JP7745371B2 - Zonisamide drug substance particles and their uses - Google Patents

Description

The present invention relates to zonisamide drug substance particles formed from zonisamide, which is used as an antiepileptic drug, and uses thereof.

Zonisamide is used as an antiepileptic drug and an anti-Parkinson's disease drug. Zonisamide is usually administered orally, and when administered in the form of orally disintegrating tablets (OD tablets), rapid dissolution is required.

WO 2009/102038 (Patent Document 1) discloses an orally disintegrating tablet containing an active ingredient, mannitol, crystalline cellulose, and at least two specific ingredients selected from the group consisting of low-substituted hydroxypropyl cellulose, cornstarch, and carmellose. This document states that the average particle size of the active ingredient is typically 1 to 250 μm (preferably 1 to 100 μm), and in the examples, zonisamide with an average particle size of approximately 7 μm is used.

WO 2014/030656 (Patent Document 2) discloses drug-containing hollow particles that are composed of a shell and a hollow portion, the shell containing a drug and a polymer, and the volume ratio of the hollow portion to the entire particle is 1 to 50%. In the examples of this document, the drug is zonisamide or the like, which is jet-milled and has a volume-based cumulative 50% particle size (D ₅₀ ) of 2.7 μm, and the polymer is a polymer such as hydroxypropyl cellulose.

WO 2019/130749 (Patent Document 3) discloses a composition for imparting sustained-release, enteric, gastric, bitter-masking, or photostability to drug-containing hollow particles comprising a shell and a hollow portion, including coatable fine particles, as a composition capable of providing a formulation that allows absorption of a target component at a desired site over a desired time period and achieves a desired medicinal effect. In the examples of this document, zonisamide, etc., having a volume-based cumulative 50% particle size (D ₅₀ ) of 1.99 μm is used as the drug.

International Publication No. 2009/102038 International Publication No. 2014/030656 International Publication No. 2019/130749

However, it was difficult to ensure sufficient dissolution properties with the zonisamide drug substances described in Patent Documents 1 to 3.

Therefore, an object of the present invention is to provide zonisamide drug substance particles that can improve dissolution properties and uses thereof.

As a result of extensive research to achieve the above object, the present inventors have found that dissolution can be improved by adjusting the volume-based cumulative 50% particle diameter (D ₅₀ ) of zonisamide drug substance particles to 18 μm or less, and have completed the present invention.

That is, the drug substance particles of the present invention are formed of zonisamide or a salt thereof, and have a volume-based cumulative 50% particle size ( _D50 ) of 18 μm or less. The drug substance particles may also have a volume-based cumulative 10% particle size ( _D10 ) of less than 3.6 μm and a volume-based cumulative 90% particle size ( _D90 ) of 15 μm or more.

The present invention also includes granules containing the above-mentioned drug substance particles. The granules may be solid. The granules are preferably substantially free of cellulose ether having a hydroxy _C2-4 alkyl group.

The present invention also includes an orally disintegrating tablet comprising the granules and rapidly disintegrating particles. The rapidly disintegrating particles may contain ethyl cellulose. The rapidly disintegrating particles may further contain sugar alcohol, carmellose, silicic acids, and crospovidone. The orally disintegrating tablet is preferably substantially free of crystalline cellulose. The orally disintegrating tablet is preferably substantially free of cellulose ethers having a hydroxy _C2-4 alkyl group and starches.

The present invention also includes a method for improving the dissolution rate of zonisamide or a salt thereof in water by adjusting the volume-based cumulative 50% particle diameter (D ₅₀ ) of drug substance particles formed from zonisamide or a salt thereof to 18 μm or less.

In the present invention, the volume-based cumulative 50% particle size (D ₅₀ ) of the zonisamide drug substance particles is adjusted to 18 μm or less, thereby improving the dissolution property of the zonisamide drug substance.

[Zonisamide drug substance particles]
The drug substance particles of the present invention are formed from zonisamide (1,2-benzisoxazol-3-yl-methanesulfonamide) or a salt thereof.

There are no particular limitations on the salt, so long as it is pharmaceutically acceptable. Examples of salt forms include alkali metal salts (lithium salt, sodium salt, potassium salt, etc.).

The shape of the drug substance particles is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, granular, etc., and is usually amorphous, granular, etc.

The volume-based cumulative 50% particle size (D ₅₀ ) of the drug substance particles may be 18 μm or less, for example, 3 to 16 μm, preferably 3 to 15 μm, and more preferably 3 to 12 μm. If the particle size of the drug substance particles is too small, there is a risk that dissolution properties and the feeling of taking the drug will be reduced.

The volume-based cumulative 10% particle diameter (D ₁₀ ) of the drug substance particles may be less than 3.6 μm, for example, 1.5 to 3 μm, preferably 1.5 to 2.5 μm.

The volume-based cumulative 90% particle diameter (D ₉₀ ) of the drug substance particles may be 15 μm or more, for example, 15 to 50 μm, preferably 15 to 40 μm.

In this specification and claims, particle sizes such as the volume-based cumulative 50% particle size (D ₅₀ ) can be measured on a volume basis using a laser diffraction particle size distribution analyzer, and in detail, can be measured by the method described in the examples below.

[Granules containing drug substance particles]
The granules of the present invention contain the drug substance particles as an active ingredient, and may further contain an excipient in addition to the drug substance particles. The proportion of the drug substance particles in the granules may be about 10 to 90% by mass, for example, 30 to 80% by mass, preferably 40 to 75% by mass, more preferably 50 to 70% by mass, and most preferably 60 to 65% by mass.

