WO2014157264A1 - Comprimé à désintégration orale revêtu d'un film - Google Patents

Comprimé à désintégration orale revêtu d'un film Download PDF

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Publication number
WO2014157264A1
WO2014157264A1 PCT/JP2014/058395 JP2014058395W WO2014157264A1 WO 2014157264 A1 WO2014157264 A1 WO 2014157264A1 JP 2014058395 W JP2014058395 W JP 2014058395W WO 2014157264 A1 WO2014157264 A1 WO 2014157264A1
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WIPO (PCT)
Prior art keywords
tablet
orally disintegrating
film
coated
manufactured
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Ceased
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PCT/JP2014/058395
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English (en)
Japanese (ja)
Inventor
由紀子 横井
崇也 小河
忠正 池田
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Meiji Seika Kaisha Ltd
Meiji Seika Pharma Co Ltd
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Meiji Seika Kaisha Ltd
Meiji Seika Pharma Co Ltd
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Priority to JP2015508567A priority Critical patent/JP6258920B2/ja
Publication of WO2014157264A1 publication Critical patent/WO2014157264A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof

Definitions

  • the present invention relates to an orally disintegrating film-coated tablet that does not change its appearance over time. More specifically, the present invention relates to a stable orally disintegrating film-coated tablet which is subjected to a film coating of a cellulose-based resin containing at least one sweetener and in which no slight change in appearance over time is observed.
  • Film coating is one of the processes to form a thin film-like substance on the tablet surface, and has various functions such as improving appearance, imparting water resistance, improving wear resistance, stabilizing light, and improving discrimination. It is carried out for the purpose of granting.
  • orally disintegrating tablets that rapidly disintegrate in the oral cavity has been actively developed as an easy-to-use dosage form for patients with reduced swallowing function due to various causes such as diseases, aging, and decreased salivary secretion.
  • the orally disintegrating tablet is a special dosage form that pursues the disintegration rate because the disintegration rate required is higher than that of a general tablet from the viewpoint of patient ingestion.
  • fast disintegrating properties and high tablet hardness are contradictory properties. Therefore, orally disintegrating tablets suffer from tablet chipping and cracking when taking out tablets from PTP due to insufficient tablet hardness and high friability. As a result, problems in handling have been pointed out when using an automatic packaging machine at the dispensing site.
  • the tablets are stored in a non-wrapping form in the pre-packaging machine and in a simple packaging form after the packaging, and thus are easily affected by storage environments such as light, temperature, and humidity.
  • storage environments such as light, temperature, and humidity.
  • it cannot be applied to active ingredients that are weak to the external environment, for example, it decomposes by light, but due to moisture absorption, the hardness of the orally disintegrating tablet itself decreases, and it cannot be handled until taking. It has been pointed out.
  • the film coating technique is useful, but the present situation is that it is difficult to apply the film coating to the orally disintegrating tablet due to concern about the delay of disintegration due to the coating layer.
  • Patent Document 1 A stable orally disintegrating coated tablet that does not cause cracks in the coating layer is disclosed (Patent Document 1).
  • Patent Document 1 A stable orally disintegrating coated tablet that does not cause cracks in the coating layer is disclosed (Patent Document 1).
  • Patent Document 1 no change in appearance other than cracks has been reported, and since a water-soluble substance is blended, a change in appearance at high humidity is expected.
  • Patent Document 2 As in the previous section, no change in appearance other than breakage has been reported.
  • a nucleated fast-disintegrating tablet has been disclosed as a method for coating an orally disintegrating tablet that does not rely on film coating (Patent Document 3).
  • the outer diameter layer is thicker than that of film-coated tablets, so that the tablet diameter is often increased.
  • An orally disintegrating tablet is not only disintegrated in the oral cavity but also taken, and since it may be taken with water in the same manner as a normal tablet, it is not preferable that the tablet diameter increases.
  • An object of the present invention is to provide a stable orally disintegrating film-coated tablet.
  • tablet film coating is performed for the purpose of improving the appearance, imparting water resistance, improving wear resistance, stabilizing the light, and improving discrimination.
