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WO1999052492A1 - Comprime et procedes de fabrication de comprime - Google Patents

Comprime et procedes de fabrication de comprime Download PDF

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Publication number
WO1999052492A1
WO1999052492A1 PCT/JP1999/001939 JP9901939W WO9952492A1 WO 1999052492 A1 WO1999052492 A1 WO 1999052492A1 JP 9901939 W JP9901939 W JP 9901939W WO 9952492 A1 WO9952492 A1 WO 9952492A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
lubricant
active ingredient
tablets
granules
Prior art date
Application number
PCT/JP1999/001939
Other languages
English (en)
Japanese (ja)
Inventor
Hiroyuki Morimoto
Eiji Hayakawa
Motohiro Ohta
Kiyoshi Morimoto
Yasushi Watanabe
Tomohiko Goto
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.
Priority to JP2000543105A priority Critical patent/JP4568427B2/ja
Priority to CA2328100A priority patent/CA2328100C/fr
Priority to KR1020007011267A priority patent/KR20010042593A/ko
Priority to AU31693/99A priority patent/AU764325B2/en
Priority to EP99913634A priority patent/EP1070497A4/fr
Publication of WO1999052492A1 publication Critical patent/WO1999052492A1/fr

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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 method for producing a tablet, and in particular, to a method for producing a tablet in which the tablet disintegrates immediately at a target site, and a tablet or a tablet with a marking or a score line can be produced without producing a stateing or the like.
  • the present invention relates to a method for producing a tablet, and a method for producing a tablet, which can easily produce a tablet containing granules coated with a film or the like (so-called multiple unit tablet) without impairing the function of the granules.
  • the present invention also provides tablets that disintegrate immediately at a target site in a living body, such as in the oral cavity, tablets containing granules in which the functions of the granules contained in the tablets are not impaired, and functions such as sustained release. And a tablet that does not lose its function even when divided.
  • Tablets and capsules are extremely convenient preparations for carrying and taking. Particularly, tablets do not float on water when taken with water, etc. It has various advantages such as ease of taking for patients and low production cost. It is the most widely used dosage form for oral administration and oral use.
  • tablets with a different shape from circular tablets, tablets with a company name or a drug code stamped on the tablet A scored tablet is rapidly spreading, in which a tablet is provided with a score line, and the tablet is broken according to the score line so that the optimal dose of the drug can be administered to the patient according to the age and weight of the patient.
  • tablets are prepared by simply compressing powder or granules into uncoated tablets, or on tableted tablets for the purpose of sustaining, sustained release, immediate release, gastric solubility, enteric solubility, and bitterness prevention.
  • Tablets Multiple-unit tablets
  • Each of the granules 102 containing the active ingredient contained in the 101 is continuously released in a fixed amount for a certain amount of time in a single dose of the tablet 101
  • the active ingredient-containing portion 102 a as shown in FIG. 20 (b) is used.
  • the active ingredient 102 c is dispersed in a base matrix 102 d such as a base material or hydrophobic polymer material such as silicone rubber or plastic, and the active ingredient 10 2 d from the base matrix 102 d is dispersed. With the release of 2c, the interface of the base matrix 102d recedes and the active ingredient 102c is released continuously Granules or the like is used which is to be.
  • a base matrix 102 d such as a base material or hydrophobic polymer material such as silicone rubber or plastic
  • Such tablets or imprinted tablets with imprints or score lines, and tablets containing granules (multiple unit tablets) are generally manufactured by an internal lubrication method or an external lubrication method.
  • the molding material to be tableted adheres to a punch and a die
  • the molding material to be tableted adheres to a punch and a die
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are added to the molding material to be compressed in addition to the active ingredient and excipients. Kneading, compression molding this It refers to a method of manufacturing a tablet.
  • FIG. 21 is a process diagram schematically showing a method for producing a tablet described in Japanese Patent Publication No. 41-112773.
  • This tablet manufacturing method comprises the steps of filling a predetermined amount of a material to be tableted into a tablet, compressing the filled material using a pair of upper and lower punches to form a tablet, As shown in Fig. 21 (a), the step preceding the step of filling the molding material m into the dies 151, as shown in Fig. 21 (a), comprises the following steps: An injection nozzle 1559 for injecting the lubricant L is installed at a predetermined upper position, and an upper punch 15 3 provided corresponding to the mill 15 1 at the position where the injection nozzle 1559 is installed.
  • Lubricant L is sprayed from the spray nozzle 1559 onto the surface (lower surface) 15 5 s and the surface (upper surface) 15 4 s of the lower punch 15 4 Then, as shown in FIG. 21 (b), the molding material is filled into the dies 151, and the molding material m filled in the dies 15 1 is shown in FIG. 21 (c).
  • the surface ( Lower punch 15 3 s with lubricant L applied to 15 3 s and lower punch 15 4 coated with lubricant L on the surface (upper end) 15 4 s Compress and manufacture tablets.
  • a member denoted by 152 indicates a rotary table provided with a die 151 (hereinafter, the same applies to FIG. 22).
  • FIG. 22 is a process diagram schematically showing a tablet production method described in Japanese Patent Application Laid-Open No. 56-14098.
  • the method for producing this tablet is as follows: in the first step of the step of filling the molding material into the above-mentioned 151, a sprayer 1556 for spraying the lubricant L at a predetermined position above the above-mentioned 151, and A nozzle 159 for jetting the air is provided, and as shown in Fig. 22 (a), the mortar 155 comes to the position where the scatterer 156 is installed, and slides into the scatterer 156.
  • the surface of the lower punch 154 (upper end surface) 154 s provided corresponding to the above-mentioned 151 is smoothly slid to the surface 154s.
  • the internal lubrication method requires high tableting pressure (usually 1 ton (ton) / cm 2 to 2 ton (ton) / cm 2 ) to obtain practical hardness for tablets.
  • high tableting pressure usually 1 ton (ton) / cm 2 to 2 ton (ton) / cm 2
  • the film 102 formed on the surfaces of the granules 102 contained in the tablets 101 is compressed at the time of tableting.
  • the granules 102 are plastically deformed or broken due to excessive force applied to the granules 102, or the granules 102 are subjected to excessive force.
  • a function of dissolving granules at a target site cannot be obtained due to a function of immediate release, a function of sustained release, a function of sustained release, and a target.
  • tablets containing granules are limited in the applicable tablets, and so-called microcapsule-containing preparations are not tablets that are easy to take.
  • capsules and granules, which are difficult to take, are mainly used.
  • tablets with functions such as sustained release, sustained release, immediate release, gastric dissolution, enteric dissolution, and bitterness prevention are coated with sugar coating or film coating on the surface of uncoated tablets.
  • Single-unit tablets that have been subjected to film treatment such as treatment are the mainstream.However, due to the structure of such single-unit tablets, if they are made into dividable tablets with a scored line on the tablet surface, When the tablet is divided, the film is also destroyed and the function given to the tablet is lost, so sustainability and sustained release from clinicians and pharmacists in hospitals and clinics, etc. I want to sell dividable tablets that have functions such as immediate release, gastric dissolution, enteric dissolution, bitterness prevention, etc. that can be finely and appropriately set for each patient. To meet the request Such have o
  • the present invention has been made to solve the above problems, and a first object of the present invention is to disintegrate a tablet immediately at a target site, such as a rapidly disintegrating tablet in the oral cavity. It is an object of the present invention to provide a tablet manufacturing method for manufacturing a tablet required to perform the above-mentioned steps. Further, a second object of the present invention is to produce a tablet or a deformed tablet with an engraved or scored line in the production of a tablet or a deformed tablet with an engraved or scored line. Another object of the present invention is to provide a method for producing a tablet which is less likely to cause binding or the like.
  • a third object of the present invention is to produce a tablet containing granules (multiple unit tablets) without impairing the function of the granules (also referred to as microcapsules) contained in the tablets.
  • the present inventors have been conducting research on the tablet manufacturing method for many years, and as a result, have housed a punch and a mortar of a tableting machine in a spraying chamber, and generated air pulsating waves in the spraying chamber.
  • a lubricant is applied to the surface and the surface of the mortar, and the molding material is tableted using a punch with the lubricant applied to the surface and a statement that the lubricant is applied to the surface.
  • Experiments have shown that even if a tablet or a modified tablet with a score is manufactured, it is unlikely that the manufactured imprinted or scored tablet or the modified tablet will have a stateing, caving, laminating, binding, etc. As a result of intensive efforts, the present invention has been completed.
  • the present inventors have already proposed a method for producing a tablet described in Japanese Patent Application Laid-Open No. 7-124231, which is proposed by the present inventors. Prevents sticking and enables smooth, long-term, stable and continuous tableting, and the molding material adheres to punches and dies even if the amount of lubricant used is significantly reduced. It is found that tablets can be produced without using the method, and if this method is used, the tablets produced will have sufficient practical hardness even when compressed at extremely low pressure, and will have a disintegration time. Thought that it would be possible to produce a tablet without delay, and worked diligently to complete the present invention.
  • the method for producing a tablet according to claim 1 is a method for producing a tablet comprising, at least, using a pair of upper and lower punches to produce a tablet containing at least an active ingredient.
  • the process of preparing the molding material including, and a pair of punches and a pair of upper and lower punches are housed in a spraying chamber, and a pulsating air is generated in the spraying chamber, and a lubricant mixed with air is sprayed to pulsate the air.
  • a pair of punches and a pair of punches housed in a spraying room while mixed with waves A step of applying a lubricant to the surface of the mold, and a step of tableting the molding material using a pair of upper and lower punches having the lubricant applied to the surface.
  • lubricant used in the tablet manufacturing method according to the present invention various lubricants can be used, and there is no particular limitation.
  • metal stearates eg, magnesium stearate, stearic acid
  • Commonly used such as calcium phosphate), stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, gum arabic powder, carnauba ⁇ , silicic anhydride, magnesium oxide, silicic acid hydrate, starch, boric acid, fatty acid sodium salt, leucine, etc.
  • Any lubricant (powder) can be used and, depending on the purpose, may be used alone or in combination of two or more of these lubricants.
  • an excipient is appropriately added to the molding material in addition to the active ingredient to give the form of the tablet.
  • excipients can be used as such excipients, such as sugars (lactose, sucrose, glucose, mannitol, etc.), starch (eg, potato, wheat, corn, etc.), and inorganic substances (calcium carbonate, Examples include powders of calcium sulfate, sodium hydrogen carbonate, sodium chloride, etc., crystalline cellulose, and plant powders (eg, Kanzo powder, gentian powder).
  • sugars lactose, sucrose, glucose, mannitol, etc.
  • starch eg, potato, wheat, corn, etc.
  • inorganic substances calcium carbonate
  • examples include powders of calcium sulfate, sodium hydrogen carbonate, sodium chloride, etc., crystalline cellulose, and plant powders (eg, Kanzo powder, gentian powder).
  • binders in addition to the active ingredient excipient, if necessary, binders, solubilizers, solubilizers, disintegrants, and other auxiliary agents, flavoring agents, coloring agents, and preparations Powders that may contain additives, antioxidants, preservatives, sunscreens, antistatics, fragrances, sweeteners, fluidizers, flavors, etc., but do not contain lubricants Means material.
  • air pulsation wave of the present invention means a wave of air whose air pressure fluctuates. Air pulsation waves generate air vibrations throughout the spraying chamber regardless of whether the air pressure is positive or negative, forcibly diffusing the lubricant particles sprayed into the spraying chamber. Air pulsation waves under various conditions (amplitude, wavelength, waveform, frequency, period) can be used as long as they exert the effect of causing the air to pulsate.
  • the “positive pressure air pulsation wave” means that both the peak and the valley of the air pulsation wave are higher than the atmospheric pressure outside the spray chamber, and the peak of the air pulsation wave is higher than the atmospheric pressure outside the spray chamber.
  • Valleys mean both air pulsating waves whose valley is approximately equal to the atmospheric pressure outside the spray chamber.
  • air pulsation wave of negative pressure means that both the peak and the valley of the air pulsation wave are lower than the atmospheric pressure outside the spray chamber, and the peak of the air pulsation wave is almost equal to the atmospheric pressure outside the spray chamber.
  • the valley means both air pulsation waves below atmospheric pressure outside the spray chamber.
  • an air pulsation wave is generated and a lubricant is sprayed in the spraying chamber.
  • the lubricant sprayed into the spray chamber mixes with the air pulsation wave.
  • the lubricant is mixed in a state where the lubricant is mixed with the air pulsating wave, that is, in an environment where the lubricant hardly adheres to the surface of the pair of punches. , Mortar and upper and lower pairs of punches are attached to the surface.
  • the lubricant is evenly attached to the surface of the mortar and the pair of upper and lower punches without unevenness.
  • the amount of lubricant used per tablet can be reduced by the conventional internal lubricant. Even if the amount is significantly reduced as compared with the Sawaho method or the external lubrication method, the manufactured tablets are less likely to cause stateing or the like.
  • the tablet produced according to this tablet production method is caused by the water repellency of the lubricant.
  • the phenomenon that the disintegration time of tablets is delayed does not occur.
  • a tablet in which the tablet disintegrates immediately at a target site such as a target site of a living body can be manufactured.
  • the tableting pressure is reduced by the conventional tableting pressure when the tablet is compressed using a pair of upper and lower punches. Even if the pressure is lower than the tablet pressure, tablets having practical hardness can be produced.
  • the method for producing a tablet according to claim 2 is a method for producing a tablet containing at least an active ingredient by using a pair of upper and lower punches.
  • the process of preparing the material, the mortar and the pair of upper and lower pestle are housed in the spraying room, the lubricant mixed with the air pulsating wave is sprayed into the spraying room,
  • the method includes a step of applying a lubricant to the surface of the lower set of punches, and a step of tableting the molding material using a die coated with the lubricant and a pair of upper and lower punches.
  • a lubricant mixed with the air pulsation wave is sprayed into the spraying chamber.
  • the lubricant is mixed in a state where the lubricant is mixed with the air pulsating wave, that is, the lubricant is hardly attached to the surface of the pair of punches. Is attached to the surface of the mortar and a pair of upper and lower punches.
  • the lubricant is evenly attached to the surface of the mortar and the pair of upper and lower punches without unevenness.
  • the amount of lubricant used per tablet can be reduced by the conventional internal lubricant. Even if the amount is significantly reduced as compared with the Sawaho method or the external lubrication method, the manufactured tablets are less likely to cause stateing or the like.
  • the tablet produced according to the tablet production method does not have the phenomenon that the disintegration time of the tablet is delayed due to the water repellency of the lubricant.
