WO2013125350A1 - Excipient à compression directe permettant de désintégrer oralement un comprimé et procédé de production de celui-ci, et comprimé à désintégration orale - Google Patents

Excipient à compression directe permettant de désintégrer oralement un comprimé et procédé de production de celui-ci, et comprimé à désintégration orale Download PDF

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WO2013125350A1
WO2013125350A1 PCT/JP2013/052738 JP2013052738W WO2013125350A1 WO 2013125350 A1 WO2013125350 A1 WO 2013125350A1 JP 2013052738 W JP2013052738 W JP 2013052738W WO 2013125350 A1 WO2013125350 A1 WO 2013125350A1
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orally disintegrating
tablet
direct compression
disintegrant
tablets
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PCT/JP2013/052738
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English (en)
Japanese (ja)
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研二 古川
利枝 白土
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フロイント産業株式会社
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Priority to JP2014500641A priority Critical patent/JP6040218B2/ja
Publication of WO2013125350A1 publication Critical patent/WO2013125350A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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

Definitions

  • the present invention relates to a direct compression excipient for orally disintegrating tablets, a method for producing the same, and an orally disintegrating tablet.
  • wet tableting As a method for producing the orally disintegrating tablet, various methods have been proposed such as wet tableting and humidification drying after tableting.
  • wet tablets have low hardness, they cannot be provided in PTP packaging (packaging for extruding tablets or capsules), cannot be packaged, and require special manufacturing equipment. There is a problem that it becomes complicated.
  • the oral cavity is excellent in hardness and stability of oral disintegration even when stored for a long period of time.
  • the present invention makes it a subject to solve the said conventional problems and to achieve the following objectives. That is, the present invention maintains hardness and stability of oral disintegration even when stored for a long period of time while maintaining the performance required for tablets, such as tablet moldability, disintegration in the oral cavity, friability, and drug content uniformity.
  • An object of the present invention is to provide an orally disintegrating tablet direct injection excipient for producing an orally disintegrating tablet having excellent properties, a method for producing the same, and an orally disintegrating tablet.
  • the present inventors have made extensive studies and obtained the following knowledge. That is, it is obtained by spraying and granulating a mixture containing at least one of sugar and sugar alcohol on a mixture containing at least one of sugar and sugar alcohol and a disintegrant.
  • the present invention is based on the above findings by the present inventors, and means for solving the above problems are as follows. That is, ⁇ 1> It is obtained by spraying a mixture containing at least one of sugar and sugar alcohol onto a mixture containing at least one of sugar and sugar alcohol and a disintegrant and granulating the mixture. This is a direct compression excipient for orally disintegrating tablets. ⁇ 2> The direct compression excipient for orally disintegrating tablets according to ⁇ 1>, wherein the sugar is lactose and the sugar alcohol is at least one of mannitol, xylitol, erythritol, and lactitol.
  • ⁇ 3> The direct compression for orally disintegrating tablet according to any one of ⁇ 1> to ⁇ 2>, wherein the disintegrant is at least one of crospovidone and low-substituted hydroxypropylcellulose (L-HPC). It is a dosage form.
  • ⁇ 4> The direct compression excipient for orally disintegrating tablets according to any one of ⁇ 1> to ⁇ 3>, wherein the disintegrant has a volume average particle size of 50 ⁇ m or less.
  • ⁇ 6> The method for producing a direct compression excipient for an orally disintegrating tablet according to the above ⁇ 5>, wherein the mixture is granulated by spraying 30% to 200% by mass of a binding liquid as a solid content.
  • an orally disintegrating tablet direct injection excipient for producing an orally disintegrating tablet which is excellent in hardness and stability of orally disintegrating even when stored, a method for producing the same, and an orally disintegrating tablet.
  • FIG. 1A is a graph showing the results of tablet moldability in Test Example 1.
  • FIG. 1B is a graph showing the results of hardness stability in Test Example 1.
  • 2A is a graph showing the results of hardness stability of Test Example 2.
  • FIG. 2B is a graph showing the results of hardness stability in Test Example 2.
  • FIG. 2C is a graph showing the results of hardness stability in Test Example 2.
