JP2023180494A - Zonisamide-containing orally disintegrating tablet - Google Patents

Abstract

To provide a zonisamide-containing orally disintegrating tablet that effectively suppresses unpleasant taste of zonisamide, and has zonisamide solubility properties similar to those of original pharmaceutical, Trerief OD tablets.SOLUTION: An orally disintegrating tablet contains zonisamide-containing granules that contain 1.1-6 mass% of ethyl cellulose relative to a total amount of the tablet. Preferably, the granules contain zonisamide and ethyl cellulose in a mixed state, and such granules can be produced by high shear granulation. Also preferably, the zonisamide-containing granules are prepared by tableting together with powdered additives.SELECTED DRAWING: Figure 1

Description

The present invention relates to orally disintegrating tablets containing zonisamide.

Zonisamide (1,2-benzisoxazol-3-ylmethanesulfonamide) is an active ingredient of a therapeutic drug for Parkinson's disease, and is a compound represented by the following structural formula.

As orally disintegrating tablets containing zonisamide, Treleaf (registered trademark) OD tablets 25 mg and 50 mg (Sumitomo Dainippon Pharma Co., Ltd.) are used clinically. Treleaf OD tablet 25mg is a tablet containing D-mannitol, corn starch, crystalline cellulose, ethyl cellulose, polyvinyl alcohol (partially saponified), talc, light silicic anhydride, aspartame, and magnesium stearate as additives. OD tablet 50 mg is a tablet containing yellow iron sesquioxide in addition to these (Non-Patent Document 1).

Since zonisamide has a bitter taste, it is necessary to mask the bitter taste in order to make it an orally disintegrating tablet (OD tablet).
For example, Patent Document 1 discloses a tablet obtained by compressing a mixture containing first granules containing zonisamide and second granules containing an additive, in which the first granules contain zonisamide, a glidant, and a carrier. The mixture of zonisamide and a fluidizing agent is coated with a carrier using a fluidized bed granulation device, and the apparent specific gravity and circularity are adjusted to a specific range. Discloses a tablet comprising an alcohol and/or amino acid having an average particle size within a specific range, a disintegrant whose expansion rate upon water absorption is below a certain level, and a water-soluble binder in an amount below a certain level. ing. Patent Document 1 discloses that by forming such a tablet, the bitter taste of zonisamide can be suppressed, high hardness can be maintained for a long period of time, disintegration in the oral cavity can be improved, and content uniformity can also be improved. is teaching.

Here, in order for a generic drug to receive manufacturing approval, it is required to be biologically equivalent to the originator drug. Masking the taste of a drug that has an unpleasant taste generally reduces the dissolution of that drug from the tablet, so depending on the masking method, the dissolution properties of the drug may no longer be similar to that of the originator drug, in which case generic The product would not be approved for manufacture as a drug.

Patent No. 5680898

Treleaf OD tablet package insert

An object of the present invention is to provide a zonisamide-containing orally disintegrating tablet in which the unpleasant taste of zonisamide is masked and which has similar zonisamide dissolution properties as the original drug Treleaf OD tablet.

The present inventor conducted repeated research in order to solve the above problems and obtained the following knowledge.
(1) In orally disintegrating tablets obtained by compressing zonisamide-containing granules as they are or together with additives, 1.1 to 6% by mass of ethylcellulose is added to the zonisamide-containing granules based on the total amount of the tablet. By blending, the bitter taste of zonisamide can be effectively masked, and the dissolution properties of zonisamide become similar to that of the original drug, Treleaf OD tablets.
(2) In the orally disintegrating tablet of (1) above, even if the zonisamide-containing granule is a mixture of zonisamide and ethylcellulose rather than one coated with zonisamide and ethylcellulose, the dissolution property decreases. can be suppressed.

The present invention has been completed based on the above findings, and provides the following [1] to [7].
[1] Orally disintegrating tablet containing zonisamide-containing granules containing 1.1 to 6% by mass of ethylcellulose based on the total amount of the tablet.
[2] The orally disintegrating tablet according to [1], wherein the zonisamide-containing granules contain zonisamide and ethyl cellulose in a mixed state.
[3] The orally disintegrating tablet according to [1] or [2], wherein the zonisamide-containing granules are produced by a high-speed stirring granulation method.
[4] The orally disintegrating tablet according to any one of [1] to [3], which contains the above-mentioned zonisamide-containing granules and a powdered additive.
[5] A method for producing orally disintegrating tablets containing zonisamide, comprising the steps of granulating a mixture containing zonisamide and 1.1 to 6% by mass of ethyl cellulose based on the total amount of the tablet to obtain a granulated product; A method for producing orally disintegrating tablets, which includes the step of tableting this granulated product alone or in combination with additives.
[6] The manufacturing method according to [5], wherein the granulation is performed using a high-speed stirring granulation method.
[7] The manufacturing method according to [5] or [6], wherein the zonisamide-containing granules are mixed with a powdered additive and then tableted.

