WO2013125350A1 - Direct-compression excipient for orally disintegrating tablet and method for producing same, and orally disintegrating tablet - Google Patents
Direct-compression excipient for orally disintegrating tablet and method for producing same, and orally disintegrating tablet Download PDFInfo
- Publication number
- 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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- WIPO (PCT)
- Prior art keywords
- orally disintegrating
- tablet
- direct compression
- disintegrant
- tablets
- Prior art date
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Images
Classifications
-
- 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
Provided is a direct-compression excipient for an orally disintegrating tablet, which is obtained by spraying a liquid binder comprising at least either sugar or sugar alcohol onto a mixed product of sugars comprising at least either sugar or sugar alcohol and a disintegrant, followed by granulation.
Description
本発明は、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に関する。
The present invention relates to a direct compression excipient for orally disintegrating tablets, a method for producing the same, and an orally disintegrating tablet.
昨今、嚥下能力が低下した患者又は水分摂取制限を要する患者だけでなく、一般の患者に対しても、口腔内で崩壊して嚥下し易くした口腔内崩壊錠（ＯＤ錠）の使用が年々増加し、製剤としての有用性が明らかとなりつつある。
In recent years, the use of orally disintegrating tablets (OD tablets) that disintegrated in the oral cavity and facilitated swallowing has increased year by year, not only for patients with reduced swallowing ability or patients who require restriction on water intake, but also for general patients. However, its usefulness as a preparation is becoming clear.
前記口腔内崩壊錠の製造方法として、湿製錠や打錠後に加湿乾燥を行うなど様々な方法が提案されている。しかしながら、前記湿製錠は、硬度が低いために、ＰＴＰ包装（錠剤やカプセルなどを押し出すタイプの包装）で提供できないという問題、一包化ができないという問題、特殊な製造装置が必要となり製造が煩雑になるという問題がある。
As a method for producing the orally disintegrating tablet, various methods have been proposed such as wet tableting and humidification drying after tableting. However, since the 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.
また、前記口腔内崩壊錠用賦形剤を造粒する際の結合液として、ヒドロキシプロピルセルロースを用いる方法が知られているが、得られる錠剤の口腔内崩壊性が遅くなるという問題がある。そこで、前記口腔内崩壊錠として望ましい口腔内崩壊性を得るために、前記結合液として崩壊剤水分散液を用いて口腔内崩壊錠用賦形剤を造粒する方法が提案されている（例えば、特許文献１参照）。しかしながら、この方法で得られたＯＤ錠は、吸湿性が高く、錠剤硬度が低下し、錠剤の外観が変化するという問題がある。
In addition, a method using hydroxypropyl cellulose as a binding solution for granulating the above-mentioned excipient for orally disintegrating tablets is known, but there is a problem that the orally disintegrating property of the obtained tablet is slow. Thus, in order to obtain desirable orally disintegrating properties as the orally disintegrating tablet, a method of granulating an orally disintegrating tablet excipient using an aqueous disintegrant dispersion as the binding liquid has been proposed (for example, , See Patent Document 1). However, the OD tablet obtained by this method has a problem of high hygroscopicity, reduced tablet hardness, and changes in the appearance of the tablet.
したがって、錠剤として必要とされる、錠剤成形性、錠剤保存性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる口腔内崩壊錠を提供できる技術が強く求められているのが現状である。
Therefore, while maintaining the properties required for tablets, such as tablet formability, tablet storage, wear resistance, and drug content uniformity, the oral cavity is excellent in hardness and stability of oral disintegration even when stored for a long period of time. Currently, there is a strong demand for technology that can provide disintegrating tablets.
本発明は、前記従来における諸問題を解決し、以下の目的を達成することを課題とする。即ち、本発明は、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる口腔内崩壊錠を製造するための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を提供することを目的とする。
This 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.
前記課題を解決するため、本発明者らは鋭意検討した結果、以下のような知見を得た。即ち、糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物に、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して造粒することにより得られる「口腔内崩壊錠用直打賦形剤」と「薬剤成分」とを混合して打錠するだけで、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる口腔内崩壊錠を提供できることを見出した。
In order to solve the above-mentioned problems, 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 tablet formability, buccal disintegration, friability, and drug content uniformity required as a tablet simply by mixing the tablet directly into the orally disintegrating tablet and the drug component and compressing the tablet. It was found that an orally disintegrating tablet having excellent hardness and stability of disintegration in the oral cavity can be provided even when stored for a long period of time while maintaining the performance of the above.
本発明は、本発明者らによる前記知見に基づくものであり、前記課題を解決するための手段としては、以下の通りである。即ち、
＜１＞ 糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物に、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して造粒することにより得られることを特徴とする口腔内崩壊錠用直打賦形剤である。
＜２＞ 糖が、乳糖であり、糖アルコールが、マンニトール、キシリトール、エリスリトール、及びラクチトールの少なくともいずれかである前記＜１＞に記載の口腔内崩壊錠用直打賦形剤である。
＜３＞ 崩壊剤が、クロスポビドン、及び低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）の少なくともいずれかである前記＜１＞から＜２＞のいずれかに記載の口腔内崩壊錠用直打賦形剤である。
＜４＞ 崩壊剤の体積平均粒子径が、５０μｍ以下である前記＜１＞から＜３＞のいずれかに記載の口腔内崩壊錠用直打賦形剤である。
＜５＞ 糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物を流動させながら、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して造粒することを特徴とする口腔内崩壊錠用直打賦形剤の製造方法である。
＜６＞ 混合物に対し、結合液を固形分として３０質量％～２００質量％噴霧して造粒する前記＜５＞に記載の口腔内崩壊錠用直打賦形剤の製造方法である。
＜７＞ 前記＜１＞から＜４＞のいずれかに記載の口腔内崩壊錠用直打賦形剤と、薬剤成分とを打錠して得られることを特徴とする口腔内崩壊錠である。 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 μm or less.
<5> Spray and granulate a binding liquid containing at least one of sugar and sugar alcohol while flowing a mixture containing at least one of sugar and sugar alcohol and a disintegrant. Is a method for producing a direct compression excipient for orally disintegrating tablets.
<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.
<7> An orally disintegrating tablet obtained by tableting the direct compression excipient for orally disintegrating tablet according to any one of <1> to <4> and a drug component. .
＜１＞ 糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物に、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して造粒することにより得られることを特徴とする口腔内崩壊錠用直打賦形剤である。
＜２＞ 糖が、乳糖であり、糖アルコールが、マンニトール、キシリトール、エリスリトール、及びラクチトールの少なくともいずれかである前記＜１＞に記載の口腔内崩壊錠用直打賦形剤である。
＜３＞ 崩壊剤が、クロスポビドン、及び低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）の少なくともいずれかである前記＜１＞から＜２＞のいずれかに記載の口腔内崩壊錠用直打賦形剤である。
＜４＞ 崩壊剤の体積平均粒子径が、５０μｍ以下である前記＜１＞から＜３＞のいずれかに記載の口腔内崩壊錠用直打賦形剤である。
＜５＞ 糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物を流動させながら、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して造粒することを特徴とする口腔内崩壊錠用直打賦形剤の製造方法である。
＜６＞ 混合物に対し、結合液を固形分として３０質量％～２００質量％噴霧して造粒する前記＜５＞に記載の口腔内崩壊錠用直打賦形剤の製造方法である。
＜７＞ 前記＜１＞から＜４＞のいずれかに記載の口腔内崩壊錠用直打賦形剤と、薬剤成分とを打錠して得られることを特徴とする口腔内崩壊錠である。 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 μm or less.
<5> Spray and granulate a binding liquid containing at least one of sugar and sugar alcohol while flowing a mixture containing at least one of sugar and sugar alcohol and a disintegrant. Is a method for producing a direct compression excipient for orally disintegrating tablets.
<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.
<7> An orally disintegrating tablet obtained by tableting the direct compression excipient for orally disintegrating tablet according to any one of <1> to <4> and a drug component. .
本発明によると、前記従来における諸問題を解決することができ、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる口腔内崩壊錠を製造するための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を提供することができる。
According to the present invention, it is possible to solve the above-mentioned conventional problems, and while maintaining the performance required for tablets, such as tablet formability, oral disintegration, friability, and drug content uniformity, for a long period of time. It is possible to provide 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.
（口腔内崩壊錠用直打賦形剤及びその製造方法）
本発明の口腔内崩壊錠用直打賦形剤は、糖類、崩壊剤、更に必要に応じてその他の添加剤を含む造粒物である。前記造粒物は、少なくとも前記糖類及び前記崩壊剤を含有する混合物に結合液を噴霧しながら造粒して得られる。
本発明の口腔内崩壊錠用直打賦形剤の製造方法は、糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物を流動させながら、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して製造する方法である。 (Orally disintegrating excipient for orally disintegrating tablets and production method thereof)
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.
本発明の口腔内崩壊錠用直打賦形剤は、糖類、崩壊剤、更に必要に応じてその他の添加剤を含む造粒物である。前記造粒物は、少なくとも前記糖類及び前記崩壊剤を含有する混合物に結合液を噴霧しながら造粒して得られる。
本発明の口腔内崩壊錠用直打賦形剤の製造方法は、糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物を流動させながら、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して製造する方法である。 (Orally disintegrating excipient for orally disintegrating tablets and production method thereof)
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.
前記口腔内崩壊錠用直打賦形剤は、前記糖類及び前記崩壊剤を混合して得られた混合物の表面が前記結合液によりコーティングされているため、前記糖類と前記崩壊剤との結合力が上昇するだけでなく、前記崩壊剤の吸湿性が低下する。それにより、本発明の口腔内崩壊錠用直打賦形剤は、長期間高湿度下に保存したとしても、硬度が低下せず、硬度安定性に優れる。また、吸湿による崩壊剤の膨張が抑えられることから、錠剤表面の変化が少ない。
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 | filler for orally disintegrating tablets of this invention is preserve | saved under high humidity for a long period of time, hardness does not fall and it is excellent in hardness stability. Moreover, since the expansion | swelling of the disintegrant by moisture absorption is suppressed, there are few changes of the tablet surface.
＜混合物＞
前記混合物は、前記糖類と、前記崩壊剤とを含み、更に必要に応じてその他の添加剤を含む。 <Mixture>
The mixture includes the saccharide and the disintegrant, and further includes other additives as necessary.