  • a tablet in which the tablet disintegrates immediately at a target site such as a target site of a living body can be manufactured.
  • the tableting pressure is reduced by the conventional tableting pressure when the tablet is compressed using a die and a pair of upper and lower punches. Even if the pressure is lower than the tablet pressure, tablets having practical hardness can be produced.
  • the method for producing a tablet according to claim 3 is characterized in that the air pulsation wave used in the tablet production method according to claim 2 is a positive pressure air pulsation wave.
  • a spraying device for spraying a lubricant mixed with a positive pressure air pulsating wave may be provided in the spraying chamber, so that the manufacturing apparatus can be simplified.
  • the present inventors have found that the tablet manufacturing method described in Japanese Patent Application Laid-Open No. 7-124231 disclose that even if tableting is performed at an extremely low pressure, the manufactured tablet has a sufficient practical hardness. By using this method, it is possible to damage the film of granules, so-called microcapsules, to break the granules contained in the tablet, or to cause plastic deformation. Therefore, the inventors thought that a tablet containing granules could be produced, and made intensive efforts to complete the present invention.
  • the method for producing a tablet according to claim 4 is a method for producing a tablet, comprising: using at least one pair of upper and lower punches to produce at least a tablet containing granules containing an active ingredient.
  • tablettes containing at least the active ingredient-containing granules refers to tablets obtained by compressing only the active ingredient-containing granules, at least the active ingredient-containing granules, a diluent, a bulking agent, and a filler. , Including both tablets obtained by tableting a molding material obtained by uniformly kneading excipients such as excipients and the like.
  • dissolution aids, solubilizing agents, disintegrants And other additives such as antioxidants, preservatives, light-blocking agents, antistatic agents, fragrances, sweeteners, fluidizers, flavoring agents, coloring agents, and the like.
  • the “granules containing the active ingredient” are used for at least the surface of the part containing the active ingredient (the active ingredient) for the purpose of sustaining, sustained release, immediate release, gastric solubility, enteric solubility, bitterness prevention And granules formed by dispersing the active ingredient in a base matrix.
  • the coating agent for the film that covers the surface of the portion containing the active ingredient (main drug) does not need to be special, and is generally used for sugar coating, ethylcell mouthwash.
  • EC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose phthalate
  • carmellose and other film coating agents hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylethylcellulose (CMEC), cellulose acetate such as cellulose acetate furoate (CAP), acrylic acid such as methacrylate copolymer, natural product such as shellac, etc., enteric coating agent, ethylcellulose (EC), Sugar esters, aminoalkyl methacrylate copolymers, sustained-release coating agents such as ethyl acrylate-methyl methacrylate copolymer, and the like, JP-A-57-150612, Species such as coating materials described in JP-A-62-103012 and JP-A-2-106.
  • the material can be selected.
  • a tablet having practical hardness can be manufactured at a low tableting pressure.
  • the tablet containing the granules can be applied to the surface of the part containing the active ingredient (drug) for the purpose of sustaining, sustained release, immediate release, gastric solubility, enteric solubility, bitterness prevention, etc.
  • the structure, material, and structure and material of the base matrix are not broken, without any special measures, without breaking the film, and without the phenomenon that occurs when the granules are broken or undergo plastic deformation. , Tableting can do.
  • the tablet manufacturing method wherein a tablet including at least a granule containing an active ingredient is manufactured using a die and a pair of upper and lower punches.
  • the method includes a step of tableting a molding material containing granules containing an active ingredient using a pair of upper and lower punches.
  • a tablet having practical hardness can be manufactured at a low tableting pressure.
  • the tablet containing the granules can be applied to the surface of the part containing the active ingredient (drug) for the purpose of sustaining, sustained release, immediate release, gastric solubility, enteric solubility, bitterness prevention, etc.
  • the structure, material, and structure and material of the base matrix without any special measures, do not break the film, and do not cause the phenomenon that the granules are broken or plastically deformed. Can be made into tablets.
  • a tablet manufacturing method is characterized in that the air pulsation wave used in the tablet manufacturing method according to the fifth aspect is a positive pressure air pulsation wave.
  • a spraying device for spraying a lubricant mixed with a positive pressure air pulsating wave may be provided in the spraying chamber, so that the manufacturing apparatus can be simplified.
  • the method for producing a tablet according to claim 7 proposes a preferable example of granules (so-called microcapsules) containing an active ingredient to be included in a molding material, and is described in any one of claims 4 to 6. Stipulates that the granules containing the active ingredient used in the method for producing a tablet are granules containing the active ingredient and an excipient.
  • granules containing an active ingredient and an excipient are used as granules containing the active ingredient (so-called microcapsules).
  • the particle size and size of the granules can be easily changed.
  • the tablet can be easily produced by setting the particle size and size of the granules containing the active ingredient to the particle size and size that allow the surface to be coated easily. Further, the particle size and size of the granule containing the active ingredient can be adjusted to the particle size and size that can maximize the function of the granule.
  • the method for producing a tablet according to claim 8 proposes another preferable example of granules (so-called microcapsules) containing an active ingredient to be contained in a molding material. It is specified that the granules containing the active ingredient used in the tablet manufacturing method described above are granules containing the active ingredient in a base matrix.
  • the “granules containing the active ingredient in the base matrix” is a water-insoluble base such as oils, fats, waxes, and petrolatum, or silicones, for controlled release of the drug to form a sustained release formulation.
  • tablets can be manufactured with low tableting pressure, so even if the granules contained in the tablets contain the active ingredient in the base matrix, the function of the base matrix is destroyed. It can be made into tablets without having to do it.
  • the method for producing a tablet according to claim 9 proposes another preferred example of granules (so-called microcapsules) containing an active ingredient to be contained in a molding material. Stipulates that the granules containing the active ingredient used in the method for producing a tablet described in (1) are granules in which the portion containing the active ingredient is covered with a film.
  • tablets can be manufactured at a low tableting pressure, so that even if the granules contained in the tablets are covered with a film, they can be formed into tablets without breaking the film.
  • a conventionally known coating method such as a fluidized bed coating apparatus may be used.
  • a method for manufacturing a tablet according to claim 10 is a method for manufacturing a tablet according to claim 1 or claim 4, wherein a mortar and a pair of upper and lower punches are accommodated in a spraying chamber.
  • the air pulsation wave is generated, and at the same time, the lubricant mixed with the air is sprayed, and the lubricant mixed with the air pulsation wave is contained in the spraying chamber and the surface of the pair of upper and lower punches is lubricated.
  • the use of a pair of upper and lower punches with the lubricant applied to the surface The step of tableting the molding material is performed continuously.
  • the method for producing a tablet according to claim 11 is a process for accommodating a pair of punches and a pair of upper and lower punches in the spraying chamber of the tablet manufacturing method according to claim 2 or claim 5, Spraying the lubricant mixed with the air pulsation wave to apply the lubricant to the surfaces of the mortar and the pair of upper and lower punches housed in the spraying chamber, and the lubricant was applied to the surface
  • the process of tableting the molding material using a mortar and a pair of upper and lower punches is performed continuously. In this tablet manufacturing method, in the tableting process, the molding material adheres to the punch and the die. Instead, tablets are produced continuously without taking advantage of stickiness or the like in the tablets to be produced, so tablets containing the active ingredient and granules containing the active ingredient are produced on an industrial production basis. Tablets can be produced.
  • the method for producing a tablet according to claim 12 is characterized in that, in the method for producing a tablet according to any one of claims 1 to 11, a female mold of a tablet or a deformed tablet with a stamp or score is used as a punch and a die. It is characterized by the use of the punches and dies that make up.
  • the term "irregular tablet” means a tablet other than a round tablet, for example, a truck type (capsule type), a rugby ball type, a triangular type, a quadrilateral type, a pentagonal type. It refers to tablets having the shape of a polygon, diamond, almond, shell, half moon, heart, star, etc.
  • the surface of the punch and the surface of the punch which constitutes the female die of the tablet or the irregularly shaped tablet or the irregularly shaped tablet, which generates the air pulsation wave, have a smooth surface. Since the lubricant is applied, the lubricant can be evenly applied to the surface of the punch and the surface of the die as compared with the conventional external lubrication method. As a result, in the process of stamping a tablet or a deformed tablet with an engraved or scored line, the molding material becomes less likely to adhere to the surface of the punch and the surface of the die, and a tablet or a deformed tablet with an engraved or scored line is produced. Stateing, caving, laminating, etc. are unlikely to occur.
  • the method for producing a tablet according to claim 13 is the tablet according to any one of claims 1 to 12.
  • the tableting pressure in a step of tableting a molding material using a die coated with a lubricant on the surface and a pair of upper and lower punches is characterized by a low pressure.
  • low pressure means that the tableting pressure is lower than the conventional internal lubrication method or the conventional external lubrication method. More specifically, this tablet manufacturing method can sufficiently produce a tablet having a practical level of hardness even if a tableting pressure of less than 1 ton / cm 2 is used.
  • the tableting pressure in the step of tableting the molding material is reduced, so that even if the granules contained in the tablet are covered with a film, the film is broken. No, it can be made into tablets. Further, even if the granules contained in the tablet contain the active ingredient in the base matrix, the tablet can be formed without destroying the function of the base matrix.
  • the method for producing a tablet according to claim 14 is characterized in that, in the method for producing a tablet according to any one of claims 1 to 13, the amount of the lubricant to be sprayed into the spray chamber is set to 0 per tablet. 0.001% by weight or more and 0.2% by weight or less.
  • the amount of the lubricant used is as small as possible, and the amount of the tablet to be compressed per tablet is as follows: It is preferable that the content is not less than 0.001% by weight and not more than 0.2% by weight per tablet.
  • air pulsation waves are applied to the surface of the mortar (inner peripheral surface), the surface of the upper punch (lower surface), and the surface of the lower punch (upper surface) accommodated in the spray chamber.
  • Lubricant is applied, that is, in an environment where the lubricant is unlikely to adhere to the surface of the mortar and the pair of upper and lower punches, apply the lubricant to the surface of the upper and lower pair of punches. Therefore, a small amount of lubricant can be evenly applied to the surface (inner peripheral surface), the surface of the upper punch (the lower end surface), and the surface of the lower punch (the upper end surface).
  • the amount of lubricant sprayed into the spray chamber is extremely small, but the molding material is The punch of the lock machine can prevent the state from sticking. You. Therefore, the spray amount of the lubricant used for one tableting can be extremely reduced.
  • the manufactured tablet hardly contains a lubricant therein, and since only a small amount of the lubricant is present on the surface of the manufactured tablet, the disintegration time is delayed. None do.
  • a tablet (uncoated tablet) produced by this method for producing a tablet becomes a rapidly disintegrating tablet when used as a bare tablet. Tablets that require disintegration can be easily manufactured.
  • a film coat that melts at the target site is applied to the surface, when the film coat melts, the tablet body also immediately melts at the desired site, so that a tablet that melts at the target site can be manufactured.
  • this tablet manufacturing method enables tablets to be manufactured with a low tableting pressure, when tablets containing active ingredient-containing granules are manufactured inside tablets, they are effective at the time of tableting. It is difficult for the granules containing the active ingredient to be broken or to undergo plastic deformation, so that if this tablet manufacturing method is used, the function given to the active ingredient-containing granules contained in the tablet is impaired. It is hard to be.
  • a tablet (uncoated tablet) containing the granules containing the active ingredient becomes a rapidly disintegrating tablet when used as a naked tablet.
  • the tablet itself is easily disintegrated, and a tablet which is required to dissolve the granules containing the active ingredient by exhibiting a predetermined target function can be easily produced.
  • the surface is coated with a film coat that dissolves at the target site, when the film coat is melted, the tablet body immediately disintegrates at the desired site, and the granules containing the active ingredient are converted to the predetermined purpose. Tablets, which are required to exhibit the function of dissolving and be dissolved, can be easily produced.
  • the tablet according to claim 15 has a lubricant only on the surface of a tablet body containing granules containing an active ingredient in an excipient, and the amount of the lubricant used is per tablet. , 0.001% by weight or more and 0.2% by weight or less.
  • the amount of the lubricant used is as small as possible.
  • the dose is preferably 0.001 to 0.2% by weight per tablet.
  • This tablet contains no lubricant inside the tablet and only a trace amount of lubricant is present on the surface of the tablet, so the disintegration time of the tablet is delayed due to the water repellency of the lubricant. Problem does not occur.
  • this tablet when used as a naked tablet, it becomes a rapidly disintegrating tablet, and the tablet immediately disintegrates at the intended site and is contained in the tablet, as in the case of an intraorally rapidly disintegrating tablet.
  • the released active ingredient is released immediately.
  • the tablet body also melts immediately at the target site, so the active ingredient immediately and immediately at the target site. Released.
  • the tablet according to claim 16 has a lubricant only on the surface of the tablet itself containing granules containing an active ingredient in an excipient.
  • This tablet contains no lubricant inside the tablet and only a trace amount of lubricant is present on the surface of the tablet, so the disintegration time of the tablet is delayed due to the water repellency of the lubricant. Problem does not occur.
  • this tablet when used as a naked tablet, it becomes a rapidly disintegrating tablet, and the tablet immediately disintegrates at the intended site and is contained in the tablet, as in the case of an intraorally rapidly disintegrating tablet.
  • the granules containing the active ingredient are released immediately.
  • the tablet body In addition, if the surface of the tablet body is coated with a film coat that dissolves at the target site, when the film coat is melted, the tablet body also dissolves immediately at the target site, so the granules containing the active ingredient immediately at the target site (So-called microcapsules) are released immediately.
  • the tablets described in claims 17 to 19 specifically define the preferable structure of the granules containing the active ingredient of the tablet described in claim 16. That is, the tablet according to claim 17 is characterized in that the granules containing the active ingredient in the tablet according to claim 16 are granules containing the active ingredient and an excipient.