As mentioned above, zonisamide has a bitter taste, so in order to make a tablet containing it into an orally disintegrating tablet, it is necessary to mask the bitter taste by some means. Generally, masking treatment reduces the dissolution of the active ingredient from the tablet. On the other hand, manufacturing generic drugs requires that they be biologically equivalent to the original drug, but depending on the masking method, the dissolution properties may differ significantly from the original drug. In this regard, the orally disintegrating tablet of the present invention is characterized in that ethyl cellulose is blended into the zonisamide-containing granules used for tablet manufacturing at a content of 1.1 to 6% by mass based on the total amount of the tablet. As a result, the bitterness of zonisamide is sufficiently reduced, and the dissolution properties of zonisamide are similar to those of the original drug, Treleaf OD tablets. Therefore, when developing it as a generic drug, there will be no problem with dissolution.

In addition, when making zonisamide-containing granules that are a mixture of zonisamide and ethylcellulose, rather than granules that have zonisamide-containing cores coated with ethylcellulose, a granulation method that allows for low-cost granulation should be used. Can be adopted.
That is, taste masking of drugs that exhibit an unpleasant taste is mainly carried out by fluidized bed granulation, which allows easy coating of the drug with a masking base. Fluidized bed granulation takes time to granulate and uses a large amount of solvent, which increases the cost of manufacturing tablets. Therefore, there is a desire to use a granulation method that requires a short granulation time and uses a small amount of solvent, such as a high-speed stirring granulation method. However, in high-speed agitation granulation methods and the like, the drug is granulated while being kneaded into the masking base material, so although a masking effect can be obtained, the dissolution of the drug is usually greatly reduced. For this reason, there is a risk that the dissolution properties will not be similar to those of the originator drug.
The orally disintegrating tablet of the present invention can also be used as a zonisamide-containing granule in which zonisamide and ethylcellulose are mixed, and the ethylcellulose is blended at a content of 1.1 to 6% by mass based on the total amount of the tablet. The dissolution properties of zonisamide are good. Therefore, by performing granulation using a high-speed stirring granulation method or the like, it is possible to suppress the production cost and avoid a decrease in the dissolution properties of zonisamide.

Furthermore, when mixing zonisamide-containing granules and additives and compressing them into tablets, when the additives are mixed in powder form, compared to the case where two types of granules are used as in Patent Document 1, It can be manufactured at low cost. The orally disintegrating tablet of the present invention is produced by blending ethyl cellulose into the zonisamide-containing granules in a content of 1.1 to 6% by mass based on the total amount of the tablet. The dissolution properties of zonisamide can be made similar to the originator drug without granulating the additives to be mixed with the drug.

1 is a graph showing the results of sensory evaluation of bitterness of the tablet of Example 1 and 25 mg of Treleaf OD tablets.

The present invention will be explained in detail below.
The orally disintegrating tablet of the present invention is an orally disintegrating tablet containing zonisamide-containing granules containing 1.1 to 6% by mass of ethyl cellulose based on the total amount of the tablet. In other words, the orally disintegrating tablet of the present invention is produced by compressing a granulated product containing 1.1 to 6% by mass of ethyl cellulose and zonisamide based on the total amount of the tablet, or by compressing this granulated product together with an additive. It is an orally disintegrating tablet obtained by tabletting. Due to tableting, the granules in the orally disintegrating tablet have a different shape from before tabletting.

The content of zonisamide per orally disintegrating tablet of the present invention can be 10 to 100 mg, especially 25 to 50 mg, especially 25 mg or 50 mg.