  • FIG. 3A is a photograph showing the results of the powder physical properties of Test Example 3.
  • FIG. 3B is a photograph showing the results of the powder physical properties of Test Example 3.
  • FIG. 3C is a graph showing the results of tablet moldability in Test Example 3.
  • FIG. 3D is a graph showing the results of tablet moldability in Test Example 3.
  • FIG. 3E is a graph showing the results of hardness stability in Test Example 3.
  • FIG. 3F is a graph showing the results of hardness stability in Test Example 3.
  • FIG. 4A is a graph showing the results of tablet moldability of Test Example 4.
  • FIG. 4B is a graph showing the results of friability of Test Example 4.
  • FIG. 4C is a graph showing the results of orally disintegrating in Test Example 4.
  • FIG. 4D is a graph showing the results of hardness stability in Test Example 4.
  • 4E is a graph showing the results of oral disintegration time stability in Test Example 4.
  • the direct compression excipient for orally disintegrating tablets of the present invention is a granulated product containing a saccharide, a disintegrant, and, if necessary, other additives.
  • the granulated product is obtained by granulating a mixture containing at least the saccharide and the disintegrant while spraying a binding solution.
  • the method for producing a direct-extinguishing excipient for orally disintegrating tablets according to the present invention comprises at least a sugar and a sugar alcohol while flowing a mixture containing a sugar containing at least one of a sugar and a sugar alcohol and a disintegrant. This is a method for producing by spraying a binding liquid containing any of them.
  • the direct compression excipient for the orally disintegrating tablet Since the surface of the mixture obtained by mixing the saccharide and the disintegrant is coated with the binding liquid, the direct compression excipient for the orally disintegrating tablet has a binding force between the saccharide and the disintegrant. Not only increases, but also the hygroscopicity of the disintegrant decreases. Thereby, even if the direct compression excipient
  • the mixture includes the saccharide and the disintegrant, and further includes other additives as necessary.
  • the sugar in the mixture is not particularly limited as long as it is a powder of at least one of sugar and sugar alcohol, and can be appropriately selected according to the purpose.
  • lactose, mannitol, xylitol, erythritol, and lactitol powder are preferable, and mannitol powder is particularly preferable because an orally disintegrating tablet excellent in hardness stability and orally disintegrating property can be produced.
  • the content of saccharides in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.However, the oral cavity disintegrates in that it can produce an orally disintegrating tablet excellent in hardness stability and oral disintegration.
  • the saccharide content in the direct compression excipient for disintegrating tablets is preferably 70% by mass to 99% by mass.
  • the saccharide is not particularly limited, and a commercially available product may be used.
  • the commercially available products include lactose (manufactured by DFE, trade name “Pharmacatse”), mannitol (manufactured by ROQUETTE, trade name “Pearlitol 50C”; trade name “Mannit” manufactured by Mitsubishi Corporation Foodtech Co., Ltd.), erythritol ( (Mitsubishi Chemical Foods Co., Ltd., trade name “Erythritol”), Xylitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Xylit”), Sorbitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Sorbit”), Maltitol (Mitsubishi Corporation Foodtech Co., Ltd., trade names “Amarti”, “Resis”), Lactitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Milhen”) and the like.
  • the disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include crospovidone, low-substituted hydroxypropylcellulose (L-HPC), carboxymethylcellulose (carboxymethylcellulose Na, carboxymethylcellulose Ca, etc. ) And the like, and starches such as crystalline cellulose, hydroxypropyl starch, and corn starch. These may be used alone or in combination of two or more. Among these, crospovidone and low-substituted hydroxypropylcellulose (L-HPC) are preferable in that an orally disintegrating tablet excellent in hardness stability and oral disintegration property can be produced. The combined use of crospovidone and corn starch is preferred. It is preferable in that it can further prevent a decrease in tablet hardness during moisture absorption.
  • the volume average particle size of the disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose, but is 100 ⁇ m or less in terms of producing an orally disintegrating tablet having excellent hardness stability and orally disintegrating properties. Is preferable, 50 ⁇ m or less is more preferable, and 20 ⁇ m or more and 50 ⁇ m or less is particularly preferable.