  • a method in which a water-soluble substance is blended using a polyvinyl alcohol resin having excellent solubility in the coating layer is useful because of its property of requiring rapid disintegration.
  • these tablets are stored in a non-wrapping and simple packaging form at the time of packaging and after packaging, the quality is maintained even when exposed to an external environment such as light, temperature, and humidity.
  • the coating layer in which the water-soluble substance is blended with the polyvinyl alcohol-based resin loses the gloss particularly when stored under high humidity. Such a change in appearance causes anxiety to the patient and leads to a decrease in compliance.
  • the inventors have conducted an extensive study to develop an orally disintegrating film-coated tablet that has rapid disintegration and does not change appearance even under high humidity.
  • a sweetener is combined with a cellulosic resin. Therefore, an orally disintegrating film-coated tablet that retains its fast disintegrating function and does not cause slight changes in appearance over time such as loss of gloss as well as cracks in the coating layer even under high humidity.
  • the present invention was completed.
  • the present invention [1] An orally disintegrating film-coated tablet provided with a film coating of a cellulose resin containing at least one sweetener, [2] The orally disintegrating film-coated tablet according to [1], wherein the cellulose resin is at least one selected from methylcellulose, hypromellose, hydroxypropylcellulose, and hypromellose acetate succinate. [3] The orally disintegrating film-coated tablet according to the above [1], wherein the sweetener is at least one selected from D-mannitol, erythritol, xylitol, maltitol, lactose, trehalose, lactitol and sucralose.
  • Orally disintegrating film-coated tablets [7] An orally disintegrating tablet film coating composition containing at least one sweetener and a cellulose resin, [8] The sweetener is at least one selected from D-mannitol, erythritol, xylitol, maltitol, lactose, trehalose, lactitol, and sucralose, and the cellulosic tree is methylcellulose, hypromellose, hydroxypropylcellulose, and hypromellose acetate succinate
  • a film coating method for orally disintegrating tablets comprising coating an uncoated tablet with the composition according to any one of [7] to [9] above.
  • An internally disintegrating film-coated tablet can be provided.
  • it has sufficient hardness for automatic packaging and handling until taking, and even when exposed to an external environment such as light, temperature, and humidity, the hardness is reduced and the active ingredient is decomposed by light.
  • An improved orally disintegrating film-coated tablet can be provided. More specifically, in an orally disintegrating tablet containing a light-labile active ingredient, decomposition of the active ingredient can be suppressed by blending a light stabilizer in the coating layer.
  • film hardness can be improved by film coating, it is possible to package orally disintegrating tablets that could not be automatically packaged due to insufficient hardness until now, and under high humidity, Even if it is an orally disintegrating tablet whose hardness is reduced by moisture absorption, it is possible to secure a handleable tablet strength.
  • the scanning electron micrograph of the tablet surface of the comparative example 1 (immediately after manufacture) is shown.
  • the scanning electron micrograph of the tablet surface of the comparative example 1 (30 degreeC, relative humidity 81%, one month after) is shown.
  • the scanning electron micrograph of the tablet surface of the comparative example 2 (immediately after manufacture) is shown.
  • the scanning electron micrograph of the tablet surface of the comparative example 2 (30 degreeC, relative humidity 81%, one month after) is shown.
  • the scanning electron micrograph of the tablet surface of the comparative example 3 (just after manufacture) is shown.
  • the scanning electron micrograph of the tablet surface of the comparative example 3 (30 degreeC, relative humidity 81%, one month later) is shown.
  • the scanning electron micrograph of the tablet surface of the comparative example 4 (just after manufacture) is shown.
  • the scanning electron micrograph of the tablet surface of the comparative example 4 (30 degreeC, relative humidity 81%, one month after) is shown.
  • the scanning electron micrograph of the tablet surface of Example 1 (immediately after manufacture) is shown.
  • the scanning electron micrograph of the tablet surface of Example 1 (30 degreeC, relative humidity 81%, after one month) is shown.
  • the orally disintegrating film-coated tablet of the present invention is an orally disintegrating film in which the surface of an orally disintegrating tablet that is an inner core tablet (plain tablet) is coated with a coating layer of a cellulose resin containing a sweetener and the like.
