WO2014148520A1 - Solid preparation - Google Patents

Solid preparation Download PDF

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Publication number
WO2014148520A1
WO2014148520A1 PCT/JP2014/057444 JP2014057444W WO2014148520A1 WO 2014148520 A1 WO2014148520 A1 WO 2014148520A1 JP 2014057444 W JP2014057444 W JP 2014057444W WO 2014148520 A1 WO2014148520 A1 WO 2014148520A1
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WO
WIPO (PCT)
Prior art keywords
salt
tablet
mass
sucrose
tablets
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Application number
PCT/JP2014/057444
Other languages
French (fr)
Japanese (ja)
Inventor
亜矢 桑田
孝文 湊
智宏 浜下
Original Assignee
大正製薬株式会社
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.)
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Publication date
Application filed by 大正製薬株式会社 filed Critical 大正製薬株式会社
Priority to JP2015506812A priority Critical patent/JP6341196B2/en
Publication of WO2014148520A1 publication Critical patent/WO2014148520A1/en

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Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • the present invention relates to a solid preparation that can be rapidly disintegrated or easily chewed in the oral cavity, and has a moderate hardness and is excellent in ingestibility and can be taken without water, including orally disintegrating tablets or chewable tablets About.
  • Orally disintegrating tablets are defined as tablets that can be dissolved or disintegrated rapidly in the oral cavity, and have appropriate disintegrating properties, and chewable tablets are chewable tablets (Non-patent Document 1). Since it is a formulation that can be taken without any, there is an advantage that it can be taken even in situations where there is no water, regardless of the scene.
  • Known orally disintegrating tablets include those formed by freeze-drying in a container using a substance such as gelatin, and those obtained by wet compression of a wet powder or granulated product. However, these tablets often break and chip during transport, and it is difficult to say that they have sufficient hardness, and the manufacturing method is complicated.
  • Patent Document 1 starch powder and gelatinized starch, water-soluble excipient containing mannitol, orally disintegrating tablet containing sodium stearyl fumarate and medicinal ingredients
  • Patent Document 2 low moldability saccharide and high moldability saccharide Orally-dissolved, orally-dissolved compression-molded product
  • Patent Document 3 mannitol, disintegrant, celluloses, lubricants, and starches and lactose
  • Patent Document 3 A method for producing an orally disintegrating tablet containing one kind (Patent Document 3) has been reported.
  • Patent Document 3 when starch powder and starch that has been gelatinized are used, sticking to a manufacturing apparatus or the like is likely to occur, and handling in manufacturing is difficult.
  • Patent Document 3 is an orally disintegrating tablet based on mannitol and substantially containing a super disintegrant such as crospovidone or croscarmellose. Is not preferable because of concern.
  • Japanese Patent No. 4435424 Japanese Patent No. 3212141 JP 2000-273039 A
  • An object of the present invention is a solid preparation that can be rapidly disintegrated or chewed in the oral cavity, and has a suitable hardness and can be taken without water, including an orally disintegrating tablet or chewable tablet that is excellent in dosing. Is to provide.
  • the inventors of the present invention contain mannitol, sucrose, and starch, and the mannitol content is 10 parts by mass or more per 1 part by mass of sucrose.
  • the formulation was found to be an orally disintegrating tablet or chewable tablet having an appropriate hardness while exhibiting rapid disintegration in the oral cavity, and having excellent dosing properties, thereby completing the present invention.
  • the present invention comprises (1) mannitol, sucrose and starch, wherein the content of mannitol is 10 parts by mass or more with respect to 1 part by mass of sucrose, (2) The preparation according to (1), which is an orally disintegrating tablet or chewable tablet, (3) The preparation according to (1) or (2), wherein the starch content is 0.01 parts by mass or more with respect to 1 part by mass of sucrose.
  • the drug is acetaminophen, scopolamine or a salt thereof, chlorpheniramine or a salt thereof, carbinoxamine or a salt thereof, belladonna total alkaloid, loratadine, fexofenadine or a salt thereof, mequitazine, loxoprofen or a salt thereof, meclizine or a salt thereof , Ibuprofen, caffeine, ascorbic acid, pseudoephedrine or a salt thereof, the preparation according to any one of (1) to (4), It is.
  • an orally disintegrating tablet or chewable tablet that disintegrates in the oral cavity without using special equipment, a manufacturing method, and an excipient, has a desired appropriate hardness, and is excellent in taking ability. It has become possible.
  • the orally disintegrating tablet of the present invention means a tablet having an extremely fast disintegration time in the oral cavity under normal chewing conditions.
  • the chewable tablet of the present invention means a tablet that is chewed and taken. Since orally disintegrating tablets or chewable tablets do not require water when taking them, they are suitable dosage forms for, for example, disasters and sudden onsets where it is difficult to take ordinary tablets.
  • the content of mannitol contained in a preparation that can be taken without water according to the present invention, including an orally disintegrating tablet and a chewable tablet is 10 parts by mass or more per 1 part by mass of sucrose. This is because if it is less than 10 parts by mass, it is difficult to achieve both oral disintegration time, tablet hardness, and dosage.
  • the content of mannitol contained in the preparation that can be taken without water according to the present invention including the orally disintegrating tablet and the chewable tablet is preferably 950 parts by mass or less, and 100 parts by mass or less based on 1 part by mass of sucrose. More preferred, particularly preferred is 50 parts by mass or less.
  • the mannitol content contained in the preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets is preferably 95% by mass from the viewpoint of tablet physical properties and compression moldability. .
  • starch of the present invention examples include corn starch, potato starch, rice starch, wheat starch, sweet potato starch, mung bean starch, tapioca starch and the like, preferably corn starch and potato starch.
  • corn starch contained in powdered sugar is contained in the starch of this invention.
  • the starch content contained in preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets is preferably 0.01 parts by mass to 20.0 parts by mass with respect to 1 part by mass of sucrose. From the viewpoint of the effect of the present invention, 0.01 to 15.0 parts by mass is more preferable.
  • the upper limit of the starch content contained in the preparation of the present invention is preferably 70% by mass from the viewpoint of tablet physical properties and compression moldability.
  • sucrose contained in the preparation that can be taken without water according to the present invention including the orally disintegrating tablet and the chewable tablet contains powdered sugar in the preparation
  • the sucrose contained in the powdered sugar is Included in sucrose.
  • the content of the sucrose of the present invention is usually 0.01 to 30% by mass, preferably 0.1 to 30% by mass, more preferably 0.1 to 20% by mass, and still more preferably 1% with respect to the total mass of the preparation. 0.0 to 20% by mass, more preferably 2.0 to 10% by mass.