The content of ethyl cellulose is 1.1% by mass or more, and can also be 1.2% by mass or more, or 1.3% by mass or more, based on the total amount of the tablet. The content of ethyl cellulose is 6% by mass or less, and can also be 5.8% by mass or less, 5.6% by mass or less, or 5.5% by mass or less, based on the total amount of the tablet. Within this range, the bitterness of zonisamide can be sufficiently masked, and the dissolution properties are similar to those of the original formulation, Treleaf OD tablets.

The particle size of the zonisamide-containing granules is preferably 20% or less of fine powder (100 μm or less) when measured by a sieving method. Moreover, the size of the above-mentioned zonisamide-containing granules is the size before tabletting.

The granulated material may be one in which a core containing zonisamide is coated with ethyl cellulose, or may be one in which zonisamide and ethyl cellulose are contained in a mixed state. When contained in a mixed state, it may be contained in a uniform or substantially uniform mixed state. Among these, it is preferable that zonisamide and ethyl cellulose be contained in a mixed state, particularly in a uniform or substantially uniform mixed state. This makes it possible to use a granulation method that enables granulation at lower cost.

That is, zonisamide-containing granules can be produced by wet granulation methods such as fluidized bed granulation, high-speed agitation granulation, rolling granulation, extrusion granulation, crushing granulation, and kneading granulation; It can be produced by dry granulation methods such as single granulation method, briquette granulation method, and melt granulation method, but when producing granules in which zonisamide and ethyl cellulose are uniformly or almost uniformly mixed, Granulation can be performed by a method such as a high-speed stirring granulation method. These methods are preferable because, unlike the general-purpose fluidized bed granulation method, the granulation time is short and the amount of solvent required for granulation is small, so they can be performed at low cost.

Zonisamide-containing granules may be made by granulating only zonisamide and ethyl cellulose, but in addition to zonisamide and ethyl cellulose, excipients, binders other than ethyl cellulose, disintegrants, lubricants, and fluidizing agents may be used. , brighteners, stabilizers, antioxidants, emulsifiers, surfactants, solubilizers, suspending agents, buffers, pH adjusters, thickeners, adsorbents, colorants, flavoring agents, sweeteners Additives such as agents, fragrances, preservatives or preservatives, blowing agents, antifoaming agents, etc. may be included.
One type or two or more types of additives can be used.

Excipients include erythritol, lactose/crystalline cellulose spherical granules, candy powder, gum arabic, gum arabic powder, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, potato starch, corn starch), isomal. Hydrate (ISOMALT), kaolin, reduced palatinose, xylitol, L-glutamine, croscarmellose sodium, crospovidone, silicate-treated crystalline cellulose, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, synthetic Hydrotalcite, titanium oxide, β-cyclodextrin, aluminum hydroxide gel, purified white sugar, purified white sugar spherical granules, gelatin, D-sorbitol, talc, medium-chain fatty acid triglyceride, precipitated calcium carbonate, low-substituted hydroxypropylcellulose, starch Sodium glycolate (sodium carboxymethyl starch), trehalose hydrate, lactose hydrate, sucrose, sucrose/starch spherical granules, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, glucose, pullulan, polyoxyethylene hydrogenated castor oil (N ), polyoxyethylene (N) polyoxypropylene (N) glycol, macrogol (macrogol 4000, macrogol 6000), maltitol, D-mannitol, anhydrous lactose, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, Examples include glyceryl monostearate, calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, and the like.

Binders other than ethyl cellulose include gum arabic, gum arabic powder, pregelatinized starch, partially pregelatinized starch, starch (wheat starch, rice starch, corn starch, potato starch), sodium alginate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, Gelatin, low-substituted hydroxypropyl cellulose, dextrin, sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, macrogol (macrogol 400, macrogol 4000, macrogol 6000), Ethyl acrylate/methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer E, etc.), ammonioalkyl methacrylate copolymer (aminoalkyl methacrylate copolymer RS), ethyl cellulose, carboxyvinyl polymer, carboxymethyl ethyl cellulose, carboxymethyl ethyl cellulose Sodium, carboxymethylethylcellulose calcium, agar powder, guar gum, copolyvidone, cetanol, shellac, dextrin, hydroxyethylcellulose, hypromellose acetate succinate, hypromellose phthalate, pectin, povidone, polyvinyl alcohol, polyvinyl acetal diethylamino acetate, polyvinyl Alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol (partially saponified product), polyvinyl alcohol/polyethylene glycol graft copolymer, methacrylic acid copolymer (dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic Acid copolymers S), methylcellulose, and the like.