  • the content of the disintegrant in the mixture is not particularly limited and can be appropriately selected depending on the purpose.
  • the oral cavity disintegrates in terms of hardness stability and oral disintegration, so that the oral cavity can be produced.
  • the content of the disintegrant in the directly collapsible excipient for the internally disintegrating tablet is preferably 1% by mass to 30% by mass.
  • the disintegrant is not particularly limited, and an appropriately synthesized product or a commercially available product may be used.
  • crospovidone (trade name “Polyplaston XL”, “Polyplastidone XL-10”, manufactured by ISP Co., Ltd.), (trade name “Collidon CL”, “Collidon CL-F”, manufactured by BASF) , “Collidon CL-SF”)], low-substituted hydroxypropyl cellulose (trade name “L-HPC” manufactured by Shin-Etsu Chemical Co., Ltd.), corn starch (trade name “Corn Starch W” manufactured by Nippon Shokuhin Kako Co., Ltd.), etc. Is mentioned.
  • additives in the mixture are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluidizers, sweeteners, lubricants, hygroscopic agents, dehumidifiers, coating agents, dyes, Examples include flavoring agents and solubilizing agents. These may be used alone or in combination of two or more. Other additives in the mixture may be used by dissolving or suspending in a binding solution described later. There is no restriction
  • the binding liquid contains at least one of sugar and sugar alcohol, and further contains other additives as necessary.
  • the binding liquid preferably does not contain a disintegrant.
  • the binding solution is not particularly limited as long as it is a solution containing at least one of sugar and sugar alcohol, and can be appropriately selected according to the purpose.
  • sucrose, lactose, fructose, mannitol, xylitol examples include erythritol, sorbitol, maltitol, isomalt, lactitol, sucrose, glycerin and the like. These may be used alone or in combination of two or more.
  • a lactose, mannitol, xylitol, erythritol, and lactitol solution is preferable, and a mannitol solution is more preferable because an orally disintegrating tablet excellent in hardness stability and orally disintegrating property can be produced.
  • the method for preparing the binding liquid is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method for preparing by dissolving at least one powder of the sugar and sugar alcohol in a solvent. It is done. There is no restriction
  • the concentration of at least one of the sugar and sugar alcohol in the binding solution is not particularly limited and can be appropriately selected according to the purpose. However, an orally disintegrating tablet excellent in hardness stability and oral disintegration is obtained. In the case of mannitol, it is preferably 40% by mass to 60% by mass because it can be produced.
  • the amount of spray solid content with respect to the mixture (a mixture containing at least the sugar and the disintegrant) of the binding liquid there is no particular limitation on the amount of spray solid content with respect to the mixture (a mixture containing at least the sugar and the disintegrant) of the binding liquid, and it can be appropriately selected according to the purpose. From the viewpoint that an orally disintegrating tablet having excellent properties can be produced, 30 mass% to 200 mass% is preferable.
  • the binding solution is not particularly limited, and a commercially available product may be used.
  • the commercially available products include lactose (manufactured by DFE, trade name “Pharmacatse”), mannitol (manufactured by ROQUETTE, trade name “Pearlitol 50C”; trade name “Mannit” manufactured by Mitsubishi Corporation Foodtech Co., Ltd.), erythritol ( (Mitsubishi Chemical Foods Co., Ltd., trade name “Erythritol”), Xylitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Xylit”), Sorbitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Sorbit”), Maltitol (Mitsubishi Corporation Food Tech Co., Ltd., trade names “Amarti”, “Resis”), Lactitol (Mitsubishi Corporation Food Tech Co., Ltd., trade name “Miruhen”) and the like.
  • the combination of the saccharide and the binding liquid is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the sugar can be produced in that an orally disintegrating tablet having excellent hardness stability and oral disintegration property can be produced.
  • the alcohols are preferably the same, and a combination of mannitol powder as the saccharide and a mannitol solution as the binding liquid is more preferable.
  • the particle size in the cumulative distribution diagram of the direct compression excipient (granulated product) for the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the D 10 value is preferably 30 ⁇ m to 90 ⁇ m
  • the D 50 value is preferably 70 ⁇ m to 150 ⁇ m
  • the D 90 value is preferably 160 ⁇ m to 250 ⁇ m in that an orally disintegrating tablet having excellent properties can be produced.