Examples of excipients include sugars such as lactose, glucose, fructose, maltose, sucrose, white sugar, and powdered reduced maltose syrup; sugar alcohols such as sorbitol, mannitol, reduced maltose syrup (maltitol), reduced starch syrup, xylitol, reduced palatinose, and tetraoses obtained by fermenting glucose (e.g., erythritol); celluloses such as microcrystalline cellulose, crystalline cellulose, and powdered cellulose; silicic acids such as talc, light anhydrous silicic acid, hydrous silicon dioxide (hydrous anhydrous silicic acid), calcium silicate, magnesium silicate, synthetic aluminum silicate, and magnesium aluminometasilicate; metal oxides such as magnesium oxide and titanium oxide; carbonates such as precipitated calcium carbonate and magnesium carbonate; lactate salts such as calcium lactate; phosphates such as anhydrous calcium hydrogen phosphate and calcium monohydrogen phosphate; and minerals such as bentonite, synthetic hydrotalcite, and kaolin. These excipients can be used alone or in combination.

Among these, sugar alcohols such as mannitol, and silicic acids such as talc and light anhydrous silicic acid are preferred, and a combination of a sugar alcohol and a silicic acid is particularly preferred. The volume-based cumulative 50% particle size (D ₅₀ ) of the sugar alcohol may be, for example, 1 to 350 μm, preferably 5 to 250 μm, and more preferably 20 to 150 μm. The D ₅₀ of the silicic acid may be, for example, 0.1 to 30 μm, preferably 0.5 to 10 μm, more preferably 1 to 5 μm, and most preferably 2 to 4 μm.

When sugar alcohols are combined with silicic acids, the ratio of sugar alcohol is, for example, 10 to 100 parts by mass, preferably 20 to 80 parts by mass, more preferably 30 to 70 parts by mass, and most preferably 40 to 60 parts by mass per 100 parts by mass of silicic acids. If the sugar alcohol ratio is too low, there is a risk of reduced mechanical properties, and conversely, if it is too high, there is a risk of reduced dissolution of the active pharmaceutical ingredient.

The proportion of excipient is, for example, 3 to 100 parts by mass, preferably 5 to 80 parts by mass, more preferably 10 to 50 parts by mass, and most preferably 20 to 40 parts by mass, per 100 parts by mass of drug substance particles. The proportion of excipient in the granules is 3 to 50% by mass, preferably 5 to 40% by mass, more preferably 10 to 30% by mass, and most preferably 15 to 25% by mass. If the proportion of excipient is too low, there is a risk of reduced mechanical properties, and conversely, if it is too high, there is a risk of reduced dissolution of the drug substance.

The granules may further contain a binder in addition to the active pharmaceutical ingredient particles. The binder may be formulated as a coating agent for masking. Examples of binders (or coating agents) include synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone (povidone), copolyvidone, carboxyvinyl polymer, polyacrylic acid polymers (sodium polyacrylate, acrylic acid copolymers, etc.), polylactic acid, polyethylene glycol, and polyvinyl acetate; cellulose ethers such as methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (carmellose or CMC), and carboxymethylethylcellulose (CMEC); and cellulose esters such as cellulose acetate. These binders can be used alone or in combination.

Among these, alkyl cellulose is preferred, and C _1-3 alkyl cellulose such as EC is particularly preferred. The volume-based cumulative 50% particle size (D ₅₀ ) of the alkyl cellulose may be, for example, 1 to 60 μm, preferably 3 to 45 μm, and more preferably 5 to 15 μm.

The proportion of binder (or coating agent) is, for example, 3 to 100 parts by mass, preferably 5 to 80 parts by mass, more preferably 10 to 50 parts by mass, and most preferably 20 to 40 parts by mass, per 100 parts by mass of drug substance particles. The proportion of binder in the granules is 3 to 50% by mass, preferably 5 to 40% by mass, more preferably 10 to 30% by mass, and most preferably 15 to 20% by mass. If the proportion of binder is too low, there is a risk of reduced morphological stability; conversely, if it is too high, there is a risk of reduced dissolution of the drug substance.

When the binder is used as a coating agent, inorganic particles (silicic acids, metal oxides, carbonates, lactates, phosphates, minerals, etc.) among the excipients may be added to improve the handling of the coating agent. The proportion of excipients (particularly talc) added for this purpose is, for example, 5 to 100 parts by weight, preferably 10 to 80 parts by weight, more preferably 30 to 70 parts by weight, and most preferably 40 to 60 parts by weight per 100 parts by weight of the coating agent.

In addition to the active pharmaceutical ingredient particles, the granules may further contain conventional additives incorporated into oral preparations. Examples of conventional additives include disintegrants, lubricants, plasticizers, surfactants, pH adjusters, colorants, sweeteners or flavoring agents (such as aspartame, acesulfame potassium, sucralose, ascorbic acid, stevia, crude licorice extract, and simple syrup), flavoring agents or cooling agents (such as yogurt micron, peppermint micron, menthol, and ginger oil), antioxidants (such as dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, and citric acid), preservatives (such as sodium benzoate and parahydroxybenzoic acid esters), wetting agents, antistatic agents, and disintegration aids.

Disintegrants include, for example, cross-linked polyvinylpyrrolidones such as crospovidone (cross-linked polyvinylpyrrolidone) and crospovidone copolymer; cellulose ethers such as carmellose sodium, carmellose calcium, croscarmellose sodium, and low-substituted hydroxypropyl cellulose (L-HPC); polysaccharides such as agar, carrageenan, alginic acid, sodium alginate, propylene glycol alginate, guar gum, locust bean gum, gum arabic, tragacanth gum, pullulan, xanthan gum, hyaluronic acid, pectin, and sodium chondroitin sulfate; proteins such as gelatin, casein, and soy protein; and minerals such as bentonite, synthetic hydrotalcite, and kaolin.