Disintegrants include starch (wheat starch, rice starch, potato starch, corn starch), sodium starch glycolate (sodium carboxymethyl starch), hydroxypropyl starch, hydroxypropyl cellulose, partially pregelatinized starch, croscarmellose sodium, cross Examples include povidone, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, magnesium aluminate metasilicate, carmellose, carmellose calcium, calcium silicate, sodium lauryl sulfate, and the like.

Lubricants include talc, glyceryl monostearate, dimethylpolysiloxane (for internal use), sucrose fatty acid ester, stearic acid, stearate (calcium stearate, magnesium stearate, sodium stearyl fumarate), dl-leucine, etc. can be mentioned.

Examples of the fluidizing agent include calcium silicate, talc, light anhydrous silicic acid, hydrated silicon dioxide, synthetic aluminum silicate, and magnesium aluminate metasilicate.

Examples of the brightening agent include carnauba wax, refined paraffin/carnauba wax mixed wax, white beeswax, and refined shellac.

Stabilizers include meglumine, citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, xylitol, D-sorbitol, lactose hydrate, D-mannitol, sodium citrate hydrate. , tartaric acid, citric acid anhydride, DL-malic acid, talc, light anhydrous silicic acid, magnesium aluminate metasilicate, glyceryl monostearate, sucrose fatty acid ester, stearic acid, sodium lauryl sulfate, macrogol (macrogol 400, macro Gol 4000, etc.), carboxyvinyl polymer, polyvinyl alcohol (partially saponified), polyoxyethylene hydrogenated castor oil (N), L-aspartic acid, sodium L-aspartate hydrate, DL-alanine, L-alanine, L - Arginine, sodium chloride, dry aluminum hydroxide gel, xanthan gum, glycine, acetic acid, sodium acetate hydrate, sodium hydroxide, sodium bicarbonate, tocopherol, lactic acid, concentrated glycerin, butylated hydroxyanisole, fumaric acid, propylene glycol, gallic acid. Examples include propyl acid, polysorbate 80, and anhydrous sodium monohydrogen phosphate.

Examples of the antioxidant include anhydrous citric acid, citric acid hydrate, soybean lecithin, dibutylhydroxytoluene, tocopherol, propyl gallate, and the like.

Examples of the emulsifier include glyceryl monostearate, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, medium chain fatty acid triglyceride, soybean lecithin, and lauromacrogol.

As surfactants, glyceryl monostearate, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, macrogol (such as macrogol 400), polyoxyethylene (N) polyoxypropylene (N) Glycol and the like can be mentioned.

Solubilizers include sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil (N), polysorbate 80, lauromacrogol, polyoxyethylene (N) polyoxypropylene (N) glycol, medium chain fatty acid triglyceride, soy lecithin, meglumine. , D-mannitol, sodium citrate hydrate, anhydrous citric acid, sucrose fatty acid ester, macrogol (macrogol 4000, macrogol 6000, etc.), polyvinyl alcohol (partially saponified product), L-aspartic acid, L-arginine , sodium hydroxide, sodium hydrogen carbonate, lactic acid, concentrated glycerin, hydroxypropyl cellulose, β-cyclodextrin, glycerin, soybean oil, triacetin and the like.

Suspending agents include polyoxyethylene hydrogenated castor oil (N), polysorbate 80, soybean lecithin, sucrose fatty acid ester, macrogol (macrogol 4000, macrogol 6000, etc.), sodium hydroxide, hydroxypropyl cellulose, glycerin. , D-sorbitol, magnesium aluminate metasilicate, carboxyvinyl polymer, dry aluminum hydroxide gel, xanthan gum, butylated hydroxyanisole, propylene glycol, crystalline cellulose, gum arabic, gum arabic powder, hypromellose, agar powder, povidone, methylcellulose, kaolin , carrageenan, carmellose sodium, glycerin fatty acid ester, magnesium aluminum silicate, and the like.

Buffers include sodium citrate hydrate, citric acid anhydride, sodium hydrogen carbonate, lactic acid, citric acid hydrate, sodium benzoate, tartaric acid, DL-malic acid, sodium chloride, acetic acid, sodium acetate hydrate, Examples include anhydrous sodium monohydrogen phosphate, L-glutamic acid, and dilute hydrochloric acid.