  • the D 50 value corresponds to the volume average particle diameter of the orally disintegrating tablet for direct compression excipient (granules).
  • the particle size can be measured by, for example, a laser diffraction / scattering particle size distribution measuring device (Microtrack HRA (manufactured by Nikkiso Co., Ltd.)).
  • the bulk density (loose) of the direct compression excipient (granulated product) for the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the intended purpose. In view of the ability to produce an orally disintegrating tablet excellent in the above, 0.4 g / mL to 0.6 g / mL is preferable. There is no restriction
  • the bulk density (loose) and the bulk density (tap) are, for example, A. B. It can be measured by a D powder characteristic measuring instrument (manufactured by Tsutsui Rikenki Co., Ltd.)
  • the angle of repose of the direct compression excipient (granulated product) for the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the intended purpose, but it is excellent in hardness stability and oral disintegration property.
  • the angle of 30 ° to 40 ° is preferable in that an internally disintegrating tablet can be produced.
  • the angle of repose can be measured, for example, by the Nogami / Sugihara method described in JP-A-6-205959.
  • a method for producing the direct-disintegrating excipient for orally disintegrating tablets there is no particular limitation as long as it is a method obtained by fluidized bed granulation while spraying a liquid containing the binding liquid on the saccharide and the disintegrant. And can be appropriately selected according to the purpose.
  • the fluidized bed granulation is a method of granulating by causing aggregation of liquid crosslinking between particles of the saccharide and the disintegrant by spraying the binding liquid, and can be performed by a fluidized bed granulation apparatus. it can.
  • the fluidized bed granulator sprays the binding liquid onto a fluidized (floating fluid) powder (a mixture containing the saccharide and the disintegrant), and coats the powder with the binding liquid. And granulate.
  • a fluidized (floating fluid) powder a mixture containing the saccharide and the disintegrant
  • the direct compression excipient for orally disintegrating tablets of the present invention is required as a tablet only by mixing with a pharmaceutical ingredient and tableting, tablet formability, orally disintegrating property, friability, drug content uniformity It is possible to provide an orally disintegrating tablet that is excellent in hardness and stability of disintegration in the oral cavity even when stored for a long period of time while maintaining the performances such as Moreover, since the compounding quantity of the chemical
  • the orally disintegrating tablet of the present invention contains the above-described direct compression excipient for orally disintegrating tablet and a drug component, and further contains other components as necessary.
  • the above-mentioned direct compression excipient for orally disintegrating tablets is used as the direct compression excipient for orally disintegrating tablets.
  • the content of the directly disintegrating excipient for orally disintegrating tablets in the orally disintegrating tablet is preferably 20% by mass to 99.9% by mass.
  • the drug component is not particularly limited and may be appropriately selected depending on the purpose.
  • the drug component is a hypertension drug, angina drug, bronchodilator drug, psychotropic drug, anxiolytic drug, antidepressant drug, hypnotic sedative drug.
  • Antiparkinson allergy, dental, oral, cardiotonic, antipyretic analgesic, antihistamine, antitussive, antacid, herbal medicine, antihypertensive, antibiotic, antibacterial, arrhythmia, coronary Dilators, peripheral vasodilators, hyperlipidemic drugs, antibacterial drugs, hormonal drugs, gout drugs, antirheumatic drugs, chemotherapy drugs, antidiabetic drugs, antiemetics, antiepileptic drugs, sympathomimetic drugs, Osteoporosis drugs, antineoplastic drugs, immunosuppressive drugs, urological drugs, gastrointestinal drugs, cerebral metabolism improving drugs, cerebral circulation improving drugs, respiratory stimulants, vasoconstrictors, antipruritic drugs, expectorants, drugs for central nervous system action , Drug components used for ulcer treatment, gastric mucosa repair drug, analgesic antispasmodic drug, etc.
