucosan, dextrin, glucose, pulverized sugar etc.As disintegrating agent, for example can list carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, low substitution degree hydroxy-propyl methylcellulose, crystalline cellulose, hydroxypropyl starch etc.
In addition, as lubricant, for example can list magnesium stearate, calcium stearate, stearic acid, Talcum, sucrose fatty acid ester etc.In addition, as covering, for example can list hydroxypropyl emthylcellulose, ethyl acrylate/methylmethacrylate copolymer, amino alkyl methacrylate copolymer E, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S etc.And then, as the flavoring composition, for example can list citric acid, tartaric acid, malic acid etc.As foaming agent, for example can list sodium bicarbonate etc.As the artificial sweetening, for example can list saccharin sodium, glycyrrhizic acid dipotassium, aspartame, Folium Stevlae Rebaudianae, Suo Matian etc.As screening agent, for example can list gastric solubility macromolecules such as water-insoluble macromolecule, methyl methacrylate/butyl methacrylate/diethylaminoethyl methacrylate copolymer such as ethyl cellulose etc.
Above Shuo Ming compressed-shaping formulation of the present invention can be taken into account production, the sufficient hardness when carrying and at intraoral immediately disintegrable.In addition, even in per 1 hour 50,000～200,000 such high speed tabletting for example, also the tabletting defective can not take place, wear intensity is also low, so can expect high production rate.
Embodiment
Below list embodiment, the present invention is described in more detail, but the present invention is not subjected to any restriction of these embodiment.
Embodiment 1
Orally disintegrating tablet:
Prescription and method for making according to following table 1 have been made Orally disintegrating tablet.
＜prescription 〉
[table 1]
| Tablet 1 | Tablet 2 | Tablet 3 | Tablet 4 | |
| The D-mannitol | 124.96 | 124.96 | 124.96 | 124.96 |
| δ type mannitol | 41.00 | 41.00 | 41.00 | 41.00 |
| Polyvinyl alcohol *1 | 0.9 | - | - | - |
| Polyvinyl alcohol-polyethyleneglycol-graft copolymer *2 | - | 0.9 | - | - |
| Copolyvidone *3 | - | - | 0.9 | - |
| Polyvinyl alcohol-acrylic copolymer *4 | - | - | - | 0.9 |
| Alphalysed starch | 1.80 | 1.80 | 1.80 | 1.80 |
| Polyvinylpolypyrrolidone | 9.00 | 9.00 | 9.00 | 9.00 |
| Aspartame | 0.90 | 0.90 | 0.90 | 0.90 |
| Magnesium stearate | 1.44 | 1.44 | 1.44 | 1.44 |
| Amount to | 180.00 | 180.00 | 180.00 | 180.00 |
* 1:GOHSENOL EG-05; Japan synthetic chemistry Co., Ltd. makes
* 2:Kollicoat IR; BASF AG makes
* 3:Kollidon VA64; BASF AG makes
* 4:POVACOAT; Day newly changes into company and makes
＜method for making 〉
Polyvinyl alcohol and alphalysed starch are dissolved in the water, are prepared into aqueous solution.Use this aqueous solution, the mixture of D-mannitol and δ type mannitol is carried out pelletize with fluidized bed.In this pelletize thing, add polyvinylpolypyrrolidone, aspartame and magnesium stearate and carry out compression forming, obtain the Orally disintegrating tablet of every 180mg.In addition, in the compression forming Shi Yong field make the medium-sized tablet machine of HT-X45MS-UW type (radical of the radius of rotating disk: 23cm, pestle: 45), with the tabletting pressure setting is 800kgf, and the rotating speed of rotating disk is changed between 20 times～60 times/minute, make Orally disintegrating tablet (as " tablet 1 ").In addition, about tablet 2～4, replace similarly being prepared with above-mentioned method for making the polyvinyl alcohol except using polyvinyl alcohol-polyethyleneglycol-graft copolymer (tablet 2), copolyvidone (tablet 3), polyvinyl alcohol-acrylic copolymer (tablet 4) respectively.
Embodiment 2
The evaluation of Orally disintegrating tablet (1):
For the Orally disintegrating tablet of preparation among the embodiment 1, estimate hardness, wear intensity, the having or not of gained tablet 1～4 in intraoral disintegration time and tabletting defective.It is the results are shown in table 2.
＜evaluation methodology 〉
The evaluation of projects is following to be carried out.