前記混合物は、前記糖類と、前記崩壊剤とを含み、更に必要に応じてその他の添加剤を含む。 <Mixture>
The mixture includes the saccharide and the disintegrant, and further includes other additives as necessary.
＜＜糖類＞＞
前記混合物における糖類としては、糖及び糖アルコールの少なくともいずれかの粉末であれば、特に制限はなく、目的に応じて適宜選択することができ、例えば、蔗糖、乳糖、果糖、マンニトール、キシリトール、エリスリトール、ソルビトール、マルチトール、イソマルト、ラクチトール、スクロース、グリセリン等の粉末などが挙げられる。これらは、１種単独で使用してもよく、２種以上を併用してもよい。これらの中でも、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、乳糖、マンニトール、キシリトール、エリスリトール、ラクチトールの粉末が好ましく、マンニトールの粉末が特に好ましい。 << saccharides >>
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. For example, sucrose, lactose, fructose, mannitol, xylitol, erythritol , Powders of sorbitol, maltitol, isomalt, lactitol, sucrose, glycerin and the like. These may be used alone or in combination of two or more. Among these, 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.
前記混合物における糖類としては、糖及び糖アルコールの少なくともいずれかの粉末であれば、特に制限はなく、目的に応じて適宜選択することができ、例えば、蔗糖、乳糖、果糖、マンニトール、キシリトール、エリスリトール、ソルビトール、マルチトール、イソマルト、ラクチトール、スクロース、グリセリン等の粉末などが挙げられる。これらは、１種単独で使用してもよく、２種以上を併用してもよい。これらの中でも、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、乳糖、マンニトール、キシリトール、エリスリトール、ラクチトールの粉末が好ましく、マンニトールの粉末が特に好ましい。 << saccharides >>
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. For example, sucrose, lactose, fructose, mannitol, xylitol, erythritol , Powders of sorbitol, maltitol, isomalt, lactitol, sucrose, glycerin and the like. These may be used alone or in combination of two or more. Among these, 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.
前記混合物における糖類の含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、前記口腔内崩壊錠用直打賦形剤における糖類の含有量は、７０質量％～９９質量％となるようにすることが好ましい。
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.
前記糖類としては、特に制限はなく、市販品を使用してよい。前記市販品としては、乳糖（ＤＦＥ社製、商品名「Ｐｈａｒｍａｔｏｓｅ」）、マンニトール（ＲＯＱＵＥＴＴＥ社製、商品名「Ｐｅａｒｌｉｔｏｌ ５０Ｃ」；三菱商事フードテック株式会社製、商品名「マンニット」）、エリスリトール（三菱化学フーズ株式会社製、商品名「エリスリトール」）、キシリトール（三菱商事フードテック株式会社製、商品名「キシリット」）、ソルビトール（三菱商事フードテック株式会社製、商品名「ソルビット」）、マルチトール（三菱商事フードテック株式会社製、商品名「アマルティ」、「レシス」）、ラクチトール（三菱商事フードテック株式会社製、商品名「ミルヘン」）などが挙げられる。
The saccharide is not particularly limited, and a commercially available product may be used. Examples of 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.
＜＜崩壊剤＞＞
前記崩壊剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、クロスポビドン、低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）、カルボキシメチルセルロース（カルボキシメチルセルロースＮａ、カルボキシメチルセルロースＣａ等）等のセルロース誘導体、結晶セルロース、ヒドロキシプロピルスターチ、コーンスターチ等のデンプンなどが挙げられる。
これらは、１種単独で使用してもよく、２種以上を併用してもよい。これらの中でも、クロスポビドン、低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）が、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で好ましく、クロスポビドンと、コーンスターチとの併用が、吸湿時の錠剤の硬度低下をより防ぐことができる点で、好ましい。 << Disintegrant >>
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.
前記崩壊剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、クロスポビドン、低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）、カルボキシメチルセルロース（カルボキシメチルセルロースＮａ、カルボキシメチルセルロースＣａ等）等のセルロース誘導体、結晶セルロース、ヒドロキシプロピルスターチ、コーンスターチ等のデンプンなどが挙げられる。
これらは、１種単独で使用してもよく、２種以上を併用してもよい。これらの中でも、クロスポビドン、低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）が、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で好ましく、クロスポビドンと、コーンスターチとの併用が、吸湿時の錠剤の硬度低下をより防ぐことができる点で、好ましい。 << Disintegrant >>
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.
前記崩壊剤の体積平均粒子径としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、１００μｍ以下が好ましく、５０μｍ以下がより好ましく、２０μｍ以上５０μｍ以下が特に好ましい。
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 μm or less in terms of producing an orally disintegrating tablet having excellent hardness stability and orally disintegrating properties. Is preferable, 50 μm or less is more preferable, and 20 μm or more and 50 μm or less is particularly preferable.
前記混合物における崩壊剤の含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、前記口腔内崩壊錠用直打賦形剤における崩壊剤の含有量は、１質量％～３０質量％となるようにすることが好ましい。
The content of the disintegrant in the mixture is not particularly limited and can be appropriately selected depending on the purpose. However, 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.
前記崩壊剤としては、特に制限はなく、適宜合成したものを使用してもよいし、市販品を使用してもよい。前記市販品として、クロスポビドン［（ＩＳＰ社製、商品名「ポリプラスドンＸＬ」、「ポリプラスドンＸＬ－１０」）、（ＢＡＳＦ社製、商品名「コリドンＣＬ」、「コリドンＣＬ－Ｆ」、「コリドンＣＬ－ＳＦ」）］、低置換度ヒドロキシプロピルセルロース（信越化学工業株式会社製、商品名「Ｌ－ＨＰＣ」）、コーンスターチ（日本食品化工株式会社製、商品名「コーンスターチＷ」）などが挙げられる。
The disintegrant is not particularly limited, and an appropriately synthesized product or a commercially available product may be used. As the above-mentioned commercially available products, 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.
＜＜その他の添加剤＞＞
前記混合物におけるその他の添加剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、流動化剤、甘味剤、滑沢剤、吸湿剤、除湿剤、コーティング剤、色素、矯味矯臭剤、溶解補助剤などが挙げられる。これらは１種単独で使用してもよく、２種以上を併用してもよい。
前記混合物におけるその他の添加剤は、後述する結合液に溶解乃至懸濁させて使用してもよい。
前記その他の添加剤の前記口腔内崩壊錠用直打賦形剤における含有量としては、特に制限はなく、目的に応じて適宜選択することができる。 << Other additives >>
Other 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 | limiting in particular as content in the said direct compression excipient | filler for orally disintegrating tablets of the said other additive, According to the objective, it can select suitably.
前記混合物におけるその他の添加剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、流動化剤、甘味剤、滑沢剤、吸湿剤、除湿剤、コーティング剤、色素、矯味矯臭剤、溶解補助剤などが挙げられる。これらは１種単独で使用してもよく、２種以上を併用してもよい。
前記混合物におけるその他の添加剤は、後述する結合液に溶解乃至懸濁させて使用してもよい。
前記その他の添加剤の前記口腔内崩壊錠用直打賦形剤における含有量としては、特に制限はなく、目的に応じて適宜選択することができる。 << Other additives >>
Other 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 | limiting in particular as content in the said direct compression excipient | filler for orally disintegrating tablets of the said other additive, According to the objective, it can select suitably.
＜結合液＞
前記結合液は、糖及び糖アルコールの少なくともいずれかを含み、更に必要に応じてその他の添加剤を含む。
前記結合液は、崩壊剤を含まないことが好ましい。
前記結合液としては、糖及び糖アルコールの少なくともいずれかを含有する溶液であれば、特に制限はなく、目的に応じて適宜選択することができ、例えば、蔗糖、乳糖、果糖、マンニトール、キシリトール、エリスリトール、ソルビトール、マルチトール、イソマルト、ラクチトール、スクロース、グリセリン等の溶液などが挙げられる。これらは、１種単独で使用してもよく、２種以上を併用してもよい。これらの中でも、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、乳糖、マンニトール、キシリトール、エリスリトール、ラクチトールの溶液が好ましく、マンニトールの溶液がより好ましい。 <Binding liquid>
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. For example, 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. Among these, 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.
前記結合液は、糖及び糖アルコールの少なくともいずれかを含み、更に必要に応じてその他の添加剤を含む。
前記結合液は、崩壊剤を含まないことが好ましい。
前記結合液としては、糖及び糖アルコールの少なくともいずれかを含有する溶液であれば、特に制限はなく、目的に応じて適宜選択することができ、例えば、蔗糖、乳糖、果糖、マンニトール、キシリトール、エリスリトール、ソルビトール、マルチトール、イソマルト、ラクチトール、スクロース、グリセリン等の溶液などが挙げられる。これらは、１種単独で使用してもよく、２種以上を併用してもよい。これらの中でも、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、乳糖、マンニトール、キシリトール、エリスリトール、ラクチトールの溶液が好ましく、マンニトールの溶液がより好ましい。 <Binding liquid>
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. For example, 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. Among these, 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.
前記結合液の調製方法としては、特に制限はなく、目的に応じて適宜選択することができるが、前記糖及び糖アルコールの少なくともいずれかの粉末を溶媒に溶解させることにより調製する方法などが挙げられる。前記溶媒としては、特に制限はなく、目的に応じて適宜選択することができるが、前記糖及び糖アルコールの少なくともいずれかの溶解性が良好となる点で、水が好ましい。
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 | limiting in particular as said solvent, Although it can select suitably according to the objective, Water is preferable at the point from which the solubility of at least any one of the said sugar and sugar alcohol becomes favorable.
前記結合液における前記糖及び糖アルコールの少なくともいずれかの濃度としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、マンニトールの場合は４０質量％～６０質量％が好ましい。
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.
前記結合液の前記混合物（少なくとも前記糖類及び前記崩壊剤を含有する混合物）に対する噴霧固形分量としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、３０質量％～２００質量％が好ましい。
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.