As a pH adjuster, L-glutamine, sodium citrate hydrate, anhydrous citric acid, sodium hydrogen carbonate, lactic acid, citric acid hydrate, tartaric acid, DL-malic acid, acetic acid, sodium acetate hydrate, anhydrous phosphorus. Examples include sodium monohydrogen acid, dilute hydrochloric acid, sodium hydroxide, meglumine, succinic acid, and aqueous ammonia.

Thickening agents include guar gum, hydroxypropyl cellulose, carboxyvinyl polymer, xanthan gum, propylene glycol, hypromellose, carrageenan, carmellose sodium, concentrated glycerin, gelatin, hydroxyethyl cellulose, carob bean gum, α-cyclodextrin, locust bean gum, etc. can be mentioned.

Examples of the adsorbent include magnesium aluminate metasilicate, kaolin, light anhydrous silicic acid, synthetic aluminum silicate, magnesium silicate, and precipitated calcium carbonate.

Colorants include titanium oxide, indigo carmine, yellow iron sesquioxide, carmine, black iron oxide, iron sesquioxide, synthetic food colors (Food Blue No. 1, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4, Food Yellow 4). Examples include Aluminum Lake No. 5, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), and natural food dyes.

Flavoring agents include erythritol, xylitol, refined white sugar, D-sorbitol, lactose hydrate, white sugar, glucose, D-mannitol, aspartame, cacao powder, reduced maltose starch syrup, reduced starch syrup, licorice, licorice extract, citric acid. Hydrate, sodium citrate hydrate, L-glutamic acid, succinic acid, saccharin, sodium saccharin hydrate, tartaric acid, sucralose, purified stevia extract, peppermint oil, citric acid anhydride, l-menthol, DL-malic acid, etc. can be mentioned.

Sweeteners include xylitol, refined white sugar, D-sorbitol, lactose hydrate, white sugar, glucose, D-mannitol, aspartame, reduced maltose starch syrup, licorice, licorice extract, saccharin, sodium saccharin hydrate, sucralose, and stevia extract. Examples include purified products, maltitol, acesulfame potassium, and thaumatin.

Flavoring agents include peppermint oil, l-menthol, vanillin, and the like.

Preservatives or preservatives include citric acid hydrate, sodium benzoate, sodium edetate hydrate, dibutylhydroxytoluene, paraoxybenzoic acid esters (isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate). butyl benzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, etc.).

Examples of the blowing agent include hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), carbonates (magnesium carbonate, calcium carbonate, etc.).

Examples of antifoaming agents include dimethylpolysiloxane (for internal use).

The orally disintegrating tablet of the present invention may be obtained by compressing the zonisamide-containing granules alone, or may be obtained by compressing the zonisamide-containing granules together with additives. It's okay. Examples of additives include those exemplified for the zonisamide-containing granules, and one or more of them can be used. Ethylcellulose may or may not be included in the additives mixed with the zonisamide-containing granules (additives added later).
Moreover, the additive added later may be a powder, or a part or all of it may be a granulated product. Since granulation increases costs accordingly, it is preferable to use the additives added later in powder form. Powdered additives become lumpy after tableting, but in this specification, they are expressed as "contained in powdered form in the tablet" to distinguish them from the case of tableting in the form of granules.

The orally disintegrating tablet of the present invention may be a coated tablet such as a film-coated tablet as long as sufficient orally disintegrating properties can be obtained. Water-soluble coating agents can be used, such as xanthan gum, karaya gum, locust bean gum, tragacanth gum, guar gum, acacia gum, tamarind gum, tara gum, gum arabic, carnauba wax, alginic acid, sodium alginate, pregelatinized starch, and casein. Sodium, carrageenan, carboxyvinyl polymer, sodium carboxymethyl starch, sucrose fatty acid ester, dextran, dextrin, pullulan, chitin, chitosan, galactomannan, casein, gelatin, water-soluble pullulan ether (pullulan methyl ether, pullulan ethyl ether, pullulan propyl) ether, etc.), water-soluble pullulan esters (pullulan acetate, pullulan butyrate, etc.), agar, vinyl resins (povidone, copolyvidone, polyvinyl acetate, polyvinyl alcohol-polyethylene glycol graft copolymer, etc.), polyoxyethylene-polyoxypropylene glycol, macro Gol, glycyrrhizic acid, sugars (white sugar, fructose, lactose, maltose, glucose, cyclodextrin, etc.), sugar alcohols (mannitol, xylitol, maltitol, sorbitol, etc.), hydroxypropylcellulose, hypromellose, propylene glycol, concentrated glycerin, glycerin, Examples include methylcellulose, polyvinyl alcohol (partially saponified), triacetin, talc, titanium oxide, and triethyl citrate.
One type or two or more types of coating agents can be used.