Lubricants include, for example, fatty acids or metal salts thereof such as stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sodium cocoate; silicon oxides such as hydrous silicon dioxide and silicon dioxide; polyorganosiloxanes such as dimethylpolysiloxane; fats and oils such as hydrogenated oil and cocoa butter; and waxes such as beeswax, white beeswax, carnauba wax, lanolin, paraffin, and petrolatum.

Examples of plasticizers include hydrophilic plasticizers such as ethylene glycol, propylene glycol, and glycerin; and fat-soluble plasticizers such as triacetin, triethyl citrate, diethyl phthalate, dioctyl adipate, lauric acid, stearyl alcohol, and cetanol.

Examples of surfactants include macrogols such as polyethylene glycol with a weight-average molecular weight of 300 to 6000; polyoxyethylene polyoxypropylene glycols such as Pluronic (registered trademark) and poloxamer; polyoxyethylene sorbitan fatty acid esters (polysorbates) such as polysorbate 80; polyoxyethylene hydrogenated oils such as polyoxyethylene hydrogenated castor oil; glycerin fatty acid esters such as glycerin monostearate; sorbitan fatty acid esters such as sorbitan monostearate and sorbitan monolaurate; sucrose fatty acid esters such as sucrose laurate; and fatty acid metal salts such as sodium lauryl sulfate.

Examples of pH adjusters include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic acids such as acetic acid and citric acid; inorganic bases such as sodium hydroxide and sodium bicarbonate; and organic bases such as amines.

Examples of coloring agents include yellow ferric oxide, ferric oxide, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, food lake color, red iron oxide, turmeric extract, riboflavin, riboflavin phosphate sodium, carotene solution, tar color, and caramel.

These additives can be used alone or in combination. The total amount of these additives in the granules may be 50% by mass or less, for example, 0.01 to 30% by mass, preferably 0.05 to 20% by mass, and more preferably 0.1 to 10% by mass.

From the viewpoint of improving the dissolution property of the active pharmaceutical ingredient, the granules are preferably substantially free of cellulose ethers having a hydroxy _C2-4 alkyl group, such as hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), etc. The proportion of cellulose ethers having a hydroxy _C2-4 alkyl group in the granules may be 1% by mass or less, preferably 0.5% by mass or less, more preferably 0.1% by mass or less, and even more preferably 0.01% by mass or less, and it is most preferred that the granules are free of cellulose ethers having a hydroxy _C2-4 alkyl group.

The shape of the granules is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, or granular, and is usually amorphous or granular. Furthermore, the shape of the granules may be hollow, but a solid shape is preferred from the standpoint of ease of administration.

The volume-based cumulative 50% particle size (D ₅₀ ) of the granules is, for example, 50 to 1000 μm, preferably 70 to 800 μm, more preferably 80 to 700 μm, still more preferably 100 to 600 μm, and most preferably 150 to 500 μm. If the particle size of the granules is too small, there is a risk that the feeling of taking the granules will be reduced, and if it is too large, there is a risk that the dissolution of the active ingredient will be reduced.

The moisture content of the granules is preferably, for example, 1.5% by mass or less, and more preferably 1.0% by mass or less.

[Fast-disintegrating particles]
The orally disintegrating tablet (OD tablet) of the present invention contains the granules and rapidly disintegrating particles, and since the granules containing the active pharmaceutical ingredient particles are combined with the rapidly disintegrating particles, the oral disintegration property can be highly improved. Furthermore, by combining the granules with specific rapidly disintegrating particles, in addition to the oral disintegration property, the feeling of taking the tablet can be improved, and the mechanical properties such as hardness required for an OD tablet can also be ensured.

(Sugar alcohol)
The rapidly disintegrating particles preferably contain a sugar alcohol as an excipient. Examples of sugar alcohols include sorbitol, mannitol, reduced maltose syrup (maltitol), reduced starch syrup, xylitol, reduced palatinose, and tetraoses obtained by fermenting glucose (e.g., erythritol). These sugar alcohols can be used alone or in combination. Among these, mannitol, sorbitol, erythritol, xylitol, and the like are commonly used, with mannitol being preferred and D-mannitol being particularly preferred.

The shape of the sugar alcohol (raw material sugar alcohol) is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, granular, or the like, and is usually amorphous or granular.

The volume-based cumulative 50% particle size (D ₅₀ ) of the sugar alcohol (raw material sugar alcohol) is, for example, 1 to 350 μm, preferably 5 to 250 μm, and more preferably 20 to 150 μm. If the particle size of the sugar alcohol is too small, the mechanical properties of the rapidly disintegrating particles may be reduced, whereas if it is too large, the feeling of ingestion may be reduced.

The proportion of sugar alcohol (particularly mannitol) in the rapidly disintegrating particles may be 30% by mass or more, for example, 30 to 95% by mass, preferably 50 to 90% by mass, even more preferably 60 to 85% by mass, even more preferably 65 to 80% by mass, and most preferably 70 to 75% by mass. If the proportion of sugar alcohol is too low, there is a risk that the sensation of taking the tablet will be reduced, and conversely, if it is too high, there is a risk that oral disintegration will be reduced.

(Ethyl cellulose)
The rapidly disintegrating particles preferably contain ethyl cellulose as a binder, which can improve oral disintegration properties.

The shape of ethyl cellulose is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, granular, etc., and is usually amorphous or granular.