  • a drug can be mix
  • a drug that can be incorporated into a preparation that can be taken without water according to the present invention, including an orally disintegrating tablet and a chewable tablet it may be solid or crystalline, such as antipyretic analgesic anti-inflammatory drugs, nourishing tonic health drugs, Hypnotic sedatives, antispasmodics, gastrointestinals, antacids, antitussives, antiemetics, respiratory stimulants, bronchodilators, allergic agents, antihistamines, central nervous stimulants, vitamins, oral and oral medicines, antispasmodics One or more components selected from agents, etc.
  • Examples include caffeine, ascorbic acid, pseudoephedrine or a salt thereof.
  • the content of the drug is usually 0.01 to 90% by mass, preferably 0.01 to 80% by mass, more preferably 0.1 to 80% by mass, and further preferably 0.1 to 70% by mass with respect to the total mass of the preparation. %, More preferably 0.5 to 50% by mass.
  • compositions that can be taken without water according to the present invention including orally disintegrating tablets and chewable tablets, are generally used in the production of orally disintegrating tablets or chewable tablets as long as the effects of the present invention are not hindered. May be included.
  • additives include excipients, disintegrants, binders, sour agents, foaming agents, sweeteners, fragrances, lubricants, and coloring agents.
  • the size and shape of preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets are not particularly limited, and may be divided tablets having a score line.
  • the granulation method is not particularly limited, and may be produced by either a wet granulation method or a dry granulation method. You may dry suitably after a granulation process or granulation manufacture. Examples of the wet granulation method include a fluidized bed granulation method, an agitation granulation method, a kneading granulation method, a rolling granulation method, and a molten solvent method.
  • the dry granulation method includes a slug method, a roller method, and the like. Although a compactor method is mentioned, it is preferable to manufacture by a fluidized-bed granulation method and a stirring granulation method.
  • a formulation that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, is obtained by adding a suitable additive to the resulting granulated product and performing general compression molding such as tableting. can get.
  • the granulation solvent is preferably water or an aqueous solution containing at least one of mannitol, low-substituted hydroxypropyl cellulose, and light anhydrous silicic acid, and in particular, a granulation solvent containing mannitol. Is more preferable because the hardness of the tablet and the ingestibility, which are the effects of the present invention, are further improved.
  • the tableting device a device generally used for tablet formation is used, and for example, a single-shot tableting machine, a rotary tableting machine, or the like is used.
  • the orally disintegrating tablet or chewable tablet thus obtained exhibits excellent disintegration properties in the oral cavity, and preferably disintegration time is within 60 seconds in the disintegration test by the Japanese Pharmacopoeia or the oral disintegration test by humans. Preferably, it is within 30 seconds. In addition, it has a moderate strength that is not damaged in the preparation process and further in the distribution process, and has a tablet hardness of 0.7 MPa or higher in terms of tableting strength in terms of tensile strength.
  • Table 1 shows the disintegration time, tensile strength, and dosing results of each tablet.
  • Examples 1 to 8 which are solid preparations containing mannitol, sucrose and starch, and containing 10 parts by mass or more of mannitol with respect to 1 part by mass of sucrose, are disintegrated. It showed excellent disintegration for less than 30 seconds, and all showed good values in tensile strength and ingestibility.
  • Comparative Example 1 in which sucrose was not blended in the formulation could not produce a tablet having a hardness of 0.7 MPa or more even when it was produced at a high tableting pressure, and was not satisfactory in dosage.
  • Comparative Example 2 in which corn starch was not blended in the formulation and in Comparative Example 3 in which mannitol was 10 parts by mass or less with respect to 1 part by mass of sucrose, either disintegration time or ingestion was not satisfactory.
  • Example 9 Using acetaminophen as a drug, the granulated granule components shown in Table 4 were weighed and mixed, and a granulated product was produced with a fluidized bed granulator (trade name: FLO-1; manufactured by Freund Corporation). After weighing and mixing the powdered ingredients shown in Table 4 into the resulting granulated product, the resulting tablet has a tensile strength of 0 using a small rotary tablet machine (trade name: VELA 5; Kikusui Seisakusho). The tableting pressure was set to 600 MPa or higher (600-1500 kgf), and tablets with a tablet diameter of 8-10 mm were obtained.
  • Example 10 Tablets were produced in the same manner as in Example 9 using scopolamine hydrobromide hydrate and chlorpheniramine maleate as drugs.
  • Example 11 Tablets were produced in the same manner as in Example 9 using belladonna total alkaloid and chlorpheniramine maleate as drugs.
  • Example 12 Tablets were produced in the same manner as in Example 9 using loratadine as a drug.
  • Example 13 Tablets were produced in the same manner as in Example 9 using belladonna total alkaloid and carbinoxamine maleate as drugs.
  • Example 14 Tablets were produced in the same manner as in Example 9 using scopolamine hydrobromide hydrate and meclizine hydrochloride as drugs.
  • Example 15 Using loxoprofen sodium dihydrate as a drug, tablets were produced in the same manner as in Example 9.
  • Example 17 Tablets were produced in the same manner as in Example 16 using caffeine as a drug.
  • Example 18 Tablets were produced in the same manner as in Example 16 using ascorbic acid as a drug.
  • Example 19 Using fexofenadine hydrochloride as a drug, tablets with a tablet mass of 150 mg were produced in the same manner as in Example 16.
  • Example 20 Tablets were produced in the same manner as in Example 16 using mequitazine as a drug.
  • Example 21 Tablets were produced in the same manner as in Example 16 using pseudoephedrine hydrochloride as the drug.
  • ⁇ Evaluation method 2> For the orally disintegrating tablets of Examples 16 to 21, the disintegration time was measured by the following test methods, and the ingestibility (roughness, powderiness) was evaluated according to the following evaluation criteria and scored.
  • Hardness test It carried out similarly to the evaluation method 1.
  • Disintegration test oral disintegration test
  • Two healthy adult panelists measured the time until the tablet completely disintegrated in the oral cavity, and determined the average value.
  • Ingestion test 1 Roughness It was carried out in the same manner as in the evaluation method 1 by two healthy adult panelists.
  • Ingestion test 2 powdery The same as evaluation method 1 was conducted by two healthy adult panelists.
  • Table 5 shows the disintegration time, tablet hardness, and dosing results of the tablets obtained in Examples 16-21. Also in the solid preparations (Examples 16 to 21) containing the drugs shown in Table 5, all the results satisfying the standard values in the disintegration time, the tensile strength, and the ingestibility were obtained.