前記結合液としては、特に制限はなく、市販品を使用してよい。前記市販品としては、乳糖（ＤＦＥ社製、商品名「Ｐｈａｒｍａｔｏｓｅ」）、マンニトール（ＲＯＱＵＥＴＴＥ社製、商品名「Ｐｅａｒｌｉｔｏｌ ５０Ｃ」；三菱商事フードテック株式会社製、商品名「マンニット」）、エリスリトール（三菱化学フーズ株式会社製、商品名「エリスリトール」）、キシリトール（三菱商事フードテック株式会社製、商品名「キシリット」）、ソルビトール（三菱商事フードテック株式会社製、商品名「ソルビット」）、マルチトール（三菱商事フードテック株式会社製、商品名「アマルティ」、「レシス」）、ラクチトール（三菱商事フードテック株式会社製、商品名「ミルヘン」）などが挙げられ、これらの市販品（粉末）を、親水性溶媒等を用いて溶解液とすることにより調製したものを使用することができる。
The binding solution is not particularly limited, and a commercially available product may be used. Examples of 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. Use a solution prepared by using a hydrophilic solvent, etc. Door can be.
前記糖類と前記結合液との組合せとしては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、糖アルコールどうしが同種であることが好ましく、前記糖類としてマンニトール粉末と、前記結合液として、マンニトール溶液との組合せがより好ましい。
The combination of the saccharide and the binding liquid is not particularly limited and may be appropriately selected depending on the intended purpose. However, 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.
＜口腔内崩壊錠用直打賦形剤（造粒物）の粉体物性＞
前記口腔内崩壊錠用直打賦形剤（造粒物）の累積分布図における粒径としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、Ｄ１０値としては、３０μｍ～９０μｍが好ましく、Ｄ５０値としては、７０μｍ～１５０μｍが好ましく、Ｄ９０値としては、１６０μｍ～２５０μｍが好ましい。なお、前記Ｄ５０値は、前記口腔内崩壊錠用直打賦形剤（造粒物）の体積平均粒子径に相当する。
前記粒径は、例えば、レーザー回析／散乱式粒度分布測定装置（マイクロトラックＨＲＡ（日機装株式会社製）により測定することができる。 <Powder Physical Properties of Oral Disintegrating Tablet Direct Injection Excipient (Granulated Product)>
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 μm to 90 μm, the D 50 value is preferably 70 μm to 150 μm, and the D 90 value is preferably 160 μm to 250 μm in that an orally disintegrating tablet having excellent properties can be produced. Incidentally, 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.)).
前記口腔内崩壊錠用直打賦形剤（造粒物）の累積分布図における粒径としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、Ｄ１０値としては、３０μｍ～９０μｍが好ましく、Ｄ５０値としては、７０μｍ～１５０μｍが好ましく、Ｄ９０値としては、１６０μｍ～２５０μｍが好ましい。なお、前記Ｄ５０値は、前記口腔内崩壊錠用直打賦形剤（造粒物）の体積平均粒子径に相当する。
前記粒径は、例えば、レーザー回析／散乱式粒度分布測定装置（マイクロトラックＨＲＡ（日機装株式会社製）により測定することができる。 <Powder Physical Properties of Oral Disintegrating Tablet Direct Injection Excipient (Granulated Product)>
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 μm to 90 μm, the D 50 value is preferably 70 μm to 150 μm, and the D 90 value is preferably 160 μm to 250 μm in that an orally disintegrating tablet having excellent properties can be produced. Incidentally, 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.)).
前記口腔内崩壊錠用直打賦形剤（造粒物）の篩目７５μｍの通過率としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、５％～５０％が好ましい。
There is no restriction | limiting in particular as the passage rate of the 75 micrometers sieve mesh of the said direct-disintegrating tablet for oral disintegrating tablets (granulated material), Although it can select suitably according to the objective, Hardness stability and oral disintegration From the viewpoint that an orally disintegrating tablet having excellent properties can be produced, 5% to 50% is preferable.
前記口腔内崩壊錠用直打賦形剤（造粒物）の嵩密度（ルーズ）としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、０．４ｇ／ｍＬ～０．６ｇ／ｍＬが好ましい。
前記口腔内崩壊錠用直打賦形剤（造粒物）の嵩密度（タップ）としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、０．５ｇ／ｍＬ～０．７ｇ／ｍＬが好ましい。
前記嵩密度（ルーズ）、及び嵩密度（タップ）は、例えば、Ａ．Ｂ．Ｄ粉体特性測定器（筒井理化学器械株式会社製）により測定することができる。 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 | limiting in particular as a bulk density (tap) of the said direct compression excipient | filler (granulated material) for orally disintegrating tablets, Although it can select suitably according to the objective, Hardness stability and orally disintegrating property 0.5 g / mL to 0.7 g / mL is preferable in that an orally disintegrating tablet excellent in the above can be produced.
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.)
前記口腔内崩壊錠用直打賦形剤（造粒物）の嵩密度（タップ）としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、０．５ｇ／ｍＬ～０．７ｇ／ｍＬが好ましい。
前記嵩密度（ルーズ）、及び嵩密度（タップ）は、例えば、Ａ．Ｂ．Ｄ粉体特性測定器（筒井理化学器械株式会社製）により測定することができる。 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 | limiting in particular as a bulk density (tap) of the said direct compression excipient | filler (granulated material) for orally disintegrating tablets, Although it can select suitably according to the objective, Hardness stability and orally disintegrating property 0.5 g / mL to 0.7 g / mL is preferable in that an orally disintegrating tablet excellent in the above can be produced.
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.)
前記口腔内崩壊錠用直打賦形剤（造粒物）の安息角としては、特に制限はなく、目的に応じて適宜選択することができるが、硬度安定性及び口腔内崩壊性に優れる口腔内崩壊錠を製造できる点で、３０°～４０°が好ましい。
前記安息角は、例えば、特開平６－２０５９５９号公報に記載されている野上・杉原法により測定することができる。 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.
前記安息角は、例えば、特開平６－２０５９５９号公報に記載されている野上・杉原法により測定することができる。 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.
＜口腔内崩壊錠用直打賦形剤の製造方法＞
前記口腔内崩壊錠用直打賦形剤の製造方法としては、前記糖類及び前記崩壊剤に前記結合液を含む液を噴霧しながら流動層造粒して得られる方法であれば、特に制限はなく、目的に応じて適宜選択することができる。 <Method for Producing Direct Excipient for Orally Disintegrating Tablet>
As 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.
前記口腔内崩壊錠用直打賦形剤の製造方法としては、前記糖類及び前記崩壊剤に前記結合液を含む液を噴霧しながら流動層造粒して得られる方法であれば、特に制限はなく、目的に応じて適宜選択することができる。 <Method for Producing Direct Excipient for Orally Disintegrating Tablet>
As 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.
－流動層造粒－
前記流動層造粒は、前記結合液を噴霧することにより前記糖類及び前記崩壊剤の粒子間に液体架橋の凝集を起こさせて造粒する方法であり、流動層造粒装置により実施することができる。 -Fluidized bed granulation-
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.
前記流動層造粒は、前記結合液を噴霧することにより前記糖類及び前記崩壊剤の粒子間に液体架橋の凝集を起こさせて造粒する方法であり、流動層造粒装置により実施することができる。 -Fluidized bed granulation-
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.
前記流動層造粒装置は、流動化（浮遊流動）された粉粒体（前記糖類と前記崩壊剤とを含有する混合物）に前記結合液をスプレーし、前記粉粒体を前記結合液によりコーティングして造粒する装置である。
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.
前記流動層造粒装置の市販装置としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、フローコーター、スパイラフロー、グラニュレックス（いずれも、フロイント産業株式会社製）などが挙げられる。
There is no restriction | limiting in particular as a commercially available apparatus of the said fluidized bed granulation apparatus, According to the objective, it can select suitably, For example, a flow coater, Spiraflow, Granurex (all are the Freund Sangyo Co., Ltd. product) etc. Can be mentioned.
＜口腔内崩壊錠用直打賦形剤の効果＞
本発明の口腔内崩壊錠用直打賦形剤は、薬剤成分と混合して打錠するだけで、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる口腔内崩壊錠を提供することができる。また、本発明の口腔内崩壊錠用直打賦形剤を用いることにより、口腔内崩壊錠における薬剤成分の配合量を簡便に調節することができるため、従来と比して口腔内崩壊錠の製剤設計が容易となる。 <Effect of direct compression excipient for orally disintegrating tablets>
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 | medical component in an orally disintegrating tablet can be easily adjusted by using the direct compression excipient | filler for orally disintegrating tablets of this invention, compared with the former, an orally disintegrating tablet Formulation design becomes easy.
本発明の口腔内崩壊錠用直打賦形剤は、薬剤成分と混合して打錠するだけで、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる口腔内崩壊錠を提供することができる。また、本発明の口腔内崩壊錠用直打賦形剤を用いることにより、口腔内崩壊錠における薬剤成分の配合量を簡便に調節することができるため、従来と比して口腔内崩壊錠の製剤設計が容易となる。 <Effect of direct compression excipient for orally disintegrating tablets>
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 | medical component in an orally disintegrating tablet can be easily adjusted by using the direct compression excipient | filler for orally disintegrating tablets of this invention, compared with the former, an orally disintegrating tablet Formulation design becomes easy.
（口腔内崩壊錠）
本発明の口腔内崩壊錠は、上述の口腔内崩壊錠用直打賦形剤、及び薬剤成分を含み、更に必要に応じてその他の成分を含む。 (Orally disintegrating tablets)
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.
本発明の口腔内崩壊錠は、上述の口腔内崩壊錠用直打賦形剤、及び薬剤成分を含み、更に必要に応じてその他の成分を含む。 (Orally disintegrating tablets)
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.
＜口腔内崩壊錠用直打賦形剤＞
前記口腔内崩壊錠用直打賦形剤は、上述の口腔内崩壊錠用直打賦形剤を用いる。
前記口腔内崩壊錠用直打賦形剤の前記口腔内崩壊錠における含有量としては、２０質量％～９９．９質量％が好ましい。 <Direct compression excipient for orally disintegrating tablets>
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.
前記口腔内崩壊錠用直打賦形剤は、上述の口腔内崩壊錠用直打賦形剤を用いる。
前記口腔内崩壊錠用直打賦形剤の前記口腔内崩壊錠における含有量としては、２０質量％～９９．９質量％が好ましい。 <Direct compression excipient for orally disintegrating tablets>
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.