The volume-based cumulative 50% particle size (D ₅₀ ) of ethyl cellulose is, for example, 1 to 60 μm, preferably 3 to 45 μm, and more preferably 5 to 15 μm. If the particle size of ethyl cellulose is too small, the mechanical properties of the rapidly disintegrating particles may be reduced, whereas if it is too large, the feeling of taking the ethyl cellulose may be reduced.

The proportion of ethyl cellulose is, for example, 0.1 to 10 parts by mass, preferably 1 to 5 parts by mass, more preferably 1.5 to 4 parts by mass, and most preferably 2 to 3.5 parts by mass, per 100 parts by mass of sugar alcohol. The proportion of ethyl cellulose in the rapidly disintegrating particles may be 0.1 to 10% by mass, preferably 0.5 to 5% by mass, more preferably 1 to 3% by mass, and most preferably 1.5 to 2.5% by mass. If the proportion of ethyl cellulose is too low, the mechanical properties of the particles may be reduced; conversely, if the proportion is too high, oral disintegration may be reduced.

(Carmellose)
The rapidly disintegrating particles preferably contain carmellose as a disintegrant. When rapidly disintegrating particles are prepared by combining a sugar alcohol with carmellose without substantially containing crystalline cellulose, not only the oral disintegration property but also the feeling of taking the tablet can be improved. In particular, by combining the sugar alcohol with the ethyl cellulose, the silicic acid compounds described below, and crospovidone, the water conductivity of carmellose acts synergistically with the other ingredients, which can highly improve the oral disintegration property and the feeling of taking the tablet, while also ensuring the mechanical properties required for an orally disintegrating tablet.

In carmellose, the average degree of substitution (or average degree of etherification) of carboxymethyl groups is, for example, 0.1 to 1, preferably 0.2 to 0.8, more preferably 0.3 to 0.7, and most preferably 0.4 to 0.6. If the average degree of substitution is too low, oral disintegration may be impaired. Note that this average degree of substitution is the average value of the degree of substitution (substitution ratio) for the hydroxyl group at the 6-position of the glucose units that make up cellulose, with a maximum value of 1.

The shape of carmellose (raw material carmellose) is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, granular, etc., and is usually amorphous, granular, etc.

The volume-based cumulative 50% particle size (D ₅₀ ) of carmellose (raw material carmellose) is, for example, 1 to 70 μm, preferably 3 to 50 μm, and more preferably 5 to 30 μm. If the particle size of carmellose is too small, oral disintegration may be impaired, whereas if it is too large, the feeling of ingestion may be impaired.

The bulk density of carmellose is, for example, 100 to 800 g/L, preferably 200 to 500 g/L, and more preferably 300 to 400 g/L.

The proportion of carmellose can be selected from a range of approximately 1 to 100 parts by mass per 100 parts by mass of sugar alcohol, for example, 3 to 50 parts by mass, preferably 5 to 45 parts by mass, more preferably 10 to 40 parts by mass, even more preferably 20 to 35 parts by mass, and most preferably 25 to 30 parts by mass. The proportion of carmellose in the rapidly disintegrating particles may be 3 to 50% by mass, preferably 5 to 40% by mass, more preferably 10 to 30% by mass, and most preferably 15 to 25% by mass. If the proportion of carmellose is too low, oral disintegrability may be reduced, while if it is too high, the swallowing sensation may be reduced.

(silicic acids)
The rapidly disintegrating particles may further contain silicic acids as a binder and/or disintegrant in addition to the sugar alcohol and carmellose. Although silicic acids are generally used as excipients, when combined with the sugar alcohol and carmellose, they not only improve hardness but also contribute to oral disintegration and a comfortable feeling when taken, and the selection of silicic anhydride can highly improve oral disintegration and a comfortable feeling when taken, probably due to improved water conductivity.

Examples of silicic acids include those exemplified as excipients in the granule section above. The silicic acids may be used alone or in combination. Of these, anhydrous silicic acid is preferred, with light anhydrous silicic acid being particularly preferred.

The shape of the silicic acids (raw silicic acids) is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, tabular, granular, etc., and is usually amorphous or granular.

The volume-based cumulative 50% particle size (D ₅₀ ) of the silicic acid (particularly silicic anhydride) is, for example, 0.1 to 30 μm, preferably 0.5 to 10 μm, more preferably 1 to 5 μm, and most preferably 2 to 4 μm. If the particle size of the silicic acid is too small, oral disintegration may be impaired, whereas if it is too large, the feeling of ingestion may be impaired.

The BET specific surface area of the silicic acid (raw material silicic acid) is, for example, 50 to 1000 ^{m 2} /g, preferably 100 to 500 ^{m 2} /g, more preferably 150 to 450 ^{m 2} /g, and most preferably 200 to 400 m ² /g. If the BET specific surface area is too small, there is a risk of reduced hardness, whereas if it is too large, there is a risk of reduced oral disintegrability.

In this specification and claims, the BET specific surface area of silicates can be measured by conventional methods, such as the nitrogen adsorption method.

The proportion of silicic acid (particularly silicic anhydride) is, for example, 0.1 to 10 parts by mass, preferably 0.3 to 5 parts by mass, more preferably 0.5 to 3 parts by mass, and most preferably 1 to 2 parts by mass, per 100 parts by mass of sugar alcohol. The proportion of silicic acid (particularly silicic anhydride) in the rapidly disintegrating particles may be 0.1 to 5% by mass, preferably 0.3 to 3% by mass, more preferably 0.5 to 2% by mass, and most preferably 0.5 to 1.5% by mass. If the proportion of silicic acid is too low, the effect of improving hardness and oral disintegration may be reduced, while if the proportion is too high, the feeling of taking the drug may be reduced.

(crospovidone)
The rapidly disintegrating particles may contain crospovidone as a disintegrant.