  • Film-coated tablet The composition for coating an orally disintegrating tablet film of the present invention comprises at least one sweetener and a cellulose resin, and is a component used for coating the surface of an orally disintegrating tablet that is an inner core tablet (plain tablet). It is a combination.
  • the combination may be a mixture of powders of each component, may be in a state where the powder is mixed and dissolved or suspended in a suitable solvent, or a combination of a plurality of liquids in which the powder is dissolved or suspended alone in a suitable solvent However, it may be a combination of components that form a film as a coating layer.
  • the “sweetener” used in the present invention refers to a substance that quickly dissolves in water and exhibits a suitable sweetness in the oral cavity, and comprises at least one selected from these groups.
  • Examples of pharmaceutically acceptable sweeteners include lactose, sucrose, purified sucrose, glucose, fructose, mannitol, erythritol, xylitol, maltitol, lactitol, sorbitol, trehalose, xylose, glycine, glycerin, sucralose, acesulfame potassium, glycyrrhizin
  • Examples thereof include dipotassium acid, aspartame, sodium saccharin, stevia, thaumatin and the like, preferably mannitol, erythritol, lactose, maltitol, lactitol, trehalose, xylitol, and more preferably mannitol and erythritol.
  • the “cellulosic resin” used in the present invention refers to a pharmaceutically acceptable cellulose derivative, and one or two or more of these groups can be used in combination.
  • examples include methylcellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, hydroxypropylcellulose, carboxymethylethylcellulose, and the like, preferably methylcellulose, hypromellose, hydroxypropylcellulose, hypromellose acetate succinate And methyl cellulose and hypromellose are more preferable.
  • the weight ratio of the sweetener to the cellulosic resin in the coating layer and coating composition of the present invention is not particularly limited, but preferably the sweetener is about 0.1 to about 9 parts by weight with respect to 1 part by weight of the cellulosic resin. More preferably about 0.3 to about 1.1 parts by weight. The reason for this is that when the amount of the sweetener is large, the film formability is lowered, and when the amount of the sweetener is small, the rapid disintegration property cannot be secured.
  • the “stable orally disintegrating film-coated tablet with no slight change in appearance over time” of the present invention refers to moisture absorption even when the orally disintegrating film-coated tablet is exposed to high humidity. This means that not only an apparent change in appearance such as a crack in the coating layer but also a slight change in appearance that can be observed with the naked eye such as loss of gloss on the surface does not occur. Specifically, it can be evaluated by storing the orally disintegrating film-coated tablet in an atmosphere of 30 ° C. and a relative humidity of 81% for one month, and visually observing the appearance of the coating layer.
  • the degree of “change in appearance” of the present invention is evaluated in four stages, 1 (no change) when there is no change compared with immediately after production, 1 month immediately after production and in an atmosphere of 30 ° C. and relative humidity 81%.
  • 1 no change
  • 1 month immediately after production and in an atmosphere of 30 ° C. and relative humidity 81%.
  • the “8 ° gloss value” of the present invention is a numerical value measured by a spectrocolorimeter set so as to approximate a JIS 60 ° gloss meter. Indicates a high degree. Since the tablet has a small surface area and a gloss meter cannot be used, a spectrocolorimeter was used.
  • the 8 ° gloss value is a numerical value that objectively shows the result of visual observation of the appearance. From the viewpoint of indicating that there is no loss of recognizable gloss, it is preferably maintained at 80% or more immediately after production.
  • the spectrocolorimeter used in the present invention can simultaneously perform SCI (special component include) measurement including specular reflection light and SCE (special component exclusive) measurement not including specular reflection light. This is a mechanism for calculating an 8 ° gloss value.
  • the coating layer and coating composition of the present invention can be blended with a light stabilizer as required in addition to the above-described components.
  • a light stabilizer examples thereof include titanium oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, talc, and kaolin. Among these specific examples, one kind or two or more kinds can be used in combination.
  • the amount of the light stabilizer varies depending on the amount of the active ingredient contained in the present invention and the sensitivity to light, but is preferably 50% or less of the coating amount from the viewpoint of not impairing the effects of the present invention. These are merely examples and are not intended to be limiting.