  • temocapril hydrochloride cabergoline, amlodipine besylate, omeprazole, lansoprazole, famotidine, lafutidine, ecabet sodium, mosapride citrate, rebamipide, voglibose, risperidone, imidapril hydrochloride, meloxicam, milnacipran hydrochloride Salt, levofloxacin, clarithromycin, sarpogrelate hydrochloride, tosufloxacin tosylate, tamsulosin hydrochloride, mizoribine, tacrolimus hydrate, fluvoxamine maleate, glimepiride, ramosetron hydrochloride, nicorandil, donepezil hydrochloride, zolpidem tartrate, pioglitazone hydrochloride Salt, sodium alendronate hydrate, sodium risedronate hydrate, ator
  • the other component is not particularly limited as long as it is a component used in the orally disintegrating tablet and can be appropriately selected depending on the purpose, but a lubricant, a fluidizing agent, a sweetening agent, and the like are preferable.
  • moisture absorption, a dehumidifying agent, a coating agent, a pigment, a flavoring agent, a solubilizing agent, and the like can be given. These may be used alone or in combination of two or more.
  • the lubricant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include magnesium stearate, stearic acid, calcium stearate, talc, and hardened oil.
  • the fluidizing agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • hydrophilic silica hydrophobic silica, calcium silicate, alkyl phosphate (PAP), water-soluble polymer compound,
  • PAP alkyl phosphate
  • Anhydrous calcium hydrogen phosphate, magnesium silicate, calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium oxide and the like can be mentioned.
  • the sweetener is not particularly limited and may be appropriately selected depending on the intended purpose.For example, aspartame, glucose, galactose, mannose, ribose, arabinose, maltose, lactose, isomaltose, cellobiose, gentiobiose, palatinose Can be mentioned.
  • the method for producing the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the purpose.
  • Examples thereof include a method of producing by tableting into tablets. At this time, generally used mixers and tableting machines can be used.
  • the orally disintegrating tablet of the present invention maintains hardness and oral cavity even when stored for a long period of time while maintaining the performance required for tablets, such as tablet moldability, orally disintegrating property, friability, and drug content uniformity. Excellent collapse stability. Moreover, since the compounding amount of the drug component and the disintegrant in the orally disintegrating tablet can be easily adjusted by using the direct compression excipient for the orally disintegrating tablet of the present invention, The formulation design of disintegrating tablets becomes easy.
  • Test Example 1 Comparative test with different granulation methods
  • Test Example 1 when producing a direct compression excipient for orally disintegrating tablets, the obtained direct compression excipient for orally disintegrating tablets was obtained due to the difference in granulation method (difference in timing of adding disintegrant).
  • the differences in the physical properties of the oral cavity and how the hardness stability and oral disintegration property of the orally disintegrating placebo tablets produced using the direct-dissolving excipient for orally disintegrating tablets are evaluated.
  • the direct compression excipient for orally disintegrating tablets was produced by subjecting a saccharide and a disintegrant to fluid bed granulation while spraying a binding solution in a flow coater (FLO-5, manufactured by Freund Corporation).
  • the materials used are shown in Table (1-1), the composition of the materials used are shown in Table (1-2), and the powder physical properties of the obtained direct compression excipients are shown in Table (1-3) and FIG. 1A. It was shown to.
  • the comparative direct-disintegrating tablet for orally disintegrating tablets is prepared by adding saccharides into a granulator (flow coater (FLO-5, manufactured by Freund Sangyo Co., Ltd.)) and spraying 4 kg of a binding solution, A fluidizing agent was added to the granulator as necessary, and the remaining binder solution was sprayed to produce fluidized bed granulation (post-addition).
  • the materials used are shown in Table (1-1), the composition is shown in Table (1-2), and the powder physical properties of the obtained direct hitting excipient are shown in Table (1-3).
  • the orally disintegrating tablet was prepared by mixing the direct compression excipient and lubricant described in Table (1-4) under the conditions described in Table (1-4) and obtaining the resulting mixture (500 g) (Table (1)). It was produced by tableting under the conditions described in 1-4).
  • the comparative orally disintegrating tablet was prepared by mixing the direct compression excipient and lubricant described in Table (1-4) under the conditions described in Table (1-4) and expressing the resulting mixture (500 g). It was produced by tableting under the conditions described in (1-4).