The shape of crospovidone (raw material crospovidone) is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, granular, or the like, and is usually amorphous or granular.

The volume-based cumulative 50% particle size (D ₅₀ ) of crospovidone is, for example, 0.5 to 50 μm, preferably 1 to 30 μm, more preferably 3 to 20 μm, and most preferably 5 to 10 μm. If the particle size of crospovidone is too small, oral disintegrability may decrease, whereas if it is too large, the feeling of ingestion may decrease.

The proportion of crospovidone is, for example, 3 to 20 parts by mass, preferably 5 to 15 parts by mass, more preferably 6 to 10 parts by mass, and most preferably 7 to 9 parts by mass, per 100 parts by mass of sugar alcohol. The proportion of crospovidone in the rapidly disintegrating particles may be 3 to 15% by mass, preferably 5 to 10% by mass, more preferably 5 to 8% by mass, and most preferably 6 to 7% by mass. If the proportion of crospovidone is too low, oral disintegrability may be reduced; conversely, if it is too high, the mechanical properties of the particles may be reduced.

(Other ingredients)
The rapidly disintegrating granules may further contain conventional additives that are incorporated into oral preparations, such as disintegrants (excluding crospovidone), excipients (excluding sugar alcohols and silicic acids), binders (excluding ethyl cellulose and carmellose), lubricants, plasticizers, surfactants, pH adjusters, colorants, sweeteners or flavoring agents, flavoring agents or cooling agents, antioxidants, preservatives or preservatives, wetting agents, antistatic agents, disintegration aids, etc.

These additives can be used alone or in combination. The total amount of these additives in the rapidly disintegrating particles may be 50% by mass or less (e.g., 0.01 to 50% by mass), for example, 30% by mass or less, preferably 20% by mass or less, more preferably 10% by mass or less, and most preferably 5% by mass or less (e.g., 0.1 to 5% by mass).

The rapidly disintegrating particles may contain zonisamide active ingredient, but from the standpoint of formulation design, etc., particles that are substantially free of zonisamide active ingredient are preferred, and it is more preferable that they do not contain zonisamide active ingredient.

(Characteristics of fast-disintegrating particles)
The shape of the rapidly disintegrating particles is not particularly limited, and may be amorphous, fibrous, ellipsoidal, spherical, tabular, granular, or the like, with amorphous, granular, and spherical shapes being preferred, and isotropic shapes such as spheres being particularly preferred.

The volume-based cumulative 50% particle diameter (D ₅₀ ) of the rapidly disintegrating particles is, for example, 10 to 200 μm, preferably 30 to 130 μm, more preferably 50 to 110 μm, and most preferably 70 to 90 μm. If the particle diameter of the rapidly disintegrating particles is too small, there is a risk that the oral disintegration property will decrease, whereas if it is too large, there is a risk that the feeling of taking the drug will decrease.

The volume-based cumulative 10% particle size (D ₁₀ ) of the rapidly disintegrating particles is, for example, 1 μm or more (e.g., 1 to 75 μm), preferably 5 μm or more (e.g., 5 to 50 μm), further preferably 10 μm or more (e.g., 10 to 40 μm), more preferably 20 μm or more (e.g., 20 to 35 μm), and most preferably 25 μm or more (e.g., 25 to 30 μm). If _{D 10} is too small, there is a risk that oral disintegrability will decrease.

The volume-based cumulative 90% particle diameter (D ₉₀ ) of the rapidly disintegrating particles is, for example, 300 μm or less (e.g., 80 to 300 μm), preferably 250 μm or less (e.g., 100 to 250 μm), more preferably 200 μm or less (e.g., 130 to 200 μm), and most preferably 180 μm or less (e.g., 150 to 180 μm). If _{D 90} is too large, there is a risk of the feeling of taking the tablet being reduced.

In the orally disintegrating tablet (OD tablet), the proportion of rapidly disintegrating particles is, for example, 10 to 1000 parts by mass, preferably 30 to 500 parts by mass, even more preferably 50 to 400 parts by mass, even more preferably 100 to 300 parts by mass, and most preferably 150 to 200 parts by mass, per 100 parts by mass of granules. If the proportion of rapidly disintegrating particles is too low, oral disintegration and swallowing comfort may be reduced, while if it is too high, formulation designability may be compromised.

(Method for producing rapidly disintegrating particles)
The rapidly disintegrating particles can be obtained by granulation using a conventional granulation method, such as tumbling granulation, fluidized bed granulation, mixing and stirring granulation, spray drying granulation, vibration granulation, etc. Of these, fluidized bed granulation is preferred from the viewpoint of productivity, etc.

Conventional fluidized bed granulation methods can be used, but when the rapidly disintegrating particles contain sugar alcohol, carmellose, ethyl cellulose, silicic acid, and crospovidone, a preferred method is to premix the ingredients other than crospovidone in a fluidized bed granulator and then spray an aqueous dispersion (granulation liquid) containing crospovidone to granulate. Mixing solid sugar alcohol and solid carmellose makes it easier to prepare rapidly disintegrating particles that combine oral disintegrability and a pleasant feeling when taken.

The solvent contained in the granulation liquid is not particularly limited, but water, lower alcohols (e.g., C _1-4 alcohols such as ethanol and isopropanol), aliphatic ketones (e.g., acetone), or mixtures thereof are commonly used. From the viewpoint of safety, water and/or ethanol are preferred, with water being particularly preferred. The proportion of the solvent relative to 100 parts by mass of crospovidone is, for example, 1,000 to 3,000 parts by mass, preferably 1,200 to 2,500 parts by mass, and more preferably 1,500 to 2,000 parts by mass.