  • an orally disintegrating tablet that rapidly disintegrates or dissolves in the oral cavity without using special equipment, a manufacturing method, and an excipient, has a desired appropriate hardness, and is excellent in dosage.
  • a chewable tablet can be provided.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Emergency Medicine (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A solid preparation containing mannitol, sucrose, and starch; the mannitol content being at least 10 mass parts in relation to 1 mass part of sucrose and the starch content being preferably at least 0.01 mass parts in relation to 1 mass part of sucrose; the solid preparation preferably further containing a drug such as acetaminophen, scopolamine or a salt thereof, chlorpheniramine or a salt thereof, carbinoxamine or a salt thereof, a belladonna total alkaloid, loratadine, fexofenadine or a salt thereof, mequitazine, loxoprofen or a salt thereof, meclizine or a salt thereof, ibuprofen, caffeine, ascorbic acid, or pseudoephedrine or a salt thereof; and the solid preparation being an orally disintegrating tablet or a chewable tablet exhibiting a speedy disintegrating performance in the oral cavity while having a high hardness and excellent dosability. This orally disintegrating tablet or chewable tablet can be manufactured without using special equipment, manufacturing methods, or excipients.

Description

固形製剤Solid preparation
　本発明は、口腔内で速やかに崩壊あるいは簡単に噛み砕くことができる固形製剤に関し、適度な硬度を有し、服用性にも優れた口腔内崩壊錠またはチュアブル錠を含む水なしで服用可能な製剤に関する。 The present invention relates to a solid preparation that can be rapidly disintegrated or easily chewed in the oral cavity, and has a moderate hardness and is excellent in ingestibility and can be taken without water, including orally disintegrating tablets or chewable tablets About.
　口腔内崩壊錠は口腔内で速やかに溶解または崩壊させて服用でき、適切な崩壊性を有する錠剤、チュアブル錠は咀嚼して服用する錠剤と定義されており（非特許文献１）、両者とも水なしで服用可能な製剤のため、服用シーンを選ばず、水がない状況下でも服用できるというメリットがある。
　従来の口腔内崩壊錠としては、ゼラチン等の物質を用いて容器中で凍結乾燥することにより成型されたものや、湿った粉体もしくは造粒物を湿式打錠したもの等が知られているが、これらの錠剤は輸送の際に錠剤の割れ、欠けが発生することもしばしばあり、充分な硬度を有するとは言い難く、また製造方法も煩雑である。そのため、口腔内崩壊錠またはチュアブル錠の製造では口腔内崩壊時間と錠剤の硬度を両立する工夫が必要となる。また、口腔内で崩壊するため、服用性に考慮が必要となる。
　これまでに、速やかな崩壊性と高い硬度を有する口腔内崩壊錠を得るべく種々検討がなされてきた。例えば、デンプン粉末と糊化したデンプン、マンニトールを含む水溶性賦形剤、フマル酸ステアリルナトリウム及び薬効成分を含有する口腔内崩壊錠剤（特許文献１）、成形性の低い糖類及び成形性の高い糖類を含有してなる、口腔内において速やかな崩壊性、溶解性を有する口腔内溶解型圧縮成型物（特許文献２）、マンニトール、崩壊剤、セルロース類、滑沢剤、並びにデンプン類及び乳糖の少なくとも１種を含有する口腔内崩壊錠の製造方法（特許文献３）、等が報告されている。
　しかしながら、特許文献１は、デンプン粉末と糊化したデンプンを用いると製造装置への貼り付き等が生じ易く、製造上の取り扱いが困難である。また、特許文献２の方法では、口腔内崩壊錠を製造するためには低圧で打錠した後の加湿・乾燥工程が必須条件のため、製造工程数が多くなり、操作も煩雑である。特許文献３はマンニトールをベースとして実質的にクロスポビドン、クロスカルメロースなどのスーパー崩壊剤を含有する口腔内崩壊錠であるが、スーパー崩壊剤の多量の配合は吸湿による硬度の低下及び外観変化等が懸念されるため、好ましくない。 Orally disintegrating tablets are defined as tablets that can be dissolved or disintegrated rapidly in the oral cavity, and have appropriate disintegrating properties, and chewable tablets are chewable tablets (Non-patent Document 1). Since it is a formulation that can be taken without any, there is an advantage that it can be taken even in situations where there is no water, regardless of the scene.
Known orally disintegrating tablets include those formed by freeze-drying in a container using a substance such as gelatin, and those obtained by wet compression of a wet powder or granulated product. However, these tablets often break and chip during transport, and it is difficult to say that they have sufficient hardness, and the manufacturing method is complicated. For this reason, in the production of orally disintegrating tablets or chewable tablets, it is necessary to devise a technique that balances the oral disintegration time and the hardness of the tablets. Moreover, since it disintegrates in the oral cavity, it is necessary to consider the ingestibility.
So far, various studies have been made to obtain an orally disintegrating tablet having rapid disintegration and high hardness. For example, starch powder and gelatinized starch, water-soluble excipient containing mannitol, orally disintegrating tablet containing sodium stearyl fumarate and medicinal ingredients (Patent Document 1), low moldability saccharide and high moldability saccharide Orally-dissolved, orally-dissolved compression-molded product (Patent Document 2), mannitol, disintegrant, celluloses, lubricants, and starches and lactose A method for producing an orally disintegrating tablet containing one kind (Patent Document 3) has been reported.
However, in Patent Document 1, when starch powder and starch that has been gelatinized are used, sticking to a manufacturing apparatus or the like is likely to occur, and handling in manufacturing is difficult. Moreover, in the method of patent document 2, since the humidification / drying process after tableting at low pressure is an indispensable condition in order to manufacture an orally disintegrating tablet, the number of manufacturing processes increases and the operation is complicated. Patent Document 3 is an orally disintegrating tablet based on mannitol and substantially containing a super disintegrant such as crospovidone or croscarmellose. Is not preferable because of concern.
特許第４４３５４２４号公報Japanese Patent No. 4435424 特許第３１２２１４１号公報Japanese Patent No. 3212141 特開２０００－２７３０３９号公報JP 2000-273039 A
　本発明の目的は、口腔内で速やかに崩壊あるいは噛み砕ける固形製剤であって、適度な硬度を有し、服用性に優れた口腔内崩壊錠またはチュアブル錠を含む水なしで服用可能な製剤を提供することである。 An object of the present invention is a solid preparation that can be rapidly disintegrated or chewed in the oral cavity, and has a suitable hardness and can be taken without water, including an orally disintegrating tablet or chewable tablet that is excellent in dosing. Is to provide.