  • the granules containing the active ingredient and the excipient are used as the granules (so-called microcapsules) containing the active ingredient, the particle size of the granules containing the active ingredient depends on the excipient. The size can be easily changed.
  • the tablet can be easily produced by setting the particle size and size of the granules containing the active ingredient to the particle size and size that allow the surface to be coated easily. Further, the particle size and size of the granule containing the active ingredient can be adjusted to the particle size and size that can maximize the function of the granule.
  • the tablet according to claim 18 is characterized in that the granules containing the active ingredient of the tablet according to claim 16 are granules containing the active ingredient in a base matrix. .
  • This tablet does not contain a lubricant in the excipients used for bulking, so the disintegration time of the tablet is delayed due to the water repellency of the lubricant. I do not.
  • the base matrix exerts the intended function.
  • the base matrix is In cases where the purpose is to improve the potency, the base matrix also makes the tablet also have a long-lasting effect.
  • a tablet is coated with granules containing an active ingredient, which is not coated, and granules containing the active ingredient in a base matrix
  • the tablet is immediately converted into a tablet.
  • the granules containing the uncoated active ingredient and the granules containing the active ingredient in the base matrix are released from the tablet.
  • the active ingredient contained in the uncoated granules is absorbed into the body as soon as the tablet disintegrates. As a result, this tablet has excellent immediate effect.
  • granules containing the active ingredient in the base matrix can be used, for example, when the base matrix is intended for sustainability. Are better. That is, this tablet has both immediate effect and sustainability.
  • the tablet is not coated with granules containing the analgesic, analgesic anti-inflammatory or antipyretic, and
  • the drug matrix By mixing the drug matrix with granules containing analgesics, analgesics and anti-inflammatory agents or antipyretics, patients can immediately improve their pain, inflammation and fever if taken, and have analgesic and anti-inflammatory effects.
  • New tablets such as once-daily tablets (once daily) (once a once-daily tablet) and long-lasting antipyretic effects (Quick & S1owrelease Tablet) can be realized.
  • This tablet does not contain a lubricant in the excipients used for bulking, so the disintegration time of the tablet is delayed due to the water repellency of the lubricant. I do not.
  • the film applied on the surface of the granules containing the active ingredient exhibits a predetermined purpose function.
  • the film applied to the surface of the granules to be contained is a film for the purpose of persistence, the film also has a long-lasting effect due to this film.
  • a tablet is coated with granules containing an active ingredient that has not been coated and granules that contain a coated film and containing the active ingredient, the tablet immediately disintegrates in this tablet, Immediately after disintegration, the granules containing the uncoated active ingredient and the granules containing the coated active ingredient are released from the tablet.
  • the active ingredient contained in the uncoated granules is absorbed into the body as soon as the tablet disintegrates. This makes this tablet excellent in immediate effect.
  • the tablet has excellent sustainability. .
  • this tablet has both immediate effect and sustainability.
  • the tablet is provided with an uncoated, granule containing the analgesic, analgesic anti-inflammatory or antipyretic, and a film.
  • an analgesic anti-inflammatory or antipyretic that has been treated, if taken, the patient will immediately improve the patient's pain, inflammation and fever, as well as have an analgesic and anti-inflammatory effect.
  • New tablets such as once-daily tablets (Oncedailytab 1 et) that have a long-lasting, antipyretic effect and immediate effect, that is, Quick & S 1 owrelease Tablets Can be realized.
  • the tablet according to claim 20 is characterized in that the amount of the lubricant used in the tablet according to any one of claims 16 to 19 is from 0.001% to 0.2% by weight per tablet. It has been.
  • the amount of the lubricant used is preferably as small as possible. More preferably, the amount of the lubricant used is not less than 0.001% by weight and less than 0.1% by weight per tablet. This tablet does not have a prolonged disintegration time because only a small amount of lubricant is present on the tablet surface.
  • a score line for dividing the tablet main body is provided on the surface of the tablet main body of the tablet according to any one of claims 15 to 20.
  • the tablet Since the tablet has a score line, the tablet can be easily divided according to the score line. This allows the patient to take the optimal dose of the drug based on the patient's weight, age, and the like.
  • a tablet according to claim 22 is characterized in that the shape of the tablet body of the tablet according to any one of claims 15 to 21 is irregular.
  • the tablet according to claim 23 is the tablet according to any one of claims 15 to 22, wherein the standard deviation of the disintegration time of the tablet itself or the elution time of the active ingredient is the average disintegration time or the average elution of the active ingredient. Within 15% of the time.
  • the present inventors have determined that the standard deviation of the disintegration time of the tablet body or the elution time of the active ingredient can be within 15% of the average disintegration time or the average elution time of the active ingredient. This is an effect confirmed based on experiments.
  • the standard deviation of the disintegration time of the tablet body or the dissolution time of the active ingredient in this tablet should be within 10% of the average disintegration time or the average dissolution time of the active ingredient.
  • this tablet has a standard deviation of the disintegration time of the tablet body or the dissolution time of the active ingredient within 7.5% of the average disintegration time or the average dissolution time of the active ingredient, and further, within 7.0%. and c the tablets also revealed also be referred to is on the surface of the tablet body (uncoated), since lubricant is uniformly adhered, elution disintegration time or active ingredients of the tablet body There is little variation in time.
  • the standard deviation of the disintegration time of the tablet body or the elution time of the active ingredient which was difficult to manufacture with conventional tablets, is within 15% of the average disintegration time or the average elution time of the active ingredient. Tablets can be manufactured very easily.
  • the standard deviation of the disintegration time of the tablet body or the dissolution time of the active ingredient is within 10% of the average disintegration time or the average dissolution time of the active ingredient, which was extremely difficult to manufacture with conventional tablets. Can be easily produced.
  • the standard deviation of the disintegration time of the tablet body or the elution time of the active ingredient which has been considered impossible to produce with the conventional tablets, as far as the present inventors know, is the average disintegration time or the active ingredient. Tablets with an average dissolution time of 7.5% or less, or even 7.0% or less, can be produced.
  • the tablet Since the lubricant is uniformly adhered to the surface of the tablet body (uncoated tablet), the tablet has less variation in the disintegration time of the tablet body or the elution time of the active ingredient.
  • the tablet according to claim 24 is characterized in that the lubricant of the tablet according to any one of claims 15 to 23 is magnesium stearate.
  • magnesium stearate When magnesium stearate is used as a lubricant, the content of the lubricant contained in the tablet can be easily measured with an atomic absorption spectrometer for magnesium.
  • FIG. 1 shows a rotary table of a rotary tablet machine used to carry out the present invention.
  • FIG. 2 is a configuration diagram schematically showing an enlarged part of the center.
  • FIG. 2 is a cross-sectional view schematically showing an enlarged part of the rotary table shown in FIG.
  • Fig. 3 is a schematic diagram mainly showing the configuration of the spraying chamber.
  • Fig. 3 (a) is a schematic diagram schematically showing the configuration of the spraying chamber.
  • FIG. 2 is a configuration diagram exemplifying the configuration of the device.
  • FIG. 4 is an explanatory diagram showing a specific example of the air pulsation wave.
  • FIGS. 4 (a) and 4 (b) show specific examples of the negative pressure air pulsation wave, respectively.
  • Fig. 5 is a schematic diagram mainly showing the configuration of the spray chamber.
  • Fig. 5 (a) is a schematic diagram schematically showing the configuration of the spray chamber.
  • FIG. 2 is a configuration diagram exemplifying the configuration of the device.
  • FIG. 6 is an explanatory diagram showing a specific example of an air pulsation wave.
  • FIGS. 6 (a) and 6 (b) each show a specific example of a positive pressure air pulsation wave.
  • FIG. 7 is a diagram schematically illustrating tablets of various shapes manufactured in the experimental examples.
  • the left column shows a schematic plan view of each tablet, and the right column shows each tablet.
  • 1 shows a schematic side view of a tablet of the present invention.
  • FIG. 8 is a diagram schematically illustrating tablets of various shapes manufactured in the experimental examples.
  • the left column shows a schematic plan view of each tablet, and the right column shows each tablet.
  • 1 shows a schematic side view of a tablet of the present invention.
  • FIG. 9 is a diagram schematically illustrating tablets of various shapes manufactured in the experimental examples.
  • the left column shows a schematic plan view of each tablet, and the right column shows each tablet.
  • 1 shows a schematic side view of a tablet of the present invention.
  • FIG. 10 is a diagram schematically illustrating tablets of various shapes manufactured in the experimental examples.
  • the left column shows a schematic plan view of each tablet
  • the right column shows FIG. 2 shows a schematic side view of each tablet.
  • FIG. 11 is a diagram schematically illustrating tablets of various shapes manufactured in the experimental examples.
  • the left column shows a schematic plan view of each tablet
  • the right column shows FIG. 2 shows a schematic side view of each tablet.
  • FIG. 12 is a graph showing the correlation between the tableting pressure and the hardness of the tablet to be produced. You.
  • FIG. 13 is a graph showing the correlation between the time and the dissolution rate.
  • FIG. 14 is a graph showing the correlation between time and elution rate.
  • FIG. 15 is a cross-sectional view schematically showing an apparatus (quantitative feeder) for quantitatively supplying the lubricant contained in the hopper into the conduit.
  • FIG. 16 is a plan view schematically showing an example of an elastic film used in the device (quantitative feeder) shown in FIG.
  • FIG. 17 is an explanatory view schematically explaining the operation of the apparatus (quantitative feeder) shown in FIG.
  • FIG. 18 is a plan view schematically showing another example of the elastic film used in the device (quantitative feeder) shown in FIG.
  • FIG. 19 is a cross-sectional view schematically showing another example of the air pulsation wave generator.
  • FIG. 20 is an explanatory view schematically illustrating the structure of a tablet
  • FIG. 20 (a) is an explanatory view illustrating a multiple unit type tablet
  • FIG. 20 (b) and FIG. c) is an explanatory diagram illustrating the configuration of the granules contained in the multi-unit tablet.
  • FIG. 21 is a process chart schematically showing a method for producing a tablet described in Japanese Patent Publication No. 41-111273.
  • FIG. 22 is a process chart schematically showing a conventional tablet manufacturing method described in Japanese Patent Application Laid-Open No. 56-14098. BEST MODE FOR CARRYING OUT THE INVENTION
  • Embodiment 1 of the present invention a tablet manufacturing method for manufacturing a tablet which is required to be immediately disintegrated at a target site will be described with reference to the drawings.
  • FIG. 1 shows a rotary table of a rotary tablet machine used to carry out the present invention.
  • FIG. 2 is a configuration diagram schematically showing an enlarged part of the center.
  • FIG. 2 is a cross-sectional view schematically showing an enlarged part of the rotary table shown in FIG.
  • this one-piece tableting machine A is provided with a rotatable table and a rotary table 2 provided with a plurality of dies 1 in the circumferential direction.
  • a spraying chamber 8 is installed at a position P1 before the position P2 where the molding material is filled into the mortar 1, and an air pulsating wave generator 7 is connected to the spraying chamber 8, and
  • the spraying chamber 8 has a configuration in which a spray nozzle 9 for spraying the lubricant L is installed.
  • an air source 10 such as a cylinder filled with compressed air is connected to the injection nozzle 9, and the lubricant generated by the air from the air source 10 is supplied from the injection nozzle 9. L is sprayed.
  • the rotary table 2 is rotated at a predetermined speed, and with the rotation of the rotary table 2, the air pulsating wave generator 7 is driven, The air pulsation wave is generated in the chamber 8 and the lubricant L is sprayed from the injection nozzle 9, and the surface of the mortar 1 (the inner peripheral surface) is 1 s, and the surface of the upper punch 3 (the lower end surface) is 3 s. And, apply lubricant L to the surface (upper surface) 4 s of lower punch 4.
  • the molding material m is filled into the die 1 at the position P2 where the molding material m is filled, and after the excess molding material m is scraped off, the molding material m
  • the upper punch 3 with the lubricant L applied to the surface (lower end surface) 3 s and the surface (Upper surface)
  • a tablet is manufactured by compressing the molding material m with the lower punch 4 coated with the lubricant L for 4 s. Further, when 1 comes to the position P 4, The tablets T are discharged to produce tablets.
  • FIG. 3A is a schematic configuration diagram mainly showing the configuration of the spraying chamber 8, and FIG. 3B is a configuration diagram exemplifying the air pulsation wave generator 7.
  • the air pulsating wave generator 7 is connected to the spraying chamber 8 via a conduit 13 ing.
  • 71 is a blower
  • 72 is a cylindrical cylinder
  • 73 is rotatable inside a cylinder 72 around a rotation shaft 74
  • Valve bodies provided so as to divide the inside of the cylinder 72 into two parts are shown.
  • a conduit 13 and a conduit 14 connected to the blower 71 are connected at predetermined positions.
  • the valve body 73 can be rotated at a desired rotation speed by a valve body rotation control device (not shown).
  • valve body 7 is located between the spray chamber 8 and the blower 71.
  • Fig. 4 (a) for example, an air pulsation wave with a mountain at atmospheric pressure and a valley with negative pressure as shown in Fig. 4 (a) is generated in the spray chamber 8, As shown in (b), both the peak and the valley can generate an air pulsation wave of negative pressure in the spraying chamber 8.
  • negative pressure means that the pressure in the spraying chamber 8 is lower than the pressure outside the spraying chamber 8.
  • the lubricant L is uniformly applied to the surface (inner surface) of 1 s, the surface (lower surface) of the upper punch 3 for 3 s, and the surface (upper surface) of the lower punch 4 for 4 s.
  • the amount of the lubricant L sprayed into the spraying chamber 8 can be applied regardless of the type of the active ingredient, the type of the excipient, and the type of the lubricant. It is possible to prevent the molding material m from being stuck on the upper punch 3 and the lower punch 4 of the tableting machine A. For this reason, the spray amount of the lubricant L used for one tableting can be extremely reduced.
  • This manufacturing method is characterized in that the amount of the lubricant L sprayed into the spraying chamber 8 is extremely reduced by utilizing this effect, and that the spraying of the lubricant L sprayed into the spraying chamber 8 is performed.
  • the amount is adjusted to be 0.001 to 0.2% by weight per tablet weight.
  • the spray amount of the lubricant L sprayed into the spraying chamber 8 may be adjusted so as to be 0.001% by weight or more and less than 0.1% by weight per one tablet. .
  • the tablet T to be manufactured is provided only on its surface, the surface of the mortar 1 (inner peripheral surface) ls, the surface of the upper punch 3 (lower surface) 3 s, and the surface of the lower punch 4 (upper surface). ) Only a part of the lubricant L applied to 4 s adheres, and only a very small amount of the lubricant L is present on the surface of the tablet T to be produced. Contains almost no lubricant L. As a result, the amount of the lubricant L contained in the tablet T is remarkably smaller than that of the tablet manufactured by the conventional manufacturing method, so that the tablet T is produced in the same manner as the conventional tablet. There is no problem that the disintegration time of the tablet T is delayed due to the water repellency of the lubricant L.
