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WO2012091049A1 - Comprimé orodispersible - Google Patents

Comprimé orodispersible Download PDF

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Publication number
WO2012091049A1
WO2012091049A1 PCT/JP2011/080292 JP2011080292W WO2012091049A1 WO 2012091049 A1 WO2012091049 A1 WO 2012091049A1 JP 2011080292 W JP2011080292 W JP 2011080292W WO 2012091049 A1 WO2012091049 A1 WO 2012091049A1
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WO
WIPO (PCT)
Prior art keywords
drug
mass
water
particles
orally disintegrating
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2011/080292
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English (en)
Japanese (ja)
Inventor
哲矢 西山
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taiho Pharmaceutical Co Ltd
Original Assignee
Taiho Pharmaceutical 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 Taiho Pharmaceutical Co Ltd filed Critical Taiho Pharmaceutical Co Ltd
Priority to CN2011800636774A priority Critical patent/CN103282051A/zh
Priority to JP2012551003A priority patent/JP5876418B2/ja
Publication of WO2012091049A1 publication Critical patent/WO2012091049A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a tablet having rapid disintegration even in a small amount of water or without water in the oral cavity.
  • Orally disintegrating tablets are desired to have both rapid disintegration and high hardness.
  • a sugar alcohol having an appropriate sweetness and coolness is suitable.
  • D-mannitol having a low hygroscopic property is particularly suitable.
  • ordinary powdered mannitol has low moldability, and in addition, tableting troubles such as binding and sticking often occur during tableting.
  • a method of blending granulated mannitol and starches has been proposed in the past, and an orally disintegrating tablet that has both rapid disintegration and high hardness and excellent productivity is proposed.
  • Various developments have been made to obtain this.
  • Patent Document 1 discloses an orally disintegrating tablet further blended with granulated mannitol having excellent moldability but poor disintegration for the purpose of supplementing the moldability of powdered mannitol. By complementing each other's characteristics, the mechanical strength and disintegration of the orally disintegrating tablet are improved.
  • Patent Document 2 discloses an orally disintegrating tablet obtained by blending processed starches having a specific degree of pregelatinization with powdered mannitol in addition to drugs and sugars, granulating with starch paste, and tableting. It is said that starches having a specific degree of pregelatinization are useful as an excipient for orally disintegrating tablets having both rapid disintegration and high hardness.
  • Patent Document 3 an orally disintegrating tablet having rapid disintegration and high hardness is obtained by improving mannitol itself and making it into spherical crystal particles using a spray drying method. It has been shown that
  • JP 2008-260709 A International Publication No. 2008/032767 International Publication No. 2010/021300
  • Patent Document 3 describes that partially pregelatinized starch can be used in addition to hydroxypropylcellulose and the like as a binder, but any partially pregelatinized starch can be specifically selected. There has been no discussion about this. In particular, in the tableting process, when there is a risk of segregation of drugs and formed components, it is generally assumed that granulation using a binder is employed. The choice of binder used is very important because it can hinder disintegration. In addition, Patent Document 3 shows only a specific example of the drug content of 1 part by weight, and no consideration is given to the uniformity of the content. Therefore, it is still unclear whether sufficient disintegration and high hardness can be exhibited even when the drug content is increased in order to expand the application range as a tablet.
  • An object of the present invention is to provide an oral cavity that has rapid disintegration in the oral cavity, is not damaged in the distribution process, has an appropriate hardness that can withstand practical use even after moisture absorption, and does not cause a delay in disintegration time. It is to provide a disintegrating tablet.
  • the inventor has prepared pharmaceutical properties and by producing orally disintegrating tablets using drug-containing particles having a specific average particle size, spherical mannitol crystal particles, partially pregelatinized starch having a specific viscosity, and starch powder.
  • the present inventors have found that an orally disintegrating tablet excellent in production suitability can be obtained, and have completed the present invention.
  • the present invention provides (1) drug-containing particles having an average particle size of 150 to 300 ⁇ m, (2) Spherical mannitol crystal particles, (3) A partially pregelatinized starch having a viscosity of 5 to 45 mPa ⁇ s at 25 ° C. and a 10% by mass water suspension, and (4) an orally disintegrating tablet containing starch powder.
  • the orally disintegrating tablet of the present invention has an appropriate strength that does not cause damage in the distribution process, while providing a good disintegration property while exhibiting rapid disintegration in the oral cavity. Further, even after moisture absorption, the disintegration time is not delayed while effectively maintaining the practical hardness, so that it can withstand equipment such as an automatic tablet packaging machine during dispensing. Furthermore, even when a drug with an unpleasant taste is contained, the unpleasant taste can be effectively shielded, and even when a drug-containing particle having a range of particle sizes is included, the content is uniform in a wide range of drug contents. It is possible to ensure the sex.
  • the average particle diameter referred to in the drug-containing particles (1) and the spherical mannitol crystal particles (2) is generally referred to as a median diameter, and gives a particle diameter that gives 50% of the powder particle cumulative distribution. Means.
  • the drug-containing particles (1) used in the present invention have an average particle size of 150 to 300 ⁇ m, preferably 150 to 250 ⁇ m, more preferably 150 to 200 ⁇ m. In this way, by adopting finer particles than the conventional one, it is possible to greatly contribute to exerting excellent dosing feeling in the obtained tablet.
  • the average particle size of the drug-containing particles (1) is determined by dry / one-shot measurement using a laser diffraction / scattering particle size distribution analyzer “LMS-30” (manufactured by Seishin Enterprise Co., Ltd.). Means the measured value.
  • the drug-containing particles having such a particle size for example, drug-containing particles produced according to the production method described in Japanese Patent No. 4019374, Japanese Patent No. 4277904, or Japanese Patent No. 3317444 can be considered. Examples thereof include drug-containing particles produced according to the same method.
  • the drug contained in the drug-containing particles (1) is not particularly limited as long as it is effective as a pharmaceutically active ingredient for treating or preventing a disease when taken, and may be appropriately selected as desired. it can.
  • Such drugs include central nervous system drugs, peripheral nervous system drugs, sensory organ drugs, circulatory organ drugs, respiratory organ drugs, gastrointestinal drugs, hormone drugs, urogenital and anal drugs, vitamin drugs , Nourishing tonics, blood and body fluids, other metabolic drugs, cell stimulants, oncology drugs, allergic drugs, herbal medicines, herbal medicines, antibiotic preparations, chemotherapeutic agents, parasitic animal drugs, alkaloids
  • One or more components selected from narcotics, non-alkaloid narcotics and the like are used, but are not limited thereto.