  • Test Example 2 Comparison test with simple mixed product
  • Test Example 2 manufactured using “orally disintegrating tablet” manufactured using “orally-disintegrating tablet for orally disintegrating tablet” of the present invention and “direct-compressing excipient for comparative orally disintegrating tablet”. The difference in hardness stability and drug content uniformity of the “comparable orally disintegrating tablets” was evaluated.
  • Comparative orally disintegrating tablets were produced by mixing the materials described in Table (2-1) under the conditions described in Table (2-2) and tableting.
  • the direct compression excipient for comparative OD tablets in Table (2-1) is a mixture of “saccharide (sugar alcohol (D-mannitol))” and “disintegrant (crospovitone)” at 9: 1 ( It was obtained by hand mixing (3 minutes).
  • [Oral Disintegration (OD) Tablet 1] has the best hardness stability. Also, from Table (2-3), it was found that [Oral Disintegration (OD) Tablet 1] has the most excellent drug content uniformity.
  • [Oral Disintegration (OD) Tablet Direct Injection Excipient 1] used in [Oral Disintegration (OD) Tablet 1] has a surface obtained by mixing a saccharide and a disintegrant with a binding solution. Since it was coated, it was found that not only the binding force between the saccharide and the disintegrant was increased, but also the hygroscopicity of the disintegrant was decreased. As a result, it was found that the [Oral Disintegration (OD) Tablet 1] of the present invention is excellent in hardness stability without decreasing the hardness even when stored under high humidity for a long time.
  • Test Example 3 Comparison test with disintegrant aqueous dispersion
  • the “orally disintegrating tablet” produced using the “direct-disintegrating excipient for orally disintegrating tablets” of the present invention and “Comparative Orally Disintegrating Tablets” disclosed in JP 2010-189384 A The difference in hardness stability of “Comparative Orally Disintegrating Tablets” produced using a disintegrant aqueous dispersion was evaluated with reference to “Directly Extruded Excipient”.
  • the direct compression excipient for orally disintegrating tablets was produced by subjecting a saccharide and a disintegrant to fluid bed granulation while spraying the binding liquid in a granulator.
  • the materials used are shown in Table (3-1), the production conditions are shown in Table (3-2), and the powder physical properties of the obtained direct compression excipients are shown in Table (3-3) and FIGS. 3A to 3B. It was shown to.
  • the direct compression excipient for comparative orally disintegrating tablets was produced by fluidized bed granulation while spraying saccharides in an agglomerator using an aqueous dispersion containing a disintegrant as a binder.
  • the materials used are shown in Table (3-1), the prescriptions are shown in Table (3-2), and the powder physical properties of the obtained direct compression excipients are shown in Table (3-3) and FIGS. 3A to 3B. Indicated.
  • the orally disintegrating tablet was prepared by mixing the direct compression excipient and lubricant described in Table (3-4) under the conditions described in Table (3-4), and obtaining the resulting mixture (500 g) (Table (3-4)). It was produced by tableting under the conditions described in 3-4).
  • the comparative orally disintegrating tablet was prepared by mixing the direct compression excipient and lubricant described in Table (3-4) under the conditions described in Table (3-4) and expressing the resulting mixture (500 g). It was produced by tableting under the conditions described in (3-4).
  • the hardness stability was evaluated using the obtained “orally disintegrating placebo tablets” and “comparing orally disintegrating placebo tablets” with a hardness of 50 N to 60 N, and the placebo tablets were kept in an open state at 25 ° C. under humidity. (55% RH (constant humidity salt: Mg (NO 3 ) 2 )) and 75% RH (constant humidity salt: NaCl) for 7 days and confirming the change in hardness. These are shown in FIGS. 3E to 3F.
  • FIG. 3F shows that OD placebo tablet 4 using crospovidone and corn starch as disintegrants can prevent a decrease in hardness during moisture absorption more than OD placebo tablet 3 using crospovidone alone. It was.
  • Test Example 4 Superiority test based on particle size of disintegrant
  • Test Example 4 the superiority of tablet stability and hardness stability due to the difference in the particle size of the disintegrant among “direct compression excipients for orally disintegrating tablets” of the present invention was evaluated.