  • a lower tableting pressure specifically, 1 ton (compared to the case where a molding material containing the lubricant L is tableted) is used. Even when the tablet T is pressed using a tableting pressure of less than 2 cm 2, the tablet T produced has a practical level of hardness.
  • a tablet (uncoated tablet) T manufactured according to this tablet manufacturing method becomes a rapidly disintegrating tablet when used as a bare tablet, and immediately at a target site, such as an intraorally fast disintegrating tablet, Tablets Suitable as tablets that require T to disintegrate.
  • the tablet T contains, for example, granules containing the active ingredient which are coated with a film on the surface of the granules containing the active ingredient
  • the tablet T is molded at a low pressure (tabletting).
  • the film applied to the surface of the granules containing the active ingredient is not destroyed during compression molding (tableting).
  • the film applied to the surface of the granules containing the active ingredient exhibits a predetermined desired function.
  • the film applied to the surface of the granules containing the active ingredient is a film for the purpose of persistence
  • this film allows the tablet to have a long-lasting effect. I will have it.
  • the tablet T immediately disintegrates in the tablet T.
  • the granules containing the uncoated active ingredient and the granules containing the coated active ingredient are immediately released from the tablet T.
  • the active ingredient contained in the uncoated granules is absorbed into the body as soon as the tablet disintegrates.
  • this tablet T has excellent immediate effect.
  • the tablet has excellent sustainability. .
  • this tablet has both immediate effect and sustainability.
  • the tablet T By mixing uncoated, granules containing an analgesic, analgesic anti-inflammatory or antipyretic with granules containing a coated analgesic, analgesic anti-inflammatory or antipyretic, Once taken, it immediately improves the patient's pain, inflammation and fever, and has a long-lasting analgesic, anti-inflammatory and antipyretic effect, has an immediate effect, and is a once-daily tablet (oncedailt ablet). New tablets such as slow-release tablets (Quick & Slow release tablets) can be realized.
  • an analgesic such as morphine hydrochloride
  • an analgesic and anti-inflammatory such as indomethacin, diclofenac sodium
  • an antipyretic such as sulpyrine
  • the tablet T contains, for example, granules containing the active ingredient in the base matrix as the granules containing the active ingredient
  • the tablet T is formed at a low pressure (tableting).
  • the function of the base matrix is not lost during compression molding (tableting). This allows the base matrix to perform its intended function.
  • the tablet T is mixed with granules containing an active ingredient that is not coated and granules containing the active ingredient in a base matrix
  • the tablet T is immediately Upon disintegration, the granules containing the uncoated active ingredient and the granules containing the active ingredient in the base matrix are released immediately.
  • the active ingredient contained in the uncoated granules is absorbed into the body as soon as the tablet T disintegrates.
  • this tablet T has excellent immediate effect.
  • the granules containing the active ingredient in the base matrix include, for example, when the base matrix is a film for the purpose of persistence, the function of the base matrix makes this tablet T Excellent in nature.
  • this tablet T has both immediate effect and sustainability.
  • the active ingredient is an analgesic (such as morphine hydrochloride), an analgesic and anti-inflammatory (such as indomethacin, diclofenac sodium), or an antipyretic (such as sulpyrine) is described as an example.
  • an analgesic such as morphine hydrochloride
  • an analgesic and anti-inflammatory such as indomethacin, diclofenac sodium
  • an antipyretic such as sulpyrine
  • the amount of the lubricant L sprayed into the spraying chamber 8 should be as small as possible to prevent the molding material m from sticking to the tablet 1, the upper punch 3 and the lower punch 4 of the tableting machine A.
  • the content is 0.001% by weight or more and 0.2% by weight or less. According to experiments, even if the amount of the lubricant L is 0.001% by weight or more and less than 0.1% by weight of one tablet, the tablet T produced by tableting such as statusing can be used. It has also been clarified that continuous tableting can be performed without causing any obstacles.
  • the lubricant L is uniformly applied on the surface of the tablet body (uncoated tablet) T, the disintegration time or the elution time of the active ingredient varies between the tablets. Less is.
  • polyvinyl alcohol is sprayed on the powder having the formulation shown in Table 1 to grow the particles to produce granules having a predetermined diameter.
  • the obtained granulated product was sized using the obtained granules.
  • the sized granules were adjusted to 13 Omg / tablet with a diameter of 7 mm.
  • the tablet was continuously pressed at a speed of rotating the rotary table 2 30 times per minute using a set of Nokis.
  • Magnesium stearate was used as a lubricant, and the amount of magnesium stearate sprayed into the spray room was reduced to 0.03% by weight of the lubricant contained in each tablet.
  • the amount of air to be sprayed from the injection nozzle 9 shown in FIG. 3 (a) and the number of revolutions and suction of the air pulsation wave generator 7 were adjusted. More specifically, although not particularly limited, in this experiment, the frequency of the air pulsation wave was 1 Hz or more and 10 Hz or less, and the valley was 10 % -5% lower, and the mountain has a pressure that is equal to or slightly lower than the outside air pressure.
  • the fluid bed granulator used was WSG15 manufactured by Glatt and the tableting machine used was HATA HT-X20 manufactured by Hata Seisakusho.
  • Table 1 Ingredients Repodopa 9.0 (lactose) 57.5 Lactose starch 28.5 Polyvinyl alcohol 5.0 p 1 100.0 (Comparative Example 1)
  • Magnesium stearate was used as a lubricant in the granules produced in the same manner as in Experimental Example 1, and magnesium stearate was added so that the amount was 0.03% by weight based on the total weight of one tablet.
  • magnesium stearate was used as a lubricant in the granules produced in the same manner as in Experimental Example 1, and 0.8% by weight of magnesium stearate was added to the total weight of one tablet. %, And mixed well using a V-type mixer. Then, this molding material was adjusted to 13 Omg / tablet using a 7 mm diameter punch set for 1 minute. Continuous compression was attempted by the internal lubrication method at a speed of rotating the rotary table 30 times.
  • HATA HT-X20 manufactured by Hata Seisakusho was used as a tableting machine.
  • this molding material was adjusted to 13 Omg / tablet using a 7 mm diameter punch set similar to that in Experimental Example 1.
  • magnesium stearate was used as a lubricant on the surfaces 3 s, 4 s of the punches 3, 4 of the mortal set and the surface 1 s of the punch 1.
  • the amount of the lubricant is 0.03% by weight per one tablet to be manufactured using a tablet, and then the rotary table is rotated 30 times per minute. The tablets were pressed continuously.
  • HATA HT-X20 manufactured by Hata Seisakusho was used as a tableting machine.
  • Example 1 the lubricant was uniformly applied to the surface of the tablet.
  • the standard deviation of the disintegration time of the tablets of Experimental Example 1 was 0.2, and the disintegration time of each tablet was within 7% of the average disintegration time.
  • the standard deviation of the disintegration time of the tablet itself or the elution time of the active ingredient can be set to within 10% of the average disintegration time or the average elution time of the active ingredient.
  • the standard deviation of the disintegration time of the tablet body or the dissolution time of the active ingredient of this tablet could be within 7.0% of the average disintegration time or the average dissolution time of the active ingredient.
  • FIG. 3 (b) an apparatus as shown in FIG. 3 (b) is used as the air pulsation wave generator 7, but this is merely an example, Various types of pulsating wave generators 7 can be used.
  • a blower 71 is connected to the end of the conduit 13 and a solenoid valve for opening and closing the conduit 13 is provided in the middle of the conduit 13.
  • the conduit may be opened and closed at a predetermined cycle by a solenoid valve, or a blower 71 may be connected to the end of the conduit 13 so that the blower 71 is rotated quickly at a predetermined cycle.
  • the air in the spray chamber 8 may be strongly or weakly sucked at a predetermined cycle by rotating the spray chamber 8 slowly.
  • an air pulsation wave was generated in the spraying chamber 8 as shown in FIG. 4 (a) or FIG. 4 (b). It may be configured to generate an air pulsation wave as shown in FIG. 6 (a) or FIG. 6 (b) in the spraying chamber 8. That is, in the example shown in FIG. 5, as shown in FIG. 5 (a), the air pulsation wave generator 7A is connected to the end of the conduit 13, and the lubricant L is stored in the middle of the conduit 13. The hopper 15 is connected, and the hopper 15 is connected to a compressed air generating means 16 such as a cylinder filled with compressed air.
  • the device indicated by 17 indicates a blower that is provided as necessary. When the blower 17 is driven, the air in the spraying chamber 8 is sucked and the spraying chamber 8 is sucked. The air pulsating wave and the lubricant L sent into the inside are encouraged to be discharged from the spraying chamber 8.
  • the spraying chamber 8 may be provided with nozzle means for spraying a lubricant mixed with the positive pressure air pulsating wave, so that the structure of the spraying chamber 8 may be simplified. Can be.
  • the air pulsation wave generator 7A is a cylinder connected between the blower 71 and the position where the blower 71 of the conduit 13 and the hopper 15 are connected.
  • a conduit 13 and a conduit 14 connected to the blower 71 are connected at predetermined positions. I have.
  • the valve body 73 can be rotated at a desired rotation speed by a valve body rotation control device (not shown).
  • the force of the valve body 73 in FIG. 5 (b) is shown by a solid line.
  • the spraying chamber 8 is in the position shown, the spraying chamber 8 and the blower 71 are in communication with each other, and when the valve element 73 is in the position indicated by the imaginary line, the spraying chamber 8 and the blower 71 are in communication.
  • the valve is closed by the valve element 73, and, for example, as shown in FIG. 6 (a), a pulsating wave is generated in the spray chamber 8 in which the peak is at a positive pressure and the valley is at atmospheric pressure.
  • FIG. 6 (a) a pulsating wave is generated in the spray chamber 8 in which the peak is at a positive pressure and the valley is at atmospheric pressure.
  • both the peak and the valley may generate an air pulsating wave having a positive pressure in the spraying chamber 8.
  • the compressed air generating means 16 is driven to send out the lubricant L contained in the hopper 15 to the conduit 13, and put on the flow of the air pulsation wave, and the predetermined amount is supplied.
  • the lubricant L may be sent into the spraying chamber 8.
  • the positive pressure means that the pressure in the spraying chamber 8 is higher than the pressure outside the spraying chamber 8.
  • a blower 71 is connected to the end of the conduit 13, and a solenoid valve for opening and closing the conduit 13 is provided in the middle of the conduit 13.
  • the air is blown into the chamber 8 and the conduit is opened and closed at a predetermined cycle by the solenoid valve to generate air pulsation waves in the spraying chamber 8 and the conduit 13, while maintaining this state and generating compressed air.
  • the solenoid valve By driving the means 16, the lubricant L contained in the hopper 15 is sent out to the conduit 13, and a predetermined amount of the lubricant L is put into the spraying chamber 8 with the flow of the air pulsating wave.
  • the blower 71 may be connected to the end of the conduit 13 so that the blower 71 is rotated at a high speed or a low speed at a predetermined cycle.
  • the air is blown strongly or weakly to the spraying chamber 8 at a predetermined cycle, and the air pulsation wave is blown into the spraying chamber 8.
  • the compressed air generating means 16 is driven to send the lubricant L contained in the hopper 15 to the conduit 13, and the air pulsation wave is generated.
  • a predetermined amount of the lubricant L may be fed into the spraying chamber 8 along with the flow of the lubricant.
  • the air pulsation wave as shown in FIG. 6 (a) or FIG. 6 (b) there is no particular limitation.
  • the frequency is 1 to 10 Hz or less and the peak is about 10% to 5% higher than the outside pressure, and the peak is the same or slightly higher than the outside pressure.
  • tablets of various shapes are manufactured using the punches and stamps that constitute the female type of tablets or engraved or scored tablets as the upper punch 3 and lower punch 4 of the rotary type tablet machine A. An example will be described.
  • the upper punch 3 and the lower punch 4 used as the upper punch 3 and the lower punch 4 were used to form the female mold of the tablets shown in Figs. Tablets having the shapes shown in each of FIG. 11 were produced.
  • gribsol and mannitol are mixed at a ratio of :: 3, and polyvinyl alcohol is sprayed to obtain a predetermined particle size and a predetermined particle size distribution. After producing granules having the same, the obtained granules were sized using No. 28 wire mesh.
  • the punches 3 and 4 are stored in the spraying chamber 8, and the punches 3 and 4 are stored in the spraying chamber 8. Then, an air pulsation wave as shown in Fig. 4 (a) is generated, and magnesium stearate is applied as a lubricant L to the surfaces 3s and 4s of the punches 3 and 4 and the surface 1s of the punch 1. Then, using the punches 3, 4 and the mortar 1 with the magnesium stearate applied to the surface I s of the pestle 3, 4 and the mortar 1, the granules are rotated 30 times on the rotary table 1 for 1 minute. Tableting was performed continuously at the speed.
  • Magnesium stearate is used as a lubricant, and the amount of magnesium stearate sprayed into the spraying chamber is reduced by 0.03% by weight of the lubricant contained in each manufactured tablet.
  • the amount of air to be sprayed from the injection nozzle 9 shown in FIG. 3A and the rotation speed and suction amount of the air pulsation wave generator 7 were adjusted so that More specifically, although not particularly limited, in this experiment, the frequency of the air pulsation wave was 1 Hz or more and 10 Hz or less, and the valley was Use a material that is about 10% to 5% lower and has a mountain pressure equal to or slightly lower than the outside air pressure.
  • As the fluidized bed granulator WSG15 manufactured by Glatt Co. was used, and Hata HAT-HT-X20 was used as the main body of the tableting machine.
  • the tablet shown in Fig. 7 (a) generally indicates a circular tablet called flat plate (FLAT PLAIN), and the tablet shown in Fig. 7 (b) generally indicates a SHALLOW CONCAVE PLAIN), and the tablet shown in Fig. 7 (c) is a circular tablet generally called NORMAL CONCAVE PLAIN, and Fig. 7 (d)
  • the tablet shown in Fig. 7 shows a circular tablet generally called DEEP CONCAVE PLAIN
  • the tablet shown in Fig. 7 (e) generally shows a circular tablet called a ball or pill (BALL OR PI LL).
  • the tablet shown in FIG. 7 (f) is a circular tablet generally called a flat beveled edge (FLAT BEVELLED EDG E).
  • tablets shown in Fig. 8 (a) generally have a double radius (DOUBLE
  • RAD IUS and the tablet shown in Fig. 8 (b) generally represents a circular tablet called BEVEL AND CONCAVE
  • the tablet shown in Fig. 8 shows a circular tablet generally called a dimple (D IMPLE), and the tablet shown in Fig. 8 (d) generally shows a circular tablet called a ring (RING).
  • the tablet shown in Fig. 8 (e) generally represents a circular tablet called a rim (RIM), and the tablet shown in Fig. 8 (f) generally represents a capsule-shaped tablet called a capsule (CAPSULE). Is shown.
  • the tablet shown in Fig. 9 (a) is generally an oval tablet called OVAL, and the tablet shown in Fig. 9 (b) is generally an elliptical tablet called ELLIPSE.
  • the tablet shown in Fig. 9 (c) is generally a square tablet called SQUARE, and the tablet shown in Fig. 9 (d) is generally called a TRIANGLE
  • the triangular tablets are shown, and the tablets shown in Fig. 9 (e) are generally pentagonal tablets called PENTAGON, and the tablets shown in Fig. 9 (f) are generally hexagonal. Shows a hexagonal tablet called HEXAGON.
  • the tablet shown in Fig. 10 (a) generally represents a heptagon-shaped tablet called HEPTAGON, and the tablet shown in Fig. 10 (b) generally represents a tablet called OCTAGON.
  • the tablets shown in Fig. 10 (c) generally represent diamond-shaped tablets called diamonds (DIAMOND), and the tablets shown in Fig. 10 (d) generally represent pillows or barrels (