＜薬剤成分＞
前記薬剤成分としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、高血圧薬、狭心薬、気管支拡張薬、向精神薬、抗不安薬、抗うつ薬、催眠鎮静薬、抗パーキンソン薬、アレルギー用薬、歯科口腔用薬、強心薬、解熱鎮痛消炎薬、抗ヒスタミン薬、鎮咳薬、制酸薬、生薬、降圧薬、抗生物質、抗菌剤、不整脈用薬、冠血管拡張薬、末梢血管拡張薬、高脂血症用薬、利胆薬、ホルモン薬、痛風治療薬、抗リウマチ薬、化学療法薬、糖尿病用薬、鎮吐薬、抗てんかん薬、交感神経興奮薬、骨粗鬆症用薬、抗悪性腫瘍薬、免疫抑制薬、泌尿器科用薬、胃腸薬、脳代謝改善薬、脳循環改善薬、呼吸促進薬、血管収縮薬、鎮暈薬、去痰薬、中枢神経作用用薬、潰瘍治療薬、胃粘膜修復薬、鎮痛鎮痙薬等に使用される薬剤成分などが挙げられ、具体的には、テモカプリル塩酸塩、カベルゴリン、ベシル酸アムロジピン、オメプラゾール、ランソプラゾール、ファモチジン、ラフチジン、エカベトナトリウム、クエン酸モサプリド、レバミピド、ボグリボース、リスペリドン、イミダプリル塩酸塩、メロキシカム、ミルナシプラン塩酸塩、レボフロキサシン、クラリスロマイシン、サルポグレラート塩酸塩、トスフロキサシントシル酸塩、タムスロシン塩酸塩、ミゾリビン、タクロリムス水和物、フルボキサミンマレイン酸塩、グリメピリド、ラモセトロン塩酸塩、ニコランジル、ドネペジル塩酸塩、酒石酸ゾルピデム、ピオグリタゾン塩酸塩、アレンドロン酸ナトリウム水和物、リセドロン酸ナトリウム水和物、アトルバスタチンカルシウム水和物、フルバスタチンナトリウム、ロラタジン、ロサルタンカリウム、パロキセチン塩酸塩水和物、ラベプラゾールナトリウム、リバビリン、コハク酸スマトリプタン、ペロスピロン塩酸塩水和物、フマル酸クエチアピン、オロパタジン塩酸塩、フェキソフェナジン塩酸塩、エバスチン、セフジトレンピボキシル、塩酸セフカペンピボキシル、バルサルタン、ビカルタミド、アカルボースなどが挙げられる。 <Drug component>
The drug component is not particularly limited and may be appropriately selected depending on the purpose. For example, 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. Specific examples include 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, atorvastatin calcium hydrate, fluvastatin nato Um, loratadine, losartan potassium, paroxetine hydrochloride hydrate, rabeprazole sodium, ribavirin, sumatriptan succinate, perospirone hydrochloride hydrate, quetiapine fumarate, olopatadine hydrochloride, fexofenadine hydrochloride, ebastine, cefditoren pivoxil, Examples include cefcapene hydrochloride, valsartan, bicalutamide, and acarbose.
前記薬剤成分としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、高血圧薬、狭心薬、気管支拡張薬、向精神薬、抗不安薬、抗うつ薬、催眠鎮静薬、抗パーキンソン薬、アレルギー用薬、歯科口腔用薬、強心薬、解熱鎮痛消炎薬、抗ヒスタミン薬、鎮咳薬、制酸薬、生薬、降圧薬、抗生物質、抗菌剤、不整脈用薬、冠血管拡張薬、末梢血管拡張薬、高脂血症用薬、利胆薬、ホルモン薬、痛風治療薬、抗リウマチ薬、化学療法薬、糖尿病用薬、鎮吐薬、抗てんかん薬、交感神経興奮薬、骨粗鬆症用薬、抗悪性腫瘍薬、免疫抑制薬、泌尿器科用薬、胃腸薬、脳代謝改善薬、脳循環改善薬、呼吸促進薬、血管収縮薬、鎮暈薬、去痰薬、中枢神経作用用薬、潰瘍治療薬、胃粘膜修復薬、鎮痛鎮痙薬等に使用される薬剤成分などが挙げられ、具体的には、テモカプリル塩酸塩、カベルゴリン、ベシル酸アムロジピン、オメプラゾール、ランソプラゾール、ファモチジン、ラフチジン、エカベトナトリウム、クエン酸モサプリド、レバミピド、ボグリボース、リスペリドン、イミダプリル塩酸塩、メロキシカム、ミルナシプラン塩酸塩、レボフロキサシン、クラリスロマイシン、サルポグレラート塩酸塩、トスフロキサシントシル酸塩、タムスロシン塩酸塩、ミゾリビン、タクロリムス水和物、フルボキサミンマレイン酸塩、グリメピリド、ラモセトロン塩酸塩、ニコランジル、ドネペジル塩酸塩、酒石酸ゾルピデム、ピオグリタゾン塩酸塩、アレンドロン酸ナトリウム水和物、リセドロン酸ナトリウム水和物、アトルバスタチンカルシウム水和物、フルバスタチンナトリウム、ロラタジン、ロサルタンカリウム、パロキセチン塩酸塩水和物、ラベプラゾールナトリウム、リバビリン、コハク酸スマトリプタン、ペロスピロン塩酸塩水和物、フマル酸クエチアピン、オロパタジン塩酸塩、フェキソフェナジン塩酸塩、エバスチン、セフジトレンピボキシル、塩酸セフカペンピボキシル、バルサルタン、ビカルタミド、アカルボースなどが挙げられる。 <Drug component>
The drug component is not particularly limited and may be appropriately selected depending on the purpose. For example, 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. Specific examples include 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, atorvastatin calcium hydrate, fluvastatin nato Um, loratadine, losartan potassium, paroxetine hydrochloride hydrate, rabeprazole sodium, ribavirin, sumatriptan succinate, perospirone hydrochloride hydrate, quetiapine fumarate, olopatadine hydrochloride, fexofenadine hydrochloride, ebastine, cefditoren pivoxil, Examples include cefcapene hydrochloride, valsartan, bicalutamide, and acarbose.
＜その他の成分＞
前記その他の成分としては、前記口腔内崩壊錠に用いられる成分であれば、特に制限はなく、目的に応じて適宜選択することができるが、滑沢剤、流動化剤、甘味剤などが好適に挙げられ、この他にも、吸湿、除湿剤、コーティング剤、色素、矯味矯臭剤、溶解補助剤などが挙げられる。これらは１種単独で使用してもよく、２種以上を併用してもよい。 <Other ingredients>
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. In addition, 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.
前記その他の成分としては、前記口腔内崩壊錠に用いられる成分であれば、特に制限はなく、目的に応じて適宜選択することができるが、滑沢剤、流動化剤、甘味剤などが好適に挙げられ、この他にも、吸湿、除湿剤、コーティング剤、色素、矯味矯臭剤、溶解補助剤などが挙げられる。これらは１種単独で使用してもよく、２種以上を併用してもよい。 <Other ingredients>
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. In addition, 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.
前記滑沢剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、タルク、硬化油などが挙げられる。
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.
前記流動化剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、親水性シリカ、疎水性シリカ、ケイ酸カルシウム、アルキルホスフェイト（ＰＡＰ）、水溶性高分子化合物、無水リン酸水素カルシウム、ケイ酸マグネシウム、ケイ酸カルシウム、軽質無水ケイ酸、含水二酸化ケイ素、酸化マグネシウムなどが挙げられる。
The fluidizing agent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, hydrophilic silica, hydrophobic silica, calcium silicate, alkyl phosphate (PAP), water-soluble polymer compound, Anhydrous calcium hydrogen phosphate, magnesium silicate, calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium oxide and the like can be mentioned.
前記甘味剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、アスパルテーム、グルコース、ガラクトース、マンノース、リボース、アラビノース、マルトース、ラクトース、イソマルトース、セロビオース、ゲンチオビオース、パラチノースなどが挙げられる。
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.
＜口腔内崩壊錠の製造方法＞
前記口腔内崩壊錠の製造方法としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、前記口腔内崩壊錠用直打賦形剤と前記薬剤成分とを混合した後、打錠して錠剤化することにより製造する方法などが挙げられる。この際、使用する混合機や打錠機などは一般的に用いられるものを使用することができる。 <Method for producing orally disintegrating tablet>
The method for producing the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the purpose.For example, after mixing the direct-disintegrating excipient for the orally disintegrating tablet and the drug component, Examples thereof include a method of producing by tableting into tablets. At this time, generally used mixers and tableting machines can be used.
前記口腔内崩壊錠の製造方法としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、前記口腔内崩壊錠用直打賦形剤と前記薬剤成分とを混合した後、打錠して錠剤化することにより製造する方法などが挙げられる。この際、使用する混合機や打錠機などは一般的に用いられるものを使用することができる。 <Method for producing orally disintegrating tablet>
The method for producing the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the purpose.For example, after mixing the direct-disintegrating excipient for the orally disintegrating tablet and the drug component, Examples thereof include a method of producing by tableting into tablets. At this time, generally used mixers and tableting machines can be used.
＜口腔内崩壊錠の使用形態＞
前記口腔内崩壊錠の使用形態としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、水なしで経口投与する方法、水と共に経口投与する方法などが挙げられる。 <Usage form of orally disintegrating tablet>
There is no restriction | limiting in particular as a usage form of the said orally disintegrating tablet, According to the objective, it can select suitably, For example, the method of oral administration without water, the method of oral administration with water, etc. are mentioned.
前記口腔内崩壊錠の使用形態としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、水なしで経口投与する方法、水と共に経口投与する方法などが挙げられる。 <Usage form of orally disintegrating tablet>
There is no restriction | limiting in particular as a usage form of the said orally disintegrating tablet, According to the objective, it can select suitably, For example, the method of oral administration without water, the method of oral administration with water, etc. are mentioned.
＜口腔内崩壊錠の効果＞
本発明の口腔内崩壊錠は、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる。また、本発明の口腔内崩壊錠用直打賦形剤を用いることにより、口腔内崩壊錠における薬剤成分及び崩壊剤の配合量を簡便に調節することができるため、従来と比して口腔内崩壊錠の製剤設計が容易となる。 <Effects of orally disintegrating tablets>
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.