　本発明者らは、上記目的を達成するために種々の検討を行ったところ、マンニトールとショ糖とデンプンを含有し、マンニトールの含有量がショ糖１質量部に対し１０質量部以上含有する固形製剤は、口腔内において速やかな崩壊性を示しながら、適度な硬度を有し、且つ服用性に優れた口腔内崩壊錠またはチュアブル錠が得られることを見出し、本発明を完成した。 As a result of various studies to achieve the above-mentioned object, the inventors of the present invention contain mannitol, sucrose, and starch, and the mannitol content is 10 parts by mass or more per 1 part by mass of sucrose. The formulation was found to be an orally disintegrating tablet or chewable tablet having an appropriate hardness while exhibiting rapid disintegration in the oral cavity, and having excellent dosing properties, thereby completing the present invention.
　すなわち、本発明は
（１）マンニトール、ショ糖及びデンプンを含有し、マンニトールの含有量がショ糖１質量部に対し１０質量部以上であることを特徴とする水なしで服用可能な製剤、
（２）口腔内崩壊錠またはチュアブル錠である（１）に記載の製剤、
（３）デンプンの含有量が、ショ糖１質量部に対して、０．０１質量部以上である（１）又は（２）に記載の製剤、
（４）さらに薬物を含有する（１）～（３）のいずれかに記載の製剤、
（５）薬物がアセトアミノフェン、スコポラミン又はその塩、クロルフェニラミン又はその塩、カルビノキサミン又はその塩、ベラドンナ総アルカロイド、ロラタジン、フェキソフェナジン又はその塩、メキタジン、ロキソプロフェン又はその塩、メクリジン又はその塩、イブプロフェン、カフェイン、アスコルビン酸、プソイドエフェドリン又はその塩から選ばれる１種又は２種以上である（１）～（４）のいずれかに記載の製剤、
である。 That is, the present invention comprises (1) mannitol, sucrose and starch, wherein the content of mannitol is 10 parts by mass or more with respect to 1 part by mass of sucrose,
(2) The preparation according to (1), which is an orally disintegrating tablet or chewable tablet,
(3) The preparation according to (1) or (2), wherein the starch content is 0.01 parts by mass or more with respect to 1 part by mass of sucrose.
(4) The preparation according to any one of (1) to (3), further containing a drug,
(5) The drug is acetaminophen, scopolamine or a salt thereof, chlorpheniramine or a salt thereof, carbinoxamine or a salt thereof, belladonna total alkaloid, loratadine, fexofenadine or a salt thereof, mequitazine, loxoprofen or a salt thereof, meclizine or a salt thereof , Ibuprofen, caffeine, ascorbic acid, pseudoephedrine or a salt thereof, the preparation according to any one of (1) to (4),
It is.
　本発明により、特殊な設備、製造方法、賦形剤を使用せず、口腔内で崩壊し且つ、所望の適度な硬度を有し、服用性に優れた口腔内崩壊錠またはチュアブル錠の製造が可能となった。 According to the present invention, it is possible to produce an orally disintegrating tablet or chewable tablet that disintegrates in the oral cavity without using special equipment, a manufacturing method, and an excipient, has a desired appropriate hardness, and is excellent in taking ability. It has become possible.
　以下、口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤について詳述し説明する。 Hereinafter, preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, will be described in detail.
　本発明の口腔内崩壊錠とは、通常の咀嚼条件での口腔内における崩壊時間が極めて早い錠剤を意味する。また、本発明のチュアブル錠とは、噛み砕いて服用する錠剤を意味する。口腔内崩壊錠またはチュアブル錠は服用の際に水を必須としないため、例えば、通常の錠剤を服用しにくい災害時や突然の発症にも、好適な剤型である。 The orally disintegrating tablet of the present invention means a tablet having an extremely fast disintegration time in the oral cavity under normal chewing conditions. In addition, the chewable tablet of the present invention means a tablet that is chewed and taken. Since orally disintegrating tablets or chewable tablets do not require water when taking them, they are suitable dosage forms for, for example, disasters and sudden onsets where it is difficult to take ordinary tablets.
　口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤に含まれるマンニトールの含有量は、ショ糖１質量部に対し１０質量部以上である。１０質量部未満であると口腔内崩壊時間と錠剤の硬度、服用性の両立が難しいからである。また、口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤に含まれるマンニトールの含有量は、ショ糖１質量部に対し９５０質量部以下が好ましく、１００質量部以下がさらに好ましく、特に好ましいのは５０質量部以下である。なお、口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤中に含まれるマンニトール含有量は、錠剤物性及び圧縮成形性の観点から上限値は好ましくは９５質量％である。 The content of mannitol contained in a preparation that can be taken without water according to the present invention, including an orally disintegrating tablet and a chewable tablet, is 10 parts by mass or more per 1 part by mass of sucrose. This is because if it is less than 10 parts by mass, it is difficult to achieve both oral disintegration time, tablet hardness, and dosage. In addition, the content of mannitol contained in the preparation that can be taken without water according to the present invention including the orally disintegrating tablet and the chewable tablet is preferably 950 parts by mass or less, and 100 parts by mass or less based on 1 part by mass of sucrose. More preferred, particularly preferred is 50 parts by mass or less. The mannitol content contained in the preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, is preferably 95% by mass from the viewpoint of tablet physical properties and compression moldability. .
　本発明のデンプンとしては、例えばトウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン、甘藷デンプン、緑豆デンプン、タピオカデンプンなどが挙げられ、好ましくはトウモロコシデンプン、バレイショデンプンである。また、製剤中に粉糖を含有する場合は、粉糖中に含まれるトウモロコシデンプンは本発明のデンプンに含まれる。口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤に含まれるデンプン含有量は、ショ糖１質量部に対して０．０１質量部～２０．０質量部が好ましい。本発明の効果の点から、０．０１質量部～１５．０質量部がより好ましい。また、本発明の製剤中に含まれるデンプンの含有量は、錠剤物性及び圧縮成形性という観点から上限値は好ましくは７０質量％となる。 Examples of the starch of the present invention include corn starch, potato starch, rice starch, wheat starch, sweet potato starch, mung bean starch, tapioca starch and the like, preferably corn starch and potato starch. Moreover, when powdered sugar is contained in a formulation, the corn starch contained in powdered sugar is contained in the starch of this invention. The starch content contained in preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, is preferably 0.01 parts by mass to 20.0 parts by mass with respect to 1 part by mass of sucrose. From the viewpoint of the effect of the present invention, 0.01 to 15.0 parts by mass is more preferable. The upper limit of the starch content contained in the preparation of the present invention is preferably 70% by mass from the viewpoint of tablet physical properties and compression moldability.