  • the tablet shown in Fig. 10 (e) is a pillow-shaped tablet called PIL LOW OR BALLEL, and the tablet shown in Fig. 10 (e) is generally a rectangular tablet called RECTANGLE, and is shown in Fig. 10 (f). Tablet refers to an almond-shaped tablet commonly called almond (ALMOND).
  • the tablets shown in Fig. 11 (a) generally represent arrowhead-shaped tablets called ARROW HEAD, and the tablets shown in Fig. 11 (b) generally represent bullets (BULLET).
  • the tablets shown in Figure 11 (c) generally represent half-moon shaped tablets called HALF MOON, and the tablets shown in Figure 11 (d) generally represent A shell-shaped tablet called SHELD is shown.
  • the tablet shown in Fig. 11 (e) is generally a heart-shaped tablet.
  • HEART heart-shaped tablet
  • Fig. 11 (f) star-shaped tablet
  • Magnesium stearate was used as a lubricant L to the granules produced in the same manner as in Experimental Example 2, and magnesium stearate was added so that the total weight of one tablet was 1.0% by weight.
  • magnesium stearate was uniformly kneaded as a lubricant L by the internal lubrication method using the punches 3 and 4 and the mortar 1 used in Experimental Example 1.
  • the granules were continuously tableted at a speed of rotating the rotary table 1 30 times per minute.
  • the fluid bed granulator used was WSG 15 manufactured by Glatt, and the tableting machine used was HATA HT-X20 Hata Seisakusho.
  • the method for producing tablets according to the present invention can be suitably used not only for producing circular tablets, but also for producing engraved or scored tablets or modified tablets. It was revealed.
  • spherical granulated crystalline cellulose (trade name: selfie, manufactured by Asahi Kasei) as a core particle
  • 900 g of theophylline 50 g, corn starch 25 :, and a mixture of powdered sugar 25 g were supplied from a quantitative feeder at a mass flow rate of 10 g / min (min) while adding hydroxypropyl cellulose (trade name: HPC— L, manufactured by Nippon Soda Co., Ltd.) 100 g of an ethanol solution containing 5 g dissolved at a mass flow rate of 5 g / min (min)
  • HPC— L manufactured by Nippon Soda Co., Ltd.
  • Lactose for direct injection into 1 kg of sustained-release microcapsule granules of Reference Example 1 (trade name: Yuburetois, manufactured by Taiyo Kagaku) 700 g, crystalline cellulose (trade name: Av ice 1 PH 101, Asahi Kasei Corporation) was mixed to obtain granules for tableting.
  • the tableting pressure was set to 500 kg / punch (Punch), 1000 kg / punch (Punch), and 1500 kg / punch (Punch), respectively.
  • magnesium stearate manufactured by Sakai Chemical Co., Ltd.
  • Microcapsule tablets (multiple-unit tablets) were obtained.
  • the content of magnesium stearate contained in the scored sustained-release microcapsule tablets (multiple-unit tablets) was examined by measuring magnesium with an atomic absorption spectrophotometer.
  • the content of magnesium stearate in (multiple unit tablets) is 0.07 weight
  • the frequency of the air pulsation wave was 1 Hz or more and 10 Hz or less
  • the valley was about 10% to 5% lower than the atmospheric pressure
  • the peak was A pressure that was the same as or slightly lower than the atmospheric pressure was used.
  • 500 g of the enteric-soluble microcapsules of Reference Example 2 were mixed with 350 g of lactose for direct compression and 150 g of crystalline cellulose to obtain granules for tableting.
  • the tableting pressure was set to 50 O kgZ punch (Punc h ), 1000 kg / punch (punch), 1500 kg / punch (punch), and air pulsating waves were generated in the spraying chamber 8.
  • Dry, lubricating L magnesium stearate (Sakai Chemical) The lubricant is evenly applied to the surface of the mortar 1 (inner surface) ls, the surface of the upper punch 3 (lower surface) 3 s, and the surface of the lower punch 4 (upper surface) 4 s.
  • the granules for tableting were tableted to obtain scored enteric-soluble microcapsule tablets (multiple unit tablets).
  • the frequency of the air pulsation wave was 1112 or more and 10112 or less, the valley was about 10% to 5% lower than the external pressure, and the peak was the same as the external pressure. A slightly lower pressure was used.
  • Comparative Examples 4 and 5 show examples in which scored sustained release microcapsule tablets (multiple-unit tablets) were produced by the conventional internal lubrication method.
  • a tableting granule was obtained by mixing 1 kg of the sustained release microcapsule granules of Reference Example 1 with lactose for direct compression 700 g., Crystalline cellulose 280 g, and magnesium stearate 20 g as lubricant L.
  • tableting granules were obtained by mixing 25 g of theophylline, 700 g of lactose for direct compression, 265 g of crystalline cellulose, and 10 g of magnesium stearate as a lubricant. Next, using a scored flat punch, press the tablet at 500 kg / punch (Punch), 1000 kg / punch (Punch), and 1500 kg / punch (Punch) to obtain a scored uncoated tablet. Obtained.
  • the dissolution test is performed according to the rotating basket method described in the dissolution test method of the Japanese Pharmacopoeia, Edition 1, first. It was raised and transferred to the second solution, and the elution rate was determined again. The results are shown in Table 4 and FIG. Table 4
  • each of the tablets of Experimental Examples 5 and 6 was composed of a sustained-release microcapsule granule (Reference Example 1) and an enteric-soluble microcapsule granule (Reference Example 2). It was found that the same elution behavior was exhibited. According to the relationship between the tableting pressure and tablet hardness and the experimental results described above, in Experimental Examples 5 and 6, the tablet can be compressed with a low tableting pressure. It was clear that no damage had occurred to the formed film. On the other hand, it was found that the tablets of Comparative Example 7 and Comparative Example 8 lost the sustained release function and the enterolytic function, respectively.
  • the tablets according to the present invention can be 2 minutes split, sustained release function, Note c that intestinal solubility function is not lost, it revealed,
  • the tablet does not contain the lubricant, and the tablet does not contain the lubricant. Tablets with only a small amount of lubricant on the surface can be manufactured, so that the tablet disintegration time is not delayed. Therefore, if this tablet (uncoated tablet) is used as a naked tablet, it becomes a rapidly disintegrating tablet, and it is required that the tablet disintegrate immediately at the intended site like an oral rapidly disintegrating tablet.
  • the tablet body is suitable as a tablet, and if a film coat that melts at the target site is applied to the surface, when the film coat is melted, the tablet body also immediately melts at the target site, so it can be melted at the target site It can be suitably used as a required tablet.
  • the present inventors measured the disintegration time of the tablets prepared in Experimental Examples 1 to 4 or the elution time of the active ingredient, and found that the standard deviation of the disintegration time of the tablet or the elution time of the active ingredient was the average disintegration time or It was found that the average elution time of the active ingredient was within 10%. Also, in this example, an example was shown in which granules to be incorporated into tablets were produced using a centrifugal fluidized coating apparatus, but in the step of granulating granules having a desired particle size, a predetermined air was introduced into a hot air inlet tube.
  • the powder to be granulated and part of the granulated material are continuously dropped and deposited on the screen.
  • the coating liquid may be sprayed on the granulated material to form a film on the surface of the granulated material. This is because, in the step of granulating granules having a desired particle size, a hot air that becomes stronger or weaker at a predetermined cycle is generated in a hot air introduction pipe, and the powder to be granulated is formed in the granulating step.
  • the powder to be granulated and the granulated material are fluidized using normal, steady warm air.
  • granules having a smaller specific volume can be produced, the granules are hardened, and the granules are less likely to be broken in the tableting process. This is because the film applied to the surface of the granulated material is hard to break.
  • the step of forming a film on granules is not limited to the above fluidized bed coating method, P an, coating and compression co may be performed by a plating method c also EMBODIMENT 1
  • a one-shot tableting machine has been described as an example. However, this is merely an example, and the method for producing a tablet according to the present invention is not limited to a rotary tableting machine.
  • a tableting machine such as a single-shot tablet machine such as an eccentric tablet machine can be used.
  • a hopper 15 is connected in the middle of the conduit 13 as shown in FIG. 5, and the hopper 15 is supplied with compressed air such as a cylinder filled with compressed air.
  • compressed air such as a cylinder filled with compressed air.
  • FIG. 15 is a configuration diagram schematically illustrating such an apparatus.
  • an air pulsation wave generator 7A is connected to one end 13a of a conduit 13, and a discharge port 15a of a hopper 15 is connected to a position in the middle of the conduit 13.
  • an elastic membrane 18 having a mosquito (in this example, a slit hole) 18a is provided so as to form the bottom of the hopper 15 (see FIG. 16).
  • the elastic film 18 is made of, for example, rubber such as silicone rubber.
  • the member denoted by 15 b indicates a lid, and the lid 15 b is detachably attached to the hopper 15 and can be attached in an airtight manner. I have. Next, the operation of this device will be described.
  • FIG. 17 is an explanatory diagram schematically explaining the operation of this device.
  • the lid 15 b is airtightly attached to the hopper 15.
  • the air pulsation wave generator 7 A is driven to supply a positive pressure air pulsation wave into the conduit 13
  • the positive pressure air pulsation wave supplied into the conduit 13 is on the mountain side.
  • the air pressure in the conduit 13 is higher than the air pressure in the hopper 15, and as shown in FIG. 17 (a), the elastic film 18 becomes a belly at the center of the elastic film 18. Its peripheral edge becomes a node, and its central portion is curved upward.
  • the hole (slit hole in this example) 18a has a V-shaped cross section with an open upper side. Then, a part of the lubricant L stored in the hopper 15 falls into a V-shaped hole (slit hole in this example) 18a having an open upper side.
  • the air pressure in the conduit 13 decreases, and the air pressure in the conduit 13 and the air pressure in the hopper 15 increase. Mind The pressure gradually becomes equal, and at this time, the elastic film 18 tends to return to the original state due to its restoring force, as shown in FIG. 17 (b).
  • the lubricant L that has fallen into the V-shaped hole (the slit hole in this example) with the upper side opened is inserted into the hole (the slit hole in this example) 18 a It is in a state of being sandwiched between.
  • the elastic film 18 has a shape in which the central portion is a belly, the peripheral edge is a node, and the central portion is curved downward.
  • the mosquito (slit hole in this example) 18a has an inverted V-shaped cross section with the lower side open. Then, the lubricant sandwiched in the holes (slit holes in this example) 18 a of the elastic film 18 is discharged into the conduit 13.
  • the lubricant L discharged into the conduit 13 immediately mixes with the positive pressure air pulsation wave supplied into the conduit 13 in the conduit 13 and becomes dispersed, and is dispersed. (See spraying room 8 in Figure 5).
  • the elastic film 18 repeats vertical oscillations as shown in FIGS. 17 (a) to 17 (c) according to the amplitude, wavelength, waveform, frequency, etc. of the positive pressure air pulsation wave. . Therefore, as long as the amplitude, wavelength, waveform, frequency, etc. of the positive pressure air pulsation wave supplied into the conduit 13 are kept constant, the elastic membrane 18 vibrates up and down at a constant amplitude and frequency. Therefore, the amount of the lubricant L discharged into the conduit 13 through the moss (in this example, the slit hole) 18a is also constant.
  • a positive pressure air pulsation wave is supplied into the conduit 13, and as a result, the conduit 13, as seen when the powder is pneumatically transported using the steady pressure air, is provided.
  • the powder does not adhere to the inner wall surface and the powder does not flow through the conduit 13.
  • this device is configured such that when the lubricant L discharged into the conduit 13 through the hole (in this example, the slit hole) 18a of the elastic membrane 18 is discharged into the conduit 13, It is discharged from the other end 13b of the conduit 13 at a concentration substantially the same as that in the conduit 13.
  • this device functions as a quantitative feeder device.
  • the other end 13 b of the conduit 13 of this device is connected to the spray chamber (spray chamber 8 shown in FIG. 5).
  • the size of the hole (slit hole in this example) 18 a is constant, and the amplitude, wavelength, waveform, frequency, etc. of the positive pressure air pulsation wave supplied into the conduit 13 As long as is constant, a constant concentration of lubricant L can always be supplied into the spraying chamber (see spraying chamber 8 in FIG. 5).
  • the medium that pneumatically transports the lubricant L is air, although it is a positive pressure air pulsation wave, the amount of the lubricant L mixed with the positive pressure air pulsation wave can be extremely small. is there.
  • a very small amount of the lubricant L can always be sprayed in a stable state in the spraying chamber (see the spraying chamber 8 shown in FIG. 5).
  • the surface of the punch see the surface of the upper punch 3 (lower surface) 3 s and the surface of the lower punch 4 (upper surface) 4 s shown in Fig. 2) and the surface of the mortar 1 (Inner peripheral surface)
  • a very small amount of lubricant L can be uniformly applied to Is.
  • FIG. 16 describes the elastic film having the slit hole 18a, this is merely a preferred example, and the hole provided in the elastic film is a slit.
  • the hole is not limited to the hole 18a, and may be a small hole, and the number of such small holes is not limited to one.
  • an elastic film for example, as shown in FIG. 18, an elastic film having a plurality of small holes 18b may be used.
  • the spray chamber by changing the size and number of holes and changing the conditions (amplitude, wavelength, waveform, frequency, etc.) of the positive pressure air pulsation wave supplied into the conduit 13, the spray chamber (see Fig. 5)
  • the concentration of the lubricant sprayed into the interior can be varied to various concentrations.
  • a rotary shaft 74 is centered in a cylinder 72
  • the device is not limited to the air pulsation wave generator 7A.
  • FIG. 19 is a cross-sectional view schematically showing another example of the air pulsation wave generator.
  • the high-pressure pulsating air generator 7B includes a valve chamber 96 provided with a valve seat 93 between an input port 91 and an output port 92, and a valve body 96 opened and closed by a cam mechanism 95.
  • the cam mechanism 95 is rotatably provided by a driving means (not shown) such as a motor. And a roller 98 attached to the lower end of the valve body 96.
  • the valve seat 93 has a hole with a concave shape in the direction of the output port 92, and the valve element 96 has a tapered inverted mortar shape that matches the shape of the valve seat 93.
  • the valve seat 93 can be airtightly closed.
  • the shaft portion 96a of the valve body 96 is provided in the shaft hole 99h of the case body 99 so as to be free of air and to be vertically movable.
  • the roller 98 is rotatably held by the rotating cam 97, and by rotating the rotating cam 97, the roller 98 moves up and down while rotating according to the uneven pattern provided on the rotating cam 97. I have.
  • the rotating cam 97 includes an inner rotating cam 97a and an outer rotating cam 97b.
  • Each of the inner rotating cam 97 a and the outer rotating cam 97 b is provided with a concave / convex pattern so as to keep the gap between the apertures 98 and to be aligned with each other. Then, the roller 98 is sandwiched between the inner rotating cam 97 a and the outer rotating cam 97 b, and by rotating the rotating cam 97 without causing a splash on the valve body 96, In accordance with the concavo-convex pattern provided on the inner rotating cam 97a and the outer rotating cam 97b, it moves up and down while rotating.
  • the uneven pattern provided on the rotating cam 97 is selected from different patterns according to the physical properties of the lubricant L stored in the hopper 15.
  • a flow control device 102 is connected to the input port 91, and the input port 91 is generated by the air source 71 and adjusted to a predetermined flow rate by the flow control device 102. Compressed air is supplied.
  • conduit 13 shown in FIG. 3 or 5
  • output port 92 one end of a conduit (conduit 13 shown in FIG. 3 or 5) is connected to the output port 92.
  • reference numeral 100 denotes a flow regulating port provided as necessary, and the flow regulating port 100 represents a pressure of the air pulsation wave output from the output port 92.
  • An output adjusting valve 101 to be adjusted is provided so as to be adjustable to a desired state from a state of complete communication with the atmosphere to a state of shutoff.