本発明の口腔内崩壊錠は、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる。また、本発明の口腔内崩壊錠用直打賦形剤を用いることにより、口腔内崩壊錠における薬剤成分及び崩壊剤の配合量を簡便に調節することができるため、従来と比して口腔内崩壊錠の製剤設計が容易となる。 <Effects of orally disintegrating tablets>
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.
以下に本発明の実施例等を説明するが、本発明は、これらの実施例等に何ら限定されるものではない。
Examples of the present invention will be described below, but the present invention is not limited to these examples.
（試験例１：造粒方法の違いによる比較試験）
試験例１では、口腔内崩壊錠用直打賦形剤を製造するに際して、造粒方法の違い（崩壊剤を投入するタイミングの違い）により、得られた口腔内崩壊錠用直打賦形剤の物性、並びに該口腔内崩壊錠用直打賦形剤を用いて製造した口腔内崩壊プラセボ錠の硬度安定性及び口腔内崩壊性がどのように影響するのかについて、その違いを評価した。 (Test Example 1: Comparative test with different granulation methods)
In 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.
試験例１では、口腔内崩壊錠用直打賦形剤を製造するに際して、造粒方法の違い（崩壊剤を投入するタイミングの違い）により、得られた口腔内崩壊錠用直打賦形剤の物性、並びに該口腔内崩壊錠用直打賦形剤を用いて製造した口腔内崩壊プラセボ錠の硬度安定性及び口腔内崩壊性がどのように影響するのかについて、その違いを評価した。 (Test Example 1: Comparative test with different granulation methods)
In 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.
－口腔内崩壊錠用直打賦形剤の製造－
口腔内崩壊錠用直打賦形剤は、糖類及び崩壊剤をフローコーター（ＦＬＯ－５、フロイント産業株式会社製）内にて結合液を噴霧しながら流動層造粒することにより製造した。用いた材料を表（１－１）に示し、用いた材料の組成を表（１－２）に示し、得られた直打賦形剤の粉体物性を表（１－３）及び図１Ａに示した。 -Manufacture of direct compression excipients for orally disintegrating tablets-
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.
口腔内崩壊錠用直打賦形剤は、糖類及び崩壊剤をフローコーター（ＦＬＯ－５、フロイント産業株式会社製）内にて結合液を噴霧しながら流動層造粒することにより製造した。用いた材料を表（１－１）に示し、用いた材料の組成を表（１－２）に示し、得られた直打賦形剤の粉体物性を表（１－３）及び図１Ａに示した。 -Manufacture of direct compression excipients for orally disintegrating tablets-
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.
－比較口腔内崩壊錠用直打賦形剤の製造－
比較口腔内崩壊錠用直打賦形剤は、糖類を造粒装置（フローコーター（ＦＬＯ－５、フロイント産業株式会社製））内に添加して結合液を４ｋｇ噴霧した後に、崩壊剤、更に必要に応じて流動化剤を造粒装置に添加して、残りの結合液を噴霧して流動層造粒することにより製造（後添加）した。用いた材料を表（１－１）に示し、組成を表（１－２）に示し、得られた直打賦形剤の粉体物性を表（１－３）に示した。 -Manufacture of direct injection excipients for comparative orally disintegrating tablets-
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).
比較口腔内崩壊錠用直打賦形剤は、糖類を造粒装置（フローコーター（ＦＬＯ－５、フロイント産業株式会社製））内に添加して結合液を４ｋｇ噴霧した後に、崩壊剤、更に必要に応じて流動化剤を造粒装置に添加して、残りの結合液を噴霧して流動層造粒することにより製造（後添加）した。用いた材料を表（１－１）に示し、組成を表（１－２）に示し、得られた直打賦形剤の粉体物性を表（１－３）に示した。 -Manufacture of direct injection excipients for comparative orally disintegrating tablets-
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).
－口腔内崩壊プラセボ錠の製造－
口腔内崩壊錠は、表（１－４）に記載の直打賦形剤及び滑沢剤を表（１－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（１－４）に記載の条件で打錠することにより製造した。 -Manufacture of orally disintegrating placebo tablets-
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).
口腔内崩壊錠は、表（１－４）に記載の直打賦形剤及び滑沢剤を表（１－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（１－４）に記載の条件で打錠することにより製造した。 -Manufacture of orally disintegrating placebo tablets-
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).
－比較口腔内崩壊プラセボ錠の製造－
比較口腔内崩壊錠は、表（１－４）に記載の直打賦形剤及び滑沢剤を表（１－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（１－４）に記載の条件で打錠することにより製造した。 -Production of comparative orally disintegrating placebo tablets-
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).
比較口腔内崩壊錠は、表（１－４）に記載の直打賦形剤及び滑沢剤を表（１－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（１－４）に記載の条件で打錠することにより製造した。 -Production of comparative orally disintegrating placebo tablets-
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).
（試験例１の評価）
－錠剤成形性－
錠剤成形性の評価は、得られた「口腔内崩壊プラセボ錠」及び「比較口腔内崩壊プラセボ錠」について、硬度を測定することにより行った。測定機にはシュロイニゲル錠剤硬度計８Ｍ（フロイント産業株式会社製）を用いた。結果を図１Ａに示した。 (Evaluation of Test Example 1)
-Tablet formability-
Evaluation of tablet moldability was performed by measuring the hardness of the obtained “orally disintegrating placebo tablets” and “comparing orally disintegrating placebo tablets”. As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in FIG. 1A.
－錠剤成形性－
錠剤成形性の評価は、得られた「口腔内崩壊プラセボ錠」及び「比較口腔内崩壊プラセボ錠」について、硬度を測定することにより行った。測定機にはシュロイニゲル錠剤硬度計８Ｍ（フロイント産業株式会社製）を用いた。結果を図１Ａに示した。 (Evaluation of Test Example 1)
-Tablet formability-
Evaluation of tablet moldability was performed by measuring the hardness of the obtained “orally disintegrating placebo tablets” and “comparing orally disintegrating placebo tablets”. As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in FIG. 1A.
－硬度安定性－
硬度安定性の評価は、各プラセボ錠（硬度５０Ｎ前後のものを使用）を２５℃、８０％ＲＨの環境（恒湿塩：ＫＢｒ）で開放状態にて１週間保管し、硬度（ｎ＝３）の変化を確認することにより行った。結果を図１Ｂに示した。 -Hardness stability-
Hardness stability was evaluated by storing each placebo tablet (use a product with a hardness of around 50 N) in an open state at 25 ° C. and 80% RH (constant humidity salt: KBr) for 1 week, and hardness (n = 3 ). The results are shown in FIG. 1B.
硬度安定性の評価は、各プラセボ錠（硬度５０Ｎ前後のものを使用）を２５℃、８０％ＲＨの環境（恒湿塩：ＫＢｒ）で開放状態にて１週間保管し、硬度（ｎ＝３）の変化を確認することにより行った。結果を図１Ｂに示した。 -Hardness stability-
Hardness stability was evaluated by storing each placebo tablet (use a product with a hardness of around 50 N) in an open state at 25 ° C. and 80% RH (constant humidity salt: KBr) for 1 week, and hardness (n = 3 ). The results are shown in FIG. 1B.
－結果－
図１Ａ及び図１Ｂにより、［口腔内崩壊（ＯＤ）プラセボ錠１］は、成形性が高く、高湿度下においても硬度が低下しにくいことがわかった。一方、［比較口腔内崩壊（ＯＤ）プラセボ錠１］及び［比較口腔内崩壊（ＯＤ）プラセボ錠２］は、高湿度下における硬度低下が大きいことがわかった。よって、硬度安定性及び口腔内崩壊性を良好に保つためには、前記糖類及び前記崩壊剤を混合して得られた混合物に対し、前記結合液を固形分として２０質量％以上噴霧する必要があることがわかった。 -result-
From FIG. 1A and FIG. 1B, it was found that [Oral Disintegration (OD) Placebo Tablet 1] has high moldability and hardly decreases in hardness even under high humidity. On the other hand, [Comparative Oral Disintegration (OD) Placebo Tablet 1] and [Comparative Oral Disintegration (OD) Placebo Tablet 2] were found to have a large decrease in hardness under high humidity. Therefore, in order to maintain good hardness stability and disintegration in the oral cavity, it is necessary to spray 20% by mass or more of the binding liquid as a solid content on the mixture obtained by mixing the saccharide and the disintegrant. I found out.
図１Ａ及び図１Ｂにより、［口腔内崩壊（ＯＤ）プラセボ錠１］は、成形性が高く、高湿度下においても硬度が低下しにくいことがわかった。一方、［比較口腔内崩壊（ＯＤ）プラセボ錠１］及び［比較口腔内崩壊（ＯＤ）プラセボ錠２］は、高湿度下における硬度低下が大きいことがわかった。よって、硬度安定性及び口腔内崩壊性を良好に保つためには、前記糖類及び前記崩壊剤を混合して得られた混合物に対し、前記結合液を固形分として２０質量％以上噴霧する必要があることがわかった。 -result-
From FIG. 1A and FIG. 1B, it was found that [Oral Disintegration (OD) Placebo Tablet 1] has high moldability and hardly decreases in hardness even under high humidity. On the other hand, [Comparative Oral Disintegration (OD) Placebo Tablet 1] and [Comparative Oral Disintegration (OD) Placebo Tablet 2] were found to have a large decrease in hardness under high humidity. Therefore, in order to maintain good hardness stability and disintegration in the oral cavity, it is necessary to spray 20% by mass or more of the binding liquid as a solid content on the mixture obtained by mixing the saccharide and the disintegrant. I found out.
（試験例２：単純混合品との比較試験）
試験例２では、本願発明の「口腔内崩壊錠用直打賦形剤」を用いて製造した「口腔内崩壊錠」、及び「比較口腔内崩壊錠用直打賦形剤」を用いて製造した「比較口腔内崩壊錠」の硬度安定性及び薬物含量均一性の違いを評価した。 (Test Example 2: Comparison test with simple mixed product)
In 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.
試験例２では、本願発明の「口腔内崩壊錠用直打賦形剤」を用いて製造した「口腔内崩壊錠」、及び「比較口腔内崩壊錠用直打賦形剤」を用いて製造した「比較口腔内崩壊錠」の硬度安定性及び薬物含量均一性の違いを評価した。 (Test Example 2: Comparison test with simple mixed product)
In 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.