　口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤に含まれるショ糖は、製剤中に粉糖を含有する場合は、粉糖中に含まれるショ糖は本発明のショ糖に含まれる。本発明のショ糖の含有量は、製剤全質量に対して通常０．０１～３０質量％、好ましくは０．１～３０質量％、より好ましくは０．１～２０質量％、さらに好ましくは１．０～２０質量％、いっそう好ましくは２．０～１０質量％である。 When the sucrose contained in the preparation that can be taken without water according to the present invention including the orally disintegrating tablet and the chewable tablet contains powdered sugar in the preparation, the sucrose contained in the powdered sugar is Included in sucrose. The content of the sucrose of the present invention is usually 0.01 to 30% by mass, preferably 0.1 to 30% by mass, more preferably 0.1 to 20% by mass, and still more preferably 1% with respect to the total mass of the preparation. 0.0 to 20% by mass, more preferably 2.0 to 10% by mass.
　また、口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤には、薬物を配合することができる。口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤に配合できる薬物としては、固形状、結晶状などいずれのものでもよく、例えば解熱鎮痛消炎薬、滋養強壮保健薬、催眠鎮静薬、鎮痙薬、胃腸薬、制酸剤、鎮咳去痰剤、制吐剤、呼吸促進剤、気管支拡張剤、アレルギー用薬、抗ヒスタミン剤、中枢神経刺激薬、ビタミン剤、歯科口腔用薬、鎮けい剤、などから選ばれた１種または２種以上の成分が用いられる。例えば、アセトアミノフェン、スコポラミン又はその塩、クロルフェニラミン又はその塩、カルビノキサミン又はその塩、ベラドンナ総アルカロイド、ロラタジン、フェキソフェナジン又はその塩、メキタジン、ロキソプロフェン又はその塩、メクリジン又はその塩、イブプロフェン、カフェイン、アスコルビン酸、プソイドエフェドリン又はその塩等が挙げられる。薬物の含有量は、製剤全質量に対し通常０．０１～９０質量％、好ましくは０．０１～８０質量％、より好ましくは０．１～８０質量％、さらに好ましくは０．１～７０質量％、いっそう好ましくは０．５～５０質量％である。 Moreover, a drug can be mix | blended with the formulation which can be taken | dosed without water concerning this invention containing an orally disintegrating tablet and a chewable tablet. As a drug that can be incorporated into a preparation that can be taken without water according to the present invention, including an orally disintegrating tablet and a chewable tablet, it may be solid or crystalline, such as antipyretic analgesic anti-inflammatory drugs, nourishing tonic health drugs, Hypnotic sedatives, antispasmodics, gastrointestinals, antacids, antitussives, antiemetics, respiratory stimulants, bronchodilators, allergic agents, antihistamines, central nervous stimulants, vitamins, oral and oral medicines, antispasmodics One or more components selected from agents, etc. are used. For example, acetaminophen, scopolamine or salt thereof, chlorpheniramine or salt thereof, carbinoxamine or salt thereof, belladonna total alkaloid, loratadine, fexofenadine or salt thereof, mequitazine, loxoprofen or salt thereof, meclizine or salt thereof, ibuprofen, Examples include caffeine, ascorbic acid, pseudoephedrine or a salt thereof. The content of the drug is usually 0.01 to 90% by mass, preferably 0.01 to 80% by mass, more preferably 0.1 to 80% by mass, and further preferably 0.1 to 70% by mass with respect to the total mass of the preparation. %, More preferably 0.5 to 50% by mass.
　口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤には、本発明の効果に支障のない限り、口腔内崩壊錠またはチュアブル錠の製造に一般に用いられる種々の添加剤を含んでいてもよい。このような添加剤として、例えば、賦形剤、崩壊剤、結合剤、酸味剤、発泡剤、甘味剤、香料、滑沢剤、着色剤等が挙げられる。口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤の大きさ、形状は、特に限定されず、また、割線を有する分割錠としてもよい。 Various preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, are generally used in the production of orally disintegrating tablets or chewable tablets as long as the effects of the present invention are not hindered. May be included. Examples of such additives include excipients, disintegrants, binders, sour agents, foaming agents, sweeteners, fragrances, lubricants, and coloring agents. The size and shape of preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, are not particularly limited, and may be divided tablets having a score line.
　口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤の製造に当たっては、特に制約なく従来から行われている製造方法を使用することができる。例えば以下の方法が挙げられる。 In the production of preparations that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, conventional production methods can be used without particular limitation. For example, the following methods are mentioned.
　マンニット、ショ糖及びデンプンを混合し、必要に応じて添加剤を混合する。造粒方法は特に制限されず、湿式造粒法及び乾式造粒法のどちらで製造しても良い。造粒過程あるいは造粒製造後に適宜乾燥しても良い。湿式造粒法としては、例えば、流動層造粒法、攪拌造粒法、練合造粒法、転動造粒法、溶融溶媒法が挙げられ、乾式造粒法としては、スラッグ法、ローラーコンパクター法が挙げられるが、流動層造粒法、攪拌造粒法で製造するのが好ましい。得られた造粒物に適宜後末添加成分を添加し、打錠などの一般的な圧縮成型を行うことにより口腔内崩壊錠およびチュアブル錠を含む本発明に係る水なしで服用可能な製剤が得られる。また、湿式造粒法で製造する場合、造粒溶媒は水またはマンニトール、低置換度ヒドロキシプロピルセルロース、軽質無水ケイ酸のいずれか１種以上を含む水溶液が好ましいが、特にマンニトールを含む造粒溶媒を使用すると、本発明の効果である錠剤の硬度と服用性がより向上するのでより好ましい。 Mix mannitol, sucrose and starch, and add additives as needed. The granulation method is not particularly limited, and may be produced by either a wet granulation method or a dry granulation method. You may dry suitably after a granulation process or granulation manufacture. Examples of the wet granulation method include a fluidized bed granulation method, an agitation granulation method, a kneading granulation method, a rolling granulation method, and a molten solvent method. The dry granulation method includes a slug method, a roller method, and the like. Although a compactor method is mentioned, it is preferable to manufacture by a fluidized-bed granulation method and a stirring granulation method. A formulation that can be taken without water according to the present invention, including orally disintegrating tablets and chewable tablets, is obtained by adding a suitable additive to the resulting granulated product and performing general compression molding such as tableting. can get. In the case of producing by a wet granulation method, the granulation solvent is preferably water or an aqueous solution containing at least one of mannitol, low-substituted hydroxypropyl cellulose, and light anhydrous silicic acid, and in particular, a granulation solvent containing mannitol. Is more preferable because the hardness of the tablet and the ingestibility, which are the effects of the present invention, are further improved.