  • ranitidine hydrochloride examples include drugs for digestive organs including anti-ulcer agents such as salt, cimetidine, famotidine, and lafutidine, among which lafutidine is preferable.
  • lafutidine is ( ⁇ ) -2- (furfurylsulfinyl) -N- [4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -2-butenyl] acetamide.
  • the content of the drug is preferably 40% by mass or less, more preferably 5 to 35% by mass, and further preferably 10 to 30% by mass in 100% by mass of the total amount of the drug-containing particles (1). If the content is within the above range, even if the drug has an unpleasant taste, the desired medicinal effect can be effectively exhibited while sufficiently suppressing the unpleasant taste.
  • the drug-containing particles (1) preferably include a membrane layer (A) containing a drug and a water-swellable polymer on the surface of the core particles (P) not containing the drug and the water-swellable polymer, A plurality of film layers including a film layer (B) containing an insoluble polymer, a water-soluble substance and an inorganic compound are preferably formed.
  • a plurality of film layers are formed on the surface of the core particle (P), these layers cover the core particles, and at least one of the plurality of film layers contains a drug.
  • the core particles (P) do not contain a drug and a water-swellable polymer.
  • the plurality of membrane layers include at least two of a membrane layer (A) containing a drug and a water-swellable polymer and a membrane layer (B) containing at least a water-insoluble polymer, a water-soluble substance and an inorganic compound.
  • a layer (A) containing a drug and a water-swellable polymer is formed on the surface of the core particle (P) as the innermost layer.
  • the drug-containing particles (1) as coated particles having the above layer structure, combined with spherical mannitol crystal particles (2), specific partially pregelatinized starch (3) and starch powder (4) described later, In the case where the drug has an unpleasant taste while exhibiting excellent quick disintegration while having an appropriate hardness and disintegration time, the unpleasant taste can be effectively shielded.
  • the water-swellable polymer contained in the membrane layer (A) together with the drug is hardly soluble in water (solubility is water-swelling as stipulated in the 16th revised Japanese Pharmacopoeia.
  • the water-swelling polymer 1g is evaluated by the degree of dissolution in 30 minutes when the water-soluble polymer is put in water at 25 ⁇ 5 ° C. and shaken strongly every 5 minutes for 30 seconds. It means a case where the amount of water required for dissolution is 10,000 mL or more), and is a high-molecular substance that swells and contains water, and is not particularly limited as long as it is a high-molecular substance other than a water-insoluble polymer.
  • Examples thereof include hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose or a salt thereof, croscarmellose sodium, and crospovidone.
  • low-substituted hydroxypropylcellulose is preferable.
  • the low-substituted hydroxypropylcellulose has a hydroxypropoxyl group substitution degree (mass%) of 5.0 to 16.0 mass%, more preferably 10 to 13 mass%.
  • Those having a degree of substitution of the hydroxyproposyl group of less than 5.0% have poor swelling power, and those having a degree of substitution of more than 16.0% tend to become sticky when water is included, and thus it is easy to feel stickiness when taken. .
  • the degree of substitution of hydroxypropylcellulose means the amount (%) of hydroxypropoxyl group substituted with the hydroxyl group of cellulose's pyranose ring. Specifically, the degree of substitution is defined in the 16th revised Japanese Pharmacopoeia. It means a value measured using a gas chromatographic method in accordance with a quantitative method for low-substituted hydroxypropylcellulose.
  • the content of the water-swellable polymer is preferably 13 to 30% by mass, more preferably 15 to 25% by mass, and still more preferably 17 to 22% by mass in 100% by mass of the total amount of the drug-containing particles (1). %. If the content is within the above range, the other film layer to be formed can be sufficiently broken, and the drug contained in the film layer (A) can be effectively released. Further, as will be described later, the water-swellable polymer is efficiently disposed on the surface of the core particle (P), so that the force necessary to break the membrane layer can be obtained even with a small addition amount. It is thought that If the content exceeds the desired value, the ratio of the other coating agent in the entire drug-containing particles (1) decreases, so that the dissolution becomes too fast, and the balance between the dissolution and the bitterness shielding effect may deteriorate. There is.
  • the thickness of the film layer (A) is preferably 70 ⁇ m or less, more preferably 20 to 50 ⁇ m. When the thickness is in the above range, the size of the drug-containing particles (1) can be reduced as much as possible, so that no roughness is felt during taking.
  • the membrane layer (A) is hydroxypropylcellulose (hereinafter referred to as “hydroxypropylcellulose” unless otherwise referred to as “low-substituted hydroxypropylcellulose”. ), Binders such as hypromellose, polyvinyl alcohol and povidone, various flavors such as orange and lemon, l-menthol, mint oil, neotame, thaumatin, aspartame, stevia, sucralose, sodium saccharin, sodium glutamate, acesulfame A taste-masking agent such as potassium may be used alone or in combination of two or more as required.
  • Binders such as hypromellose, polyvinyl alcohol and povidone, various flavors such as orange and lemon, l-menthol, mint oil, neotame, thaumatin, aspartame, stevia, sucralose, sodium saccharin, sodium glutamate, acesulfame
  • a taste-masking agent such as potassium may be
  • the core particle (P) means a particle serving as a core of the coating, and is not particularly limited as long as the film layer (A) can be formed as an innermost film layer on the surface thereof. Examples thereof include spherical granulated products and commercially available spray granulated products. Further, these core particles may be produced and used by a known pulverization method or granulation method. As these core particles, commercially available products may be used as they are, or particles having a desired particle diameter may be prepared by sieving. Examples of such core particles include core particles composed of one or a combination of two or more selected from mannitol, crystalline cellulose, lactose, purified sucrose, corn starch and the like. The core particles (P) do not contain drugs and water-swellable polymers.
  • the shape of the core particle (P) is preferably a spherical particle from the viewpoint of obtaining particles having uniform physical properties and more effectively disposing the water-swellable polymer on the surface of the core particle (P). . If the shape is irregular, the thickness of the formed film layer tends to be non-uniform, especially if the drug has an unpleasant taste, the unpleasant taste shielding effect may be insufficient. .
  • the average particle diameter of the core particles (P) may be any size that does not feel rough in the oral cavity when the drug-containing particles (1) are prepared using this. Specifically, the average particle size is preferably 10 to 200 ⁇ m, more preferably 50 to 170 ⁇ m, and even more preferably 100 to 150 ⁇ m. When the size is such, the size of the obtained drug-containing particles (1) is also sufficiently small and does not feel rough in the oral cavity.