－口腔内崩壊錠の製造－
口腔内崩壊錠は、表（２－１）に記載の材料を表（２－２）に記載の条件で混合して打錠することにより製造した。なお、表（２－１）中のＯＤ錠用直打賦形剤は、試験例１で製造したもの、即ち、「糖類（糖アルコール（Ｄ－マンニトール））」及び「崩壊剤（クロスポビトン）」を造粒装置内にて結合液を噴霧しながら流動層造粒することにより製造したものを使用した。 -Manufacture of orally disintegrating tablets-
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 excipients for OD tablets in Table (2-1) were those manufactured in Test Example 1, that is, “sugars (sugar alcohol (D-mannitol))” and “disintegrant (crospoviton)” Was produced by fluidized bed granulation while spraying the binding liquid in a granulator.
口腔内崩壊錠は、表（２－１）に記載の材料を表（２－２）に記載の条件で混合して打錠することにより製造した。なお、表（２－１）中のＯＤ錠用直打賦形剤は、試験例１で製造したもの、即ち、「糖類（糖アルコール（Ｄ－マンニトール））」及び「崩壊剤（クロスポビトン）」を造粒装置内にて結合液を噴霧しながら流動層造粒することにより製造したものを使用した。 -Manufacture of orally disintegrating tablets-
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 excipients for OD tablets in Table (2-1) were those manufactured in Test Example 1, that is, “sugars (sugar alcohol (D-mannitol))” and “disintegrant (crospoviton)” Was produced by fluidized bed granulation while spraying the binding liquid in a granulator.
－比較口腔内崩壊錠の製造－
比較口腔内崩壊錠は、表（２－１）に記載の材料を表（２－２）に記載の条件で混合して打錠することにより製造した。なお、表（２－１）中の比較ＯＤ錠用直打賦形剤は、「糖類（糖アルコール（Ｄ－マンニトール））」と「崩壊剤（クロスポビトン）」とを９：１で混合（手混合、３分間）することにより得た。 -Production of comparative orally disintegrating tablets-
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).
比較口腔内崩壊錠は、表（２－１）に記載の材料を表（２－２）に記載の条件で混合して打錠することにより製造した。なお、表（２－１）中の比較ＯＤ錠用直打賦形剤は、「糖類（糖アルコール（Ｄ－マンニトール））」と「崩壊剤（クロスポビトン）」とを９：１で混合（手混合、３分間）することにより得た。 -Production of comparative orally disintegrating tablets-
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).
（試験例２の評価）
－硬度安定性－
硬度安定性の評価は、得られた「口腔内崩壊（ＯＤ）錠」及び「比較口腔内崩壊（ＯＤ）錠」を２５℃の開放状態にて、湿度の異なる環境下（５５％ＲＨ（恒湿塩：Ｍｇ（ＮＯ３）２）、７０％ＲＨ（恒湿塩：ＫＩ）、８０％ＲＨ（恒湿塩：ＫＢｒ））にて７日間保管し、硬度（ｎ＝３）の変化を確認することにより行った。結果を図２Ａ～図２Ｃに示した。 (Evaluation of Test Example 2)
-Hardness stability-
The evaluation of hardness stability was carried out by subjecting the obtained “oral disintegration (OD) tablet” and “comparative oral disintegration (OD) tablet” to an open state at 25 ° C. in an environment with different humidity (55% RH (constant Store for 7 days in wet salt: Mg (NO 3 ) 2 ), 70% RH (constant humidity salt: KI), 80% RH (constant humidity salt: KBr)) and confirm the change in hardness (n = 3) It was done by doing. The results are shown in FIGS. 2A to 2C.
－硬度安定性－
硬度安定性の評価は、得られた「口腔内崩壊（ＯＤ）錠」及び「比較口腔内崩壊（ＯＤ）錠」を２５℃の開放状態にて、湿度の異なる環境下（５５％ＲＨ（恒湿塩：Ｍｇ（ＮＯ３）２）、７０％ＲＨ（恒湿塩：ＫＩ）、８０％ＲＨ（恒湿塩：ＫＢｒ））にて７日間保管し、硬度（ｎ＝３）の変化を確認することにより行った。結果を図２Ａ～図２Ｃに示した。 (Evaluation of Test Example 2)
-Hardness stability-
The evaluation of hardness stability was carried out by subjecting the obtained “oral disintegration (OD) tablet” and “comparative oral disintegration (OD) tablet” to an open state at 25 ° C. in an environment with different humidity (55% RH (constant Store for 7 days in wet salt: Mg (NO 3 ) 2 ), 70% RH (constant humidity salt: KI), 80% RH (constant humidity salt: KBr)) and confirm the change in hardness (n = 3) It was done by doing. The results are shown in FIGS. 2A to 2C.
－薬物含量均一性－
口腔内崩壊錠の薬物含量均一性の評価は、得られた「口腔内崩壊錠」及び「比較口腔内崩壊錠」を第１５改正日局方に基づき、判定値（ｎ＝１０）を算出することにより行った。結果を表（２－３）に示した。 -Uniformity of drug content-
Evaluation of drug content uniformity of orally disintegrating tablets is based on the fifteenth revised JP on the obtained “orally disintegrating tablets” and “comparing orally disintegrating tablets”, and a determination value (n = 10) is calculated. Was done. The results are shown in Table (2-3).
口腔内崩壊錠の薬物含量均一性の評価は、得られた「口腔内崩壊錠」及び「比較口腔内崩壊錠」を第１５改正日局方に基づき、判定値（ｎ＝１０）を算出することにより行った。結果を表（２－３）に示した。 -Uniformity of drug content-
Evaluation of drug content uniformity of orally disintegrating tablets is based on the fifteenth revised JP on the obtained “orally disintegrating tablets” and “comparing orally disintegrating tablets”, and a determination value (n = 10) is calculated. Was done. The results are shown in Table (2-3).
－結果－
図２Ａ～図２Ｃにより、［口腔内崩壊（ＯＤ）錠１］が最も硬度安定性に優れることがわかった。また、表（２－３）より、［口腔内崩壊（ＯＤ）錠１］が最も薬物含量均一性に優れることがわかった。［口腔内崩壊（ＯＤ）錠１］において使用する［口腔内崩壊（ＯＤ）錠用直打賦形剤１］は、糖類及び崩壊剤を混合して得られた混合物の表面が、結合液によりコーティングされているため、糖類と崩壊剤との結合力が上昇するだけでなく、崩壊剤の吸湿性が低下することがわかった。それにより、本発明の［口腔内崩壊（ＯＤ）錠１］は、長期間高湿度下に保存したとしても、硬度が低下せず、硬度安定性に優れることがわかった。 -result-
2A to 2C, it was found that [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.
図２Ａ～図２Ｃにより、［口腔内崩壊（ＯＤ）錠１］が最も硬度安定性に優れることがわかった。また、表（２－３）より、［口腔内崩壊（ＯＤ）錠１］が最も薬物含量均一性に優れることがわかった。［口腔内崩壊（ＯＤ）錠１］において使用する［口腔内崩壊（ＯＤ）錠用直打賦形剤１］は、糖類及び崩壊剤を混合して得られた混合物の表面が、結合液によりコーティングされているため、糖類と崩壊剤との結合力が上昇するだけでなく、崩壊剤の吸湿性が低下することがわかった。それにより、本発明の［口腔内崩壊（ＯＤ）錠１］は、長期間高湿度下に保存したとしても、硬度が低下せず、硬度安定性に優れることがわかった。 -result-
2A to 2C, it was found that [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.
（試験例３：崩壊剤水分散液との比較試験）
試験例３では、本願発明の「口腔内崩壊錠用直打賦形剤」を用いて製造した「口腔内崩壊錠」、及び特開２０１０－１８９３８４号公報において開示の「比較口腔内崩壊錠用直打賦形剤」を参考に、崩壊剤水分散液を用いて製造した「比較口腔内崩壊錠」の硬度安定性の違いを評価した。 (Test Example 3: Comparison test with disintegrant aqueous dispersion)
In Test Example 3, 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”.
試験例３では、本願発明の「口腔内崩壊錠用直打賦形剤」を用いて製造した「口腔内崩壊錠」、及び特開２０１０－１８９３８４号公報において開示の「比較口腔内崩壊錠用直打賦形剤」を参考に、崩壊剤水分散液を用いて製造した「比較口腔内崩壊錠」の硬度安定性の違いを評価した。 (Test Example 3: Comparison test with disintegrant aqueous dispersion)
In Test Example 3, 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”.
－口腔内崩壊錠用直打賦形剤の製造－
口腔内崩壊錠用直打賦形剤は、糖類及び崩壊剤を造粒装置内にて結合液を噴霧しながら流動層造粒することにより製造した。用いた材料を表（３－１）に示し、製造条件を表（３－２）に示し、得られた直打賦形剤の粉体物性を表（３－３）及び図３Ａ～図３Ｂに示した。 -Manufacture of direct compression excipients for orally disintegrating tablets-
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.
口腔内崩壊錠用直打賦形剤は、糖類及び崩壊剤を造粒装置内にて結合液を噴霧しながら流動層造粒することにより製造した。用いた材料を表（３－１）に示し、製造条件を表（３－２）に示し、得られた直打賦形剤の粉体物性を表（３－３）及び図３Ａ～図３Ｂに示した。 -Manufacture of direct compression excipients for orally disintegrating tablets-
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.
－比較口腔内崩壊錠用直打賦形剤の製造－
比較口腔内崩壊錠用直打賦形剤は、糖類を、造粒装置内にて崩壊剤を含む水分散液を結合液として噴霧しながら流動層造粒することにより製造した。用いた材料を表（３－１）に示し、処方を表（３－２）に示し、得られた直打賦形剤の粉体物性を表（３－３）及び図３Ａ～図３Ｂに示した。 -Manufacture of direct injection excipients for comparative orally disintegrating tablets-
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.
比較口腔内崩壊錠用直打賦形剤は、糖類を、造粒装置内にて崩壊剤を含む水分散液を結合液として噴霧しながら流動層造粒することにより製造した。用いた材料を表（３－１）に示し、処方を表（３－２）に示し、得られた直打賦形剤の粉体物性を表（３－３）及び図３Ａ～図３Ｂに示した。 -Manufacture of direct injection excipients for comparative orally disintegrating tablets-
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.