[Oru-disintegrating tablet]
The orally disintegrating tablet (OD tablet) of the present invention may be an OD tablet containing the granules and the rapidly disintegrating particles, but is preferably an OD tablet obtained by tableting a composition for OD tablets containing the granules and the rapidly disintegrating particles.

(Other ingredients)
In addition to the granules and the rapidly disintegrating particles, the composition for OD tablets may further contain conventional additives that are incorporated into oral preparations, such as excipients, lubricants, sweeteners or flavoring agents, flavoring agents or cooling agents.

The excipient may further include the excipients and binders exemplified in the granule section above. The excipients may be used alone or in combination of two or more. Among these, alkyl cellulose is preferred, with _C1-3 alkyl cellulose such as EC being particularly preferred. The volume-based cumulative 50% particle diameter (D ₅₀ ) of the alkyl cellulose may be, for example, 1 to 60 μm, preferably 3 to 45 μm, and more preferably 5 to 15 μm. The proportion of the excipient is, for example, 1 to 100 parts by mass, preferably 2 to 50 parts by mass, more preferably 3 to 30 parts by mass, and most preferably 5 to 10 parts by mass, per 100 parts by mass of the granules.

Examples of lubricants include the lubricants exemplified in the granule section above, as well as silicic acids exemplified as excipients in the granule section above. The lubricants can be used alone or in combination. Among the lubricants, fatty acid metal salts such as magnesium stearate and silicic acids such as light anhydrous silicic acid are preferred. The volume-based cumulative 50% particle size (D ₅₀ ) of the lubricant may be, for example, 0.1 to 30 μm, preferably 0.5 to 10 μm, more preferably 1 to 5 μm, and most preferably 2 to 4 μm. The proportion of the lubricant is, for example, 0.5 to 10 parts by weight, preferably 1 to 7 parts by weight, and more preferably 2 to 5 parts by weight per 100 parts by weight of the granules.

Sweeteners or flavoring agents include those exemplified in the section on granules above. The ratio of sweetener or flavoring agent is, for example, 1 to 30 parts by weight, preferably 5 to 20 parts by weight, and more preferably 10 to 15 parts by weight per 100 parts by weight of the granules.

Flavoring agents or fresheners include those exemplified in the section on granules above. The proportion of flavoring agent or freshener is, for example, 0.01 to 3 parts by weight, preferably 0.05 to 1 part by weight, and more preferably 0.1 to 0.5 parts by weight per 100 parts by weight of the granules.

In order to achieve both oral disintegration and a comfortable feeling when taken, it is preferable that the OD tablet be substantially free of microcrystalline cellulose or crystalline cellulose. Therefore, the proportion of crystalline cellulose in the OD tablet is less than 1% by mass, preferably 0.5% by mass or less, more preferably 0.1% by mass or less, and even more preferably 0.01% by mass or less, and it is most preferable that the OD tablet be free of crystalline cellulose. If OD tablets contain crystalline cellulose, both oral disintegration and the comfortable feeling when taken will be reduced.

In order to achieve both good oral disintegration and a comfortable feeling when taken, the OD tablet is preferably substantially free of cellulose ethers having a hydroxy _C2-4 alkyl group, such as hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), etc. The proportion of cellulose ethers having a hydroxy _C2-4 alkyl group in the OD tablet may be 1% by mass or less, preferably 0.5% by mass or less, more preferably 0.1% by mass or less, and even more preferably 0.01% by mass or less, and it is most preferred that the OD tablet is free of cellulose ethers having a hydroxy _C2-4 alkyl group.

In order to achieve both oral disintegration and a comfortable feeling when taken, the OD tablet preferably contains substantially no starches, and it is particularly preferable that it contains substantially no starch.

Starches include starches such as corn starch and potato starch; and starch derivatives such as pregelatinized starch, partially pregelatinized starch, oxidized starch, dextrin, cyclodextrin, hydroxypropyl starch, carboxymethyl starch, and sodium carboxymethyl starch.

In the OD tablets, the proportion of starches (particularly starches such as corn starch) is less than 1% by mass, preferably 0.5% by mass or less, even more preferably 0.1% by mass or less, and even more preferably 0.01% by mass or less, and most preferably no starches are present. If starches (particularly starch) are present in the OD tablets, both oral disintegration and the feeling of taking them will be reduced.

The tablet diameter (average diameter) of the OD tablets of the present invention is, for example, 3 to 20 mm, preferably 5 to 15 mm, more preferably 7 to 12 mm, and most preferably 8 to 11 mm.

The moisture content of the OD tablet of the present invention is, for example, preferably 2.5% by mass or less, and more preferably 1.5% by mass or less.

The hardness of the OD tablet of the present invention is preferably, for example, 55 N or more, and more preferably 65 N or more.

In this specification and claims, the hardness of OD tablets can be measured by the method described in the Examples below.

The OD tablet of the present invention can be produced by any conventional method as long as it is a method of tableting using such an OD tablet composition.

The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples. The evaluation methods used in the following examples are as follows. All weights of raw materials used are solid weights.

[Particle size distribution]
The particle size distribution (D ₁₀ , D ₅₀ , D ₉₀ ) was measured on a volume basis using a laser diffraction particle size distribution analyzer (Malvern Instruments, trade name "Mastersizer 3000").

[Average dissolution rates of drug substance particles and OD tablets]
The average dissolution rate of the drug substance particles or OD tablets was measured in accordance with the paddle method (rotation speed: 50 rpm) of the Japanese Pharmacopoeia dissolution test.

The test was started by collecting a sample, and the eluate was collected at each sampling time and filtered through a membrane filter with a pore size of 0.45 μm or less to prepare a sample solution.