  • core particles (P) commercially available “Nonparel-108 (100)” (Freund Sangyo Co., Ltd.), “Selfia CP-102”, “Selfia SCP-100” (all manufactured by Asahi Kasei Chemicals Corporation) ), Etc., “FlowLac90”, “FlowLac100”, “Cellactose80”, “MicroceLac100”, “StarLac100” (all manufactured by Megre), “Super Tab 11SD”, “Super Tab 14SD” (all manufactured by DMV-Frontera Ex) Spray granulated products such as the above can be used.
  • the ratio of the mass of the core particles (P) is preferably 30% by mass or less, more preferably 14 to 20% by mass in 100% by mass of the total amount of the drug-containing particles (1).
  • the water-insoluble polymer contained in the membrane layer (B) As the water-insoluble polymer contained in the membrane layer (B), the water-insoluble polymer hardly dissolves in water (the solubility is 25% as defined in the 16th revised Japanese Pharmacopoeia general rules). Put in water at ⁇ 5 ° C and shake for 30 seconds strongly every 5 minutes. Evaluate from the degree of dissolution within 30 minutes. "It hardly dissolves in water” means water required to dissolve 1 g of water-insoluble polymer. And a polymer substance that does not swell even if it contains water, that is, a polymer substance other than a water-swellable polymer and generally used as an additive for pharmaceuticals There is no particular limitation, and those usually used as a coating agent can be mentioned.
  • a water-insoluble polymer examples include ethyl cellulose, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer and the like, and ethyl cellulose is particularly preferable.
  • the ethyl cellulose used in the present invention conforms to the Japanese Pharmaceutical Additives Standard, that is, the ethoxyl group content is 46.5 to 51.0%, and the viscosity of a 5% ethyl cellulose / toluene / ethanol solution at 25 ⁇ 0.1 ° C. Is preferably about 4 to about 100 cps, more preferably about 7 to about 20 cps.
  • the content of the water-insoluble polymer is preferably 7 to 11% by mass, more preferably 8 to 10% by mass in the total amount of drug-containing particles (1) of 100% by mass.
  • the water-soluble substance contained in the membrane layer (B) together with the water-insoluble polymer is soluble to some extent in water (the solubility is water-soluble as defined in the 16th revision of the Japanese Pharmacopoeia. When the polymer is put in water at 25 ⁇ 5 ° C and shaken vigorously every 5 minutes for 30 seconds, it is evaluated from the degree to which it dissolves within 30 minutes. Equivalent to the property indicated by the terms “easy” or “easy to dissolve”, meaning that the amount of water required to dissolve 1 g of water-soluble substance is less than 10 mL), or a viscous colloidal dispersion Any of those generally used as an additive for pharmaceuticals is not particularly limited, and examples thereof include those usually used as a coating agent. Examples of such water-soluble substances include purified sucrose, D-sorbitol, D-mannitol, hydroxypropylcellulose, hypromellose, povidone, methylcellulose, and carmellose sodium.
  • the content of the water-soluble substance contained in the membrane layer (B) based on 100% by mass of the drug-containing particles (1) is 100% by mass of the drug-containing particles (1).
  • the content of the water-insoluble polymer is 0.4 to 0.6 times, preferably 0.45 to 0.55 times, and most preferably 0.5 times.
  • inorganic compound As the inorganic compound further contained in the membrane layer (B), those effective for preventing aggregation and adhesion of the drug-containing particles (1) are preferable.
  • examples of such inorganic compounds include talc, titanium oxide, magnesium stearate, light anhydrous silicic acid and the like. Of these, titanium oxide is preferable.
  • the content of the inorganic compound is preferably 25 to 35% by mass, more preferably 27 to 32% by mass in 100% by mass of the membrane layer (B). If it is less than the above lower limit, there is a possibility that sufficient effects for aggregation and adhesion prevention of the resulting drug-containing particles (1) may not be obtained, and if it exceeds the above upper limit, film formation may be difficult. Further, when the amount is within the above range, even better storage stability can be imparted.
  • the content of the water-insoluble polymer the content of the water-soluble substance: the content of the inorganic compound is 1: 0.4 to 0.6: 0.5 by mass ratio. ⁇ 0.7 is preferable, and 1: 0.5: 0.6 is more preferable.
  • the drug-containing particles (1) are effectively prevented from aggregating and adhering, and the drug has good dissolution properties and the drug has an unpleasant taste. It is possible to maintain an excellent balance between the unpleasant taste shielding effect and the drug dissolution.
  • An intermediate film layer may be further included as a plurality of film layers formed on the surface of the core particle.
  • the intermediate film layer may be a single layer or a plurality of layers, and is preferably formed between the film layer (A) as the innermost film layer and the film layer (B). That is, the membrane layer (B) containing a water-insoluble polymer, a water-soluble substance and an inorganic compound is preferably the outermost membrane layer.
  • the intermediate film layer between the innermost film layer and the outermost film layer it is possible to improve storage stability, taste, and the like.
  • the component contained in the interlayer film is not limited as long as it does not interfere with the effect of the drug-containing particles (1).
  • purified sucrose, D-sorbitol, D-mannitol, hydroxypropylcellulose examples include, but are not limited to, hypromellose, povidone, methylcellulose, and carmellose sodium. These may be used alone or in combination of two or more. Of these components, D-mannitol and hypromellose are preferable, and hypromellose is more preferable from the viewpoint of easy coating.
  • talc, titanium oxide, magnesium stearate, light anhydrous silicic acid, and the like may be added as necessary for the purpose of reducing adhesion when coating the intermediate film layer.
  • the mass of the intermediate film layer is not limited as long as it does not interfere with the effect of the drug-containing particles (1), and may vary depending on the size of the core particles (P).
  • a total amount of 100 parts by weight with A) is preferably 15 to 25 parts by weight, and more preferably 18 to 22 parts by weight.
  • the content of the drug-containing particles (1) in the orally disintegrating tablet of the present invention is 100% by mass based on the total amount of the tablet from the viewpoint of sufficiently exhibiting a desired medicinal effect without inhibiting the compatibility between appropriate hardness and disintegration time.
  • the content is preferably 1 to 30% by mass, and more preferably 10 to 30% by mass.
  • the drug-containing particles (1) may be adjusted to an average particle size of 150 to 300 ⁇ m by sieving according to a conventional method. Furthermore, in order to make the drug-containing particles (1) have a plurality of film layers including the film layer (A) and the film layer (B) formed on the surface of the core particles (P), What is necessary is just to manufacture by spraying the coating liquid containing a component on a core particle (P). Specifically, using a fluidized bed granulator or the like, (i) First, a spray prepared by dissolving or dispersing a drug and water-swellable polymer as innermost layer components in an organic solvent such as ethanol or methanol. Spray the liquid onto the core particles (P). The content of the film component in the spray liquid is preferably up to 30% by mass. If it exceeds 30% by mass, the spray gun may be blocked and spraying may be difficult.