Hardness: use durometer (tablet breaking strength measuring device TH-303MP: measure the hardness of tablet Fushan Mountain Industry Co., Ltd).
Wear intensity: use wear intensity testing machine (tablet wear intensity testing machine: confirm the wear condition (test period 30 minutes, 100 of tablet quantity) of tablet Minatomedical Co., Ltd.)
The intraoral disintegration time:, as the experimenter tablet of manufacturing is contained in the mouth with the adult male, measures the time of tablet till the disintegrate.
Having or not of tabletting defective: to top in the tabletting split, lamination, stick together, die friction, pestle attach etc., and having or not of tabletting defective estimated.
＜result 〉
[table 2]
Consequently, be between 20～60 times/minute at rotating speed, can obtain hardness, wear intensity excellence and not have the Orally disintegrating tablet of tabletting defective, as can be known according to prescription of the present invention, can realize the per hour high speed tabletting more than 50,000.
Embodiment 3
The evaluation of Orally disintegrating tablet (2):
In the tablet 1 of embodiment 1, with the speed setting of rotating disk is 40 times/minute, and change tabletting pressure, and similarly prepare Orally disintegrating tablet in addition, estimate hardness, wear intensity, the having or not of gained tablet similarly to Example 2 in intraoral disintegration time and tabletting defective.It is the results are shown in table 3.
＜result 〉
[table 3]
By this result as can be known, even rotating speed is 40 times/minute such high speed rotating, also can obtain hardness, wear intensity excellence and not have fast disintegrating tablet in the oral cavity of tabletting defective, by under this condition, changing tabletting pressure, can obtain the Orally disintegrating tablet of hardness, intraoral disintegration asynchronism(-nization) as can be known.
Utilizability on the industry
Compressed-shaping formulation of the present invention has concurrently in intraoral immediately disintegrable and the required hardness such as production, conveying, can advantageously use in the situation of oral administration and various physiological activators.
In addition, according to the manufacture method of compressed-shaping formulation of the present invention, even if there is not the external lubrication device, can not cause yet pestle attach, push up split, the compressing tablet defective such as die friction, can stably carry out compressing tablet, even shorten the compressed-shaping formulation that the compression forming time also can obtain to have immediately disintegrable. In addition, because can be to carry out compression forming at a high speed, so productivity ratio obtains tremendous raising.
Therefore, the inventive method is highly beneficial as the manufacture method of compressed-shaping formulation.
Claims (15)
1. compressed-shaping formulation, it contains the chemical compound of sugar alcohol, starch or starch source and is selected from polymer system binding agent in the group of being made up of vinol series polymer and copolyvidone.
2. compressed-shaping formulation according to claim 1, wherein, sugar alcohol is a mannitol.
3. compressed-shaping formulation according to claim 1 and 2, wherein, all or part of of mannitol is the δ type.
4. according to each described compressed-shaping formulation in the claim 1～3, wherein, the content of sugar alcohol is with respect to whole 30～98 quality % that consist of of preparation.
5. according to each described compressed-shaping formulation in the claim 1～4, wherein, the chemical compound of starch or starch source can be dissolved in water or the hot water.
6. according to each described compressed-shaping formulation in the claim 1～5, wherein, all or part of of the chemical compound of starch or starch source is alphalysed starch.
7. according to each described compressed-shaping formulation in the claim 1～6, wherein, the content of the chemical compound of starch or starch source is with respect to whole 0.01～10 quality % that consist of of preparation.
8. according to each described compressed-shaping formulation in the claim 1～7, wherein, vinol series polymer is polyvinyl alcohol, polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol-acrylic copolymer.
9. according to each described compressed-shaping formulation in the claim 1～8, wherein, the content of polymer system binding agent is with respect to whole 0.01～10 quality % that consist of of preparation.
10. according to each described compressed-shaping formulation in the claim 1～9, it also contains physiologically active ingredient.
11. according to each described compressed-shaping formulation in the claim 1～9, it is an Orally disintegrating tablet.
12. the manufacture method of a compressed-shaping formulation, it is characterized in that, with chemical compound that is dissolved with starch or starch source and the aqueous solution that is selected from the polymer system binding agent in the group of forming by vinol series polymer and copolyvidone sugar alcohol is carried out pelletize, make granule, then with its compression forming.
13. the manufacture method of compressed-shaping formulation according to claim 12, wherein, vinol series polymer is polyvinyl alcohol, polyvinyl alcohol-polyethyleneglycol-graft copolymer and polyvinyl alcohol-acrylic copolymer.