  • a pharmaceutically acceptable additive can be added to the coating layer and coating composition of the present invention as necessary within a range that does not impair the effects of the present invention.
  • the additive include an excipient, a disintegrant, a binder, a plasticizer, a corrigent, a fragrance, a coloring agent, and a lubricant.
  • excipients include starches such as corn starch and potato starch, microcrystalline cellulose, and light anhydrous silicic acid.
  • the disintegrating agent include partially pregelatinized starch, carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • examples of the binder include polyvinyl pyrrolidone, gum arabic powder, gelatin, pullulan, aminoalkyl metal relate copolymer and the like.
  • examples of the plasticizer include polyethylene glycol, propylene glycol, triacetin, triethyl citrate and the like.
  • citric acid and the like can be mentioned as a flavoring agent.
  • fragrances include menthol, peppermint, lemon, lemon lime, orange, peppermint oil, and various flavors.
  • examples of the colorant include tar dyes, turmeric extract, caramel, carotene solution, s-carotene, copper chlorophyll, and riboflavin.
  • lubricants examples include surfactants such as liquid paraffin, silicone and long chain fatty acid esters, waxes such as beeswax, carnauba wax and paraffin. These additives are exemplified and are not limited at all. Moreover, it is also possible to add the said additive to an outer surface besides the inside of the coating layer of this invention.
  • the coating operation of the orally disintegrating film-coated tablet of the present invention methods well known to those skilled in the art can be used.
  • the coating liquid is prepared by dissolving or suspending, in addition to the sweetener of the present invention and the cellulosic resin, a pharmaceutically acceptable additive blended as necessary in water or a solvent such as ethanol or methanol. .
  • solvents can be used alone or in combination.
  • a commonly used device is used, and for example, a pan coating device or the like can be used.
  • a coating layer can be uniformly formed on the edge of the tablet by setting the number of rotations of the pan to be lower than usual. it can.
  • the coating amount varies depending on the shape and size of the preparation, it may be 0.1% or more with respect to the weight of the orally disintegrating tablet, and from the viewpoint of rapid disintegration, the upper limit may be 10% or less. % Or less, and more preferably 3% or less.
  • the oral disintegration time of an orally disintegrating tablet can be obtained by measuring the time until the tablet is completely disintegrated by saliva without chewing the tablet without taking water in the oral cavity of a healthy adult.
  • the fact that the tablet completely disintegrates means a point in time when no foreign body sensation is felt in the oral cavity.
  • orally disintegrating tablets are designed to disintegrate within 60 seconds without water in the oral cavity. Therefore, the oral disintegration time of the orally disintegrating film-coated tablet is also preferably less than 60 seconds.
  • the dissolution time of the coating layer in the oral cavity is the time it takes for a healthy adult to feel that the coating layer is dissolved by saliva without chewing and the inner core tablet is exposed when water is not taken and the tablet is in the mouth. It is obtained by measuring.
  • the dissolution time of the coating layer in the oral cavity may be less than 20 seconds, depending on the oral disintegration time of the core tablet. Preferably, the time is less than 15 seconds.
  • the orally disintegrating film-coated tablet of the present invention is not limited to being taken without water, and may be taken with water.
  • the inner core tablet that is an orally disintegrating tablet in the present invention is not particularly limited with respect to the production method and composition as long as the disintegration time in the oral cavity is less than about 60 seconds.
  • those produced by conventional methods in the pharmaceutical field such as direct tableting method, indirect tableting method, and molding method can be used.
  • Such production methods include, for example, a method in which wet particles are tableted to obtain a porous tablet, a method using physicochemical properties such as crystallization of sugars, a method using freeze-drying technology, and a disintegration of crospovidone. And a production method using an external agent and a production method using an external lubricant method.
  • the active ingredient contained in the orally disintegrating film-coated tablet in the present invention may be contained in any of the coating layer, the inner core tablet, or both of them, and the active ingredient is not particularly limited, and is physiologically active. If it is an active ingredient which has, it will not restrict
  • the active ingredient contains at least one of amlodipine, ebastine, cefditoren pivoxil, selegiline, brotizolam, midodrine and ramosetron, and pharmacologically acceptable salts and solvates thereof, these active ingredients are light. Therefore, it is preferable to add a light stabilizer to the coating layer.
