[go: up one dir, main page]

EP1070497A1 - Comprime et procedes de fabrication de comprime - Google Patents

Comprime et procedes de fabrication de comprime Download PDF

Info

Publication number
EP1070497A1
EP1070497A1 EP99913634A EP99913634A EP1070497A1 EP 1070497 A1 EP1070497 A1 EP 1070497A1 EP 99913634 A EP99913634 A EP 99913634A EP 99913634 A EP99913634 A EP 99913634A EP 1070497 A1 EP1070497 A1 EP 1070497A1
Authority
EP
European Patent Office
Prior art keywords
tablet
lubricant
active substance
die
punches
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99913634A
Other languages
German (de)
English (en)
Other versions
EP1070497A4 (fr
Inventor
Hiroyuki Morimoto
Eiji Hayakawa
Motohiro Ohta
Kiyoshi Morimoto
Yasushi Watanabe
Tomohiko Goto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kyowa Kirin Co Ltd
Original Assignee
Kyowa Hakko Kogyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co Ltd filed Critical Kyowa Hakko Kogyo Co Ltd
Publication of EP1070497A1 publication Critical patent/EP1070497A1/fr
Publication of EP1070497A4 publication Critical patent/EP1070497A4/fr
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B30—PRESSES
    • B30B—PRESSES IN GENERAL
    • B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
    • B30B15/0005—Details of, or accessories for, presses; Auxiliary measures in connection with pressing for briquetting presses
    • B30B15/0011—Details of, or accessories for, presses; Auxiliary measures in connection with pressing for briquetting presses lubricating means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/005—Coating of tablets or the like