－口腔内崩壊プラセボ錠の製造－
口腔内崩壊錠は、表（３－４）に記載の直打賦形剤及び滑沢剤を表（３－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（３－４）に記載の条件で打錠することにより製造した。 -Manufacture of orally disintegrating placebo tablets-
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).
口腔内崩壊錠は、表（３－４）に記載の直打賦形剤及び滑沢剤を表（３－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（３－４）に記載の条件で打錠することにより製造した。 -Manufacture of orally disintegrating placebo tablets-
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).
－比較口腔内崩壊プラセボ錠の製造－
比較口腔内崩壊錠は、表（３－４）に記載の直打賦形剤及び滑沢剤を表（３－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（３－４）に記載の条件で打錠することにより製造した。 -Production of comparative orally disintegrating placebo tablets-
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).
比較口腔内崩壊錠は、表（３－４）に記載の直打賦形剤及び滑沢剤を表（３－４）に記載の条件で混合して、得られた混合物（５００ｇ）を表（３－４）に記載の条件で打錠することにより製造した。 -Production of comparative orally disintegrating placebo tablets-
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).
（試験例３の評価）
－錠剤成形性－
錠剤成形性の評価は、得られた「口腔内崩壊（ＯＤ）プラセボ錠」及び「比較口腔内崩壊（ＯＤ）プラセボ錠」について、硬度を測定することにより行った。測定機にはシュロイニゲル錠剤硬度計８Ｍ（フロイント産業株式会社製）を用いた。結果を表（３－５）、（３－６）、及び図３Ｃ～図３Ｄに示した。 (Evaluation of Test Example 3)
-Tablet formability-
Evaluation of tablet moldability was performed by measuring the hardness of the obtained “orally disintegrating (OD) placebo tablet” and “comparing orally disintegrating (OD) placebo tablet”. As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in Tables (3-5) and (3-6) and FIGS. 3C to 3D.
－錠剤成形性－
錠剤成形性の評価は、得られた「口腔内崩壊（ＯＤ）プラセボ錠」及び「比較口腔内崩壊（ＯＤ）プラセボ錠」について、硬度を測定することにより行った。測定機にはシュロイニゲル錠剤硬度計８Ｍ（フロイント産業株式会社製）を用いた。結果を表（３－５）、（３－６）、及び図３Ｃ～図３Ｄに示した。 (Evaluation of Test Example 3)
-Tablet formability-
Evaluation of tablet moldability was performed by measuring the hardness of the obtained “orally disintegrating (OD) placebo tablet” and “comparing orally disintegrating (OD) placebo tablet”. As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in Tables (3-5) and (3-6) and FIGS. 3C to 3D.
－硬度安定性－
硬度安定性の評価は、得られた「口腔内崩壊プラセボ錠」及び「比較口腔内崩壊プラセボ錠」の硬度５０Ｎ～６０Ｎのものを使用し、該プラセボ錠を２５℃の開放状態にて、湿度の異なる環境下（５５％ＲＨ（恒湿塩：Ｍｇ（ＮＯ３）２）、７５％ＲＨ（恒湿塩：ＮａＣｌ）にて７日間保管し、硬度の変化を確認することにより行った。結果を図３Ｅ～図３Ｆに示した。 -Hardness stability-
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.
硬度安定性の評価は、得られた「口腔内崩壊プラセボ錠」及び「比較口腔内崩壊プラセボ錠」の硬度５０Ｎ～６０Ｎのものを使用し、該プラセボ錠を２５℃の開放状態にて、湿度の異なる環境下（５５％ＲＨ（恒湿塩：Ｍｇ（ＮＯ３）２）、７５％ＲＨ（恒湿塩：ＮａＣｌ）にて７日間保管し、硬度の変化を確認することにより行った。結果を図３Ｅ～図３Ｆに示した。 -Hardness stability-
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.
－結果－
表（３－５）、（３－６）、及び図３Ｃ～図３Ｄより、結合液として、糖アルコール（マンニトール）を用いたプラセボ錠は、成形性に優れることがわかった。これは、図３Ａ～図３Ｂからもわかるように、結合液として糖アルコール（マンニトール）を用いたプラセボ錠は、他の結合液を用いたプラセボ錠と比較して、糖類及び崩壊剤の表面が糖アルコール（マンニトール）によりコーティングされることにより、糖類と崩壊剤の結合力が上昇したため、成形性に優れる結果となったことが示唆された。
また、図３Ｅ～図３Ｆより、結合液として糖アルコール（マンニトール）を用いたプラセボ錠は、高湿度環境下においても、一定の硬度を安定的に有することがわかった。また、他の結合液を用いたプラセボ錠と比較して、錠剤表面の凹凸が見られず、吸湿による錠剤表面の変化が低いこともわかった。これらの結果から、結合液として糖アルコール（マンニトール）を用いたプラセボ錠は、硬度安定性に優れることがわかった。更に、図３Ｆより、崩壊剤として、クロスポビドンと、コーンスターチとを併用したＯＤプラセボ錠４では、クロスポビドンのみを用いたＯＤプラセボ錠３よりも吸湿時の硬度低下をより防ぐことができることがわかった。 -result-
From Tables (3-5), (3-6), and FIGS. 3C to 3D, it was found that placebo tablets using sugar alcohol (mannitol) as a binding solution have excellent moldability. As can be seen from FIGS. 3A to 3B, the placebo tablets using sugar alcohol (mannitol) as the binding solution have a surface of saccharides and disintegrants as compared to the placebo tablets using other binding solutions. It was suggested that coating with sugar alcohol (mannitol) increased the binding force between the saccharide and the disintegrant, resulting in excellent moldability.
From FIG. 3E to FIG. 3F, it was found that placebo tablets using sugar alcohol (mannitol) as a binding solution stably have a certain hardness even in a high humidity environment. It was also found that the tablet surface was not uneven as compared with the placebo tablets using other binding solutions, and the tablet surface change due to moisture absorption was low. From these results, it was found that the placebo tablet using sugar alcohol (mannitol) as the binding solution is excellent in hardness stability. Furthermore, FIG. 3F shows thatOD 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.
表（３－５）、（３－６）、及び図３Ｃ～図３Ｄより、結合液として、糖アルコール（マンニトール）を用いたプラセボ錠は、成形性に優れることがわかった。これは、図３Ａ～図３Ｂからもわかるように、結合液として糖アルコール（マンニトール）を用いたプラセボ錠は、他の結合液を用いたプラセボ錠と比較して、糖類及び崩壊剤の表面が糖アルコール（マンニトール）によりコーティングされることにより、糖類と崩壊剤の結合力が上昇したため、成形性に優れる結果となったことが示唆された。
また、図３Ｅ～図３Ｆより、結合液として糖アルコール（マンニトール）を用いたプラセボ錠は、高湿度環境下においても、一定の硬度を安定的に有することがわかった。また、他の結合液を用いたプラセボ錠と比較して、錠剤表面の凹凸が見られず、吸湿による錠剤表面の変化が低いこともわかった。これらの結果から、結合液として糖アルコール（マンニトール）を用いたプラセボ錠は、硬度安定性に優れることがわかった。更に、図３Ｆより、崩壊剤として、クロスポビドンと、コーンスターチとを併用したＯＤプラセボ錠４では、クロスポビドンのみを用いたＯＤプラセボ錠３よりも吸湿時の硬度低下をより防ぐことができることがわかった。 -result-
From Tables (3-5), (3-6), and FIGS. 3C to 3D, it was found that placebo tablets using sugar alcohol (mannitol) as a binding solution have excellent moldability. As can be seen from FIGS. 3A to 3B, the placebo tablets using sugar alcohol (mannitol) as the binding solution have a surface of saccharides and disintegrants as compared to the placebo tablets using other binding solutions. It was suggested that coating with sugar alcohol (mannitol) increased the binding force between the saccharide and the disintegrant, resulting in excellent moldability.
From FIG. 3E to FIG. 3F, it was found that placebo tablets using sugar alcohol (mannitol) as a binding solution stably have a certain hardness even in a high humidity environment. It was also found that the tablet surface was not uneven as compared with the placebo tablets using other binding solutions, and the tablet surface change due to moisture absorption was low. From these results, it was found that the placebo tablet using sugar alcohol (mannitol) as the binding solution is excellent in hardness stability. Furthermore, FIG. 3F shows that
（試験例４：崩壊剤の粒径による優位性試験）
試験例４では、本願発明の「口腔内崩壊錠用直打賦形剤」のうち、崩壊剤の粒径の違いによる錠剤安定性及び硬度安定性の優位性を評価した。 (Test Example 4: Superiority test based on particle size of disintegrant)
In 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.
試験例４では、本願発明の「口腔内崩壊錠用直打賦形剤」のうち、崩壊剤の粒径の違いによる錠剤安定性及び硬度安定性の優位性を評価した。 (Test Example 4: Superiority test based on particle size of disintegrant)
In 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.
－口腔内崩壊錠用直打賦形剤の製造－
口腔内崩壊錠用直打賦形剤は、糖類及び崩壊剤を造粒装置内にて結合液を噴霧しながら流動層造粒することにより製造した。用いた材料を表（４－１）に示し、組成を表（４－２）に示し、得られた直打賦形剤の粉体物性の結果を表（４－３）に示した。 -Manufacture of direct compression excipients for orally disintegrating tablets-
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).
口腔内崩壊錠用直打賦形剤は、糖類及び崩壊剤を造粒装置内にて結合液を噴霧しながら流動層造粒することにより製造した。用いた材料を表（４－１）に示し、組成を表（４－２）に示し、得られた直打賦形剤の粉体物性の結果を表（４－３）に示した。 -Manufacture of direct compression excipients for orally disintegrating tablets-
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).
－口腔内崩壊錠の製造－
口腔内崩壊錠は、表（４－４）に記載の材料を表（４－５）に記載の条件で混合して打錠することにより製造した。 -Manufacture of orally disintegrating tablets-
Orally disintegrating tablets were produced by mixing the materials described in Table (4-4) under the conditions described in Table (4-5) and tableting.
口腔内崩壊錠は、表（４－４）に記載の材料を表（４－５）に記載の条件で混合して打錠することにより製造した。 -Manufacture of orally disintegrating tablets-
Orally disintegrating tablets were produced by mixing the materials described in Table (4-4) under the conditions described in Table (4-5) and tableting.