Separately, 28 mg of the standard was accurately weighed and the dissolving solution was added to make exactly 50 mL. 2.5 mL of this solution was accurately weighed and the dissolving solution was added to make exactly 50 mL to prepare the standard solution.

The sample solution and standard solution were tested using ultraviolet-visible absorbance measurement, and the absorbance of each solution at a wavelength of 285 nm was measured.

[hardness]
The hardness was measured using a hardness tester (manufactured by ERWEKA, trade name "TBH425") The hardness values shown in the following Examples 5 to 8 are the average values of five OD tablets.

[Disintegration time (Japanese Pharmacopoeia, 17th Edition)]
A disintegration tester (compliant with the Japanese Pharmacopoeia) was used. 900 mL of water at 37°C was placed in a glass container, and a basket (with a mesh bottom) containing tablets was moved up and down in the water in the container, and the time until the tablets were completely disintegrated was measured.

Comparative Example 1
The particle size distribution of the unground zonisamide was measured, and the volume-based cumulative 50% particle size (D ₅₀ ) was 19.8 μm, the volume-based cumulative 10% particle size (D ₁₀ ) was 3.6 μm, and the volume-based cumulative 90% particle size (D ₉₀ ) was 116.0 μm.

Example 1
Unground zonisamide was crushed at 6,000 rpm using an impact crusher to produce zonisamide drug substance particles, and the particle size distribution was measured. The volume-based cumulative 50% particle size (D ₅₀ ) was 11.7 μm, the volume-based cumulative 10% particle size (D ₁₀ ) was 2.5 μm, and the volume-based cumulative 90% particle size (D ₉₀ ) was 38.1 μm.

Example 2
Unground zonisamide was crushed at 10,000 rpm using an impact crusher to produce zonisamide drug substance particles, and the particle size distribution was measured. The volume-based cumulative 50% particle size (D ₅₀ ) was 8.7 μm, the volume-based cumulative 10% particle size (D ₁₀ ) was 2.1 μm, and the volume-based cumulative 90% particle size (D ₉₀ ) was 22.3 μm.

Example 3
Unground zonisamide was ground using an impact grinder at 14,000 rpm to produce zonisamide drug substance particles, and the particle size distribution was measured. The volume-based cumulative 50% particle size (D ₅₀ ) was 7.0 μm, the volume-based cumulative 10% particle size (D ₁₀ ) was 1.9 μm, and the volume-based cumulative 90% particle size (D ₉₀ ) was 18.1 μm.

Example 4
Unground zonisamide was crushed at 18,000 rpm using an impact crusher to produce zonisamide drug substance particles, and the particle size distribution was measured. The volume-based cumulative 50% particle size (D ₅₀ ) was 5.9 μm, the volume-based cumulative 10% particle size (D ₁₀ ) was 1.7 μm, and the volume-based cumulative 90% particle size (D ₉₀ ) was 15.7 μm.

The results of measuring the average dissolution rates of the drug substance particles in Comparative Example 1 and Examples 1 to 4 are shown in Table 1.

As is clear from the results in Table 1, the drug substance particles of Examples 1 to 4 had higher dissolution rates than those of Comparative Example 1.

Example 5
(Preparation of Zonisamide Granules)
1) 7.5 mg of ethyl cellulose was added to 67.5 mg of ethanol (99.5) and dissolved therein, and 7.5 mg of purified water was added thereto, and then 3.75 mg of talc was dispersed therein to obtain a dispersion.

2) 25 mg of zonisamide drug substance particles (D ₅₀ : 6.35 μm, D ₁₀ : 1.76 μm, D ₉₀ : 15.1 μm), 2.8 mg of D-mannitol (D ₅₀ : 55 μm) and 1.2 mg of light anhydrous silicic acid (D ₅₀ : 2.75 μm) were placed in a fluidized bed granulation dryer and mixed, and the dispersion was sprayed and dried.

3) The granules were sized using a 30M sieve (mesh opening: 500 μm) to obtain zonisamide granules.

(Preparation of rapidly disintegrating particles)
1) 5.115 mg of crospovidone (D ₅₀ : 15.6 μm) was dispersed in purified water, and this dispersion was used as a granulation liquid.

2) 60.5275 mg of D-mannitol (D ₅₀ : 55 μm), 1.705 mg of ethyl cellulose (D ₅₀ : 10.3 μm), 0.8525 mg of light anhydrous silicic acid (D ₅₀ : 2.75 μm), and 17.05 mg of carmellose (D ₅₀ : 54.2 μm) were placed in a fluidized bed granulation dryer and mixed, and the granulation liquid was sprayed onto the mixture, followed by drying and sizing to obtain rapidly disintegrating particles.

(Mixing, tableting, packaging)
1) 40.25 mg of zonisamide granules, 85.25 mg of rapidly disintegrating particles, 3 mg of ethyl cellulose (D ₅₀ : 10.3 μm), 5 mg of aspartame, and 0.75 mg of light anhydrous silicic acid (D ₅₀ : 2.75 μm) were placed in a diffusion mixer and mixed to obtain a mixed powder.

2) 0.75 mg of magnesium stearate was added to the mixed powder and mixed to obtain a tablet powder.

3) The tablet powder was compressed using a rotary tablet press to obtain 135 mg OD tablets (tablet diameter 7.0 mm, hardness 73 N, disintegration time 19 seconds). Sensory evaluation showed favorable results in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegration.

The average dissolution rate of the OD tablets in Example 5 was measured and the results are shown in Table 2.

As is clear from the results in Table 2, the OD tablets of Example 5 exhibited good dissolution properties.