Definitions

  • the present invention relates to a tablet production method, particularly a method wherein a tablet can be immediately disintegrated at an objective part, a method wherein a tablet with an engraved mark or a dividing line or an anomalous tablet can be produced without causing sticking and so on, and a method wherein a tablet including granule covered with film (so called multiple unit tablet) can be easily manufactured without damaging function of the granule.
  • the present invention also relates to a tablet which can be rapidly disintegrated at a target region of a living body such as oral cavity, a tablet wherein function of the contained granule isn't damaged, and a tablet added with function such as sustained release which isn't damaged when divided.
  • a tablet and a capsule are very useful pharmaceuticals for carrying and dosing and a tablet is easy to be taken for elder person or a patient because it doesn't float on the water when dosing with water. Further, it has many advantages such that production cost can be held down. Therefore, it is a most multipurpose dosage form for oral administration and intrabuccal administration.
  • tablets such as an uncoated tablets made by compressing powder or granule, a coating tablet covered with a film on the tablet body for the purpose of prolongation, sustained release, rapid release, high solubility in stomach, high solubility in intestine, prevention of bitter taste, and so on, a matrix type tablet (single unit tablet) tabletted by dispersing active substance in a base matrix of release inhibition material with hydrophobic property or hydrophilic property, and a tablet (multiple unit tablet) 101 including granule produced by tabletting molding material in which granule 102 containing active substance, diluting agent 103, and lubricant 104 are uniformly mixed liken in Fig.20(a).
  • granule 102 containing active substance included in the tablet (multiple unit tablet) 101 in order that a fixed amount of active substance is continuously released for a fixed time by one dosage of the tablet 101 or the granule 102 is dissolved at an objective region such as intestine, there are granule of which part 102a containing active substance is covered with a film 102b having sustained release or high solubility in intestine as shown in Fig.20(b) or granule wherein the active substance 102c is dispersed in a base insoluble in water such as fat, wax, and Vaseline or in the base matrix 102d of hydrophobic high molecular material such as silicon rubber, and plastic and an interface of the base matrix 102d is retreated accompanied with release of the active substance 102c from the base matrix 102d so that the active substance 102c is continuously leased as shown in Fig.20(c).
  • lubricant such as magnesium stearate, lauryl sodium sulphate, and talc are mixed in a molding material other than active substance and diluting agent in order to execute smooth tabletting by preventing adhering of molding material on punches and dies and griding between the punches and the dies at the time of producing tablets by compressing molding material by means of the punches and the dies, and for the purpose of preventing defective tablets causing sticking (phenomenon causing hurt on a tablet surface when molding material is adhered on the punch surface), capping (phenomenon showing peeling of the top of tablet like a cap), laminating (phenomenon showing peeling of the tablet like a layer), and binding (phenomenon causing lengthwise hurt on the tablet surface when a tablet is discharged from the die).
  • lubricant such as magnesium stearate, lauryl sodium sulphate, and talc are mixed in a molding material other than active substance and diluting agent in order to execute smooth tabletting by preventing
  • Fig.21 shows a production method disclosed in JP-B-41-11273.
  • a spray nozzle 159 for spraying lubricant L is provided above the die 151 and lubricant L is applied on a surface 153s (lower surface) of the upper punch 153 and a surface 154s (upper surface) of the lower punch 154, both of which are provided for the die 151 which comes to a place where the spray nozzle 159 is placed.
  • molding material is charged in the die 151 as shown in Fig.21(b), and the charged material m is compressed by means of the upper punch 153 on which lower surface 153s is applied with lubricant L and the lower punch 154 of which upper surface 154s is applied with lubricant as shown in Fig.21(c).
  • the member indicated by the numeral 152 in Fig.21 shows a rotary table provided with the die 151 (The same numeral is used in Fig.22.).
  • Fig.22 shows a tablet production method described in JP-A-56-14098.
  • a spray 156 for spraying lubricant L and a nozzle 159 for spraying air are provided above the die 151.
  • Lubricant L is sprayed in the spray 156 when the die 151 comes where the spray 156 is provided as shown in Fig.22(a), lubricant is applied on a surface 154s (upper surface) of a lower punch 154 provided for the die 151 as shown in Fig.22(b).
  • compressed air is sprayed on the lower punch 154 at a position where the nozzle 159 is provided, lubricant L applied on the upper surface 154s of the lower punch 154 is blown upwardly to be dispersed, then the dispersed lubricant L is attached on an inner wall 151s of the die 151 and a surface 153s (lower surface) of an upper punch 153.
  • molding material m is compressed to produce a tablet by means of lubricated inner wall 151s of the die 151, lubricated lower surface 153s of the upper punch 153, and lubricated upper surface 154s of the lower punch 154.
  • a tablet produced by an internal lubricant method includes lubricant therein and has a problem wherein disintegrating time of a tablet is delayed because of water repellency of lubricant so that it becomes hard to produce a tablet which is required to be rapidly disintegrated at a target region like an intrabuccally rapidly disintegrable tablet.
  • a tablet with an engraved mark a tablet with a dividing line or an anomalous tablet with different shape are produced according to prior internal lubricant method or external lubricant spraying method, the produced tablet is apt to cause sticking, capping, laminating and binding.
  • high tabletting pressure is required (generally 1 ton/cm 2 - 2 ton/cm 2 ) in order to obtain practical hardness. Therefore, when a tablet containing granule (multiple unit tablet) 101 is produced according to this method, the film 102b formed on the surface of the granule 102 contained in the tablet 101 is damaged when tabletted, or the granule 102 is plastically deformed or destroyed when unreasonable force is applied to the granule 102 so that functions of the granule 102 contained in the tablet 101 such as rapid release, sustained release, prolongation of mode of action, or function of dissolving at an objective region can't be obtained.
  • a tablet containing granule multiple unit tablet
  • pharmaceuticals containing granule, so called microcapsule are not launched on the marked as a formulation such as tablet which is easily taken by a patient or patients but as formulations such as capsule or granule which are not easily taken by a patient or patients.
  • a single unit type tablet which is coated with such as film or sugar on the surface of the tabletted uncoated tablet is popular as a tablet having the functions such as prolongation of made of action, sustained release, rapid release, high solubility in stomach, high solubility in intestine or prevention of bitter taste.
  • a single unit type tablet is formed as a dividable tablet having a dividing line on the surface, the film is destroyed and the function added to the tablet is lost when the tablet is divided.
  • the present invention is proposed to solve the above-mentioned problems.
  • the first object of the present invention is to provide a production method of a tablet which is required to be immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet.
  • the second object of the present invention is to provide a production method of a tablet with an engraved mark or a dividing line or an anomalous tablet without causing sticking, capping, laminating and binding.
  • the third object of the present invention is to provide a tablet production method wherein a tablet containing granule (multiple unit tablet) can be produced without damaging the function of the granule (which may be called as a microcapsule) contained therein, to provide a tablet containing granule (multiple unit tablet) which can be immediately dissolved at an objective region, a tablet containing granule (multiple unit tablet) of which function isn't damaged without specially devising the construction and the material of the film formed on the granule.
  • the object of the present invention is to provide a dividable tablet with a dividing line which has prolongation of mode of action, sustained release, rapid release, high solubility in stomach, high solubility in intestine, prevention of bitter taste, and such functions aren't damaged when the tablet is divided.
  • the inventors of the present invention have done research on a tablet production method for a long time and found by experiments that when punches and a die of a tabletting machine are housed in a spraying chamber, pulsating vibration air is generated in the spraying chamber, lubricant is applied on the surfaces of the punches and the die, and molding material is tabletted by means of the lubricated punches and die to produce a tablet with an engraved mark or a dividing line or an anomalous tablet, such tablets haven't caused sticking, capping, laminating and binding. After hard endeavor, they have completed the present invention.
  • JP-A-7-124231 a tablet production method in JP-A-7-124231 wherein molding material is prevented from adhering on the punches and the dies so that molding material can be continuously tabletted smoothly and stably for a long time and moreover a tablet can be produced without adhering molding material on the punches and the dies even if the amount of used lubricant is remarkably reduced.
  • the inventors have thought that when this method is used, a tablet which has enough practical hardness and further its disintegrant time isn't delayed can be produced even if tabletting pressure is low. After hard endeavor, they have completed the present invention.
  • a tablet including at least active substance is produced by means of a die and a pair of punches.
  • the method is comprised of preparing molding material including active substance; housing the pair of punches and the die in a spraying chamber; generating pulsating vibration air and spraying lubricant mixed in air in the spraying chamber; applying lubricant on the surfaces of the pair of punches and the die housed in the spraying chamber while the lubricant sprayed in the spraying chamber is mixed with the pulsating vibration air, and tabletting the molding material by means of the pair of punches and the die on which surfaces the lubricant is applied.
  • Lubricant isn't specifically limited, for example, there are stearate acid metal salt (magnesium stearate, calcium stearate and so on), stearic acid, sodium lauryl sulfate, sodium lauryl magnesium, powdered gum arabic, carnauba wax, anhydrous silicic acid, magnesium oxide, silic acid hydrate, boric acid, fatty acid sodium salt, leucine, and so on which have been commonly used. One of them may be used solely or more than two of them may be combined.
  • stearate acid metal salt magnesium stearate, calcium stearate and so on
  • stearic acid sodium lauryl sulfate
  • sodium lauryl magnesium powdered gum arabic, carnauba wax, anhydrous silicic acid, magnesium oxide, silic acid hydrate, boric acid, fatty acid sodium salt, leucine, and so on which have been commonly used.
  • stearate acid metal salt magnesium stearate, calcium stearate and so
  • diluting agent is added in molding material for forming the shape of a tablet other than active substance.
  • diluting agent there are several kinds, such as saccharides (lactose, sucrose, glucose, mannitol, and so on), starch (for example, potato, wheat, corn and so on), inorganic substance (calcium carbonate, calcium sulfate, sodium bicarbonate, sodium chloride, and so on), crystalline cellulose, powdered plant (powdered glycyrrhiza, powdered gentian, and so on).
  • saccharides lactose, sucrose, glucose, mannitol, and so on
  • starch for example, potato, wheat, corn and so on
  • inorganic substance calcium carbonate, calcium sulfate, sodium bicarbonate, sodium chloride, and so on
  • crystalline cellulose powdered plant (powdered glycyrrhiza, powdered gentian, and so on).
  • Molding material containing active substance may include binder, supplement such as solution adjuvant, solubilizer, or disintegrant, corrigent, colorant, adjuvant for pharmaceiticals, antioxidant, preservative, opacifying agent, antistatic agent, aroma, sweetening agent, fluidizing agent, flavoring agent, and so on if required other than active substance and diluting agent.
  • binder supplement such as solution adjuvant, solubilizer, or disintegrant, corrigent, colorant, adjuvant for pharmaceiticals, antioxidant, preservative, opacifying agent, antistatic agent, aroma, sweetening agent, fluidizing agent, flavoring agent, and so on if required other than active substance and diluting agent.
  • molding material is powdered or granular material which doesn't include lubricant.
  • Pulsating vibration air in the present invention means a wave of air of which air pressure is changed. Positive or negative pulsating vibration air may be used and of which amplitude, wave length, wave shape, frequency, and period may not be limited if it can generate air vibration all over the spraying chamber and forcibly diffuse the particle of lubricant sprayed therein.
  • Pulsitive pulsating vibration air used in this invention includes both positive pulsating vibration air of which peak and valley are positive and positive pulsating vibration air of which peak is higher than atmospheric pressure and valley is almost the same as atmospheric pressure.
  • Negative pulsating vibration air used in this invention includes both pulsating vibration air of which peak and valley are negative and pulsating vibration air of which peak is almost the same as atmospheric pressure and valley is negative.
  • Conditions of pulsating vibration air depend on size and shape of punches and dies of a tabletting machine, size and shape of a spraying chamber, how a lubricant spraying means is provided, and description of active substance. Therefore, conditions can't be simply defined, however it is easily defined based on experiments.
  • pulsating vibration air is generated and lubricant is sprayed in the spraying chamber.
  • the sprayed lubricant is mixed with pulsating vibration air.