　また造粒工程を必要としない直接打錠法で製造してもよい。打錠装置としては、一般に錠剤の成型に使用される装置が用いられ、例えば、単発式打錠機、回転式打錠機等が用いられる。 Alternatively, it may be produced by a direct tableting method that does not require a granulation step. As the tableting device, a device generally used for tablet formation is used, and for example, a single-shot tableting machine, a rotary tableting machine, or the like is used.
　かくして得られる口腔内崩壊錠またはチュアブル錠は、口腔内で優れた崩壊性を示すものであり、好ましくは日本薬局方による崩壊試験もしくはヒトによる口腔内崩壊試験において、崩壊時間が６０秒以内、さらに好ましくは３０秒以内である。また製剤工程、さらには流通過程において損傷することのない適度な強度を有し、錠剤硬度は引張強度に換算して０．７ＭＰａ以上の服用性の良好な製剤である。 The orally disintegrating tablet or chewable tablet thus obtained exhibits excellent disintegration properties in the oral cavity, and preferably disintegration time is within 60 seconds in the disintegration test by the Japanese Pharmacopoeia or the oral disintegration test by humans. Preferably, it is within 30 seconds. In addition, it has a moderate strength that is not damaged in the preparation process and further in the distribution process, and has a tablet hardness of 0.7 MPa or higher in terms of tableting strength in terms of tensile strength.
　以下に実施例及び比較例を挙げ、本発明をより詳しく説明するが、本発明はこれら実施例等に限定されるものではない。なお、比較例及び実施例の粉糖は、徳倉社製の粉糖（ショ糖９８．３％、トウモロコシデンプン１．７％）を使用した。 Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples, but the present invention is not limited to these examples. In addition, the powdered sugar made from Tokukura (sucrose 98.3%, corn starch 1.7%) was used for the powdered sugar of a comparative example and an Example.
　（比較例１）
　表１の混合末に示す成分を秤量、混合した粉体に、同じく表１の造粒溶媒に示す成分を溶解・分散させた水溶液を添加した後、乳鉢で練合し、十分乾燥させた。その後２２メッシュの篩に通し、造粒物を製造した。得られた造粒物に表１に示す後末添加成分を秤量、混合した後、卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機）を用いて得られた錠剤の引張強度が０．７ＭＰａ以上になるように打錠圧を設定し（６～１５ｋＮ）、錠剤径８ｍｍの錠剤を得た。 (Comparative Example 1)
An aqueous solution in which the components shown in Table 1 were dissolved and dispersed was added to the powder obtained by weighing and mixing the components shown in Table 1, and then kneaded in a mortar and sufficiently dried. Thereafter, it was passed through a 22 mesh sieve to produce a granulated product. After weighing and mixing the powdered ingredients shown in Table 1 into the obtained granulated product, the tablet obtained using a tabletop simple tablet molding machine (trade name: HANDTAB; Ichibashi Seiki) has a tensile strength of 0.7 MPa. The tableting pressure was set so that it was as described above (6 to 15 kN), and tablets with a tablet diameter of 8 mm were obtained.
　（比較例２～３、実施例１～６、８）
　表１に示す処方に従い、比較例１と同様にして錠剤を製造した。
　（実施例７）
　表１の混合末及び後末添加成分を秤量、混合し、２２メッシュの篩に通した粉体を比較例１と同様にして錠剤を製造した。 (Comparative Examples 2-3, Examples 1-6, 8)
According to the formulation shown in Table 1, tablets were produced in the same manner as in Comparative Example 1.
(Example 7)
Tablets were produced in the same manner as in Comparative Example 1 except that the powdered powder and the powder added in Table 1 were weighed and mixed, and the powder passed through a 22 mesh sieve was passed through.
　（試験例）
＜評価方法１＞
　実施例１～１５及び各比較例の口腔内崩壊錠について、以下の各試験方法により錠剤の硬度、崩壊時間を測定し、服用性（ざらつき、粉っぽさ）については以下の評価基準に従って評価し、点数化した。 (Test example)
<Evaluation method 1>
For the orally disintegrating tablets of Examples 1 to 15 and each Comparative Example, the hardness and disintegration time of the tablets were measured by the following test methods, and the dosage (roughness, powderiness) was evaluated according to the following evaluation criteria. And scored.
　（１）硬度試験
　シュロイニゲル錠剤硬度計（シュロイニゲル社製）を用いて測定した。それぞれの錠剤の硬度を３回ずつ測定した。また得られた結果を下記の［数１］を用い計算し、引張強度を算出し、その平均値を求めた。 (1) Hardness test It measured using the Schleunigel tablet hardness tester (made by Schleunigel). The hardness of each tablet was measured in triplicate. The obtained results were calculated using the following [Equation 1], the tensile strength was calculated, and the average value was obtained.
Figure JPOXMLDOC01-appb-M000001
Figure JPOXMLDOC01-appb-M000001
Ｆ：錠剤硬度(N)
Ｄ：錠剤直径(mm)
ｔ：錠剤厚さ(mm) F: Tablet hardness (N)
D: Tablet diameter (mm)
t: Tablet thickness (mm)
　（２）崩壊試験
　日本薬局方第十六改正に記載されている崩壊試験法に従い測定した。それぞれの錠剤の崩壊時間を３回ずつ測定し、その平均値を求めた。 (2) Disintegration test The disintegration test was measured according to the disintegration test method described in the 16th revision of the Japanese Pharmacopoeia. The disintegration time of each tablet was measured three times, and the average value was determined.
　（３）服用性試験１：ざらつき
　健康な成人パネラー３名が、口腔内でかまずに、舌で軽く触れた状態でのざらつきを下記評価基準に従って評価し、その平均値を求めた。
　ざらつきの評価基準
　非常にざらつく　　：４ポイント
　ややざらつく　　：３ポイント
　ほとんどざらつかない：２ポイント
　ざらつき無し　　：１ポイント (3) Ingestion test 1: Roughness Three healthy adult panelists evaluated the roughness in a state where they were lightly touched with the tongue without being irritated in the oral cavity, and the average value was obtained.
Roughness evaluation criteria Very rough: 4 points Roughly rough: 3 points Almost rough: 2 points No roughening: 1 point
　（４）服用性試験２：粉っぽさ
　健康な成人パネラー３名が、口腔内でかまずに、舌で軽く触れた状態での粉っぽさを評価し、その平均値を求めた。
　粉っぽさの評価基準
　非常に粉っぽい　　　　：４ポイント
　やや粉っぽい　　　　　：３ポイント
　粉っぽさをほとんど感じない　：２ポイント
　粉っぽさを全く感じない　　：１ポイント (4) Ingestibility test 2: Powderiness Three healthy adult panelists evaluated the powderiness in a state where they were lightly touched with the tongue without being irritated in the oral cavity, and the average value was obtained.