  • the rotating cam 97 which can easily mix the lubricant L with the air, is driven by the driving means of the high-pressure pulsating air generator 7 B (not shown). ) Is attached to the rotation axis Ma.
  • the rotating cam 97 is rotated at a predetermined rotation speed.
  • the pressure of the air pulsation wave output from the output port 92 is adjusted by adjusting the output adjustment valve 101.
  • valve element 96 moves up and down in accordance with the concavo-convex pattern provided on the rotating cam 97.
  • the valve seat 93 is controlled to be fully closed, half-opened, fully opened, or the like, for example, in accordance with the concavo-convex pattern provided on the rotating cam 97, thereby outputting a desired air pulsation wave from the output port 92. I do.
  • a driving means (not shown) is controlled to control the rotation cam 97 What is necessary is just to change a rotation speed. Also, in order to make the amplitude of the air pulsation wave output from the output port 92 to a desired amplitude, the air source 71, the flow control device 102, and / or the output adjustment valve 1 ⁇ 1 may be appropriately adjusted. .
  • an air pulsation wave is generated and a lubricant is sprayed in the spraying chamber.
  • the lubricant mixes with the air pulsation wave.
  • the lubricant is mixed in a state where the lubricant is mixed with the air pulsating wave, that is, the lubricant is hardly attached to the surface of the pair of punches. Is attached to the surface of the mortar and a pair of upper and lower punches.
  • the lubricant adheres evenly to the surface of the mortar and the pair of upper and lower punches without unevenness.
  • the amount of lubricant used per tablet is reduced by the conventional amount of internal lubricant. Even if the amount is significantly reduced as compared with the Sawaho method or the external lubrication method, the manufactured tablets are less likely to have a statusking or the like.
  • the tablet produced according to this tablet production method is caused by the water repellency of the lubricant.
  • the phenomenon that the disintegration time of tablets is delayed does not occur.
  • a tablet in which the tablet disintegrates immediately at a target site such as a target site of a living body can be manufactured.
  • the tableting pressure is reduced by the conventional tableting pressure when the tablet is compressed using a pair of upper and lower punches. Even if the pressure is lower than the tablet pressure, tablets having practical hardness can be produced.
  • a lubricant mixed with the air pulsation wave is sprayed into the spraying chamber.
  • the lubricant is mixed in a state where the lubricant is mixed with the air pulsating wave, that is, the lubricant is hardly attached to the surface of the pair of punches. Is attached to the surface of a pair of punches.
  • the lubricant is evenly attached to the surface of the mortar and the pair of upper and lower punches without unevenness.
  • the amount of lubricant used per tablet can be reduced by the conventional internal lubricant. Even if the amount is significantly reduced as compared with the Sawaho method or the external lubrication method, the manufactured tablets are less likely to cause stateing or the like.
  • the tablet produced according to this tablet production method is caused by the water repellency of the lubricant.
  • the phenomenon that the disintegration time of tablets is delayed does not occur.
  • a tablet in which the tablet disintegrates immediately at a target site such as a target site of a living body can be manufactured.
  • the tableting pressure is reduced by the conventional tableting pressure when the tablet is compressed using a die and a pair of upper and lower punches. Even if the pressure is lower than the tablet pressure, tablets having practical hardness can be produced.
  • the spraying means for spraying the lubricant mixed with the positive pressure air pulsating wave may be provided in the spraying chamber, the manufacturing apparatus can be simplified.
  • a lubricant is not contained in the molding material, a tablet having practical hardness can be manufactured at a low tableting pressure. This allows the tablet containing the granules to be applied to the surface of the part containing the active ingredient (main drug) for the purpose of sustaining, sustained release, immediate release, gastric solubility, enteric solubility, bitterness prevention, etc.
  • the material, the structure of the base matrix, and the material are not broken, without any special measures, without any breakage of the film, and no phenomenon that occurs when the granules are destroyed or undergo plastic deformation.
  • the tablet can be.
  • a lubricant is not contained in the molding material. Therefore, tablets having practical hardness can be produced at a low tableting pressure. This allows the tablet containing the granules to be applied to the surface of the part containing the active ingredient (main drug) for the purpose of sustaining, sustained release, immediate release, gastric solubility, enteric solubility, bitterness prevention, etc.
  • the material, the structure of the base matrix, and the material are not broken, without any special measures, without causing phenomena such that the film is not broken, and the granules are not broken or undergo plastic deformation.
  • the tablet can be.
  • the spraying means for spraying the lubricant mixed with the positive pressure air pulsating wave may be provided in the spraying chamber, the manufacturing apparatus can be simplified.
  • the granules containing the active ingredient and the excipient are used as the granules containing the active ingredient (so-called microcapsules), the effective The particle size and size of the granules containing the ingredients can be easily changed.
  • the tablet can be easily produced by setting the particle size and size of the granules containing the active ingredient to the particle size and size that allow the surface to be coated easily. Further, the particle size and size of the granule containing the active ingredient can be adjusted to the particle size and size that can maximize the function of the granule.
  • the tablet can be produced at a low tableting pressure, even if the granules contained in the tablet contain the active ingredient in the base matrix, Can be made into tablets without destroying the function of the matrix.
  • the tablet can be manufactured with a low tableting pressure, so that even if the granules contained in the tablet are covered with a film, the film is not broken and the tablet is not broken.
  • continuous tableting is performed by utilizing the fact that a molding material does not adhere to a punch and a die in a tableting step, and that the manufactured tablet does not have a stateing or the like. Therefore, tablets containing the active ingredient and tablets containing granules containing the active ingredient can be produced on an industrial production basis.
  • the tableting step continuous tableting is performed by utilizing the fact that the molding material does not adhere to the punch and that the tablet to be manufactured does not have stateing or the like. So, on an industrial production basis, tablets containing active ingredients, Tablets containing granules containing the active can be manufactured.
  • the surface of the punch and the inside of the spray chamber where the air pulsating wave is generated are applied to the punch and the die that constitute the female mold of the engraved or scored tablet or the deformed tablet. Since the lubricant is applied to the surface of the punch, the lubricant can be evenly applied to the surface of the punch and the surface of the punch as compared with the conventional external lubrication method. As a result, in the process of stamping tablets or deformed tablets with engraved or scored lines, the molding material becomes less likely to adhere to the surface of the punch and the surface of the die, and the tablets or shaped tablets with engraved or scored lines to be manufactured are produced. Sticking, cabbing, laminating, etc. are unlikely to occur.
  • the tableting pressure in the step of tableting the molding material is set to a low pressure, even if the granules contained in the tablet are covered with a film, Can be made into tablets without breaking the film. Even if the granules contained in the tablet contain the active ingredient in the base matrix, the tablet can be formed without destroying the function of the base matrix.
  • the tablet manufacturing method of the present invention even if the spraying amount of the lubricant used for one tableting is extremely small, the tablet can be manufactured without sticking or the like.
  • the tablet (uncoated tablet) has only a small amount of lubricant attached to the surface and contains little lubricant inside the tablet, so that the tablet disintegration time is not delayed.
  • a tablet (uncoated tablet) containing the granules containing the active ingredient becomes a rapidly disintegrating tablet when used as a naked tablet.
  • the tablet itself is easily disintegrated, and a tablet which is required to dissolve the granules containing the active ingredient by exhibiting a predetermined target function can be easily produced.
  • the surface is coated with a film coat that dissolves at the target site, when the film coat is melted, the tablet body immediately disintegrates at the desired site, and the granules containing the active ingredient are converted to the predetermined purpose. Tablets can be easily manufactured because they are required to exhibit the function of dissolving and dissolve.
  • the tablet according to claim 15 does not contain a lubricant inside the tablet and has only a trace amount of the lubricant on the surface of the tablet, so that the tablet disintegrates due to the water repellency of the lubricant.
  • the problem of time delay does not occur.
  • this tablet when used as a naked tablet, it becomes a rapidly disintegrating tablet, and the tablet immediately disintegrates at the intended site and is contained in the tablet, as in the case of an intraorally rapidly disintegrating tablet.
  • the released active ingredient is released immediately.
  • the tablet body also melts immediately at the target site, so the active ingredient immediately and immediately at the target site. Released.
  • the tablet according to claim 16 does not contain a lubricant inside the tablet, and only a trace amount of the lubricant is present on the surface of the tablet, so that the tablet is disintegrated due to the water repellency of the lubricant. The problem of time delay does not occur.
  • this tablet when used as a naked tablet, it becomes a rapidly disintegrating tablet, and the tablet immediately disintegrates at the intended site and is contained in the tablet, as in the case of an intraorally rapidly disintegrating tablet.
  • the granules containing the active ingredient are released immediately.
  • the tablet body In addition, if the surface of the tablet body is coated with a film coat that dissolves at the target site, when the film coat is melted, the tablet body also dissolves immediately at the target site, so the granules containing the active ingredient immediately at the target site (So-called microcapsules) are released immediately.
  • the active ingredient is contained by the excipient.
  • the particle size and size of the granules can be easily changed.
  • the tablet can be easily produced by setting the particle size and size of the granules containing the active ingredient to the particle size and size that allow the surface to be coated easily.
  • the particle size and size of the granule containing the active ingredient can be adjusted to the particle size and size that can maximize the function of the granule.
  • the tablet according to claim 18 does not contain a lubricant in the excipient used for bulking, so that the disintegration time of the tablet is delayed due to the water repellency of the lubricant. Do Does not occur.
  • the base matrix exerts the intended function.
  • the base matrix is In cases where the purpose is to improve the potency, the base matrix also makes the tablet also have a long-lasting effect.
  • a tablet is coated with granules containing an active ingredient, which is not coated, and granules containing the active ingredient in a base matrix
  • the tablet is immediately converted into a tablet.
  • the granules containing the uncoated active ingredient and the granules containing the active ingredient in the base matrix are released from the tablet.
  • the active ingredient contained in the uncoated granules is absorbed into the body as soon as the tablet disintegrates. As a result, this tablet has excellent immediate effect.
  • granules containing the active ingredient in the base matrix can be used, for example, when the base matrix is intended for sustainability. Are better.
  • this tablet has both immediate effect and sustainability.
  • the tablet is not coated with granules containing the analgesic, analgesic anti-inflammatory or antipyretic, and
  • the drug matrix By mixing the drug matrix with granules containing analgesics, analgesics and anti-inflammatory agents or antipyretics, patients can immediately improve their pain, inflammation and fever if taken, and have analgesic and anti-inflammatory effects.
  • New tablets such as once-daily tablets (oncedailytab 1 et), that is, quick and long-lasting, antipyretic effects, that is, Quick & S 1 owrelease Tablets it can.
  • the tablet according to claim 19 does not contain a lubricant in the excipient used for bulking, the disintegration time of the tablet is delayed due to the water repellency of the lubricant. Problem does not occur.
  • the tablet contains granules containing the active ingredient in the tablet
  • the film formed on the surface of the granules containing the active ingredient exhibits the desired function ⁇
  • this film also provides the tablet with a long-lasting effect.
  • a tablet is coated with granules containing an active ingredient, which is not coated, and granules containing a coated, active ingredient
  • the tablet is immediately disintegrated in this tablet, Immediately after disintegration, the granules containing the uncoated active ingredient and the granules containing the coated active ingredient are released from the tablet.
  • the active ingredient contained in the uncoated granules is absorbed into the body as soon as the tablet disintegrates. This makes this tablet excellent in immediate effect.
  • the tablet has excellent sustainability. .
  • this tablet has both immediate effect and sustainability.
  • the tablet when the active ingredient is an analgesic, an analgesic anti-inflammatory or antipyretic, the tablet is provided with an uncoated, granule containing the analgesic, analgesic anti-inflammatory or antipyretic, and a film.
  • the drug By mixing the drug with granules containing an analgesic, an analgesic anti-inflammatory or antipyretic, the patient will immediately improve the patient's pain, inflammation and fever, and at the same time have an analgesic and anti-inflammatory effect.
  • New tablets such as tablets with long-lasting, antipyretic effects, immediate effects, once-a-day tablets (once daily & ablet), that is, quick and slow release tablets (Quick & S 1 ow release Tablets) Tablets can be realized.
  • the tablet according to claim 20 does not delay the disintegration time because only a small amount of the lubricant is present on the surface of the tablet.
  • the tablet according to claim 21 has a score line, the tablet can be easily divided according to the score line. This allows the patient to take the optimal drug dose based on the patient's weight, age, and the like.
  • the shape of the tablet body is irregular, the medicine can be easily identified by this shape. Therefore, medication errors do not occur in the clinical setting.
  • the lubricant is uniformly attached to the surface of the tablet body (uncoated tablet), there is little variation in the disintegration time of the tablet body or the elution time of the active ingredient. Tablets with a standard deviation of the disintegration time of the tablet body or the dissolution time of the active ingredient that are difficult to manufacture with the conventional tablets are within 15% of the average disintegration time or the average dissolution time of the active ingredient. It can be easily manufactured.
  • the standard deviation of the disintegration time of the tablet body or the dissolution time of the active ingredient is within 10% of the average disintegration time or the average dissolution time of the active ingredient, which was extremely difficult to manufacture with conventional tablets. Can be easily produced.
  • the standard deviation of the disintegration time of the tablet body or the dissolution time of the active ingredient which has been considered impossible to manufacture by the present inventors with conventional tablets, is the average disintegration time or active ingredient. Tablets within 7.5% of the average dissolution time can be produced. Since the lubricant is uniformly adhered to the surface of the tablet body (uncoated tablet), the tablet has less variation in the disintegration time of the tablet body or the elution time of the active ingredient.
  • the tablet according to claim 24 uses magnesium stearate as a lubricant, the content of the lubricant contained in the tablet can be easily measured.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Mechanical Engineering (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