  • the direct compression excipient for orally disintegrating tablets was produced by subjecting a saccharide and a disintegrant to fluid bed granulation while spraying the binding liquid in a granulator.
  • the materials used are shown in Table (4-1), the composition is shown in Table (4-2), and the results of the powder physical properties of the obtained direct hitting excipient are shown in Table (4-3).
  • a disintegrant having a volume average particle diameter of 50 ⁇ m or less more preferably a disintegrant having a volume average particle diameter in the range of 25 ⁇ m to 35 ⁇ m as a disintegrant (crospovidone), It was found to be excellent in internal disintegration and hardness stability.
  • the direct compression excipient for orally disintegrating tablets of the present invention is required as a tablet only by mixing with a pharmaceutical ingredient and tableting, tablet formability, orally disintegrating property, friability, drug content uniformity While maintaining the performance of the above, it is possible to provide an orally disintegrating tablet that is excellent in hardness and stability of disintegration in the oral cavity even when stored for a long period of time, and thus can be suitably used for the production of orally disintegrating tablets. .

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Abstract

La présente invention concerne un excipient à compression directe permettant de désintégrer oralement un comprimé, qui est obtenu en pulvérisant un liant liquide comprenant au moins soit du sucre soit un alcool glucidique sur un produit mélangé de sucres comprenant au moins soit du sucre soit de l'alcool glucidique et un délitant, suivi d'une granulation.
PCT/JP2013/052738 2012-02-23 2013-02-06 Excipient à compression directe permettant de désintégrer oralement un comprimé et procédé de production de celui-ci, et comprimé à désintégration orale WO2013125350A1 (fr)

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JP2014500641A JP6040218B2 (ja) 2012-02-23 2013-02-06 口腔内崩壊錠用直打賦形剤及びその製造方法、並びに口腔内崩壊錠

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JP2012037537 2012-02-23
JP2012-037537 2012-02-23

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WO2015198483A1 (fr) * 2014-06-27 2015-12-30 フロイント産業株式会社 Granulés d'excipient, et comprimé
JP2017002045A (ja) * 2015-06-12 2017-01-05 ゼリア新薬工業株式会社 口腔内崩壊錠
CN107823144A (zh) * 2017-11-15 2018-03-23 山东天力药业有限公司 一种高纯度甘露醇直压颗粒的制备方法
WO2018091048A1 (fr) * 2016-11-18 2018-05-24 Fertin Pharma A/S Véhicule d'administration orale
WO2018091050A1 (fr) * 2016-11-18 2018-05-24 Fertin Pharma A/S Comprimé comprenant un liant séparé et de l'érythritol
US10543205B2 (en) 2016-11-18 2020-01-28 Fertin Pharma A/S Oral delivery vehicle containing nicotine
US10632076B2 (en) 2016-11-18 2020-04-28 Fertin Pharma A/S Tablet comprising separate binder and erythritol
US11052047B2 (en) 2018-05-17 2021-07-06 Fertin Pharma A/S Oral tablet suitable for fast release of active pharmaceutical ingredients
US11058633B2 (en) 2018-05-17 2021-07-13 Fertin Pharma A/S Disintegrating oral tablet suitable for active pharmaceutical ingredients
US11058641B2 (en) 2018-05-17 2021-07-13 Fertin Pharma A/S Oral tablet for taste masking of active ingredients
US11090263B2 (en) 2018-05-22 2021-08-17 Fertin Pharma A/S Tableted chewing gum suitable for active pharmaceutical ingredients
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US11096894B2 (en) 2018-05-17 2021-08-24 Fertin Pharma A/S Oral tablet for induced saliva generation