  • lubricant is applied on the surfaces of the die and the pair of punches under a Condition wherein lubricant is mixed with pulsating vibration air, namely a condition wherein lubricant is hardly attached on the surfaces of the punches and the die.
  • lubricant When lubricant is designed to be applied on the surfaces of the punches and the die under such a hard condition, lubricant can be uniformly applied thereon. This fact has been confirmed by an experiment by the present inventors.
  • the produced tablet doesn't cause sticking even if the amount of used lubricant per a tablet is remarkably reduced comparing with the prior internal lubricant method and the prior external lubricant spraying method.
  • a tablet of which surface a minute amount of lubricant is attached can be produced. Such a tablet doesn't happen that disintegrant time doesn't delay because of water repellency of lubricant.
  • a tablet which can be rapidly disintegrated at an object region such as target region of living body can be produced.
  • lubricant isn't included in molding material, a tablet with practical hardness can be produced even if tabletting pressure is lower than that of prior art when molding material is tabletted by means of a pair of punches and a die.
  • a tablet including at least active substance is produced by means of a die and a pair of punches.
  • the method is comprised of the steps of; preparing molding material including active substance; housing the pair of punches and the dies in a spraying chamber; spraying lubricant mixed in pulsating vibration air in the spraying chamber; applying lubricant on the surfaces of the pair of punches and the die housed in the spraying chamber; and tabletting the molding material by means of the pair of punches and the die on which surfaces the lubricant is applied.
  • lubricant mixed with pulsating vibration air is designed to be sprayed in the spraying chamber.
  • lubricant is applied on the surfaces of the die and the pair of punches under a condition wherein lubricant is mixed with pulsating vibration air, namely a condition wherein lubricant is hardly attached on the surfaces of the punches and the die.
  • lubricant When lubricant is designed to be applied on the surfaces of the punches and the die under such a hard condition, lubricant can be uniformly applied thereon.
  • the produced tablet doesn't cause sticking even if the amount of used lubricant per a tablet is remarkably reduced comparing with the prior internal lubricant method and the prior external lubricant spraying method.
  • a tablet of which surface a minute amount of lubricant is attached can be produced. Such a tablet doesn't happen that disintegrant time delays because of water repellency of lubricant.
  • a tablet which can be rapidly disintegrated at an object region such as target region of living body can be produced.
  • lubricant isn't included in molding material, a tablet with practical hardness can be produced even if tabletting pressure is lower than that of prior art when molding material is tabletted by means of a pair of punches and a die.
  • the tablet production method as set forth in claim 3 is characterized in that pulsating vibration air used in the method of claim 2 is positive pulsating vibration air.
  • a spraying means for spraying lubricant mixed with positive pulsating vibration air is required to be provided so that the system can be simplified.
  • JP-A-7-124231 when material is tabletted at a remarkably low pressure, the produced tablet has enough practical hardness. They have thought that a tablet including granule can be produced by this method without damaging the coated film of the granule, so called microcapsule, damaging the contained granule, nor deforming plasticity. After hard endeavor, they have completed the present invention.
  • a tablet including granule containing at least active substance is produced by means of a die and a pair of punches.
  • the method is comprised of the steps of; mixing granule containing active substance and diluting agent uniformly and preparing molding material including granule containing active substance; housing the pair of punches and the dies in a spraying chamber; generating pulsating vibration air and spraying lubricant mixed in air in the spraying chamber; applying lubricant on the surfaces of the pair of punches and the dies housed in the spraying chamber while the lubricant sprayed in the spraying chamber is mixed with the pulsating vibration air; and tabletting the molding material including granule containing the active substance by means of the pair of punches and the die on which surfaces the lubricant is applied.
  • a tablet including granule containing at least active compound includes a tablet produced by tabletting only granule containing active substance and a tablet produced by tabletting molding material in which granule containing at least active substance, diluent, bulking agent, filler, and other diluting agent such as excipient are uniformly mixed. Further molding material may include supplement such as solution adjuvant, solubilizer, and disintegrant, antioxidant, preservative, opacifying agent, antistatic agent, aroma, sweetening agent, fluidizing agent, flavoring agent, colorant and so on.
  • Gram including active substance includes granule which is provided with film on the part including at least active substance (therapeutic main ingredient) for the purpose of prolongation of mode of action, sustained release, rapid release, high solubility in stomach, high solubility in intestine, prevention of bitter taste, and granule in which active substance is dispersed in a base matrix.
  • Coating material for the film covering the surface of the part including active substance (therapeutic main ingredient) isn't required to be special. It may be generally used film coating agent such as sugar coating, ethylcellulose (EC), hydroxypropylsellulose (HPC), hydroxypropylmethylcellulose phthalate (HPMC), carboxymethylcellulose, and cellulose group such as hydroxypropylmethylcellulose, acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC), and cellulose acetate phthalate (CAP), acrylic acid group such as methaacrylic acid copolymer, enteric coating agent such as natural product like shellac, sustained release coating agent such as ethylcellulose (EC), sucrose ester, aminoalkylmetaacrilate copolymer, copolymer of ethylacrylate - methylmethacrylate, and several kinds of material such as coating material disclosed in JP-A-57-150612, JP-A-62-103012, and JP-A-2-106.
  • a tablet with practical hardness can be produced at low tabletting pressure because lubricant isn't included in molding material. Therefore, a tablet can be produced without breaking film and granule and without causing plastic deformation even if the construction and material of the film provided for the purpose of prolongation of mode of action, sustained release, rapid release, high solubility in stomach, high solubility in intestine, prevention of bitter taste and the base matrix aren't devised.
  • the production method of a tablet including granule containing at least active substance by means of a die and a pair of punches as set forth in claim 5 is comprised of the steps of; mixing granule containing active substance and diluting agent uniformly and preparing molding material including granule containing active substance; housing the pair of punches and the die in a spraying chamber; spraying lubricant mixed in pulsating vibration air in the spraying chamber; applying lubricant on the surfaces of the pair of punches and the die housed in the spraying chamber; and tabletting the molding material including granule containing the active substance by means of the pair of punches and the die on which surfaces the lubricant is applied.
  • a tablet with practical hardness can be produced at low tabletting pressure because lubricant isn't included in molding material. Therefore, a tablet can be produced without breaking film and granule and without causing plastic deformation even if the construction and material of the film provided for the purpose of prolongation of mode of action, sustained release, rapid release, high solubility in stomach, high solubility in intestine, prevention of bitter taste and the base matrix aren't devised.
  • the tablet production method as set forth in claim 6 is characterized in that the pulsating vibration air used in the tablet production method in claim 5 is a positive pulsating vibration air.
  • a spraying means for spraying lubricant mixed with positive pulsating vibration air is required to be provided so that the system can be simplified.
  • the tablet production method as set forth in claim 7 proposes a preferable embodiment of granule containing active substance (so called microcapsule) to be included in molding material and defies granule containing active substance described in any one of claims 4 - 6 is granule containing active substance and diluting agent.
  • granule containing active substance and diluting agent is used as granule containing active substance (so called microcapsule) so that the particle diameter and particle size of the granule containing active substance can be easily changed by the diluting agent.
  • a tablet can be easily produced by controlling the diameter and the size of granule containing active substance so as to facilitate coating a film on the surface.
  • the diameter and the size of granule containing active substance can be made so as to derive the function of granule to the full extent.
  • the tablet production method as set forth in claim 8 proposes another preferable embodiment of granule containing active substance (so called microcapsule) to be included in molding material and defies granule containing active substance used in the method as set forth in any one of claims 4 - 6 is granule containing active substance in base matrix.
  • Gram containing active substance in base matrix means granule wherein active substance (powder) is uniformly dispersed in a base insoluble in water such as fat, wax, and Vaseline or in a base matrix of hydrophobic high molecular material such as silicon rubber, and plastic.
  • the tablet production method as set forth in claim 9 proposes further preferable embodiment of granule containing active substance (so called microcapsule) to be included in molding material and defies granule containing active substance used in the method as set forth in any one of claims 4 - 8 is granule of which part containing active substance is coated with film.
  • a coating method such as well known fluidized bed coating may be used as a method for coating granule with a film.
  • the following steps as set forth in claim 1 or 4 are continuously executed; housing the pair of punches and the die in the spraying chamber; generating pulsating vibration air, spraying lubricant mixed in air in the spraying chamber; and applying the lubricant on the surfaces of the pair of punches and the die while the lubricant sprayed in the spraying chamber is mixed with pulsating vibration air; and tabletting the molding material by means of the pair of punches and the die on which surfaces the lubricant is applied.
  • tabletting is continuously executed utilizing the fact that molding material isn't adhered on the punches and the die so that sticking isn't caused.
  • a tablet including active substance and a tablet including granule containing active substance can be produced at industrial production base.
  • the tablet production method as set forth in claim 11 is characterized in that the following steps in claim 2 or 5 are continuously executed; housing the pair of punches and the die in the spraying chamber; spraying lubricant mixed in positive pulsating vibration air in the spraying chamber, and applying the lubricant on the surfaces of the pair of punches and the die; and tabletting the molding material by means of the pair of punches and the die on which surfaces the lubricant is applied.
  • tabletting is continuously executed utilizing the fact that molding material isn't adhered on the punches and the die so that sticking isn't caused.
  • a tablet including active substance and a tablet including granule containing active substance can be produced at industrial production base.
  • the tablet production method as set forth in claim 12 is characterized in that in the method of any one of claims 1 - 11 punches and a die construct a female mold of a tablet having an engraved mark or a dividing line and an anomalous tablet.
  • “Anomalous tablet” in this specification means a tablet with a shape except for round, for example, track (capsule), rugby ball, polygon such as triangle, rectangle, pentagon, and so on, diamond, almond, bombshell, half moon, heart, star, and so on.
  • lubricant is applied on the surface of the punches and the die constructing a female mold for a tablet with an engraved mark or a dividing line and for an anomalous tablet in the spraying chamber in which pulsating vibration air is generated, lubricant can be applied uniformly comparing with the prior external lubricant spraying method.
  • molding material is hardly attached on the surface of the punches and the die while compressing a tablet with an engraved mark or a dividing line or an anomalous tablet so that sticking, capping, and laminating of such a tablet are prevented.
  • the tablet production method as set forth in claim 13 is characterized in that in the production method in any one of claims 1 - 12 tabletting pressure of the step for tabletting the molding material by means of the lubricated pair of punches and die is low.
  • Low pressure in this specification means that tabletting pressure is lower comparing with the prior internal lubricant method and the prior external lubricant spraying method. More concretely explained, this tablet production method can produce a tablet having enough practical level hardness even if its tabletting pressure is less than or equal to 1 ton/cm 2 .
  • tabletting pressure for compressing molding material is low, tabletting can be executed without destroying a film even if granule contained in the tablet is covered with a film. Further, if granule contained in a tablet includes active substance in a base matrix, tabletting can be executed without destroying the function of the base matrix.
  • the tablet production method as set forth in claim 14 is characterized in that in the production method in any one of claims 1 - 13 the amount of lubricant sprayed in the spraying chamber is greater than or equal to 0.0001 weight percent and less than or equal to 0.2 weight percent per a tablet.
  • the amount of lubricant used for a tablet to be compressed is greater than or equal to 0.0001 weight percent and less than or equal to 0.2 weight percent per a tablet.
  • lubricant is applied on the surface (inner wall) of the die, the surface (lower surface) of the upper punch, and the surface (upper surface) of the lower punch, all of which are housed in the spraying chamber, by means of pulsating vibration air.