L'invention porte sur un procédé de fabrication de comprimés, ce procédé comprenant une étape de moulage de matériaux tels que des ingrédients efficaces, une étape d'application d'un lubrifiant sur les surfaces d'un mortier et de l'eau de mauve placée dans une cabine de pulvérisation, cette étape consistant à générer une onde d'impulsion d'air et à appliquer le lubrifiant à l'intérieur de la cabine, et enfin une étape de compression des matériaux de moulage à l'aide du mortier recouvert de lubrifiant et de l'eau de mauve.
PCT/JP1999/001939 1998-04-10 1999-04-09 Comprime et procedes de fabrication de comprime WO1999052492A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2000543105A JP4568427B2 (ja) 1998-04-10 1999-04-09 錠剤の製造方法及び錠剤
CA2328100A CA2328100C (fr) 1998-04-10 1999-04-09 Comprime et procedes de fabrication de comprime
KR1020007011267A KR20010042593A (ko) 1998-04-10 1999-04-09 정제의 제조방법 및 정제
AU31693/99A AU764325B2 (en) 1998-04-10 1999-04-09 Tablet manufacturing methods and tablet
EP99913634A EP1070497A4 (fr) 1998-04-10 1999-04-09 Comprime et procedes de fabrication de comprime

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/98635 1998-04-10
JP9863598 1998-04-10