Example 6
(Preparation of Zonisamide Granules)
1) 15 mg of ethyl cellulose was added to 135 mg of ethanol (99.5) and dissolved therein, and 15 mg of purified water was added thereto, and then 7.5 mg of talc was dispersed therein to obtain a dispersion.

2) 50 mg of zonisamide drug substance particles (D ₅₀ : 6.35 μm, D ₁₀ : 1.76 μm, D ₉₀ : 15.1 μm), 5.6 mg of D-mannitol and 2.4 mg of light anhydrous silicic acid were placed in a fluidized bed granulation dryer and mixed, and the dispersion was sprayed and dried.

3) The granules were sized using a 30M sieve (mesh opening: 500 μm) to obtain zonisamide granules.

(Preparation of rapidly disintegrating particles)
1) 10.23 mg of crospovidone and 0.189 mg of yellow ferric oxide were dispersed in purified water, and this dispersion was used as a granulation liquid.

2) 121.055 mg of D-mannitol, 3.41 mg of ethyl cellulose, 1.705 mg of light anhydrous silicic acid, and 34.1 mg of carmellose were mixed in a fluidized bed granulation dryer, and the granulation liquid was sprayed onto the mixture. The mixture was then dried and sized to obtain rapidly disintegrating particles.

(Mixing, tableting, packaging)
1) 80.5 mg of zonisamide granules, 170.5 mg of rapidly disintegrating particles, 6 mg of ethyl cellulose, 10 mg of aspartame, and 1.5 mg of light anhydrous silicic acid were placed in a diffusion mixer and mixed to obtain a mixed powder.

2) 1.5 mg of magnesium stearate was added to the mixed powder and mixed to obtain tablet powder.

3) The tablet powder was compressed using a rotary tablet press to obtain 270 mg OD tablets (tablet diameter 9.0 mm, hardness 81 N, disintegration time 17 seconds). Sensory evaluation showed favorable results in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegration.

The average dissolution rate of the OD tablets of Example 6 was measured and the results are shown in Table 3.

As is clear from the results in Table 3, the OD tablets of Example 6 exhibited good dissolution properties.

Example 7
Except for using zonisamide bulk particles with different particle sizes ( _D50 : 3.3 μm, _D10 : 1.1 μm, _D90 : 6.8 μm), 135 mg of OD tablets (tablet diameter 7.0 mm, hardness 69.4 N) containing 25 mg of active ingredient were obtained using the same formulation and manufacturing method as in Example 5. Sensory evaluation showed good results in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegrability.

The average dissolution rate of the OD tablets of Example 7 was measured and the results are shown in Table 4.

As is clear from the results in Table 4, the OD tablets of Example 7 exhibited good dissolution properties.

Example 8
Except for using zonisamide bulk particles with different particle sizes ( _D50 : 3.3 μm, _D10 : 1.1 μm, _D90 : 6.8 μm), 270 mg of OD tablets (tablet diameter 9.0 mm, hardness 70.1 N) containing 50 mg of active ingredient were obtained using the same formulation and manufacturing method as in Example 6. Sensory evaluation showed good results in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegrability.

The average dissolution rate of the OD tablets of Example 8 was measured and the results are shown in Table 5.

As is clear from the results in Table 5, the OD tablets of Example 8 exhibited good dissolution properties.

The zonisamide drug substance particles of the present invention can be effectively used as a benzisoxazole antiepileptic drug that has anticonvulsant and antiparkinsonian effects.

Claims (10)

The pharmaceutical composition comprises drug substance particles formed from zonisamide or a salt thereof, the drug substance particles having a volume-based cumulative 50% particle size (D ₅₀ ) of 3 to 12 μm and a volume-based cumulative 10% particle size (D ₁₀ ) of 1.5 to 3 μm;
Solid granules free from cellulose ethers having hydroxy _C2-4 alkyl groups. An orally disintegrating tablet comprising the solid granules of claim 1 and rapidly disintegrating particles. The orally disintegrating tablet according to claim 2, wherein the rapidly disintegrating particles contain ethyl cellulose. The orally disintegrating tablet according to claim 2, wherein the rapidly disintegrating particles contain sugar alcohol, carmellose, silicic acid, and crospovidone. The orally disintegrating tablet according to claim 3, wherein the rapidly disintegrating particles further contain sugar alcohol, carmellose, silicic acid, and crospovidone. 6. The orally disintegrating tablet according to claim 4, wherein the rapidly disintegrating particles do not contain crystalline cellulose. The orally disintegrating tablet according to any one of claims 2 to 6, which does not contain crystalline cellulose. The orally disintegrating tablet according to any one of claims 2 to 7, which does not contain cellulose ethers having a hydroxy _C2-4 alkyl group and starches. solid granules which are formed from zonisamide or a salt thereof and contain drug substance particles having a volume-based cumulative 50% particle size (D ₅₀ ) of 3 to 12 μm and which do not contain a cellulose ether having a hydroxy C _2-4 alkyl group;
An orally disintegrating tablet comprising ethyl cellulose, a sugar alcohol, carmellose, silicic acids and crospovidone, and also comprising rapidly disintegrating particles which do not contain crystalline cellulose, a cellulose ether having a hydroxy _C2-4 alkyl group and starches. adjusting the volume-based cumulative 50% particle diameter (D ₅₀ ) of the drug substance particles formed from zonisamide or a salt thereof to 3 to 12 μm and the volume-based cumulative 10% particle diameter (D ₁₀ ) to 1.5 to 3 μm;
Furthermore, the present invention provides a method for improving the dissolution rate of zonisamide or a salt thereof in water by preparing solid granules containing the above-mentioned drug substance particles and not containing a cellulose ether having a hydroxy _C2-4 alkyl group.