Additives such as plasticizers can be added to the coating layer.
Plasticizers include polyethylene glycol, propylene glycol, glycerin, glycerin fatty acid esters such as triacetin (glycerol triacetic acid), liquid paraffin, sorbitan monolaurate, monostearin, triethyl citrate, tributyl citrate, diethyl phthalate, and phthalate. Examples include dibutyl acid, diethyl sebacate, dibutyl sebacate, poloxamer, and polyoxyethylene hydrogenated castor oil.
The coating layer may contain one or more additives. Specific examples of these additives are as exemplified for the zonisamide-containing granules.

The present invention also provides a method for producing an orally disintegrating tablet containing zonisamide, in which a granulated product is obtained by granulating a mixture containing zonisamide and 1.1 to 6% by mass of ethyl cellulose based on the total amount of the tablet. The present invention provides a method for producing an orally disintegrating tablet, comprising the steps of: and tableting the granulated product alone or by mixing it with an additive. The resulting orally disintegrating tablet has a dissolution property of zonisamide similar to that of Treleaf OD tablet, and the bitter taste of zonisamide is masked.

"The dissolution properties of zonisamide are similar to those of Treleaf OD tablets" is stated in the second dissolution test method (rotating paddle method) of the 18th edition of the Japanese Pharmacopoeia. ) The dissolution rate of each zonisamide at 10 minutes and 30 minutes after the start of the test is within ±15% of the dissolution rate of zonisamide in Treleaf OD tablets when carried out using 900 mL of test solution at a temperature of 37°C and a paddle rotation speed of 50 rpm. It means something in . “Within ±15%” is a standard established by the bioequivalence guidelines for manufacturing approval of generic drugs.
Each Treleaf OD tablet to be compared contains the same amount of zonisamide as the test tablet. The zonisamide content in one Treleaf OD tablet is 25 mg or 50 mg, but if the zonisamide content in one test tablet is other than this, the composition other than the zonisamide content may be used as Treleaf OD tablet. The same tablets are used for comparison.
In the method of the present invention, the components and contents in the tablet, the classification of granules/powder, the method for producing granules and tablets, the size of granules, etc. are as explained for the orally disintegrating tablet of the present invention. It is.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.
(1) Manufacture of orally disintegrating tablets
Example 1
62.50 g of zonisamide, 254.00 g of D-mannitol (Granutol S, Freund Sangyo), 6.50 g of ethylcellulose (Ethocel Standard 7FP, Dow Chemical), and 2.50 g of sucralose (Sucralose (P), San-Ei Gen F. F.I.) was placed in a high-speed stirring granulator (High Speed Mixer FS-2, Earth Technica) and mixed. Thereafter, 37.50 g of ethanol was added and granulated. The granulated product was placed in a fluidized bed granulation dryer (FLO-LABO, Freund Sangyo) and dried. The dried product was sized using a pulverizer (Power Mill P-04S, Dalton) using a 0.8 mm screen to obtain zonisamide-containing granules.
Zonisamide-containing granules 286.44g, crystalline cellulose 75.24g (CEOLUS UF-711, Asahi Kasei), corn starch 44.00g (Nikkiku Cornstarch, Nihon Shokuhin Kako), crospovidone 13.2g (Koridon CL-SF, BASF) Japan), croscarmellose sodium 13.20 g (Ac-Di-Sol, Du Pont), light anhydrous silicic acid (Ad Solider 101, Freund Sangyo), and magnesium stearate 3.52 g (magnesium stearate vegetable, Ohira Kagaku Sangyo) ) were mixed in a bag. The mixed product was compressed using a rotary tabletting machine (VIRGO24, Kikusui Seisakusho) so that the tablet weight was 200 mg and the tablet thickness was 3.2 mm, and 1.3% by mass of ethyl cellulose was added to the total amount of the tablets. Orally disintegrating tablets containing zonisamide-containing granules were obtained.

Examples 2 to 7, Comparative Examples 1 to 5
Example 1 except that the amount of ethylcellulose in the zonisamide-containing granules was changed to 1.3 to 5.5% by mass based on the total tablet amount, and the amounts of other ingredients were changed accordingly. Orally disintegrating tablets were produced in the same manner.