  • a pharmaceutically acceptable additive can be added to the orally disintegrating tablet, which is an inner core tablet, as necessary within a range that does not impair the effects of the present invention.
  • Examples of the additive include an excipient, a disintegrant, a binder, a plasticizer, a corrigent, a fragrance, a coloring agent, and a lubricant.
  • excipients include starches such as corn starch and potato starch, microcrystalline cellulose, and light anhydrous silicic acid.
  • examples of the disintegrating agent include partially pregelatinized starch, carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • binder examples include polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, gum arabic powder, gelatin, pullulan, carmellose sodium, ethyl cellulose, aminoalkyl metal relate copolymer and the like.
  • plasticizer examples include polyethylene glycol, propylene glycol, triacetin, triethyl citrate and the like.
  • aspartame, sucralose, sodium saccharin, dipotassium glycyrrhizin, stevia, thaumatin, citric acid and the like can be mentioned.
  • fragrances examples include menthol, peppermint, lemon, lemon lime, orange, peppermint oil, and various flavors.
  • colorant examples include tar dyes, turmeric extract, caramel, carotene solution, s-carotene, copper chlorophyll, and riboflavin.
  • lubricant examples include surfactants such as polyethylene glycol, liquid paraffin, silicone, and long chain fatty acid ester, and waxes such as beeswax, carnauba wax, and paraffin. These additives are exemplified and are not limited at all.
  • D-mannitol is manufactured by Mitsubishi Foodtech's Mannite Q
  • crospovidone is ISP polyplastidone INF-10
  • aspartame is Ajinomoto Ajinomoto KK Aspartame
  • sucrose fatty acid ester is DK Ester (registered trademark) manufactured by Daiichi Pharmaceutical ) SS
  • crystalline cellulose is manufactured by Asahi Kasei Chemicals Magnesium stearate, NOF Magnesium stearate GV, manufactured by Mallinckrodt or Taihei Chemical Industry
  • crystalline cellulose is manufactured by Asahi Kasei Chemicals, SEORUS (registered trademark) KG-1000
  • light anhydrous silicic acid is Adsolider (registered trademark) -101 manufactured by Freund Corporation was used.
  • Comparative Examples 1 to 4 Comparative Examples 1 to 3 were prepared in Reference Example 1 and Comparative Example 4 was prepared in the orally disintegrating tablet of Reference Example 2 by preparing an aqueous dispersion at the blending ratio shown in Table 2, and using a film coating machine (HiCoater® HCT- 30: Freund Sangyo Co., Ltd.) and then coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet.
  • a film coating machine HiCoater® HCT- 30: Freund Sangyo Co., Ltd.
  • Polyvinyl alcohol / polyethylene glycol graft copolymer is BASF Kollicoat (registered trademark) IR
  • maltitol is Hayashibara Biochemical Laboratory Crystal Mabit (registered trademark) fine powder
  • lactose hydrate is DMV Pharmatose (registered trademark) DCL-11 and D-mannitol are manufactured by Mitsubishi Foodtech's Mannite P
  • sucralose is sucralose P manufactured by Saneigen FFI
  • titanium oxide is manufactured by Wako Pure Chemical Industries
  • yellow ferric oxide is A polishing wax-103 manufactured by Freund Sangyo Co., Ltd. was used as a product made by Hatake Kasei.
  • Test example 1 After the orally disintegrating film-coated tablets of Comparative Examples 1 to 4 were stored at 30 ° C. and 81% relative humidity for 1 month, the appearance was compared with the naked eye immediately after production. The degree of change was evaluated according to the following four levels. The results are shown in Table 3. In any composition, the luster disappears, and it has been found that the coating layer in which the water-soluble substance is blended with the polyvinyl alcohol-based resin undergoes a remarkable change in appearance under high humidity.
  • Examples 1 and 2 After preparing an aqueous dispersion of the orally disintegrating tablet of Reference Example 1 at the blending ratio shown in Table 4, and applying film coating using a film coating machine (Hicoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet.