  • lubricant is applied on the surfaces under a condition where lubricant is hardly attached on the surfaces. Therefore, a minute amount of lubricant can be applied on the surface (inner wall) of the die, the surface (lower surface) of the upper punch, and the surface (upper surface) of the lower punch.
  • the produced tablet doesn't include lubricant therein and minute amount of lubricant is attached on the surface so that disintegration time isn't delayed.
  • the tablet produced by this method becomes rapidly disintegrable tablet and a tablet which is required to be immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet can be easily produced. Further if a film coat which can be dissolved at an objective region is executed on the surface of a tablet, the tablet itself is immediately dissolved at a desired region when a film coat is dissolved, so that a tablet which can be dissolved at an objective region can be produced.
  • tablet can be produced at a low tabletting pressure.
  • a tablet including granule containing active substance is produced, the granule is hardly damaged or plastic deformation is hardly caused when tabletting. Therefore, the function of the granule containing active substance in the tablet isn't apt to be damaged.
  • the produced tablet including granule containing active substance is used as an uncoated tablet, it becomes rapidly disintegrable tablet and a tablet which is required to be immediately disintegrated at an objective region and the granule containing active substance can be dissolved while showing its function like an intrabuccally rapidly disintegrable tablet can be easily produced. Further if a film coat which can be dissolved at an objective region is executed on the surface of a tablet, the tablet which is required that it is immediately dissolved at a desired region when a film coat is dissolved can be produced.
  • the tablet as set forth in claim 15 is provided with lubricant only on the surface of a tablet including granule containing active substance in diluting agent and the amount of lubricant is greater than or equal to 0.0001 weight percent and less than or equal to 0.2 weight percent per a tablet.
  • the amount of lubricant used for a tablet to be compressed is greater than or equal to 0.0001 weight percent and less than or equal to 0.2 weight percent per a tablet.
  • the tablet As lubricant isn't included therein and a minute amount is attached on the surface, there is no problem such that disintegration time of the tablet delays because of water repellency of lubricant.
  • the tablet is used as an uncoated tablet, it becomes a rapidly disintegrable tablet and the tablet is immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet and active substance contained in the tablet is immediately released.
  • the tablet itself can be dissolved at the objective region when the film coat is dissolved, so that active substance contained in the tablet is immediately released.
  • the tablet as set forth in claim 16 has lubricant only on the surface of the tablet including granule containing active substance in diluting agent.
  • the tablet As lubricant isn't included therein and a minute amount is attached on the surface, there is no problem such that disintegration time of the tablet delays because of water repellency of lubricant.
  • the tablet is used as an uncoated tablet, it becomes a rapidly disintegrable tablet and the tablet is immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet and granule containing active substance (so called microcapsule) included in the tablet is immediately released.
  • the tablet itself can be dissolved at the objective region when the film coat is dissolved, so that granule containing active substance (so called microcapsule) included in the tablet is immediately released.
  • the tablet as set forth in claim 17 - 19 defines preferable construction of the granule containing active substance of the tablet as set forth in claim 16.
  • the tablet as set forth in claim 16 is characterized in that the granule containing active substance is granule containing active substance and diluting agent.
  • granule containing active substance and diluting agent is used as granule containing active substance (so called microcapsule)
  • the particle diameter and size of the granule can be easily modified by diluting agent.
  • a tablet production can be easily executed by controlling the particle diameter and size of the granule so as to be easily coated with a film on the surface of the tablet.
  • the diameter and the size of granule containing active substance can be made so as to derive the function of granule to the full extent.
  • the tablet in claim 16 is characterized in that the granule containing active substance is granule including active substance in base matrix.
  • diluting agent used as bulking agent doesn't include lubricant, there is no problem such that disintegration time of the tablet delays because of water repellency of lubricant.
  • the base matrix can achieve its desired objective function.
  • the tablet also becomes to have a function of sustained release by the base matrix.
  • unfilmed granule containing active substance and granule containing active substance in base matrix are mixed in a tablet, they are immediately released from the tablet when the tablet is dissolved.
  • the active substance contained in the unfilmed granule is immediately absorbed in a body when the tablet is disintegrated. Therefore, the tablet has superior rapid onset of action.
  • the tablet also becomes to have a function of prolongation of mode of action by the base matrix.
  • the tablet yields both rapid onset of action and prolongation of mode of action.
  • the active substance is analgesic, anti-inflammatory agent, or antidote
  • unfilmed granule containing such agent and granule containing such agent in the base matrix are mixed.
  • a new tablet such as a once daily tablet, namely a quick & slow release tablet, by which pain, inflammation or fever of a patient is immediately remedied and analgesic action, anti-inflammatory action, or antidote action is kept long when a patient takes this medicine can be obtained.
  • the tablet as set forth in claim 19 is characterized in that the granule containing active substance of the tablet of any one of claims 16 - 18 is granule of which part containing active substance is covered with film.
  • diluting agent used as bulking agent doesn't include lubricant, there is no problem such that disintegration time of the tablet delays because of water repellency of lubricant.
  • the tablet includes granule containing active substance
  • a film coated on the surface of the granule containing active substance brings out a desired objective function.
  • the film coated on the granule containing active substance aims at prolongation of mode of action
  • the tablet also yields prolongation of mode of action because of the film.
  • unfilmed granule containing active substance and filmed granule containing active substance are mixed in a tablet, they are released from the tablet when the tablet is dissolved.
  • the active substance contained in the unfilmed granule is immediately absorbed in a body when the tablet is disintegrated. Therefore, the tablet has superior rapid onset of action.
  • the tablet As for the filmed granule containing active substance, for example, if the film aims at prolongation of mode of action, the tablet also becomes to have prolongation of mode of action because of the function of the film. Namely, the tablet has both rapid onset of action and prolongation of mode of action.
  • the active substance is analgesic, anti-inflammatory agent, or antidote
  • unfilmed granule containing such agent and filmed granule containing such agent are mixed.
  • a new tablet such as a once daily tablet, namely a quick & slow release tablet, by which pain, inflammation or fever of a patient is immediately remedied and analgesic action, anti-inflammatory action, or antidote action is kept long when a patient takes this medicine can be obtained.
  • the amount of lubricant used in the tablet described in any one of claims 16 - 19 is greater than or equal to 0.0001 weight % and less than or equal to 0.2 weight percent per a tablet.
  • the tablet is provided with a minute amount of lubricant on the surface, its disintegration time doesn't delay.
  • the tablet described in any one of claims 15 - 20 is provided with a dividing line on the surface thereof.
  • the tablet has a dividing line, it can be easily divided along the line. Therefore, appropriate amount of drug depending on the weight or age of a patient can be taken by a patient.
  • the tablet as set forth in claim 22 is characterized in that the shape of the tablet described in any one of claims 15 - 21 is anomalous.
  • the tablet has anomalous shape, drugs can be easily distinguished by its shape. Therefore, medication error is hardly happened.
  • the tablet as set forth in claim 23 is characterized in that the standard deviation of disintegration time of the tablet or elution time of the active substance described any one of claims 15 - 22 is less than or equal to 15 percent of average disintegrating time or average elution time.
  • the standard deviation of disintegration time of the tablet or elution time of the active substance could be less than or equal to 10.0 percent of average disintegrating time of the tablet or average elution time fo the active substance. Further it was also found that the standard deviation of disintegrating time of the tablet or elution time of the active substance could be less than or equal to 7.5 percent of average disintegrating time or average elution time, further less than or equal to 7.0 percent.
  • the tablet of which standard deviation of disintegrating time of the tablet or elution time of the active substance is less than or equal to 15.0 percent of average disintegrating time or average elution time can be easily produced.
  • the tablet of which standard deviation of disintegrating time of the tablet or elution time of the active substance is less than or equal to 10.0 percent of average disintegrating time or average elution time, which has been considered to be difficult in the prior art, can be easily produced.
  • the tablet of which standard deviation of disintegrating time of the tablet or elution time of the active substance is less than or equal to 7.5 percent, further 7.0 percent, of average disintegrating time or average elution time, which has been impossible to produce in the prior art as far as the inventors know, can be produced.
  • the tablet as set forth in claim 24 is characterized in that the lubricant of the tablet described in any one of claims 15 - 23 is magnesium stearate.
  • magnesium stearate When magnesium stearate is used as lubricant, the amount of lubricant contained in the tablet can be easily measured by atomic absorption spectrometry.
  • Fig.1 shows schematic construction by enlarging one part around a rotary table of a rotary type tabletting machine used for executing the present invention.
  • Fig.2 is a schematic section when one part of Fig.1 around the rotary table is enlarged.
  • the rotary type tabletting machine A is comprised of a rotatably provided rotary table 2 having plural dies 1, ⁇ in circumferential direction, plural upper punches 3, ⁇ and plural lower punches 4, ⁇ provided so as to correspond to each dies 1, ⁇ .
  • a spraying chamber 8 is provided at P1 which is before a point P2 where molding material is charged in the die 1.
  • a pulsating vibration air generation means 7 is connected to the spraying chamber 8 and a spray nozzle 9 for spraying lubricant L is provided in the spraying chamber 8.
  • an air source 10 such as a cylinder charging compressed air is connected to the spray nozzle 9 and lubricant L is designed to be sprayed from the spray nozzle 9 by the air generated from the source 10.
  • the rotary table 2 is rotated at a fixed speed, pulsating vibration air is generated in the spraying chamber 8 by driving the pulsating vibration air generation means 7 when the die 1 comes to the point P1 where the spraying chamber 8 is provided according to rotation of the rotary table 2, lubricant L is simultaneously sprayed from the spray nozzle 9, and lubricant L is applied on a surface (inner wall) 1s of the die 1, a surface (lower surface) 3s of the upper punch 3, and a surface (upper surface) 4s of the lower punch 4.
  • molding material m is charged in the die 1 which comes to the point P2 for charging molding material m in the die 1 accompanied with rotation of the rotary table 2 and extra molding material m is scraped. Thereafter, when the die 1 charged with molding material m comes to a point P3 for compressing molding material m, molding material m in the die 1 is compressed to produce a tablet by means of the upper punch 3 of which surface (lower surface) 3s is applied with lubricant L and the lower punch 4 of which surface (upper surface) 4s is applied with lubricant L. Further, when the die 1 comes to a point P4, a tablet T is discharged from the die 1 so that the tablet T is produced.
  • Fig.3(a) shows schematic construction around the spraying chamber 8 and Fig.3(b) illustrates construction by an example of pulsating vibration air generation means 7.
  • the pulsating vibration air generation means 7 is connected to the spraying chamber 8 via a conduit 13.
  • the numeral 71 shows a blower
  • 72 shows a cylindrical tube
  • 73 shows a valve element provided rotatably around a rotary axis 74 so as to divide inside of the tube 72 into two parts.
  • the conduit 13 and a conduit 14 coupled to the blower 71 are connected at a given place of the side of the tube 72.
  • the valve element 73 is designed to be rotated at a desired rotational velocity by means of a valve rotation control means (not shown).
  • negative pressure means that the pressure in the spraying chamber 8 is lower than outside pressure (atmospheric pressure).
  • sprayed lubricant L is diffused by the pulsating vibration air and is uniformly applied on the surface (inner wall) 1s of the die 1, the surface (lower surface) 3s of the upper punch 3 and the surface (upper surface) 4s of the lower punch 4 both of which are provided so as to correspond to the die 1 housed in the spraying chamber 8.
  • lubricant L can be uniformly applied on the surface (inner wall) 1s of the die 1, the surface (lower surface) 3s of the upper punch 3, and the surface (upper surface) 4s of the lower punch 4, molding material m can be prevented from adhering on the die 1, the upper punch 3, and the lower punch 4 of the tabletting machine A even if the amount of lubricant L sprayed in the spraying chamber 8 is only a little regardless of the kinds of active substance, diluting agent, and lubricant.