  • a desired film component is dissolved in water or the like to prepare a spray solution, and sprayed onto the particles obtained in (i).
  • the content of the film component in the spray liquid is preferably 5 to 15% by mass, more preferably 8 to 12% by mass. If the content is less than the above lower limit, the film layer formation efficiency may deteriorate and the productivity may decrease, and if the content exceeds the upper limit, the drug-containing particles (1) aggregate to form aggregates. There is a fear.
  • a spray solution prepared by dissolving or dispersing a water-insoluble polymer, a water-soluble substance and an inorganic compound in a mixed solution of an organic solvent such as ethanol and methanol and water is added to the particles obtained in (ii).
  • the desired drug-containing film-coated particles are obtained by spraying.
  • the content of the film component in the spray liquid is preferably 3 to 7% by mass, and more preferably 4 to 6% by mass. If the content is less than the above lower limit, the film layer formation efficiency may be deteriorated and the productivity may be lowered. If the content exceeds the upper limit, the drug-containing particles (1) aggregate, There is a risk.
  • various methods such as an upper spray method, a side spray method, and a lower spray method can be selected.
  • the proportion of the mass of the core particles (P) is 30% by mass or less, the content of the drug is 40% by mass or less, and the content of the water-swellable polymer is from 13 to 30% by mass, the content of the water-insoluble polymer is 7 to 11% by mass, and the content of the water-soluble substance contained in the membrane layer (B) is 0.4 to 0.6 of the content of the water-insoluble polymer.
  • the content of the inorganic compound is preferably 25 to 35% by mass in 100% by mass of the membrane layer (B).
  • the content of the drug is 5 to 35% by mass
  • the content of the polymer is 15 to 25% by mass
  • the content of the water-insoluble polymer is 8 to 10% by mass
  • the content of the inorganic compound is 27 to 32 in 100% by mass of the membrane layer (B). What is mass% is more preferable.
  • the drug-containing particles (1) used for the orally disintegrating tablet of the present invention a plurality of film layers including a film layer (A) and a film layer (B) are formed on the surface of the core particles (P) as described above.
  • the dissolution of the drug is suppressed as much as possible while staying in the oral cavity immediately after taking the tablet, and the particles in the tablet are in the stage of transferring from the oral cavity to the body while collapsing.
  • the drug is rapidly eluted, particularly when the drug has an unpleasant taste, a favorable elution profile excellent in the balance between the unpleasant taste shielding property and the drug elution property is exhibited.
  • the preferable dissolution profile was specifically tested using the second method (50 rpm) using 900 mL of the dissolution test second solution described in the Japanese Pharmacopoeia General Test Method, Preparation Test Method Listed Dissolution Test Method.
  • the elution rate after 2 minutes is 5% or less, preferably 2% or less, and the elution rate after 30 minutes is 85% or more, preferably the elution rate after 15 minutes is 85% or more. Means.
  • the unpleasant taste shielding time in the drug-containing particles (1) may vary depending on the type of drug, but is preferably 30 to 300 seconds, more preferably 120 to 300 seconds.
  • the orally disintegrating tablet of the present invention comprises drug-containing particles (1) prepared in advance as described above, spherical mannitol crystal particles (2) described later, specific partially pregelatinized starch (3), and starch powder (4). Containing.
  • the spherical mannitol crystal particles (2) used in the present invention have a shape close to a true sphere and a unique structure having voids inside.
  • the tablet can be disintegrated in a short time while maintaining good tablet hardness. This is because the spherical mannitol crystal particles (2) are composed of very fine needle-like crystals, and when the spherical particles collapse due to tableting, the needle-like crystals are entangled with each other, thereby exhibiting high moldability. It is presumed that rapid disintegration is obtained by water permeating into the voids between the shaped crystals and the voids in the remaining spherical particles.
  • the shape of the spherical mannitol crystal particles (2) is maintained in the granulated particles from observation in an electron micrograph. The characteristics are not lost by granulation.
  • the spherical mannitol crystal particles (2) are preferably spherical particles having a low bulk density and a high sphericity.
  • the bulk density is preferably 0.3 to 0.7 g / mL, and more preferably 0.35 to 0.50 g / mL.
  • the bulk density of the spherical mannitol crystal particles (2) can be usually obtained by a known measurement method. For example, according to the method described in International Publication No. 2010/021300, spherical mannitol crystal particles (2) are lightly piled up into a 100 mL volume cup (mass Wa), and the weight Wb is measured by the following formula (I). What is necessary is just to measure the calculated
  • require the average value. Bulk density (g / mL) (Wb ⁇ Wa) / 100 (I)
  • the sphericity of the spherical mannitol crystal particles (2) may be determined based on the aspect ratio (ratio between the major axis and the minor axis), and specifically, the aspect ratio is preferably 1.2 or less. 1.1 or less is more preferable.
  • the aspect ratio is determined by taking a photograph of spherically placed spherical mannitol crystal particles (2) with a scanning electron microscope and measuring the length (major axis) and long axis of a plurality of spherical particles. The length (minor axis) of the minor axis perpendicularly drawn from the midpoint of the axis was measured, the ratio of the major axis to each minor axis was determined, and the average value of the ratios was obtained.
  • the voids present in the spherical mannitol crystal particles (2) can be evaluated based on the oil absorption 1 and 2 by the test method A shown below, the oil absorption 1 is 25 to 60%, and the oil absorption 2 is 15 to 40%. It is preferable that
  • the oil absorption rate according to Test Method A can be determined by the following procedure. 30 g of medium-chain fatty acid triglyceride and 15 g of sample mannitol were put into a 100 mL glass beaker, and the oil and powder sample were gently mixed with a spatula so as not to damage the powder. Depressurize to 67 Pascals and impregnate with oil for 3 hours. Next, the tube is transferred to a centrifuge tube (having holes at the bottom) using a filter cloth having a mesh of 325 mesh (aperture 45 ⁇ m), and centrifuged at about 1300 G for 10 minutes using a centrifuge.
  • the centrifuge tube containing the sample after centrifugation is placed in a 100 mL glass beaker, 20 g of n-hexane is added from above the powder sample, and centrifuged at about 1300 G for 10 minutes using a centrifuge.