  • a film coating machine Hicoater (registered trademark) HCT-30: Freund Sangyo
  • P and PEG400 were manufactured by Nikko Pharmaceutical, titanium oxide was manufactured by Wako Pure Chemical Industries, yellow ferric oxide was manufactured by Kasei Kasei, and carnauba wax was polished wax 103 manufactured
  • Test example 2 The disintegration properties of Comparative Examples 1 to 4 and Examples 1 and 2 immediately after production and the appearance change of Examples 1 and 2 were evaluated and compared with the results of Test Example 1. Disintegration was evaluated by measuring the disintegration time according to the 16th revised Japanese Pharmacopoeia disintegration test method (with water and an auxiliary board), and measuring the oral intimal dissolution time and oral tablet disintegration time by two healthy adults. did. The tablet is taken in the mouth without taking water, the dissolution time of the oral membrane is the time until the coating layer dissolves and the core tablet is exposed, the oral tablet disintegration time is the tablet completely disintegrates The time to do was measured. In addition, after changing the orally disintegrating film-coated tablet at 30 ° C.
  • Example 1 For reference, the surface state of Example 1 was also observed with a scanning electron microscope (no evaporation, 30 MPa, acceleration voltage 5 kV, reflected electron image, 1000 times). The results are shown in FIGS. As a result of comparing immediately after production (FIG. 9) with 30 ° C., 81% relative humidity and one month later (FIG. 10), no change was observed in the surface state of the coating layer. Thus, the superiority of the present invention was shown in that no slight change in appearance over time occurred.
  • Examples 3-5 After preparing an aqueous dispersion with the mixing ratio shown in Table 6 on the orally disintegrating tablet of Reference Example 1, and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet.
  • methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd.
  • Metros (registered trademark) SM-4, D-mannitol is manufactured by Mitsubishi Corporation Foodtech Mannit P
  • sucralose sucralose P manufactured by Saneigen FFI
  • PEG400 is manufactured by Nikko Pharmaceutical. Titanium was manufactured by Wako Pure Chemical Industries, yellow ferric oxide was manufactured by Kasei Kasei, and carnauba wax was polished wax 103 manufactured by Freund Sangyo.
  • Test example 3 The orally disintegrating film-coated tablets of Examples 1 and 3 to 5 were evaluated for disintegration and appearance changes immediately after production.
  • Disintegration is a test example by measuring the disintegration time according to the 16th revised Japanese Pharmacopoeia disintegration test method (with water and an auxiliary board), and measuring the oral intimal dissolution time and oral tablet disintegration time by two healthy adults. The evaluation was performed based on the same criteria as in No. 2.
  • the orally disintegrating film-coated tablet at 30 ° C. and relative humidity of 81% for 1 month the appearance was compared with the naked eye immediately after production. Note that the degree of change was evaluated in a four-step manner as in Test Example 1. The results are shown in Table 7.
  • the disintegration property was improved, and all showed fast disintegration properties preferable as an orally disintegrating tablet.
  • no change in appearance was observed under high humidity, indicating that the present invention did not cause a slight change in appearance over time while maintaining a rapidly disintegrating function.
  • Comparative Example 5 Examples 6 and 7 After preparing an aqueous dispersion in the orally disintegrating tablet of Reference Example 1 at a blending ratio shown in Table 8, and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet.
  • a film coating machine HiCoater (registered trademark) HCT-30: Freund Sangyo)
  • Methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd.
  • Test example 4 The orally disintegrating film-coated tablets of Comparative Example 5, Examples 1, 3, 6 and 7 were evaluated for disintegration and appearance change immediately after production and 8 ° gloss value.
  • Disintegration is a test example by measuring the disintegration time according to the 16th revised Japanese Pharmacopoeia disintegration test method (with water and an auxiliary board), and measuring the oral intimal dissolution time and oral tablet disintegration time by two healthy adults. The evaluation was performed based on the same criteria as in No. 2. In addition, after storing the orally disintegrating film-coated tablet at 30 ° C. and relative humidity of 81% for 1 month, the change in appearance is the same four-stage evaluation as in Test Example 1, and the appearance is compared with the naked eye immediately after production.