  • This method is characterized in that the amount of lubricant sprayed in the spraying chamber is remarkably reduced utilizing this effect.
  • the spray amount of lubricant L to be sprayed in the spraying chamber 8 is controlled to be greater than or equal to 0.0001 weight % and less than or equal to 0.2 weight % per the weight of tablet. Further it may be controlled greater than or equal to 0.0001 weight % and less than or equal to 0.1 weight %.
  • lubricant L isn't included in the molding material m, produced tablet can obtain practical hardness even if tabletting pressure is low (practically less than 1 ton/c m 2 ) comparing with the case that molding material m including lubricant L is tabletted.
  • the tablet T produced by the production method becomes a rapidly disintegrable tablet and is suitable as a tablet which is required to be disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet.
  • the tablet itself can be immediately dissolved at the objective region so that a tablet which can be dissolved at an objective region can be produced.
  • the film coated on the surface isn't destroyed at the time of compression (tabletting) because the tablet T can be compressed (tabletted) at low pressure. Accordingly, the film coated on the granule containing active substance can bring out a desired objective function.
  • the film coated on the granule containing active substance aims at prolongation of mode of action, the tablet also has sustained release because of the film.
  • unfilmed granule containing active substance and filmed granule containing active substance are mixed in the tablet T, they are immediately released from the tablet T when the tablet T is disintegrated.
  • the active substance contained in the unfilmed granule is immediately absorbed in a body when the tablet is disintegrated. Therefore, the tablet has superior rapid onset of action.
  • the film As for the filmed granule containing active substance, for example, it the film aims at prolongation of mode of action, the tablet also becomes to have prolongation of mode of action because of the function of the film.
  • the tablet has both rapid onset of action and prolongation of mode of action.
  • the active substance is analgesic (morphine hydrochloride and so on), anti-inflammatory agent (indometacin, diclofenac sodium and so on), or antidote(sulphyrine and so on), unfilmed granule containing such agent and filmed granule containing such agent are mixed in the tablet T.
  • a new tablet such as a once daily tablet, namely a quick & slow release tablet, by which pain, inflammation or fever of a patient is immediately remedied and analgesic action, anti-inflammatory action, or antidote action is kept long and also has rapid onset of action when a patient takes this medicine can be obtained.
  • the function of the base matrix isn't destroyed at the time of compression (tabletting) because the tablet T can be compressed (tabletted) at low pressure. Accordingly, the base matrix can bring out a desired objective function.
  • unfilmed granule containing active substance and granule containing active substance in the base matrix are mixed in the tablet T, they are immediately released from the tablet T when the tablet T is disintegrated.
  • the active substance contained in the unfilmed granule is immediately absorbed in a body when the tablet T is disintegrated. Therefore, the tablet has superior rapid onset of action.
  • the tablet T also becomes to have prolongation of mode of action because of the function of the base matrix.
  • the tablet T has both rapid onset of action and prolongation of mode of action.
  • the active substance is analgesic (morphine hydrochloride and so on), anti-inflammatory agent (indometacin, diclofenac sodium and so on), or antidote(sulphyrine and so on), unfilmed granule containing such agent and granule containing such agent in the base matrix are mixed in the tablet T.
  • a new tablet such as a once daily tablet, namely a quick & slow release tablet, by which pain, inflammation or fever of a patient is immediately remedied and analgesic action, anti-inflammatory action, or antidote action is kept long and also has rapid onset of action when a patient takes this medicine can be obtained.
  • the amount of lubricant L sprayed in the spraying chamber 8 is preferably greater than or equal to 0.0001 weight percent and less than or equal to 0.2 weight percent per a tablet, although it depends on the nature of the molding material. According to an experiment, when the amount of lubricant L was greater than or equal to 0.001 weight percent and less than or equal to 0.1 weight percent per a tablet, it was found that problems such as sticking did't caused and continuous tabletting could be executed.
  • lubricant L is uniformly applied on the surface of the tablet T (uncoated tablet), there is no wide variation of disintegration time of the tablet and elution time of the active substance.
  • polyvinyl alcohol was sprayed on the powder of which prescription was shown in the following table 1, particle was grown, and granulated material with prescribed size was manufactured. Then, the obtained granule was sized by means of a No.28 mesh. Next, it was tabletted to produce a 130mg tablet at a speed of rotating a rotary table 2 at 30 times per a minute by means of the tabletting machine A with 7mm diameter punch and die set.
  • magnesium stearate was used as lubricant.
  • the amount of air sprayed from the nozzle 9 shown in Fig.3(a), rotation number and suction amount of the pulsating vibration air generation means 7 were controlled in such a manner that the amount of the magnesium stearate sprayed in the spraying chamber 8 was adjusted such that weight % of lubricant L included in one produced tablet became 0.03 weight % for the entire amount of the tablet.
  • Magnesium stearate was added as lubricant for the granule produced like the experiment 1 in a ratio of 0.03 weight % for the entire amount of a tablet. After they were well mixed by a V type mixer, they were continuously tabletted by an internal lubricant method at a speed of rotating the rotary table at 30 times per minute by means of a set of 7mm punch and die so as to produce the material into a 130mg tablet. However, tablet wasn't continuously produced because molding material adhered on the punches and the dies.
  • magnesium stearate was added as lubricant for the granule used in the experiment 1 in a ratio of 0.8 weight % for the entire amount of a tablet. After they were well mixed by a V type mixer, they were continuously tabletted by an internal lubricant method at a speed of rotating the rotary table at 30 times per minute by means of a set of 7mm punch and die so as to produce the material into a 130mg tablet.
  • HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as the tabletting machine A.
  • the granule produced like the experiment 1 was tabletted by means of a set of 7mm punch and die so as to produce a 130mg tablet.
  • Stearate magnesium was applied on the surfaces 3s, 4s of the punches 3, 4 and the surface 1s of the die 1 according to the method described in JP-B-41-11273 so that the weight % of lubricant became 0.03 weight % per a produced tablet. Then the material was continuously tabletted at a speed of rotating the rotary table at 30 times per minute.
  • HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as the tabletting machine A.
  • the standard deviation of the disintegration time of the tablet in the experiment 1 was 0.2 and the disintegration time of each tablet was less than or equal to 7%. From the above experiment, it was found that the standard deviation of the disintegration time of the tablet or the diluting time of active substance could easily become less than or equal to 15% of the average disintegration time of the tablet or the average diluting time of active substance.
  • the standard deviation of the disintegration time of the tablet or the diluting time of active substance could easily become less than or equal to 10% of the average disintegration time of the tablet or the average diluting time of active substance. Furthermore, it was also found that the standard deviation of the disintegration time of the tablet or the diluting time of active substance could easily become less than or equal to 7.0% of the average disintegration time of the tablet or the average diluting time of active substance.
  • the system shown in Fig.3(b) was used as a pulsating vibration air generation means 7.
  • the blower 71 may be connected to the end of the conduit 13, a solenoid valve may be provided in the middle of the conduit 13 for opening and closing the conduit 13, the blower 71 may be rotated at a given rotation number so as to suck air in the spraying chamber 8, and the conduit 13 may be opened or closed at a prescribed period by the solenoid valve.
  • the blower 71 may be connected to the end of the conduit 13, the blower 71 may be rotated fast or slowly at a given period, and air in the spraying chamber 8 may be sucked strongly and weakly.
  • the pulsating vibration air shown in Fig.4(a) or Fig.4(b) was generated.
  • the system shown in Fig.5 may be constructed and the pulsating vibration air shown in Fig.6(a) or Fig.6(b) may be generated in the spraying chamber 8.
  • a pulsating vibration air generation means 7A is connected to the end of the conduit 13
  • a hopper 15 storing lubricant L is connected in midstream of the conduit 13
  • a compressed air generation means 16 such as a cylinder charging compressed air is connected to the hopper 15 as shown in Fig.5(a).
  • FIG. 5(a) shows a blower provided if required.
  • air in the spraying chamber 8 is sucked and pulsating vibration air supplied in the spraying chamber 8 and lubricant L are induced to be discharged from the spraying chamber 8.
  • the system shown in Fig.5 is provided with the nozzle means for spraying lubricant mixed with positive pulsating vibration air so that the construction of the spraying chamber 8 can be simplified.
  • the pulsating vibration air generation means 7A is provided with the blower 71, the cylindrical tube 72 connected to the conduit 13 between the blower 71 and the hopper 15, and the valve element 73 which is rotatable around the rotary axis 74 in the tube 72 and is designed to divide the inside of the tube 72 into two parts.
  • the conduit 13 and the conduit 14 coupled to the blower 71 are connected to the side of the tube 72.
  • the valve element 73 is constructed so as to be rotated at a desired rotational velocity by means of a valve rotation control means (not shown).
  • the spraying chamber 8 and the blower 71 are connected when the valve element 73 is located at the place shown as a slid line in the figure.
  • the valve element 73 is located at a dotted line, the spraying chamber 8 and the blower 71 are blocked off by the valve element 73. Accordingly pulsating vibration air with its peak at positive pressure and its valley at atmospheric pressure as shown in Fig.6(a) is generated in the spraying chamber 8. Otherwise, pulsating vibration air with its peak and valley at positive pressure as shown in Fig.6(b) may be generated in the spraying chamber 8.
  • the compressed air generation means 16 may be driven to feed lubricant L contained in the hopper 15 to the conduit 13 and a fixed amount of lubricant L may be supplied in the spraying chamber 8 together with the current of pulsating vibration air.
  • positive pressure means that the pressure in the spraying chamber 8 is higher than the pressure outside of the spraying chamber 8.
  • the blower 71 may be provided at the end of the conduit 13, the solenoid valve for opening and closing the conduit 13 may be provided in the midstream of the conduit 13, the blower 71 may be rotated at a given rotation number to feed air in the spraying chamber 8, the conduit 13 may be opened and closed periodically by the solenoid valve, then pulsating vibration air may be generated in the spraying chamber 8 and the conduit 13. While keeping such a condition, the compression air generation means 16 may be driven to feed lubricant L contained in the hopper 15 to the conduit 13 and a fixed amount of lubricant L is supplied in the spraying chamber 8 together with the current of pulsating vibration air.
  • the blower 71 may be connected at the end of the conduit 13, the blower 71 may be rotated fast or slowly at a given period so as to feed air strongly or weekly in the spraying chamber 8, and pulsating vibration air may be generated in the spraying chamber 8 and the conduit 13. While keeping this condition, the compression air generation means 16 may be driven so as to feed lubricant L contained in the hopper 15 to the conduit 13 and a fixed amount of lubricant L may be supplied in the spraying chamber 8 together with the current of pulsating vibration air.
  • glybuzole and mannitol were mixed at a ratio of 7 : 3, polyvinyl alcohol was sprayed, granule having a prescribed particle size and prescribed particle size distribution was manufactured, and the obtained granule was sized by means of a No.28 mesh.
  • the punches 3, 4 and the die 1 for constructing a female mold of the tablets shown in Fig.7 - Fig.11 were housed in the spraying chamber 8, pulsating vibration air shown in Fig.4(a) was generated, magnesium stearate was applied as lubricant L on the surface 3s, 4s of the punches 3, 4 and the surface 1s of the die 1, and granule was continuously tabletted at a speed of rotating the rotary table 1 at 30 times per a minute by means of the lubricated punches 3, 4 and the die 1.
  • magnesium stearate was used as lubricant.
  • the amount of air sprayed from the nozzle 9 shown in Fig.3(a), rotation number and suction amount of the pulsating vibration air generation means 7 were controlled in such a manner that the amount of the magnesium stearate sprayed in the spraying chamber 8 was adjusted such that weight % of lubricant L included in one produced tablet became 0.03 weight % for the entire amount of the tablet.
  • WSG-type 15 by Glatt Co., Ltd. was used as a fluid-bed granulator and HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as a main body of a tabletting machine.
  • the tablet in Fig.7(a) shows a circular tablet generally called flat plain
  • the tablet in Fig.7(b) shows a circular tablet generally called shallow concave plain
  • the tablet in Fig.7(c) shows a circular tablet generally called normal concave plain
  • the tablet in Fig.7(d) shows a circular tablet generally called deep concave plain
  • tablet in Fig.7(e) shows a circular tablet generally called ball or pill
  • tablet in Fig.7(f) shows a circular tablet generally called flat beveled edge.
  • the tablet in Fig.8(a) shows a circular tablet generally called double radius
  • the tablet in Fig.8(b) shows a circular tablet generally called bevel and concave