Publications (1)

Publication Number Publication Date
WO1999052492A1 true WO1999052492A1 (fr) 1999-10-21

Family

ID=14224973

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/001939 WO1999052492A1 (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 (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5373283B2 (ja) * 2005-07-08 2013-12-18 武田薬品工業株式会社 錠剤
CN113262170A (zh) * 2021-05-18 2021-08-17 孙德忠 一种片状药品智能加工设备及其加工方法

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US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
FR2790387B1 (fr) 1999-03-01 2001-05-18 Prographarm Laboratoires Comprime orodispersible presentant une faible friabilite et son procede de preparation
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, 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
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
DE102004051006B4 (de) * 2004-10-20 2009-07-02 Fette Gmbh Rundlaufpresse
NZ709754A (en) 2004-10-21 2017-02-24 Adare Pharmaceuticals Inc Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
US9161918B2 (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
JP5309262B2 (ja) 2009-12-02 2013-10-09 アプタリス ファーマ リミテッド フェキソフェナジン・マイクロカプセル及びそれを含む組成物

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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
JPS62187598A (ja) * 1985-12-10 1987-08-15 ユニバ−シテイ　オブ　バス 成形物の改善された製造方法
JPH02106A (ja) 1987-11-16 1990-01-05 Mcneil Consumer Prod Co 味覚遮蔽剤を含有している咀嚼可能な薬物錠剤
JPH06190267A (ja) * 1992-12-28 1994-07-12 Fuso Yakuhin Kogyo Kk マイクロカプセル
JPH07124231A (ja) 1993-11-01 1995-05-16 Kyowa Hakko Kogyo Co Ltd 外部滑沢式打錠機
JPH08277218A (ja) * 1995-04-04 1996-10-22 Kyowa Hakko Kogyo Co Ltd 割溝付き錠剤および割溝形成凸部付き杵

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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
JPS62187598A (ja) * 1985-12-10 1987-08-15 ユニバ−シテイ　オブ　バス 成形物の改善された製造方法
JPH02106A (ja) 1987-11-16 1990-01-05 Mcneil Consumer Prod Co 味覚遮蔽剤を含有している咀嚼可能な薬物錠剤
JPH06190267A (ja) * 1992-12-28 1994-07-12 Fuso Yakuhin Kogyo Kk マイクロカプセル
JPH07124231A (ja) 1993-11-01 1995-05-16 Kyowa Hakko Kogyo Co Ltd 外部滑沢式打錠機
JPH08277218A (ja) * 1995-04-04 1996-10-22 Kyowa Hakko Kogyo Co Ltd 割溝付き錠剤および割溝形成凸部付き杵

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Title
See also references of EP1070497A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5373283B2 (ja) * 2005-07-08 2013-12-18 武田薬品工業株式会社 錠剤
CN113262170A (zh) * 2021-05-18 2021-08-17 孙德忠 一种片状药品智能加工设备及其加工方法

Also Published As

Publication number Publication date
JP4568427B2 (ja) 2010-10-27
EP1070497A4 (fr) 2009-01-21
AU764325B2 (en) 2003-08-14
CA2328100A1 (fr) 1999-10-21
AU3169399A (en) 1999-11-01
KR20010042593A (ko) 2001-05-25
CA2328100C (fr) 2011-01-18
EP1070497A1 (fr) 2001-01-24

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