  • the 8 ° gloss value was measured using a spectrocolorimeter (CM-700d: Konica Minolta, wearing a target mask with a hole diameter of 3 mm, C light source, 2 ° field of view).
  • CM-700d Konica Minolta
  • the results are shown in Table 9.
  • the oral intimal dissolution time and the oral tablet disintegration time were long, which is not preferable as an orally disintegrating tablet.
  • the disintegration is good, and since no change in appearance and no decrease in 8 ° gloss value were observed under high humidity, at least one sweetener is required. It was shown that seeds are good.
  • Comparative Examples 6-9 and Example 8 After preparing an aqueous dispersion in the orally disintegrating tablet of Reference Example 3 at the blending ratio shown in Table 10, and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet.
  • a film coating machine HiCoater (registered trademark) HCT-30: Freund Sangyo)
  • Polyvinyl alcohol / polyethylene glycol graft copolymer PVA-PEG graft copolymer
  • BASF Kollicoat registered trademark
  • methylcellulose is Shin-Etsu Chemical Co., Ltd.
  • Metros (registered trademark) SM-4, and maltitol is Hayashibara Biochemical Research Institute.
  • Crystal Mabit (registered trademark) fine powder
  • lactose hydrate is Pharmatose (registered trademark) DCL-11 manufactured by DMV
  • D-mannitol is Mannitol P manufactured by Mitsubishi Foodtech
  • sucralose is Sucralose P manufactured by Saneigen FFI PEG400 was manufactured by Nikko Pharmaceutical
  • titanium oxide was manufactured by Wako Pure Chemical Industries
  • yellow ferric oxide was manufactured by Kasei Kasei
  • carnauba wax was polished wax 103 manufactured by Freund Corporation.
  • Test Example 5 The orally disintegrating film-coated tablets of Comparative Examples 1 to 4 and 6 to 9 and Examples 5 and 8 were evaluated for disintegration and appearance change immediately after production and 8 ° gloss value in the same manner as in Test Example 4. . The results are shown in Table 11.
  • the inner core tablet is an actual drug tablet or a placebo tablet
  • no significant difference was observed in disintegration, appearance change under high humidity, and 8 ° gloss value
  • the characteristics shown in Test Example 2 That is, the orally disintegrating tablet coated with a water-soluble substance blended with a polyvinyl alcohol resin exhibits good disintegration, while the appearance change under high humidity is remarkable, whereas the oral cavity of the present invention
  • the disintegrating film-coated tablet showed good disintegration, and the property that no change in appearance was observed even under high humidity was shown to be due to the composition of the coating layer.
  • Examples 9-11 After preparing an aqueous dispersion in the orally disintegrating tablet of Reference Example 3 at the blending ratio shown in Table 12, and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet.
  • a film coating machine HiCoater (registered trademark) HCT-30: Freund Sangyo
  • Shin-Etsu AQOAT registered trademark
  • methylcellulose is Shin-Etsu Chemical Co., Ltd.
  • Test Example 6 The orally disintegrating film-coated tablets of Examples 8 to 11 were evaluated for disintegration immediately after production, change in appearance, and 8 ° gloss value by the same method as in Test Example 4. The results are shown in Table 13. Even when the types of the cellulose resin and the sweetener were changed, it was shown that the present invention does not cause a slight change in appearance over time while maintaining a fast disintegrating function.
  • Example 12 An aqueous dispersion was prepared at the blending ratio shown in Table 14, and Amurodin (registered trademark) OD tablet 2.5 mg manufactured by Sumitomo Dainippon Pharma containing amlodipine besylate was added to a film coating machine (HiCoater (registered trademark) HCT- 30: Freund Sangyo Co., Ltd.) and then coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. Note that methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd.
  • Test Example 7 With respect to Example 12 and 2.5 mg of Amrodin (registered trademark) OD tablet which is an inner core tablet thereof, disintegration and appearance change immediately after production, 8 ° gloss value and hardness were evaluated. The disintegration, appearance change, and 8 ° gloss value were evaluated in the same manner as in Test Example 4, and the hardness was evaluated using a tablet hardness tester (8M: Schleunigel). The results are shown in Table 15. Even when the active ingredient contained is amlodipine besylate, it has been shown that the present invention does not cause a slight change in appearance over time while maintaining a rapidly disintegrating function. In addition, it was shown that the absolute hardness immediately after the production was improved by applying the coating of the present invention, and the absolute hardness under high humidity was kept higher than that without the coating.