  • the tablet in Fig.8(c) shows a circular tablet generally called dimple
  • the tablet in Fig.8(d) shows a circular tablet called ring
  • the tablet in Fig.8(e) shows a a circular tablet generally called rim
  • the tablet in Fig.8(f) shows a capsule type tablet generally called capsule.
  • the tablet in Fig.9(a) shows an oval tablet generally called oval
  • the tablet in Fig.9(b) shows an elliptical tablet generally called ellipse
  • the tablet in Fig.9(c) shows a rectangular tablet generally called square
  • the tablet in Fig.9(d) shows a triangular tablet generally called triangle
  • the tablet in Fig.9(e) shows a pentangular tablet generally called pentagon
  • the tablet in Fig.9(f) shows a hexagonal tablet generally called hexagon.
  • the tablet in Fig.10(a) shows a heptagonal tablet generally called heptagon
  • the tablet in Fig.10(b) shows an octagonal tablet generally called octagon
  • the tablet in Fig.10(c) shows a diamond-shaped tablet generally called diamond
  • the tablet in Fig.10(d) shows a pillow-shaped tablet generally called pillow or ballel
  • the tablet in Fig.10(e) shows a rectangular tablet generally called rectangle
  • the tablet in Fig.10f) shows an almond-shaped tablet generally called almond.
  • the tablet in Fig.11(a) shows a sagittal tablet generally called arrow head
  • the tablet in Fig.11(b) shows a bullet-shaped tablet generally called bullet
  • the tablet in Fig.11(c) shows a semilunar tablet generally called half moon
  • the tablet shown in Fig.11(d) shows a shell-shaped tablet generally called shelled
  • the tablet in Fig.11(e) shows a heart-shaped tablet generally called heart
  • the tablet in Fig.11(f) shows a star-shaped tablet generally called star.
  • Magnesium stearate was added as lubricant for the granule produced like the experiment 2 in a ratio of 1.0 weight % for the entire amount of a tablet. After they were well mixed by a V type mixer, they were continuously tabletted by means of the punches 3, 4 and the die 1 used in the experiment 1 according to an internal lubricant method at a speed of rotating the rotary table at 30 times per minute.
  • WSG-type 15 by Glatt Co., Ltd. was used as a fluid-bed granulator and HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as a main body of a tabletting machine.
  • the tablet production method of the present invention could be preferably used for producing a tablet with an engraved mark or a dividing line, or an anomalous tablet.
  • Reference 1 production of sustained release microcapsule granule containing theophylline as active substance
  • lactose for direct tabletting brand name : tabletose, Taiyo Kagaku Co., Ltd.
  • 300g of crystalline cellulose brand name : AvicelPH101, Asahi Chemical Industry Co., Ltd.
  • Magnesium stearate (Sakai Chemical Industry Co., Ltd.) was uniformly sprayed as lubricant L as dry type on the surface (inner wall) 1s of the die 1, the surface (lower surface) 3s of the upper punch 3, and the surface (lower surface) 4s of the lower punch 4 while pulsating vibration air is generated in the spraying chamber 8.
  • the granule was tabletted at a tabletting pressure of 500kg/punch, 1000kg/punch, and 1500kg/punch by means of a flat punch with a dividing line. Then sustained release microcapsule tablet (multiple unit tablet) with a dividing line was obtained.
  • the amount of magnesium stearate contained in the obtained sustained release microcapsule tablet was measured. It was 0.07 weight %.
  • Magnesium stearate (Sakai Chemical Industry Co., Ltd.) was uniformly sprayed as lubricant L as dry type on the surface (inner wall) 1s of the die 1, the surface (lower surface) 3s of the upper punch 3, and the surface (lower surface) 4s of the lower punch 4 while pulsating vibration air is generated in the spraying chamber 8.
  • the granule was tabletted at a tabletting pressure of 500kg/punch, 1000kg/punch, and 1500kg/punch by means of a flat punch with a dividing line as the punch 3 of the rotary type tabletting machine A shown in the embodiment of the invention 1. Then enteric microcapsule tablet (multiple unit tablet) with a dividing line was obtained.
  • the comparisons 4 and 5 show examples when sustained release microcapsule tablet (multiple unit tablet) with a dividing line is produced according to the prior internal lubricant method.
  • the granule was tabletted at a tabletting pressure of 500kg/punch, 1000kg/punch, and 1500kg/punch by means of a flat punch with a dividing line and sustained release microcapsule tablet (multiple unit tablet) with a dividing line was obtained.
  • the granule was tabletted at a tabletting pressure of 500kg/punch, 1000kg/punch, and 1500kg/punch by means of a flat punch with a dividing line and enteric microcapsule tablet (multiple unit tablet) with a dividing line was obtained.
  • sustained release microcapsule tablet single unit tablet
  • the granule was tabletted at a tabletting pressure of 500kg/punch, 1000kg/punch, and 1500kg/punch by means of a flat punch with a dividing line and uncoated tablet with a dividing line was obtained.
  • the tablet produced at a tabletting pressure of 500kg/punch in the experiments 3 and 4 (hereinafter called experiment 5 and experiment 6 respectively) and the tablet produced at a tabletting pressure of 1000kg/punch in the comparisons 4 and 5 (hereinafter called comparison 7 and comparison 8 respectively) were used as specimen of dissolution test.
  • dissolution rate was measured by a first liquid by Japanese Pharmacopoeia the 11 th edition for first two hours, the specimen was pulled up after two hours and transferred to a second liquid to obtain dissolution rate again according to a rotary basket method described in dissolution test of Japanese Pharmacopoeia the 11 th edition.
  • the multiple unit tablet of which granule surface was film coated was used.
  • a tablet having practical hardness can be produced at a low tabletting pressure according to the tablet production method of the present invention, a multiple unit tablet including active substance in a base matrix can be produced without destroying or plastically deforming the granule contained in the tablet.
  • a tablet which doesn't contain lubricant therein and is provided with a minute amount of lubricant thereon can be produced, so that disintegration time of the tablet doesn't delay. Therefore, if the tablet is used as an uncoated tablet, it becomes a rapidly disintegrable tablet and it is suitable as a tablet which is required to be immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet. Further, if a film which can be dissolved at an objective region is coated on the surface, the tablet can be dissolved at the objective region when the film coat is dissolved. Accordingly, it is suitably used as a tablet which is required to be dissolved at the objective region.
  • the inventors of the present invention measured the disintegration time of the tablet and the dissolution time of active substance produced in the experiments 1 - 4. They found that the standard deviation thereof was within 10% of the average disintegration time of the tablet and the average dissolution time of active substance.
  • This embodiment showed an example in which a centrifugal fluid coating machine was used to produce granule to be contained in the tablet.
  • warm air which is strengthened or weakened at a prescribed period may generated in a warm air conduit at a procedure of pelletizing the granule with a desired particle size
  • the granule may be pelletized in such a manner that a part of powder to be granulated and material under granulated always falls to be piled on a screen while pelletizing, and a film may be formed on the granulated material by spraying coating liquid on the granulated material.
  • the granule when material is granulated while warm air which is strengthened or weakened at a prescribed period may generated in the warm air conduit at a procedure of pelletizing the granule with a desired particle size, the granule may be pelletized in such a manner that a part of powder to be granulated and material under granulated always falls to be piled on a screen while pelletizing, granulated material with small specific volume can be produced comparing with the granulated material which is produced by fluidizing powder to be granulated and material under granulated by means of steady flow warm air.
  • the granulated material becomes hard so as to be scarcely damaged at the time of tabletting, therefore, a film coated on the granulated material becomes hardly damaged.
  • the process for coating a film on the granulated material isn't limited to the above-mentioned fluid-bed coating method. It may be executed according to a Pan coating method or a compression coating method.
  • Fig.15 schematically shows a construction of such a system.
  • a pulsating vibration air generation means 7A is connected to one end 13a of the conduit 13, a discharge port 15a of the hopper 15 is connected in midway of the conduit 13, and an elastic membrane 18 having an aperture (a slit in this example) 18a is provided for the discharge port 15a so as to become a bottom of the hopper 15 (see Fig.16).
  • the elastic membrane 18 is made of rubber such as a silicon rubber.
  • the member shown as 15b in Fig.15 is a lid and is provided for the hopper 15 removably and airtightly.
  • Fig.17 is an explanatory figure schematically showing operation of the system.
  • the lid 15b is airtightly attached on the hopper 15 after lubricant L is contained in the hopper 15.
  • the pulsating vibration air generation means 7A is driven to supply positive pulsating vibration air to the conduit 13
  • the air pressure in the conduit 13 becomes higher than that in the hopper 15 while positive pulsating vibration air is at peak side.
  • the elastic membrane 18 is deformed with its center curved upwardly in such a manner that the center becomes an antinode and the circumferential edge becomes a node.
  • the section of the aperture (slit in this example) 18a becomes V-shaped with its upper end opened. A part of lubricant L stored in the hopper 15 drops in the V-shaped aperture (slit in this example) 18a.
  • the air pressure in the conduit 13 is generally lowered so as to be the same as that in the hopper 15.
  • the elastic membrane 18 is going to get back to its original shape because of its resilience as shown in Fig.17(b).
  • the lubricant L dropped in the V-shaped aperture (slit in this example) 18a is caught in the aperture 18a.
  • the section of the aperture (slit in this example) 18a becomes reverse V-shaped with its lower end opened.
  • the lubricant L caught in the aperture 18a is discharged to the conduit 13.
  • the lubricant L discharged in the conduit 13 is immediately mixed with positive pulsating vibration air supplied in the conduit 13 to be dispersed therein and is pneumatically transported to a spraying chamber (refer to the spraying chamber 8 in Fig.5).
  • the elastic membrane 18 repeats up and down vibration as shown in Fig.17(a) - Fig.17(c) according to vibration amplitude, wave length, wave shape, and vibration frequency of positive pulsating vibration air.
  • the elastic membrane 18 vibrates up and down at a fixed vibration amplitude and frequency. Accordingly the amount of lubricant L discharged in the conduit 13 via the aperture (slit in this sample) 18a is constant.
  • lubricant L is discharged from the other end 13b of the conduit 13 at the same density as the lubricant L discharged to the conduit 13.
  • this system can be functioned as a metering feeder.
  • a media for pneumatically transporting lubricant L is air even if it is a positive pulsating vibration air so that the amount of lubricant L mixed with positive pulsating vibration air can be extremely minimized.
  • minute amount of lubricant L can be always sprayed in stable condition in the spraying chamber (refer to spraying chamber 8 in Fig.5), minute amount of lubricant L can be applied on the surfaces of the punches(the surface (lower surface) 3s of the upper punch and the surface (upper surface) 4s of the lower punch 4 as shown in Fig.2) and the surface (inner wall) 1s of the die 1.
  • the elastic membrane has a slit 18a, however, this is only a preferable example.
  • the aperture provided for the elastic membrane isn't limited to the slit 18a and the aperture may be small ones or the number isn't limited to one.
  • an elastic membrane with plural small apertures 18b may be used as shown in Fig.18.
  • the density of lubricant L supplied in the spraying chamber (refer to the spraying chamber 8 in Fig.5) can be changed diversely.
  • a rotary type pulsating vibration air generation means 7A shown in Fig.3(b) and Fig.5(b) wherein the valve element 73 is provided rotatably around the rotary axis 74 so as to divide inside of the tube 72 into two parts is explained as a pulsating vibration air generation means.
  • a pulsating vibration air generation means 7A it isn't limited to such means 7A.
  • Fig.19 shows a section of other embodiment of pulsating vibration air generation means.
  • the high pressure pulsating vibration air generation means 7B is provided with a valve chamber 94 having a valve seat 9. between an input port 91 and an output port 92 and a valve plug 96 which is opened and closed by a cam mechanism 95.
  • the cam mechanism 95 is provided with a rotary cam 97 rotatable by a driving means such as a motor (not shown) and a roller 98 attached at the lower end of the valve plug 96.
  • the valve seat 93 is formed with a hole narrowing into the output port 92 and the valve plug 96 is formed like a reverse mortar so as to conform to the shape of the valve seat 93 and designed to airtightly close the valve seat 93.
  • an axis 96a of the valve plug 96 is provided in an axis hole 99h of a case 99 so as not to leak air and so as to be movably up and down.
  • the roller 98 is rotatably pinched by the rotary cam 97 and moves up and down according to a concavo-convex pattern on the rotary cam 97 while rotating.
  • the rotary cam 97 is provided with an inner rotary cam 97a and an outside rotary cam 97b.
  • Concavo-convex pattern is provided for the inner rotary cam 97a and the outside rotary cam 97b respectively so as to keep distance of the roller 98 and to keep in line each other.
  • the roller 98 is pinched between the inner rotary cam 97a and the outside rotary cam 97b and is moved up and down while rotating according to the concavo-convex pattern provided for the inner rotary cam 97a and the outside rotary cam 97b by rotating the rotary cam 97 without causing jumping of the valve plug 96.
  • the convavo-convex pattern provided for the rotary cam 97 is selected according to physical property of lubricant L stored in the hopper 15.