US11096895B2 (en) 2018-05-17 2021-08-24 Fertin Pharma A/S Oral tablet suitable for active pharmaceutical ingredients
US11135157B2 (en) 2018-05-17 2021-10-05 Fertin Pharma A/S Oral tablet for delivery of active ingredients to the throat
US11260030B2 (en) 2018-05-17 2022-03-01 Fertin Pharma A/S Oral tablet for delivery of active ingredients to the gastrointestinal tract
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CN114732792A (zh) * 2022-03-25 2022-07-12 北京诺康达医药科技股份有限公司 一种尼可地尔口腔崩解片及其制备方法

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WO2015198483A1 (fr) * 2014-06-27 2015-12-30 フロイント産業株式会社 Granulés d'excipient, et comprimé
JP2017002045A (ja) * 2015-06-12 2017-01-05 ゼリア新薬工業株式会社 口腔内崩壊錠
JP2019535821A (ja) * 2016-11-18 2019-12-12 フェルティン ファルマ アー／エス 経口送達ビヒクル
AU2016429743B2 (en) * 2016-11-18 2020-10-08 Fertin Pharma A/S Oral delivery vehicle
WO2018091050A1 (fr) * 2016-11-18 2018-05-24 Fertin Pharma A/S Comprimé comprenant un liant séparé et de l'érythritol
CN109952092A (zh) * 2016-11-18 2019-06-28 费尔廷制药公司 包含独立的黏合剂和赤藓糖醇的片剂
CN109963553A (zh) * 2016-11-18 2019-07-02 费尔廷制药公司 经口递送载剂
JP2019535729A (ja) * 2016-11-18 2019-12-12 フェルティン ファルマ アー／エス 別個の結合剤及びエリスリトールを含む錠剤
US11351103B2 (en) 2016-11-18 2022-06-07 Johnson & Johnson Consumer Inc. Method of providing oral care benefits
US10543205B2 (en) 2016-11-18 2020-01-28 Fertin Pharma A/S Oral delivery vehicle containing nicotine
US10632076B2 (en) 2016-11-18 2020-04-28 Fertin Pharma A/S Tablet comprising separate binder and erythritol
WO2018091048A1 (fr) * 2016-11-18 2018-05-24 Fertin Pharma A/S Véhicule d'administration orale
AU2017360584B2 (en) * 2016-11-18 2020-12-17 Fertin Pharma A/S Tablet comprising separate binder and erythritol
CN109963553B (zh) * 2016-11-18 2022-11-22 费尔廷制药公司 经口递送载剂
US11351162B2 (en) 2016-11-18 2022-06-07 Fertin Pharma A/S Oral delivery vehicle containing flavoring agents
US11484503B2 (en) 2016-11-18 2022-11-01 Fertin Pharma A/S Tablet comprising separate binder and erythritol
EP3854383A1 (fr) * 2016-11-18 2021-07-28 Fertin Pharma A/S Véhicule d'administration orale
CN109952092B (zh) * 2016-11-18 2022-08-23 费尔廷制药公司 包含独立的黏合剂和赤藓糖醇的片剂
CN107823144A (zh) * 2017-11-15 2018-03-23 山东天力药业有限公司 一种高纯度甘露醇直压颗粒的制备方法
US11058633B2 (en) 2018-05-17 2021-07-13 Fertin Pharma A/S Disintegrating oral tablet suitable for active pharmaceutical ingredients
US11096895B2 (en) 2018-05-17 2021-08-24 Fertin Pharma A/S Oral tablet suitable for active pharmaceutical ingredients
US11135157B2 (en) 2018-05-17 2021-10-05 Fertin Pharma A/S Oral tablet for delivery of active ingredients to the throat
US11260030B2 (en) 2018-05-17 2022-03-01 Fertin Pharma A/S Oral tablet for delivery of active ingredients to the gastrointestinal tract
US11096894B2 (en) 2018-05-17 2021-08-24 Fertin Pharma A/S Oral tablet for induced saliva generation
US11096896B2 (en) 2018-05-17 2021-08-24 Fertin Pharma A/S Tablet dosage form for buccal absorption of active ingredients
US11058641B2 (en) 2018-05-17 2021-07-13 Fertin Pharma A/S Oral tablet for taste masking of active ingredients
US11052047B2 (en) 2018-05-17 2021-07-06 Fertin Pharma A/S Oral tablet suitable for fast release of active pharmaceutical ingredients
US11090263B2 (en) 2018-05-22 2021-08-17 Fertin Pharma A/S Tableted chewing gum suitable for active pharmaceutical ingredients
CN114732792A (zh) * 2022-03-25 2022-07-12 北京诺康达医药科技股份有限公司 一种尼可地尔口腔崩解片及其制备方法

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