（試験例４の評価）
－錠剤成形性－
錠剤成形性の評価は、表（４－５）に記載する製造条件にて得られた錠剤の硬度（ｎ＝２０）を測定することにより行った。測定機にはシュロイニゲル錠剤硬度計８Ｍ（フロイント産業株式会社製）を用いた。結果を図４Ａに示した。 (Evaluation of Test Example 4)
-Tablet formability-
The tablet moldability was evaluated by measuring the hardness (n = 20) of the tablets obtained under the production conditions described in Table (4-5). As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in FIG. 4A.
－錠剤成形性－
錠剤成形性の評価は、表（４－５）に記載する製造条件にて得られた錠剤の硬度（ｎ＝２０）を測定することにより行った。測定機にはシュロイニゲル錠剤硬度計８Ｍ（フロイント産業株式会社製）を用いた。結果を図４Ａに示した。 (Evaluation of Test Example 4)
-Tablet formability-
The tablet moldability was evaluated by measuring the hardness (n = 20) of the tablets obtained under the production conditions described in Table (4-5). As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in FIG. 4A.
－摩損性－
摩損性の評価は、表（４－５）に記載する製造条件にて得られた錠剤の摩損度を測定することにより行った。結果を図４Ｂに示した。
前記摩損度は、錠剤摩損度試験機（萱垣医理科工業株式会社）により測定した。 -Abrasion-
The friability was evaluated by measuring the friability of the tablets obtained under the production conditions described in Table (4-5). The results are shown in FIG. 4B.
The friability was measured by a tablet friability tester (Higaki Medical Science Co., Ltd.).
摩損性の評価は、表（４－５）に記載する製造条件にて得られた錠剤の摩損度を測定することにより行った。結果を図４Ｂに示した。
前記摩損度は、錠剤摩損度試験機（萱垣医理科工業株式会社）により測定した。 -Abrasion-
The friability was evaluated by measuring the friability of the tablets obtained under the production conditions described in Table (4-5). The results are shown in FIG. 4B.
The friability was measured by a tablet friability tester (Higaki Medical Science Co., Ltd.).
－口腔内崩壊性－
口腔内崩壊性の評価は、表（４－５）に記載する製造条件にて得られた錠剤の口腔内崩壊時間（ｎ＝１）を測定することにより行った。結果を図４Ｃに示した。 -Oral disintegration-
The oral disintegration was evaluated by measuring the oral disintegration time (n = 1) of the tablets obtained under the production conditions described in Table (4-5). The results are shown in FIG. 4C.
口腔内崩壊性の評価は、表（４－５）に記載する製造条件にて得られた錠剤の口腔内崩壊時間（ｎ＝１）を測定することにより行った。結果を図４Ｃに示した。 -Oral disintegration-
The oral disintegration was evaluated by measuring the oral disintegration time (n = 1) of the tablets obtained under the production conditions described in Table (4-5). The results are shown in FIG. 4C.
－硬度安定性及び口腔内崩壊時間安定性－
硬度安定性及び口腔内崩壊時間安定性の評価は、各口腔内崩壊錠（硬度５０Ｎ前後のものを使用）を、２５℃で５５％ＲＨの環境（恒湿塩：Ｍｇ（ＮＯ３）２）、２５℃で７５％ＲＨの環境（恒湿塩：ＮａＣｌ）で開放状態にて１週間保管し、硬度（ｎ＝５）及び口腔内崩壊時間の変化（ｎ＝５）を確認することにより行った。結果を図４Ｄ～図４Ｅに示した。 -Hardness stability and oral disintegration time stability-
Evaluation of hardness stability and orally disintegrating time stability is based on each orally disintegrating tablet (having a hardness of around 50 N) in an environment of 55% RH at 25 ° C. (constant humidity salt: Mg (NO 3 ) 2 ). , Stored for 1 week in an open condition in an environment of 75% RH (constant humidity salt: NaCl) at 25 ° C., and confirming changes in hardness (n = 5) and disintegration time in the oral cavity (n = 5) It was. The results are shown in FIGS. 4D to 4E.
硬度安定性及び口腔内崩壊時間安定性の評価は、各口腔内崩壊錠（硬度５０Ｎ前後のものを使用）を、２５℃で５５％ＲＨの環境（恒湿塩：Ｍｇ（ＮＯ３）２）、２５℃で７５％ＲＨの環境（恒湿塩：ＮａＣｌ）で開放状態にて１週間保管し、硬度（ｎ＝５）及び口腔内崩壊時間の変化（ｎ＝５）を確認することにより行った。結果を図４Ｄ～図４Ｅに示した。 -Hardness stability and oral disintegration time stability-
Evaluation of hardness stability and orally disintegrating time stability is based on each orally disintegrating tablet (having a hardness of around 50 N) in an environment of 55% RH at 25 ° C. (constant humidity salt: Mg (NO 3 ) 2 ). , Stored for 1 week in an open condition in an environment of 75% RH (constant humidity salt: NaCl) at 25 ° C., and confirming changes in hardness (n = 5) and disintegration time in the oral cavity (n = 5) It was. The results are shown in FIGS. 4D to 4E.
－結果－
図４Ａ～図４Ｅより、崩壊剤（クロスポビドン）として、５０μｍ以下の体積平均粒子径を有する崩壊剤、より好ましくは２５μｍ～３５μｍの範囲に体積平均粒子径を有する崩壊剤を用いることにより、口腔内崩壊性、及び硬度安定性に優れることがわかった。 -result-
From FIG. 4A to FIG. 4E, by using a disintegrant having a volume average particle diameter of 50 μm or less, more preferably a disintegrant having a volume average particle diameter in the range of 25 μm to 35 μm as a disintegrant (crospovidone), It was found to be excellent in internal disintegration and hardness stability.
図４Ａ～図４Ｅより、崩壊剤（クロスポビドン）として、５０μｍ以下の体積平均粒子径を有する崩壊剤、より好ましくは２５μｍ～３５μｍの範囲に体積平均粒子径を有する崩壊剤を用いることにより、口腔内崩壊性、及び硬度安定性に優れることがわかった。 -result-
From FIG. 4A to FIG. 4E, by using a disintegrant having a volume average particle diameter of 50 μm or less, more preferably a disintegrant having a volume average particle diameter in the range of 25 μm to 35 μm as a disintegrant (crospovidone), It was found to be excellent in internal disintegration and hardness stability.
本発明の口腔内崩壊錠用直打賦形剤は、薬剤成分と混合して打錠するだけで、錠剤として必要とされる、錠剤成形性、口腔内崩壊性、摩損性、薬物含量均一性等の性能を維持しつつ、長期間保存しても硬度及び口腔内崩壊の安定性に優れる口腔内崩壊錠を提供することができるため、口腔内崩壊錠の製造に好適に利用することができる。
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. .
Claims (7)
- 糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物に、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して造粒することにより得られることを特徴とする口腔内崩壊錠用直打賦形剤。 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. A direct compression excipient for orally disintegrating tablets.
- 糖が、乳糖であり、
糖アルコールが、マンニトール、キシリトール、エリスリトール、及びラクチトールの少なくともいずれかである請求項１に記載の口腔内崩壊錠用直打賦形剤。 Sugar is lactose,
The direct compression excipient for orally disintegrating tablets according to claim 1, wherein the sugar alcohol is at least one of mannitol, xylitol, erythritol, and lactitol. - 崩壊剤が、クロスポビドン、及び低置換度ヒドロキシプロピルセルロースの少なくともいずれかである請求項１から２のいずれかに記載の口腔内崩壊錠用直打賦形剤。 The direct compression excipient for orally disintegrating tablets according to any one of claims 1 to 2, wherein the disintegrant is at least one of crospovidone and low-substituted hydroxypropylcellulose.
- 崩壊剤の体積平均粒子径が、５０μｍ以下である請求項１から３のいずれかに記載の口腔内崩壊錠用直打賦形剤。 The direct compression excipient for orally disintegrating tablets according to any one of claims 1 to 3, wherein the disintegrant has a volume average particle diameter of 50 µm or less.
- 糖及び糖アルコールの少なくともいずれかを含有する糖類と、崩壊剤とを含有する混合物を流動させながら、糖及び糖アルコールの少なくともいずれかを含有する結合液を噴霧して造粒することを特徴とする口腔内崩壊錠用直打賦形剤の製造方法。 It is characterized by spraying and granulating a binding liquid containing at least one of sugar and sugar alcohol while flowing a mixture containing at least one of sugar and sugar alcohol and a disintegrant. A method for producing a direct compression excipient for orally disintegrating tablets.
- 混合物に対し、結合液を固形分として３０質量％～２００質量％噴霧して造粒する請求項５に記載の口腔内崩壊錠用直打賦形剤の製造方法。 6. The method for producing a direct compression excipient for orally disintegrating tablets according to claim 5, wherein the mixture is granulated by spraying 30% by mass to 200% by mass of the binding liquid as a solid content.
- 請求項１から４のいずれかに記載の口腔内崩壊錠用直打賦形剤と、薬剤成分とを打錠して得られることを特徴とする口腔内崩壊錠。 An orally disintegrating tablet obtained by tableting the direct compression excipient for orally disintegrating tablet according to any one of claims 1 to 4 and a drug component.
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| US12102714B2 (en) | 2018-05-17 | 2024-10-01 | Fertin Pharma A/S | Disintegrating oral tablet suitable for active pharmaceutical ingredients |
| US12109312B2 (en) | 2018-05-17 | 2024-10-08 | Fertin Pharma A/S | Oral tablet for taste masking of active ingredients |
| US12156943B2 (en) | 2018-05-17 | 2024-12-03 | Fertin Pharma A/S | Tablet dosage form for buccal absorption of active ingredients |
| US11090263B2 (en) | 2018-05-22 | 2021-08-17 | Fertin Pharma A/S | Tableted chewing gum suitable for active pharmaceutical ingredients |
| CN114732792A (en) * | 2022-03-25 | 2022-07-12 | 北京诺康达医药科技股份有限公司 | Nicorandil orally disintegrating tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6040218B2 (en) | 2016-12-07 |
| JPWO2013125350A1 (en) | 2015-07-30 |
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