  • a flow rate control means 102 is provided for the input port 91 and compressed air which is generated by an air source 71 and of which flow rate is adjusted properly by the flow rate control means 102 is supplied in the input port 91.
  • conduit 13 is connected to the output port 92.
  • the numeral 100 in Fig.19 shows a flow rate control port provided if required.
  • An output control valve 101 for adjusting pressure of pulsating vibration air generated from the output port 92 is provided so as to be adjustable at a desired condition from full communication to atmospheric air and shut down from atmospheric air.
  • the rotary cam 97 which is easy to mix lubricant L with air according to physical property of lubricant L stored in the hopper 15 is attached to a rotary axis Ma of a driving means (not shown) of the high pressure pulsating vibration air generation means 7B.
  • the air source 71 is driven and a fixed amount of compressed air is supplied to the input port 92 by adjusting the flow rate control means 102.
  • the rotary cam 97 is rotated at a fixed rotational velocity by actuating the driving means (not shown).
  • the pressure of pulsating vibration air discharged from the output port 92 is controlled by adjusting the output control valve 101, if required.
  • rotational velocity of the rotary cam 97 may be changed by controlling the driving means (not shown) in order to obtain a desired period of pulsating vibration air discharged from the output port 92.
  • the air source 71, the flow rate control means 102, and/or the output control valve 101 may be appropriately controlled in order to obtain a desired vibration amplitude of pulsating vibration air discharged from the output port 92.
  • lubricant is sprayed at the same time pulsating vibration air is generated in the spraying chamber.
  • lubricant is mixed with pulsating vibration air.
  • lubricant is applied on the surfaces of a pair of punches and a die while lubricant is mixed with pulsating vibration air, namely under difficult condition to apply lubricant on the surfaces thereof.
  • the produced tablet hardly causes sticking and so on comparing with the prior internal lubricant method and the prior external lubricant spraying method eve if the amount of lubricant used for a tablet is remarkably reduced.
  • the tablet produced by this method doesn't happen disintegration time delay because of water repellency of lubricant.
  • a tablet which can be disintegrated at an objective region such as target region of living body can be produced.
  • molding material doesn't include lubricant therein, a tablet having practical hardness can be produced even if its tabletting pressure is lower than that of prior art when molding material is tabletted with the die and the pair of punches.
  • lubricant mixed with pulsating vibration air is designed to be sprayed in the spraying chamber.
  • lubricant is applied on the surfaces of a pair of punches and a die while lubricant is mixed with pulsating vibration air, namely under difficult condition to apply lubricant on the surfaces thereof.
  • the produced tablet hardly causes sticking and so on comparing with the prior internal lubricant method and the prior external lubricant spraying method eve if the amount of lubricant used for a tablet is remarkably reduced.
  • the tablet produced by this method doesn't happen disintegration time delay because of water repellency of lubricant.
  • a tablet which can be rapidly disintegrated at an objective region such as target region of living body can be produced.
  • molding material doesn't include lubricant therein, a tablet having practical hardness can be produced even if its tabletting pressure is lower than that of prior art when molding material is tabletted with the die and the pair of punches.
  • a spraying means for spraying lubricant mixed with positive pulsating vibration air is provided in the spraying chamber, so the production system can be simplified.
  • a tablet with practical hardness can be produced at low tabletting pressure because lubricant isn't included in molding material. Therefore, a tablet can be produced without breaking film and granule and without causing plastic deformation even if the construction and material of the film and the base matrix aren't devised for the purpose of prolongation of mode of action, sustained release, rapid release, high solubility in stomach, high solubility in intestine, prevention of bitter taste.
  • a tablet with practical hardness can be produced at low tabletting pressure because lubricant isn't included in molding material. Therefore, a tablet can be produced without breaking film and granule and without causing plastic deformation even if the construction and material of the film and the base matrix aren't devised for the purpose of prolongation of mode of action, sustained release, rapid release, high solubility in stomach, high solubility in intestine, prevention of bitter taste.
  • a spraying means for spraying lubricant mixed with positive pulsating vibration air is required to be provided so that the system can be simplified.
  • granule containing active substance and diluting agent is used as granule containing active substance (so called microcapsule) so that the particle diameter and particle size containing active substance can be easily changed.
  • a tablet can be easily produced by controlling the diameter and the size of granule containing active substance so as to facilitate coating on the surface.
  • the diameter and the size of granule containing active substance can be made so as to derive the function of granule to the full extent.
  • tablet can be produced at low tabletting pressure, a tabletting can be executed without destroying the function of a base matrix even if granule contained in the tablet includes active substance in the base matrix.
  • tablette can be produced at low tabletting pressure, a tabletting can be executed without destroying the coating film even if granule contained in the tablet is coated with a film.
  • tabletting is continuously executed utilizing the fact that molding material isn't adhered on the punches and the dies so that sticking isn't caused.
  • a tablet including active substance and a tablet including granule containing active substance can be produced at industrial production base.
  • tabletting is continuously executed utilizing the fact that molding material isn't adhered on the punches and the dies so that sticking isn't caused.
  • a tablet including active substance and a tablet including granule containing active substance can be produced at industrial production base.
  • lubricant is applied on the surface of the punches and the dies constructing a female mold for a tablet with an engraved mark or a dividing line and for an anomalous tablet in the spraying chamber in which pulsating vibration air is generated, lubricant can be applied uniformly comparing with the prior external lubricant spraying method.
  • molding material is hardly attached on the surfaces of the punches and the dies while compressing a tablet with an engraved mark or a dividing line or an anomalous tablet so that sticking, capping, and laminating of such a tablet are prevented.
  • tabletting pressure for compressing molding material is low, tabletting can be executed without destroying a film even if granule contained in the tablet is covered with a film. Further, if granule contained in a tablet includes active substance in a base matrix, tabletting can be executed without destroying the function of the base matrix.
  • the tablet production method in claim 14 even if the amount of lubricant sprayed at one tabletting is remarkably reduced, a tablet can be produced without causing sticking and so on. Consequently the produced tablet doesn't include lubricant therein and minute amount of lubricant is attached on the surface so that disintegration time isn't delayed.
  • tablet can be produced at a low tabletting pressure, and the granule is hardly destroyed or plastic deformation is caused, so that the function of the granule containing active substance in the tablet isn't apt to be damaged.
  • the produced tablet if used as an uncoated tablet, it becomes a rapidly disintegrable tablet and a tablet which is required to be immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet can be easily produced. Further if a film coat which can be dissolved at an objective region is executed on the surface of a tablet, the tablet itself is immediately dissolved at a desired region when a film coat is dissolved, so that a tablet which can be dissolved at an objective region can be produced.
  • the tablet is used as an uncoated tablet, it becomes a rapidly disintegrable tablet and the tablet is immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet and active substance contained in the tablet is immediately released.
  • the tablet itself can be dissolved at an objective region when the film coat is dissolved, so that active substance contained in the tablet is immediately released.
  • the tablet is used as an uncoated tablet, it becomes a rapidly disintegrable tablet and the tablet is immediately disintegrated at an objective region like an intrabuccally rapidly disintegrable tablet and granule containing active substance (so called microcapsule) contained in the tablet is immediately released.
  • the tablet itself can be dissolved at an objective region when the film coat is dissolved, so that granule containing active substance (so called microcapsule) contained in the tablet is immediately released.
  • granule containing active substance and diluting agent is used as granule containing active substance (so called microcapsule), the particle diameter and size of the granule can be easily modified by diluting agent.
  • a tablet production can be easily executed by controlling the particle diameter and size of the granule containing active substance so as to coat a film on the surface of the tablet.
  • the diameter and the size of granule containing active substance can be made so as to derive the function of granule to the full extent.
  • diluting agent used as bulking agent doesn't include lubricant, there is no problem such that disintegration time of the tablet delays because of water repellency of lubricant.
  • the base matrix can achieve its desired objective function.
  • the tablet also becomes to have a function of sustained release by the base matrix.
  • unfilmed granule containing active substance and granule containing active substance in base matrix are mixed in a tablet, they are immediately released from the tablet when the tablet is dissolved.
  • the active substance contained in the unfilmed granule is immediately absorbed in a body when the tablet is disintegrated. Therefore, the tablet has superior rapid onset of action.
  • the tablet also becomes to have a function of prolongation of mode of action by the base matrix.
  • the tablet has both rapid onset of action and prolongation of mode of action.
  • the active substance is analgesic, anti-inflammatory agent, or antidote
  • unfilmed granule containing such agent and granule containing such agent in the base matrix are mixed.
  • a new tablet such as a once daily tablet, namely a quick & slow release tablet, by which pain, inflammation or fever of a patient is immediately remedied and analgesic action, anti-inflammatory action, or antidote action is kept long when a patient takes this medicine can be obtained.
  • diluting agent used as bulking agent doesn't include lubricant, there is no problem such that disintegration time of the tablet delays because of water repellency of lubricant.
  • the tablet includes granule containing active substance
  • a film coated on the surface of the granule containing active substance brings out a desired objective function.
  • the film coated on the granule containing active substance aims at prolongation of mode of action
  • the tablet also has prolongation of mode of action because of the film.
  • unfilmed granule containing active substance and filmed granule containing active substance are mixed in a tablet, they are immediately released from the tablet when the tablet is dissolved.
  • the active substance contained in the unfilmed granule is immediately absorbed in a body when the tablet is disintegrated. Therefore, the tablet has superior rapid onset of action.
  • the tablet also becomes to have prolongation of mode of action because of the function of the film.
  • the tablet has both rapid onset of action and prolongation of mode of action.
  • the active substance is analgesic, anti-inflammatory agent, or antidote
  • unfilmed granule containing such agent and filmed granule containing such agent are mixed.
  • a new tablet such as a once daily tablet, namely a quick & slow release tablet, by which pain, inflammation or fever of a patient is immediately remedied and analgesic action, anti-inflammatory action, or antidote action is kept long when a patient takes this medicine can be obtained.
  • the tablet in claim 20 is provided with a minute amount of lubricant on the surface, its disintegration time doesn't delay.
  • the tablet in claim 21 has a dividing line, it can be easily divided along the line. Therefore, appropriate amount of drug depending on the weight or age of a patient can be taken by a patient.
  • the tablet in claim 22 has anomalous shape, drugs can be easily distinguished by its shape. Therefore, medication error is hardly happened.
  • the tablet in claim 23 because lubricant is uniformly applied on the surface of the tablet (uncoated tablet), there is no wide variation of disintegration time of the tablet and elution time of the active substance. Therefore, the tablet of which standard deviation of disintegrating time of the tablet or elution time of the active substance is less than 15.0 percent of average disintegrating time or average elution time can be easily produced.
  • the tablet of which standard deviation of disintegrating time of the tablet or elution time of the active substance is less than 10.0 percent of average disintegrating time or average elution time, which has been considered to be difficult in the prior art, can be easily produced.
  • the tablet of which standard deviation of disintegrating time of the tablet or elution time of the active substance is less than 7.5 percent of average disintegrating time or average elution time, which has been impossible to produce in the prior art as far as the inventors know, can be produced.
  • the amount of lubricant contained in the tablet can be easily measured.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
EP99913634A 1998-04-10 1999-04-09 Comprime et procedes de fabrication de comprime Withdrawn EP1070497A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP9863598 1998-04-10
JP9863598 1998-04-10
PCT/JP1999/001939 WO1999052492A1 (fr) 1998-04-10 1999-04-09 Comprime et procedes de fabrication de comprime