  • Amrodin registered trademark
  • an orally disintegrating film-coated tablet can be provided. Moreover, even an active ingredient unstable to light, which has not been applied so far, can be made into an orally disintegrating tablet. Furthermore, since film hardness can be improved by film coating, it enables the packaging of orally disintegrating tablets that could not be automatically packaged due to insufficient hardness until now, and under high humidity, Even if it is an orally disintegrating tablet whose hardness is reduced by moisture absorption, it is possible to secure a handleable tablet strength. These effects can improve patient compliance and improve the therapeutic effect.

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Abstract

La présente invention concerne un comprimé stable à désintégration orale revêtu d'un film, apte à conserver une fonctionnalité de désintégration rapide, et selon lequel il n'y a aucune fissuration perceptible de la couche de revêtement, ni de légers changements de son apparence au fil du temps, tels que la perte d'éclat, même dans des conditions d'humidité élevée. En combinant un édulcorant avec une résine à base de cellulose, on peut fournir un comprimé stable à désintégration orale revêtu d'un film permettant de conserver une fonctionnalité de désintégration rapide, selon lequel il n'y a aucun changement léger perceptible d'apparence de la couche de revêtement au fil du temps, même dans des conditions d'humidité élevée.
PCT/JP2014/058395 2013-03-27 2014-03-26 Comprimé à désintégration orale revêtu d'un film Ceased WO2014157264A1 (fr)

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WO2015122477A1 (fr) * 2014-02-12 2015-08-20 沢井製薬株式会社 Comprimé à désintégration orale enrobé d'un film
JP2019123707A (ja) * 2018-01-11 2019-07-25 沢井製薬株式会社 フィルムコーティングされた口腔内崩壊錠
JP2021134217A (ja) * 2020-02-26 2021-09-13 日新製薬株式会社 被覆層を有する口腔内崩壊錠
JP2022514229A (ja) * 2018-12-17 2022-02-10 ロケット フレール 改善した安定性を有する糖コーティング固体形成物

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JP2000302672A (ja) * 1999-04-16 2000-10-31 Taisho Pharmaceut Co Ltd 咀嚼可能な被覆錠剤
JP2001139495A (ja) * 1999-11-19 2001-05-22 Shin Etsu Chem Co Ltd フィルムコーティング剤及び経口固形製剤
JP2001151672A (ja) * 1999-11-19 2001-06-05 Shin Etsu Chem Co Ltd 水系フィルムコーティング剤及び経口固形製剤
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WO2015122477A1 (fr) * 2014-02-12 2015-08-20 沢井製薬株式会社 Comprimé à désintégration orale enrobé d'un film
US10588856B2 (en) 2014-02-12 2020-03-17 Sawai Pharmaceutical Co., Ltd. Orally disintegrating tablet coated with film
JP2019123707A (ja) * 2018-01-11 2019-07-25 沢井製薬株式会社 フィルムコーティングされた口腔内崩壊錠
JP7202898B2 (ja) 2018-01-11 2023-01-12 沢井製薬株式会社 フィルムコーティングされた口腔内崩壊錠
US11826473B2 (en) 2018-01-11 2023-11-28 Sawai Pharmaceutical Co., Ltd. Orally disintegrating tablet coated with film
JP2022514229A (ja) * 2018-12-17 2022-02-10 ロケット フレール 改善した安定性を有する糖コーティング固体形成物
JP7555926B2 (ja) 2018-12-17 2024-09-25 ロケット フレール 改善した安定性を有する糖コーティング固体形成物
JP2021134217A (ja) * 2020-02-26 2021-09-13 日新製薬株式会社 被覆層を有する口腔内崩壊錠
JP7219979B2 (ja) 2020-02-26 2023-02-09 日新製薬株式会社 被覆層を有する口腔内崩壊錠

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