Evaluation criteria for powderiness Very powdery: 4 points Slightly powdery: 3 points Little feeling of powderiness: 2 points Not feeling powderyness: 1 point
　（結果）
　それぞれの錠剤の崩壊時間、引張強度、服用性結果を表１に示す。 (result)
Table 1 shows the disintegration time, tensile strength, and dosing results of each tablet.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表１、３に示すように、マンニトール、ショ糖及びデンプンを含有し、且つマンニトールの含有量がショ糖１質量部に対し１０質量部以上配合した固形製剤である実施例１～８は、崩壊時間３０秒未満の優れた崩壊性を示し、かつ、引張強度、服用性において全て良好な値を示した。一方、処方中にショ糖を配合していない比較例１は高打錠圧にて製造しても０．７ＭＰａ以上の硬度を持つ錠剤を製造できず、また服用性においても満足できなかった。また、トウモロコシデンプンを処方に配合していない比較例２、ショ糖１質量部に対しマンニトールが１０質量部以下である比較例３では崩壊時間、服用性のいずれかについて満足できるものでなかった。 As shown in Tables 1 and 3, Examples 1 to 8, which are solid preparations containing mannitol, sucrose and starch, and containing 10 parts by mass or more of mannitol with respect to 1 part by mass of sucrose, are disintegrated. It showed excellent disintegration for less than 30 seconds, and all showed good values in tensile strength and ingestibility. On the other hand, Comparative Example 1 in which sucrose was not blended in the formulation could not produce a tablet having a hardness of 0.7 MPa or more even when it was produced at a high tableting pressure, and was not satisfactory in dosage. Moreover, in Comparative Example 2 in which corn starch was not blended in the formulation and in Comparative Example 3 in which mannitol was 10 parts by mass or less with respect to 1 part by mass of sucrose, either disintegration time or ingestion was not satisfactory.
　（実施例９）
　薬物としてアセトアミノフェンを用い、表４に示す造粒顆粒の成分を秤量、混合し、流動層造粒機（商品名：ＦＬＯ－１；フロイント社製）にて造粒物を製造した。得られた造粒物に表４に示す後末添加成分を秤量、混合した後、小型回転式錠剤機（商品名：VELA 5；菊水製作所）を用いて、得られた錠剤の引張強度が０．７ＭＰａ以上になるように打錠圧を設定し（６００～１５００ｋｇｆ）、錠剤径８～１０ｍｍの錠剤を得た。 Example 9
Using acetaminophen as a drug, the granulated granule components shown in Table 4 were weighed and mixed, and a granulated product was produced with a fluidized bed granulator (trade name: FLO-1; manufactured by Freund Corporation). After weighing and mixing the powdered ingredients shown in Table 4 into the resulting granulated product, the resulting tablet has a tensile strength of 0 using a small rotary tablet machine (trade name: VELA 5; Kikusui Seisakusho). The tableting pressure was set to 600 MPa or higher (600-1500 kgf), and tablets with a tablet diameter of 8-10 mm were obtained.
　（実施例１０）
　薬物としてスコポラミン臭化水素酸塩水和物、クロルフェニラミンマレイン酸塩を用い、実施例９と同様にして錠剤を製造した。 (Example 10)
Tablets were produced in the same manner as in Example 9 using scopolamine hydrobromide hydrate and chlorpheniramine maleate as drugs.
　（実施例１１）
　薬物としてベラドンナ総アルカロイド、クロルフェニラミンマレイン酸塩を用い、実施例９と同様にして錠剤を製造した。 (Example 11)
Tablets were produced in the same manner as in Example 9 using belladonna total alkaloid and chlorpheniramine maleate as drugs.
　（実施例１２）
　薬物としてロラタジンを用い、実施例９と同様にして錠剤を製造した。 Example 12
Tablets were produced in the same manner as in Example 9 using loratadine as a drug.
　（実施例１３）
　薬物としてベラドンナ総アルカロイド、カルビノキサミンマレイン酸塩を用い、実施例９と同様にして錠剤を製造した。 (Example 13)
Tablets were produced in the same manner as in Example 9 using belladonna total alkaloid and carbinoxamine maleate as drugs.
　（実施例１４）
　薬物としてスコポラミン臭化水素酸塩水和物、メクリジン塩酸塩を用い、実施例９と同様にして錠剤を製造した。 (Example 14)
Tablets were produced in the same manner as in Example 9 using scopolamine hydrobromide hydrate and meclizine hydrochloride as drugs.
　（実施例１５）
　薬物としてロキソプロフェンナトリウム二水和物を用い、実施例９と同様にして錠剤を製造した。 (Example 15)
Using loxoprofen sodium dihydrate as a drug, tablets were produced in the same manner as in Example 9.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
（結果）
　表４に示すように、薬物を配合した固形製剤である実施例９～１５においても、崩壊時間及び引張強度、服用性の全てにおいて、基準値を満たす結果が得られた。
（実施例１６）
　薬物としてイブプロフェンを用い、表５に示す造粒顆粒の成分を秤量、混合し、流動層造粒機（商品名：ＦＬＯ－１；フロイント社製）にて造粒物を製造した。得られた造粒物に表５に示す後末添加成分を秤量、混合した後、卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機）を用いて、得られた錠剤の引張強度が０．７ＭＰａ以上になるように打錠圧を設定し（６～１５ｋＮ）、錠剤質量が１２５ｍｇの錠剤径８ｍｍの錠剤を得た。
　（実施例１７）
　薬物としてカフェインを用い、実施例１６と同様にして錠剤を製造した。
　（実施例１８）
　薬物としてアスコルビン酸を用い、実施例１６と同様にして錠剤を製造した。
　（実施例１９）
　薬物としてフェキソフェナジン塩酸塩を用い、実施例１６と同様にし、錠剤質量１５０ｍｇの錠剤を製造した。
　（実施例２０）
　薬物としてメキタジンを用い、実施例１６と同様にして錠剤を製造した。
　（実施例２１）
　薬物として塩酸プソイドエフェドリンを用い、実施例１６と同様にして錠剤を製造した。 (result)
As shown in Table 4, also in Examples 9 to 15 which are solid preparations containing a drug, results satisfying the standard values were obtained in all of the disintegration time, tensile strength, and ingestibility.