The compositions (concentrations in the granules) of the zonisamide-containing granules of Examples 1 to 7 and Comparative Examples 1 to 5 are shown in Table 1. The composition (concentration in orally disintegrating tablet) is shown in Table 2.

(2) Evaluation of dissolution properties A dissolution test was conducted on each of the tablets of Examples 1 to 7, Comparative Examples 1 to 5, and 25 mg of Treleaf OD tablets. The dissolution test was conducted in accordance with Method 2 of the dissolution test (rotating paddle method) of the 18th edition of the Japanese Pharmacopoeia, and the test solution used was 900 mL of the same dissolution test second solution (pH 6.8), and the operating conditions were: test solution temperature; The test was carried out at 37° C. and a paddle rotation speed of 50 rpm (NTR-6100A, Toyama Sangyo Co., Ltd.). The amount of zonisamide eluted from the eluate sampled 10 minutes and 30 minutes after the start of the test was determined by high-performance liquid chromatography, and the dissolution rate relative to the total amount in the tablet was calculated.
(HPLC conditions)
Column: Inert Sustain Swift C18
Column temperature: 30℃
Mobile phase: 0.1% trifluoroacetic acid solution/acetonitrile/methanol mixture (16:5:4)
Mobile phase flow rate: Adjusted so that the retention time of zonisamide was approximately 3 minutes (0.9 mL/min)
Detector: Ultraviolet absorption photometer (measurement wavelength: 237 nm)

The dissolution test was conducted once for each sample, and the average value of the dissolution rate was determined (n=2 to 6).

The results are also shown in Table 1.
Since the dissolution rate after 10 minutes of Treleaf OD tablet 25 mg is 57% and the dissolution rate after 30 minutes is 91%, the dissolution rate after 10 minutes of the test tablet is in the range of 42 to 72%, and the dissolution rate after 30 minutes is 76%. -106% range (±15% range), similar to Treleaf OD tablets 25 mg.
The dissolution rate of zonisamide 10 minutes and 30 minutes after the start of the test was determined when the amount of ethylcellulose contained in the granulated part was in the range of 1.3 to 5.5% by mass based on the total amount of the tablet. It was similar to

(2) Sensory evaluation of bitterness The tablets of Example 1 and 25 mg of Treleaf OD tablets were placed in the mouths of 10 trained panelists, disintegrated without chewing, and then spitted out to remove all residue in the mouth. Rinse immediately with water. The taste immediately after the tablet disintegrated and the aftertaste after rinsing the mouth with water were evaluated on a 10-point scale. The score was 0 if it was not bitter at all, 10 if it was very bitter, and the points were equally divided into 1 to 9 points, and the average value was calculated. The same panel evaluated both the Example 1 tablets and the Treleaf OD tablets at intervals until the taste of each tablet disappeared completely.
The results are shown in Figure 1. Regarding bitterness, the tablet of Example 1 had no significant difference from the Treleaf OD tablet.

The orally disintegrating tablet of the present invention effectively masks the bitter taste of zonisamide, and the dissolution properties of zonisamide are equivalent to those of the originator drug, so that it is suitable as a generic drug.

Claims (7)

An orally disintegrating tablet containing zonisamide-containing granules containing 1.1 to 6% by mass of ethylcellulose based on the total amount of the tablet. The orally disintegrating tablet according to claim 1, wherein the zonisamide-containing granules contain zonisamide and ethyl cellulose in a mixed state. The orally disintegrating tablet according to claim 1 or 2, wherein the zonisamide-containing granules are produced by a high-speed stirring granulation method. The orally disintegrating tablet according to any one of claims 1 to 3, comprising the above-mentioned zonisamide-containing granules and powdered additives. A method for producing orally disintegrating tablets containing zonisamide, comprising the steps of granulating a mixture containing zonisamide and 1.1 to 6% by mass of ethyl cellulose based on the total amount of the tablet to obtain a granulated product, and the granulation. A method for producing orally disintegrating tablets, which includes the step of tabletting the product alone or in combination with additives. The manufacturing method according to claim 5, wherein the granulation is performed by a high-speed stirring granulation method. The manufacturing method according to claim 5 or 6, wherein the zonisamide-containing granules are mixed with a powdered additive and then tableted.