  • the mass (Wd) of the powder sample remaining in the centrifuge tube after centrifugation is obtained from the measured values of the centrifuge tube containing the sample after centrifugation and the centrifuge tube tare mass, and is calculated by the following formula (III).
  • the average particle diameter of the spherical mannitol crystal particles (2) is preferably 15 to 165 ⁇ m, more preferably 15 to 85 ⁇ m, and further preferably 15 to 65 ⁇ m.
  • the average particle diameter of the spherical mannitol crystal particles (2) is a laser diffraction / scattering type particle size distribution analyzer “MT-3000” (manufactured by Nikkiso Co., Ltd.) and 2-propanol as a dispersion solvent. Means the measured value.
  • the angle of repose of the spherical mannitol crystal particles (2) is preferably 30 to 50 degrees.
  • the angle of repose means the angle of a mountain formed in a state where powder is naturally dropped on a disc.
  • the angle of repose can be obtained by a generally known measuring method, and is measured by the following method using, for example, an ABD powder characteristic measuring device.
  • the sample put into the sample hopper is passed through a vibrating rod, net (mesh opening 1000 ⁇ m), discharge funnel, nozzle (inner diameter 1 cm), dropped on the disk of the angle of repose sample table to create a mountain, and in three different directions
  • the angle of the mountain is measured with an angle meter, and the average value is obtained.
  • the operation to obtain the angle of repose can be repeated three times, and the average value of these three times can be obtained.
  • the spherical mannitol crystal particles (2) can be produced, for example, according to the method described in International Publication No. 2010/021300, International Publication No. 2008/146590, and the like. Moreover, it can also manufacture by the manufacturing method shown below.
  • a spray dryer “ODT-20 type” manufactured by Okawara Chemical Industries Co., Ltd.
  • the hot air is a co-current type in which air is ejected in the same direction to the liquid to be sprayed to generate a vortex, and is introduced from the upper part of the apparatus and discharged from the lower part of the apparatus.
  • the mannitol aqueous solution is dissolved while heating until a solid solution is completely dissolved and becomes a clear solution by adding pure water to commercially available crystalline mannitol “Mannit P” (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.). This is obtained by spray drying.
  • a pre-prepared mannitol aqueous solution is introduced into the apparatus, and then the powder accumulated in the product can at the bottom of the spray dryer is collected, and the fluidized bed dryer “FLO-5” (manufactured by Okawara Seisakusho) is used. By drying this, spherical mannitol crystal particles (2) can be obtained.
  • the content of the spherical mannitol crystal particles (2) in the orally disintegrating tablet of the present invention is the drug (1) in the drug-containing particles (1) from the viewpoint of imparting good tablet hardness while effectively preventing the disintegration time from being extended. It is preferably 40 to 80% by mass, more preferably 45 to 60% by mass, out of 100% by mass of the total components in the tablet excluding 1a).
  • the partially pregelatinized starch (3) used in the present invention acts as a binder for the orally disintegrating tablet of the present invention, and the viscosity of a 10% by mass aqueous suspension at 25 ° C. is 5 to 45 mPa ⁇ s.
  • Partially pregelatinized starch Such a specific partially pregelatinized starch (3) does not hinder the disintegration of the tablet while exhibiting a sufficient effect as a binder.
  • the partially pregelatinized starch (3) is allowed to act as a binder to uniformly disperse these drug-containing particles (1), spherical mannitol crystal particles (2) and starch powder (4). Segregation in the tableting process can be effectively prevented, and good granulation can be exhibited even when granulating in advance before the tableting process, while maintaining sufficient tablet hardness. The uniformity of the drug content in can also be sufficiently ensured.
  • the viscosity of the partially pregelatinized starch (3) at 25 ° C. and 10% by mass in water is preferably 8 to 35 mPa ⁇ s.
  • the viscosity of the binding liquid can be measured using a rotational viscometer (R-type viscometer, manufactured by Toki Sangyo Co., Ltd.). If the viscosity of the 10% by mass aqueous suspension at 25 ° C. exceeds the upper limit, sufficient disintegration may not be obtained, and the disintegration time may be prolonged. If the viscosity of the liquid is less than the lower limit, granulation becomes difficult.
  • the preferred degree of pregelatinization in the partially pregelatinized starch (3) used in the present invention is 60 to 80%, more preferably 70 to 80%.
  • the degree of pregelatinization of the partially pregelatinized starch (3) is the measurement method of the conventional glucoamylase method (edited by Jiro Nikoku, “Starch Chemistry Handbook”, Asakura Shoten, 1977, p.242). It means a value obtained by adoption, for example, according to the method described in International Publication No. 2008/032767.
  • partially pregelatinized starch (3) commercially available “PCS (registered trademark)” (manufactured by Asahi Kasei Chemicals Corporation) can be used, and the degree of pregelatinization is 75.9% (International Publication No. 2008/032767).
  • the content of the partially pregelatinized starch (3) is preferably 3 to 7.5 in 100% by mass of the orally disintegrating tablet from the viewpoint of achieving both uniformity of drug content between tablets and disintegration of the tablet. % By mass, more preferably 3 to 6% by mass.
  • the partially pregelatinized starch (3) exhibits a sufficient effect as a binder and uses a suspension obtained by dispersing in purified water as a binder from the viewpoint of achieving uniformity in drug content among tablets.
  • it is preferable to tablet after preparing a granulated material in advance but the method of use is not particularly limited.
  • the ratio (D90 / D10) of the 90% cumulative particle size (D90) and the 10% cumulative particle size (D10) obtained from the cumulative particle size distribution curve is preferably 1 to 5, more It is preferably 1 to 3.5.
  • the cumulative particle size distribution curve means that obtained using a laser diffraction / scattering particle size distribution measuring device “LMS-30” (manufactured by Seishin Enterprise Co., Ltd.).
  • the starch powder (4) used in the present invention is a starch other than the partially pregelatinized starch (3) and has a powder form.
  • Such starch powder (4) is not particularly limited as long as it is generally used as a pharmaceutical additive, and examples thereof include wheat starch, rice starch, corn starch, and potato starch.
  • rice starch or corn starch is preferable from the viewpoint that there is little decrease in tablet hardness due to addition.
  • the content (% by mass) of the starch powder (4) is preferably 5 to 20% by mass in 100% by mass of the orally disintegrating tablet from the viewpoint of achieving both disintegration and tablet hardness. % Is more preferred.
  • preferred orally disintegrating tablets include 1 to 30% by mass of the drug-containing particles (1), 3 to 7.5% by mass of partially pregelatinized starch (3), and starch in a total amount of 100% by mass.