Publications (2)

Publication Number Publication Date
EP1070497A1 true EP1070497A1 (fr) 2001-01-24
EP1070497A4 EP1070497A4 (fr) 2009-01-21

Family

ID=14224973

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99913634A Withdrawn EP1070497A4 (fr) 1998-04-10 1999-04-09 Comprime et procedes de fabrication de comprime

Country Status (6)

Country Link
EP (1) EP1070497A4 (fr)
JP (1) JP4568427B2 (fr)
KR (1) KR20010042593A (fr)
AU (1) AU764325B2 (fr)
CA (1) CA2328100C (fr)
WO (1) WO1999052492A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004051006A1 (de) * 2004-10-20 2006-04-27 Fette Gmbh Rundlaufpresse
DE102005037773B3 (de) * 2005-08-10 2007-01-18 Voss, Gunter M. Verfahren zum Befilmen einer Oberflächenform mit einer Lösung
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US8377472B1 (en) 1999-03-01 2013-02-19 Ethypharm Orally dispersible tablet with low friability and method for preparing same
US8580313B2 (en) 2009-12-02 2013-11-12 Aptalis Pharma Limited Fexofenadine microcapsules and compositions containing them
US8747895B2 (en) 2004-09-13 2014-06-10 Aptalis Pharmatech, Inc. Orally disintegrating tablets of atomoxetine
US9040086B2 (en) 2001-10-04 2015-05-26 Aptalis Pharmatech, Inc. Timed, sustained release systems for propranolol
US9161919B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US10471017B2 (en) 2004-10-21 2019-11-12 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2614547C (fr) * 2005-07-08 2014-10-21 Takeda Pharmaceutical Company Limited Comprime
CN113262170B (zh) * 2021-05-18 2022-09-27 常州市龙城晨光药化机械有限公司 一种片状药品智能加工设备及其加工方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5614098A (en) 1979-07-13 1981-02-10 Takeda Chem Ind Ltd Externally lubricating tablet making machine
JPS57150612A (en) 1981-03-13 1982-09-17 Tanabe Seiyaku Co Ltd Immediately releasing micro-capsule and its preparation
JPS62103012A (ja) 1985-10-23 1987-05-13 Eisai Co Ltd 多重顆粒
GB8530365D0 (en) * 1985-12-10 1986-01-22 Univ Bath Manufacture of moulded products
NZ226822A (en) 1987-11-16 1990-03-27 Mcneil Consumer Prod Chewable medicament tablet containing means for taste masking
JP3343144B2 (ja) * 1992-12-28 2002-11-11 扶桑薬品工業株式会社 マイクロカプセル
JP2681601B2 (ja) * 1993-11-01 1997-11-26 協和醗酵工業株式会社 外部滑沢式打錠機
JP3670710B2 (ja) * 1995-04-04 2005-07-13 協和醗酵工業株式会社 割溝付き錠剤および割溝形成凸部付き杵
DE69739967D1 (de) * 1996-06-14 2010-09-30 Kyowa Hakko Kirin Co Ltd Eine im Mund schnell zerfallende Tablette

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8956650B2 (en) 1996-06-14 2015-02-17 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8357396B2 (en) 1996-06-14 2013-01-22 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8945618B2 (en) 1996-06-14 2015-02-03 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8377472B1 (en) 1999-03-01 2013-02-19 Ethypharm Orally dispersible tablet with low friability and method for preparing same
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, Inc. Timed, sustained release systems for propranolol
US9040086B2 (en) 2001-10-04 2015-05-26 Aptalis Pharmatech, Inc. Timed, sustained release systems for propranolol
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US8747895B2 (en) 2004-09-13 2014-06-10 Aptalis Pharmatech, Inc. Orally disintegrating tablets of atomoxetine
US10130580B2 (en) 2004-10-12 2018-11-20 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US11452689B2 (en) 2004-10-12 2022-09-27 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US10568832B2 (en) 2004-10-12 2020-02-25 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US7654814B2 (en) 2004-10-20 2010-02-02 Fette Gmbh Rotary press
DE102004051006B4 (de) * 2004-10-20 2009-07-02 Fette Gmbh Rundlaufpresse
DE102004051006A1 (de) * 2004-10-20 2006-04-27 Fette Gmbh Rundlaufpresse
US10952971B2 (en) 2004-10-21 2021-03-23 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
US10471017B2 (en) 2004-10-21 2019-11-12 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
US10045946B2 (en) 2005-05-02 2018-08-14 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9579293B2 (en) 2005-05-02 2017-02-28 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9566249B2 (en) 2005-05-02 2017-02-14 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US10500161B2 (en) 2005-05-02 2019-12-10 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US11147772B2 (en) 2005-05-02 2021-10-19 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9161919B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
DE102005037773B3 (de) * 2005-08-10 2007-01-18 Voss, Gunter M. Verfahren zum Befilmen einer Oberflächenform mit einer Lösung
US8580313B2 (en) 2009-12-02 2013-11-12 Aptalis Pharma Limited Fexofenadine microcapsules and compositions containing them
US10166220B2 (en) 2009-12-02 2019-01-01 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US9233105B2 (en) 2009-12-02 2016-01-12 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US10729682B2 (en) 2009-12-02 2020-08-04 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them

Also Published As

Publication number Publication date
KR20010042593A (ko) 2001-05-25
JP4568427B2 (ja) 2010-10-27
CA2328100C (fr) 2011-01-18
EP1070497A4 (fr) 2009-01-21
AU764325B2 (en) 2003-08-14
WO1999052492A1 (fr) 1999-10-21
AU3169399A (en) 1999-11-01
CA2328100A1 (fr) 1999-10-21

Similar Documents

Publication Publication Date Title
AU763143B2 (en) Tablet manufacturing method and tablet
TWI280141B (en) Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs
CA2328100C (fr) Comprime et procedes de fabrication de comprime
RU2420268C2 (ru) Способ программируемой плавучей доставки
US20030175355A1 (en) Fast melt multiparticulate formulations for oral delivery
EP0418596A2 (fr) Composition pharmaceutique à libération contrôlée à partir de granules sphériques sous forme d'une dose unitaire orale comprimée
US20080311162A1 (en) Solid form
CN108969490A (zh) 快速分散颗粒、口腔崩解片以及方法
NZ238131A (en) Chewable medicament tablets formed from compressed coated granules; coating is a polymer blend masking taste and providing sustained release
JP2005508330A (ja) 充填された部分を備えた複合剤形
WO2008140459A1 (fr) Forme solide
EP1978933A2 (fr) Procédés de préparation de formulations pharmaceutiques à base de particules destinées à une administration orale
JPWO1999052491A1 (ja) 錠剤の製造方法及び錠剤
US20150098995A1 (en) Tabletting Process
NZ548168A (en) Multiparticulate formulations for oral delivery, comprising a core coated by melt-coating smaller excipient particles onto the core
JPWO1999052492A1 (ja) 錠剤の製造方法及び錠剤
Ilhan et al. Mini tablets: A short review-revision
EP3854386B1 (fr) Composition pharmaceutique à désintégration orale comprenant du néfopam et son procédé de préparation
WO2001026633A1 (fr) Comprimes enrobes de gomme de caroube, de gomme de guar ou de gomme de mousse d'irlande
CN102579398A (zh) 一种具有掩盖药物不良口味作用的肠溶微囊及制备方法
JP2004026675A (ja) 咀嚼型医薬製剤用粒子、それを使用した咀嚼型医薬製剤、及び咀嚼型医薬製剤の不快味抑制方法
Jadhav et al. Pulsatile drug delivery system using core-in-cup approach: a review
KR20230038183A (ko) 팽윤성 경구 제약 조성물
Narender et al. FORMULATION AND EVALUATION OF GASTRORETENTIVE FLOATING TABLET OF LISINOPRIL
AU2005299253B2 (en) Improved tabletting process

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20001109

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

A4 Supplementary search report drawn up and despatched

Effective date: 20081219

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: KYOWA HAKKO KIRIN CO., LTD.

17Q First examination report despatched

Effective date: 20090630

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121101