14. according to the manufacture method of claim 12 or 13 described compressed-shaping formulations, it also cooperates physiologically active ingredient in the operation of any in compressed-shaping formulation.
15. according to the manufacture method of each described compressed-shaping formulation in the claim 12～14, wherein, per 1 hour tabletting number is more than 50,000.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008254536 | 2008-09-30 | ||
| JP2008-254536 | 2008-09-30 | ||
| PCT/JP2009/066753 WO2010038695A1 (en) | 2008-09-30 | 2009-09-28 | Compression-molded preparation and method for producing the same |
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| Publication Number | Publication Date |
|---|---|
| CN102170912A true CN102170912A (en) | 2011-08-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2009801387678A Pending CN102170912A (en) | 2008-09-30 | 2009-09-28 | Compression-molded preparation and method for producing the same |
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| Country | Link |
|---|---|
| JP (1) | JP5694773B2 (en) |
| CN (1) | CN102170912A (en) |
| TW (1) | TW201023850A (en) |
| WO (1) | WO2010038695A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106236717A (en) * | 2016-08-30 | 2016-12-21 | 佛山市弘泰药物研发有限公司 | A kind of Zaltoprofen oral cavity disintegration tablet and preparation method thereof |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120121703A1 (en) * | 2010-07-20 | 2012-05-17 | Japan Tobacco Inc. | Tablet containing ferric citrate |
| CN103429229A (en) * | 2010-12-17 | 2013-12-04 | 默克专利股份有限公司 | Method for producing [delta]-mannitol which can be directly tableted |
| JP6245786B2 (en) * | 2011-10-17 | 2017-12-13 | 大同化成工業株式会社 | Pharmaceutical binding agent and preparation using the binding agent |
| JP6204141B2 (en) * | 2013-04-22 | 2017-09-27 | テイカ製薬株式会社 | Oral rapidly disintegrating composition for solid preparation |
| JP2015063521A (en) * | 2013-09-02 | 2015-04-09 | 科研製薬株式会社 | Tablet with high drug content and production method thereof |
| JP6188183B1 (en) * | 2016-05-23 | 2017-08-30 | 大原薬品工業株式会社 | Method for stable production of high-drug compressed tablets |
| JP7322475B2 (en) * | 2019-04-04 | 2023-08-08 | ニプロ株式会社 | Tablets containing azilsartan |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3871791T2 (en) * | 1987-03-25 | 1993-01-21 | Du Pont | USE OF VOMYL ALCOHOL'S HOMO- AND COPOLYMERS FOR TABLETING ACTIVE SUBSTANCES. |
| WO1999033445A1 (en) * | 1997-12-29 | 1999-07-08 | The Procter & Gamble Company | Tablet composition |
| AU2571800A (en) * | 1999-02-17 | 2000-09-04 | Kyowa Hakko Kogyo Co. Ltd. | Tablets and process for producing tablets |
| JP2005306778A (en) * | 2004-04-21 | 2005-11-04 | Basf Ag | Sustained-release formulation and method for producing the same |
| JP2006282551A (en) * | 2005-03-31 | 2006-10-19 | Taiyo Yakuhin Kogyo Kk | Orally disintegrating tablet and method for producing the same |
| DK1884242T3 (en) * | 2005-05-26 | 2013-05-06 | Dainippon Sumitomo Pharma Co | PHARMACEUTICAL COMPOSITION COMPREHENSIVE LURASIDON |
| JP5142517B2 (en) * | 2005-12-20 | 2013-02-13 | 武田薬品工業株式会社 | Colored dragees |
| EP1852108A1 (en) * | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| TWI414310B (en) * | 2006-12-26 | 2013-11-11 | Daiichi Sankyo Co Ltd | Elution-improved pharmaceutical preparation |
-
2009
- 2009-09-28 CN CN2009801387678A patent/CN102170912A/en active Pending
- 2009-09-28 WO PCT/JP2009/066753 patent/WO2010038695A1/en active Application Filing
- 2009-09-28 JP JP2010531841A patent/JP5694773B2/en active Active
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106236717A (en) * | 2016-08-30 | 2016-12-21 | 佛山市弘泰药物研发有限公司 | A kind of Zaltoprofen oral cavity disintegration tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
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| JP5694773B2 (en) | 2015-04-01 |
| WO2010038695A1 (en) | 2010-04-08 |
| TW201023850A (en) | 2010-07-01 |
| JPWO2010038695A1 (en) | 2012-03-01 |
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