  • the orally disintegrating tablet of the present invention in addition to the drug-containing particles (1), the spherical mannitol crystal particles (2), the partially pregelatinized starch (3), and the starch powder (4), a range that does not impede the effects of the present invention.
  • Other additives can be used. Such additives are not particularly limited as long as they are additives for various preparations generally used in the production of orally disintegrating tablets. For example, excipients, binders, disintegrants, lubricants, coloring agents, wearing agents A fragrance
  • excipients include monosaccharides such as xylose, glucose, and fructose; oligosaccharides such as sucrose, lactose, maltose, reduced maltose, and isomaltose; sugar alcohols such as xylitol, erythritol, and sorbitol; and light anhydrous silicic acid And calcium silicate. These may be used alone or in combination of two or more.
  • binder examples include those other than the partially pregelatinized starch (3), such as hydroxypropylcellulose, hypromellose, polyvinyl alcohol, polyvinylpyrrolidone, magnesium aluminate metasilicate, and the like.
  • disintegrant examples include carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, and the like. These disintegrants may be used alone or in combination of two or more.
  • the lubricant examples include metal stearates such as magnesium stearate and calcium stearate; sodium stearyl fumarate, talc, hydrogenated oil, sucrose fatty acid ester and the like.
  • metal stearates such as magnesium stearate and calcium stearate; sodium stearyl fumarate, talc, hydrogenated oil, sucrose fatty acid ester and the like.
  • magnesium stearate is preferable from the viewpoint that a sufficient lubrication effect can be obtained with a small amount of addition.
  • These lubricants may be contained inside the tablet, or may be in a form localized on the tablet surface (external lubricant).
  • flavoring agents examples include orange and lemon flavors.
  • corrigent examples include L-menthol, camphor, mint, neotame, thaumatin, aspartame, stevia, sucralose, sodium saccharin, sodium glutamate, and acesulfame potassium. These may be used alone or in combination of two or more.
  • the orally disintegrating tablet of the present invention disintegrates rapidly by saliva when taken into the oral cavity, and the disintegration time is within 90 seconds, preferably within 60 seconds, more preferably within 30 seconds. .
  • the tablet hardness of the orally disintegrating tablet of the present invention may be a level that can withstand normal handling and load such as dispensing by a fully automatic tablet packaging machine and extrusion from an extruding drug packaging machine (PTP), Specifically, the tablet hardness / tablet mass value is preferably 0.022 kgf / mg or more (in the case of a tablet mass of 180 mg, the tablet hardness is 3.96 kgf or more) (Medical Pharmacy Vol. 29, No. 3 (2003 ), 367-374).
  • the tablet hardness of the orally disintegrating tablet of the present invention can be determined by a generally known measurement method. For example, the tablet hardness meter can be used to measure the hardness in the diameter direction and determine the average value of a plurality of tablets. .
  • the orally disintegrating tablet of the present invention can be produced by a known tablet production method.
  • a drug-containing particle (1) is prepared in advance, and spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4), and optionally a component containing magnesium stearate.
  • it can be obtained by mixing all together and then compression-molding the mixture, but is not limited to this method.
  • the drug-containing particles (1) prepared in advance are used.
  • an orally disintegrating tablet by a method in which spherical mannitol crystal particles (2) and starch powder (4) are blended and mixed, and then partially pregelatinized starch (3) is blended. That is, in this method, more specifically, drug-containing particles (1) are prepared in advance, and spherical mannitol crystal particles (2) and starch powder (4) are mixed therewith, and then partially pregelatinized starch (3 ) To prepare a granulated product by spraying, granulating and drying in advance, and adding the magnesium stearate-containing component to the resulting granulated product. After mixing, the mixture is compression-molded.
  • the granulation method for example, a fluidized bed granulation method, a stirring granulation method, a rolling granulation method or the like can be selected, but the fluidized bed granulation method is preferable from the viewpoint of productivity.
  • the supply temperature, air volume, binder liquid volume, spray air pressure, etc. are adjusted so that the product temperature of the granulated product is maintained at 35 to 50 ° C. and the moisture content of the granulated product is maintained at 5% or less. Is preferred.
  • the tableting method can be performed using a normal tableting machine such as a single tableting machine or a rotary tableting machine. Moreover, it can also be set as a tablet using an external lubrication tableting machine.
  • the pressure at the time of compression molding is preferably 400 to 1000 kgf, more preferably 600 to 900 kgf, and still more preferably 700 to 850 kgf, from the viewpoint of providing quick disintegration while maintaining sufficient tablet hardness.
  • the orally disintegrating tablet of the present invention is taken without water or with water.
  • a method of taking there are a method in which it is taken into the mouth and not swallowed as it is, a small amount of water or a method in which it is taken up with saliva in the oral cavity without water, and a method in which it is swallowed with water and taken.
  • the tablet may be taken after disintegrating with water.
  • the orally disintegrating tablet of the present invention is often used without water, when it is taken by a patient who has difficulty swallowing the tablet, or when it is a normal tablet, an elderly person or child who may clog the throat It is advantageously used when taking the medicine.
  • the orally disintegrating tablet of the present invention is [1] (1) Drug-containing particles having an average particle size of 150 to 300 ⁇ m, (2) Spherical mannitol crystal particles, (3) A partially pregelatinized starch having a viscosity of 5 to 45 mPa ⁇ s at 25 ° C. and a 10% by mass water suspension, and (4) an orally disintegrating tablet containing starch powder.
  • the drug-containing particles (1) are 1 to 30 mass%, preferably 10 to 30 mass%, and the partially pregelatinized starch (3) is 3 to 7.5 mass%.
  • the orally disintegrating tablet according to [1] or [2], wherein the drug contained in the drug-containing particles (1) is a drug with an unpleasant taste, and preferably an anti-ulcer agent.
  • the drug-containing particle (1) has a film layer (A) containing the drug and the water-swellable polymer on the surface of the core particle (P) not containing the drug and the water-swellable polymer, and is water-insoluble.
  • the orally disintegrating tablet according to any one of [1] to [7] above, wherein a plurality of film layers including a film layer (B) containing a polymer, a water-soluble substance and an inorganic compound are formed.
  • the film layer (A) is the innermost film layer, and the drug-containing particles (1) are 100% by mass in total, and the core particles
  • the proportion of the mass of (P) is 30% by mass or less, the drug content is 40% by mass or less, the water-swellable polymer content is 13 to 30% by mass, and the water-insoluble polymer content is 7 to 11% by mass. %,
  • the content of the water-soluble substance contained in the membrane layer (B) is 0.4 to 0.6 times the content of the water-insoluble polymer, and in 100% by mass of the membrane layer (B),
  • the present invention is preferably the following production method.
  • Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to and mixed with drug-containing particles (1) prepared in advance, and the resulting mixture is compression molded.
  • [1] to [12] A method for producing an orally disintegrating tablet.
  • Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to drug-containing particles (1) prepared in advance, and ingredients containing magnesium stearate are added and mixed.
  • the present invention is preferably an orally disintegrating tablet obtained by the following method.
  • Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to and mixed with drug-containing particles (1) prepared in advance, and the resulting mixture is compression molded. Orally disintegrating tablets according to the above [1] to [12].
  • Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to drug-containing particles (1) prepared in advance, and ingredients containing magnesium stearate are added and mixed.
  • the orally disintegrating tablet according to [19] which is obtained by further adding and mixing a component containing magnesium stearate to the obtained granulated product, followed by compression molding.
  • the average particle size of Non-Parallel-108 (100) was 100 ⁇ m.
  • the average particle size of the core particles described later and the average particle size of the obtained lafutidine-containing particles were determined in the same manner.
  • Reference Example 7 Production of drug-containing particles G (1) Formation of drug-containing granulated core particles 82.4 g of hydroxypropyl cellulose “HPC-SSL”, 205.9 g of lafutidine, low-substituted hydroxypropyl cellulose “L-HPC” (LH-31) ”205.9 g and lactose hydrate“ Lactochem ”(manufactured by DOMO) 205.9 g were charged into a high-speed stirring granulator (device name“ Vertical Granulator VG-05 ”, manufactured by POWREC Co., Ltd.) After mixing for 2 minutes, 127.2 g of ethanol (95) was added and granulated. After drying using a fluidized bed granulation coating apparatus “Multiplex MP-01”, the mixture was sieved with a sieve having an opening of 355 ⁇ m to obtain luffidine-containing granulated core particles.
  • HPC-SSL 205.9 g of lafutidine
  • Example preparation Each drug-containing particle equivalent to 10 mg of lafutidine was weighed, and spherical mannitol crystal particles (hereinafter referred to as spherical mannitol crystal particles) / low-substituted hydroxypropylcellulose “L-” produced according to the description of International Publication No. 2008/146590.
  • HPC (LH-21) ”/ sodium stearyl fumarate“ PRUV (manufactured by JRS) ” 160/8/1 was mixed with a mixture of 169 mg to obtain a prepared powder.
  • This prepared powder was compression-molded at 250 kgf using a ⁇ 8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain each sample.
  • Dissolution test method Method 2 (50 rpm)
  • Test solution Dissolution test second solution (900 mL)
  • Measurement wavelength: ⁇ 271 nm
  • the drug-containing particles of Reference Examples 1 and 2 showed an elution rate of 85% or more after 15 minutes, even though the elution rate was 5% or less even after 2 minutes. It was.
  • Reference Example 3 containing no water-swellable polymer in the drug layer and Reference Example 7 using drug-containing granulated core particles show an elution rate of 85% or more after 15 minutes, but elution after 2 minutes. The rate exceeded 5% and the unpleasant taste shielding was insufficient.
  • Reference Example 4 in which the amount of water-swellable polymer in the total amount of particles is insufficient
  • Reference Example 5 in which the amount of water-soluble substance is small relative to the amount of water-insoluble polymer (ethyl cellulose), and inorganic in the outermost layer
  • the elution rate after 2 minutes is 5% or less, but the elution rate after 30 minutes is 85% or less. This was a result of concern about ensuring bioequivalence with the drug product.
  • the raw material of lafutidine is a drug that strongly exhibits an unpleasant taste, but the coated particles of Reference Example 2 feel an unpleasant taste not only immediately after being put in the mouth but also after 1 minute. None or acceptable. On the other hand, the coated particles of Reference Example 3 felt an unpleasant taste.
  • Tablet B was obtained in the same manner as in Reference Example 17 except that D-mannitol “PEARLITO 50C” (manufactured by Rocket Japan Co., Ltd.) was used instead of the spherical mannitol crystal particles.
  • Tablet C was obtained according to the same method as in Reference Example 17 except that D-mannitol “PEARLITOL 200SD” (manufactured by Rocket Japan Co., Ltd.) was used instead of the spherical mannitol crystal particles.
  • Test Example 3 Measurement of tablet hardness and disintegration time (1)
  • the hardness in the diameter direction was measured using a tablet hardness tester (6D, manufactured by Schleuniger), and the tablet hardness was determined from the average value of 3 tablets.
  • the disintegration time was measured using an orally disintegrating tablet tester (ODT-101, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of test solution: water (37 ⁇ 1 ° C.), weight mass: 20 g, rotation speed: 75 rpm. did.
  • the hardness and disintegration time were measured immediately after tableting (Initial) and after standing for 1 day at 40 ° C. and 75% relative humidity in an unwrapped state (40 ° C. and 75% RH (open)). The results are shown in Table 6.
  • Example 1 Production of tablet D
  • 40 g of partially pregelatinized starch “PCS PC-10” manufactured by Asahi Kasei Chemicals Corporation was dispersed in 360 g of purified water to obtain a binding liquid (25 ° C., viscosity: 35 mPa ⁇ s).
  • magnesium stearate manufactured by Taihei Chemical Industrial Co., Ltd.
  • the prepared powder was compression molded at 1000 kgf using a ⁇ 8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet D having a mass of 200 mg.
  • Example 2 Production of tablet E
  • 40 g of corn starch “eclipse corn starch W” manufactured by Nippon Shokuhin Kako Co., Ltd.
  • a binding solution 25 ° C., viscosity: 8 mPa ⁇ s.
  • a tablet E was obtained in the same manner as in Example 1 except that this binding solution was used.
  • Test Example 4 Measurement of tablet hardness and disintegration time (2)
  • Tablet hardness and disintegration time were measured in the same manner as in Test Example 3. The results are shown in Table 7.
  • Comparative Example 2 in which starch having a suspension viscosity of less than 5 mPa ⁇ s was used as a binder, good granulation properties could not be exhibited.
  • Comparative Example 3 using hydroxypropylcellulose as a binder and Comparative Example 4 using povidone as a binder, good granulation was obtained, but fast disintegration was not obtained.
  • Example 3 Production of tablet J] 30 g of partially pregelatinized starch “PCS PC-10” (manufactured by Asahi Kasei Chemicals Corporation) was dispersed in 270 g of purified water to obtain a binding solution.