(Example 16)
Using ibuprofen as a drug, the granulated granule components shown in Table 5 were weighed and mixed, and a granulated product was produced with a fluidized bed granulator (trade name: FLO-1; manufactured by Freund Corporation). After weighing and mixing the components added to the powdered product shown in Table 5 in the obtained granulated product, the resulting tablet has a tensile strength of 0. 0 using a tabletop simple tablet molding machine (trade name: HANDTAB; Ichihashi Seiki). The tableting pressure was set so as to be 7 MPa or more (6 to 15 kN), and a tablet with a tablet diameter of 125 mg and a tablet diameter of 8 mm was obtained.
(Example 17)
Tablets were produced in the same manner as in Example 16 using caffeine as a drug.
(Example 18)
Tablets were produced in the same manner as in Example 16 using ascorbic acid as a drug.
(Example 19)
Using fexofenadine hydrochloride as a drug, tablets with a tablet mass of 150 mg were produced in the same manner as in Example 16.
(Example 20)
Tablets were produced in the same manner as in Example 16 using mequitazine as a drug.
(Example 21)
Tablets were produced in the same manner as in Example 16 using pseudoephedrine hydrochloride as the drug.
＜評価方法２＞
　実施例１６～２１の口腔内崩壊錠について、以下の各試験方法により、崩壊時間を測定し、服用性（ざらつき、粉っぽさ）については以下の評価基準に従って評価し、点数化した。
　（１）硬度試験
　評価方法１と同様に行った。
　（２）崩壊試験（口腔内崩壊試験）
　健康的な成人パネラー２名が、口腔内でかまずに、錠剤が口腔内で完全に崩壊するまでの時間を測定し、その平均値を求めた。
　（３）服用性試験１：ざらつき
　健康な成人パネラー２名により、評価方法１と同様に行った。
　（４）服用性試験２：粉っぽさ
　健康な成人パネラー２名により、評価方法１と同様に行った。 <Evaluation method 2>
For the orally disintegrating tablets of Examples 16 to 21, the disintegration time was measured by the following test methods, and the ingestibility (roughness, powderiness) was evaluated according to the following evaluation criteria and scored.
(1) Hardness test It carried out similarly to the evaluation method 1.
(2) Disintegration test (oral disintegration test)
Two healthy adult panelists measured the time until the tablet completely disintegrated in the oral cavity, and determined the average value.
(3) Ingestion test 1: Roughness It was carried out in the same manner as in the evaluation method 1 by two healthy adult panelists.
(4) Ingestion test 2: powdery The same as evaluation method 1 was conducted by two healthy adult panelists.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　（結果）
　実施例１６～２１で得た錠剤の崩壊時間、錠剤硬度、服用性結果を表５に示す。
　表５に示す薬物を配合した固形製剤（実施例１６～２１）においても、崩壊時間及び引張強度、服用性において、全て基準値を満たす結果が得られた。 (result)
Table 5 shows the disintegration time, tablet hardness, and dosing results of the tablets obtained in Examples 16-21.
Also in the solid preparations (Examples 16 to 21) containing the drugs shown in Table 5, all the results satisfying the standard values in the disintegration time, the tensile strength, and the ingestibility were obtained.
　本発明によれば、特殊な設備、製造方法、賦形剤を使用せず、口腔内で速やかに崩壊あるいは溶解し、かつ所望の適度な硬度を有し、服用性に優れた口腔内崩壊錠またはチュアブル錠の提供が可能となる。 According to the present invention, an orally disintegrating tablet that rapidly disintegrates or dissolves in the oral cavity without using special equipment, a manufacturing method, and an excipient, has a desired appropriate hardness, and is excellent in dosage. Or a chewable tablet can be provided.

Claims (5)

  1. 　マンニトール、ショ糖及びデンプンを含有し、マンニトールの含有量がショ糖１質量部に対し１０質量部以上であることを特徴とする水なしで服用可能な製剤。 A preparation containing water containing mannitol, sucrose and starch, wherein the content of mannitol is 10 parts by mass or more per 1 part by mass of sucrose.
  2. 　口腔内崩壊錠またはチュアブル錠である請求項１に記載の製剤。 The preparation according to claim 1, which is an orally disintegrating tablet or a chewable tablet.
  3. 　デンプンの含有量が、ショ糖１質量部に対して、０．０１質量部以上である請求項１又は２に記載の製剤。 The preparation according to claim 1 or 2, wherein the starch content is 0.01 parts by mass or more per 1 part by mass of sucrose.
  4. 　さらに薬物を含有する請求項１～３のいずれか一項に記載の製剤。 The preparation according to any one of claims 1 to 3, further comprising a drug.
  5. 　薬物がアセトアミノフェン、スコポラミン又はその塩，クロルフェニラミン又はその塩、カルビノキサミン又はその塩、ベラドンナ総アルカロイド、ロラタジン、フェキソフェナジン又はその塩、メキタジン、ロキソプロフェン又はその塩、メクリジン又はその塩、イブプロフェン、カフェイン、アスコルビン酸、プソイドエフェドリン又はその塩からなる群から選ばれる１種又は２種以上である請求項１～４のいずれか一項に記載の製剤。 The drug is acetaminophen, scopolamine or a salt thereof, chlorpheniramine or a salt thereof, carbinoxamine or a salt thereof, belladonna total alkaloid, loratadine, fexofenadine or a salt thereof, mequitazine, loxoprofen or a salt thereof, meclizine or a salt thereof, ibuprofen, The preparation according to any one of claims 1 to 4, which is one or more selected from the group consisting of caffeine, ascorbic acid, pseudoephedrine or a salt thereof.
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JP2017002045A (en) * 2015-06-12 2017-01-05 ゼリア新薬工業株式会社 Orally disintegrating tablet
JP2021004193A (en) * 2019-06-25 2021-01-14 小林製薬株式会社 Acetaminophen-containing granule

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JP2000515535A (en) * 1996-08-07 2000-11-21 パーク―デイヴィス Trimebutine maleate coated tablets
WO2006123678A1 (en) * 2005-05-18 2006-11-23 Dainippon Sumitomo Pharma Co., Ltd. Stable tablet containing droxidopa
WO2011071139A1 (en) * 2009-12-11 2011-06-16 大日本住友製薬株式会社 Dry-coated orally disintegrating tablet

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017002045A (en) * 2015-06-12 2017-01-05 ゼリア新薬工業株式会社 Orally disintegrating tablet
JP2021004193A (en) * 2019-06-25 2021-01-14 小林製薬株式会社 Acetaminophen-containing granule

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