  • PCS PC-10 partially pregelatinized starch
  • magnesium stearate manufactured by Taihei Chemical Industrial Co., Ltd.
  • This prepared powder was compression-molded at 1000 kgf using a ⁇ 8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain tablet J having a mass of 200 mg.
  • Example 4 Production of tablet K
  • 60 g of partially pregelatinized starch “PCS PC-10” manufactured by Asahi Kasei Chemicals Corporation was dispersed in 540 g of purified water to obtain a binding solution.
  • magnesium stearate manufactured by Taihei Chemical Industrial Co., Ltd.
  • This prepared powder was compression-molded at 1000 kgf using a ⁇ 8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet K having a mass of 200 mg.
  • Example 5 Production of tablet L] 3.0 g of drug-containing particles (particles B) produced in Reference Example 2, 5.9 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 ⁇ m), corn starch “Eclipse Corn Starch W” (Japanese food) 0.5 g of Kako Co., Ltd., 0.5 g of partially pregelatinized starch “PCS PC-10” (Asahi Kasei Chemicals Co., Ltd.) 0.5 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) is added to the glass bottle. Preparation powder was obtained by mixing for 1 minute. The prepared powder was compression-molded at 1000 kgf using a 88 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain tablets L having a mass of 200 mg.
  • Example 6 Production of tablet M] 3.0 g of drug-containing particles (particles B) produced in Reference Example 2, 5.4 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 ⁇ m), corn starch “Eclipse Corn Starch W” (Japanese food) Kakuko Co., Ltd.) 1.0 g, partially pregelatinized starch “PCS PC-10” (Asahi Kasei Chemicals Co., Ltd.) 0.5 g, 0.1 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) is added to the glass bottle. Preparation powder was obtained by mixing for 1 minute. This prepared powder was compression molded at 1000 kgf using a ⁇ 8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet M having a mass of 200 mg.
  • Example 7 Production of tablet N] 3.0 g of drug-containing particles (particle B) produced in Reference Example 2, 4.4 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 ⁇ m), corn starch “eclipse corn starch W” (Japanese food) Kagaku Co., Ltd.) 2.0 g, partially pregelatinized starch “PCS PC-10” (Asahi Kasei Chemicals Co., Ltd.) 0.5 g, 0.1 g of magnesium stearate (Taihei Chemical Sangyo Co., Ltd.) is added to the glass bottle. Preparation powder was obtained by mixing for 1 minute. This prepared powder was compression-molded at 1000 kgf using a ⁇ 8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet N having a mass of 200 mg.
  • Example 8 Production of tablet O] 0.1 g of drug-containing particles (particle B) produced in Reference Example 2, 7.9 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 ⁇ m), corn starch “Eclipse Corn Starch W” (Japanese food) 1.4 g of partially pregelatinized starch “PCS PC-10” (manufactured by Asahi Kasei Chemicals Corporation) 0.1 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) is added to the glass bottle. Preparation powder was obtained by mixing for 1 minute.
  • This prepared powder was compression-molded at 1000 kgf using a ⁇ 8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet O having a mass of 200 mg.
  • the obtained tablet had sufficient tablet hardness and sufficient disintegration, and no significant disintegration delay or hardness decrease due to moisture absorption was observed under the conditions of 40 ° C. and 75% RH (open).
  • Example 9 Production of tablet P
  • partially pregelatinized starch “PCS PC-10” manufactured by Asahi Kasei Chemicals Corporation
  • PCS PC-10 manufactured by Asahi Kasei Chemicals Corporation
  • the drug-containing particles (particle B) produced in Reference Example 2, spherical mannitol crystal particles (manufactured by Mitsubishi Corporation Foodtech Co., Ltd .; average particle size 44 ⁇ m), corn starch “ After eclipse corn starch W "(manufactured by Nippon Shokuhin Kako Co., Ltd.) and mixing, the above binding solution was sprayed to granulate and dried to obtain a granulated product.
  • Crospovidone “Kollidon CL-SF” (manufactured by BASF Japan), magnesium metasilicate aluminate “Neusilin UFL2” (manufactured by Fuji Chemical Industry Co., Ltd.), aspartame (manufactured by Ajinomoto Healthy Supply Co., Ltd.) L-menthol (manufactured by Takasago International Corporation) and magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) were added and mixed to obtain a prepared powder.
  • This prepared powder was compression-molded at 800 kgf using a ⁇ 8 mm, R12 mm punch and a rotary tableting machine “12TU-AW” (manufactured by Kikusui Seisakusho) to obtain a tablet P having a mass of 180 mg.
  • Example 10 Production of tablet Q
  • All the components shown in Table 9 were mixed together to obtain a prepared powder.
  • This prepared powder was compression-molded at 900 kgf using a ⁇ 8 mm, R12 mm punch and a rotary tableting machine “12TU-AW” (manufactured by Kikusui Seisakusho) to obtain a tablet Q having a mass of 180 mg.
  • Test Example 8 Measurement of tablet hardness and disintegration time (4)
  • the tablet hardness immediately after tableting was measured according to Test Example 3.
  • the disintegration time was determined by measuring the time until a healthy adult male had a tablet in his mouth and the tablet completely disintegrated with saliva alone.
  • C. V. Standard deviation of individual contents / average value of contents ⁇ 100 The results are shown in Table 9.
  • Examples 9 and 10 showed good results with respect to tablet hardness and disintegration time, but compared with Example 10, C.I. V. Since the value was low, it was more effective to mix the partially pregelatinized starch later than mixing all the ingredients at once, effectively suppressing variation in drug content between tablets. It has been shown that high quality tablets can be obtained.

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Abstract

La présente invention concerne un comprimé orodispersible qui est rarement endommagé pendant le processus de distribution tout en conservant des propriétés de désagrégation rapide dans la cavité orale, dont la dureté est adaptée aux applications pratiques même après l'absorption d'humidité, qui ne présente pas de retard de désagrégation et qui peut être produit facilement dans des installations courantes sans nécessiter de technique spécialisée d'élaboration de comprimés. La présente invention concerne un comprimé orodispersible comprenant (1) des particules contenant un médicament de granulométrie moyenne comprise entre 150 et 300 µm, (2) des particules cristallines sphériques de mannitol, (3) un amidon partiellement gélifié dont la viscosité d'une suspension aqueuse à 10 % en masse est comprise entre 5 et 45 mPa·s à 25 °C, et (4) une poudre d'amidon.
PCT/JP2011/080292 2010-12-28 2011-12-27 Comprimé orodispersible Ceased WO2012091049A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
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