Zonisamide drug substance particles and their uses

Abstract

To provide zonisamide drug substance particles capable of improving elution properties.SOLUTION: There is provided drug substance particles formed of zonisamide or a salt thereof and having an adjusted cumulative 50% particle size (D50) of 18 μm or less on a volume basis. The drug substance particles may have a cumulative 10% particle size (D10) of less than 3.6 μm on a volume basis and may have a cumulative 90% particle size (D90) of 15 μm or more on a volume basis. Granules comprising the drug substance particles may be prepared. The granules may be solid. Preferably, the granules may be substantially free of cellulose ether having a hydroxy C2-4 alkyl group. Orally disintegrating tablets comprising the granules and rapidly disintegrating particles may be prepared. The rapidly disintegrating particles may contain ethyl cellulose. The rapidly disintegrating particles may further contain sugar alcohols, carmellose, silicic acids, and crospovidone. Preferably, the orally disintegrating tablet may be substantially free of crystalline cellulose. Preferably, the orally disintegrating tablet is substantially free of cellulose ethers and starches having a hydroxy C2-4 alkyl group.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to zonisamide drug substance particles formed from zonisamide, which is used as an antiepileptic drug, and uses thereof. [Background technology]

[0002] 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.

[0003] 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, corn starch, and carmellose. This document describes the average particle size of the active ingredient as 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.

[0004] 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 a jet-milled product having a cumulative 50% particle diameter (D 50 ) 2.7 μm zonisamide, etc., is used, and polymers such as hydroxypropyl cellulose are used as the polymer.

[0005] WO 2019 / 130749 (Patent Document 3) discloses a composition for imparting sustained-release, enteric, gastric, bitter-masking, or light-stability functions to drug-containing hollow particles consisting of a shell and a hollow portion, including coatable fine particles, as a composition capable of providing a formulation that allows the absorption of a target component at a desired site for a desired time and achieves a desired medicinal effect. In the examples of this document, the drug is a compound having a volume-based cumulative 50% particle diameter (D 50 ) 1.99 μm zonisamide and others are used. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2009 / 102038 [Patent Document 2] International Publication No. 2014 / 030656 [Patent Document 3] International Publication No. 2019 / 130749 Summary of the Invention [Problem to be solved by the invention]

[0007] However, with the zonisamide drug substances of Patent Documents 1 to 3, it was difficult to ensure sufficient dissolution properties.

[0008] Therefore, an object of the present invention is to provide zonisamide drug substance particles that can improve dissolution properties and uses thereof. [Means for solving the problem]

[0009] As a result of extensive research into achieving the above object, the present inventors have found that the volume-based cumulative 50% particle diameter (D 50 The present inventors have found that the dissolution property can be improved by adjusting the particle size to 18 μm or less, and have completed the present invention.

[0010] That is, the drug substance particles of the present invention are formed from zonisamide or a salt thereof and have a volume-based cumulative 50% particle diameter (D 50 ) is 18 μm or less. 10 ) is less than 3.6 μm, and the volume-based cumulative 90% particle diameter (D 90 ) may be 15 μm or more.

[0011] The present invention also includes granules containing the drug substance particles. The granules may be solid. The granules contain hydroxy C 2-4 It is preferred that the composition is substantially free of cellulose ethers having alkyl groups.

[0012] The present invention also includes an orally disintegrating tablet containing 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 acid, and crospovidone. The orally disintegrating tablet is preferably substantially free of crystalline cellulose. The orally disintegrating tablet is preferably free of hydroxy C 2-4 It is preferred that the composition be substantially free of alkyl group-containing cellulose ethers and starches.

[0013] The present invention provides a pharmaceutical composition having a volume-based cumulative 50% particle diameter (D 50 ) to 18 μm or less, thereby improving the dissolution rate of zonisamide or a salt thereof in water. [Effects of the Invention]

[0014] In the present invention, the volume-based cumulative 50% particle diameter (D 50 ) is adjusted to 18 μm or less, which improves the dissolution of zonisamide active ingredient. DETAILED DESCRIPTION OF THE INVENTION

[0015] [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.

[0016] The salt is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt form include alkali metal salts (lithium salt, sodium salt, potassium salt, etc.).

[0017] The shape of the drug substance particles is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, tabular, granular, or the like, and is usually amorphous, granular, or the like.

[0018] Cumulative 50% particle size (D 50 ) 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.

[0019] Cumulative 10% particle size (D 10 ) may be less than 3.6 μm, for example, 1.5 to 3 μm, preferably 1.5 to 2.5 μm.

[0020] Cumulative 90% particle size (D 90 ) may be 15 μm or more, for example, 15 to 50 μm, preferably 15 to 40 μm.

[0021] In this specification and claims, the cumulative 50% particle diameter (D 50 The particle size of the particles such as the above 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.

[0022] [Granules containing active pharmaceutical ingredients] The granules of the present invention contain the aforementioned 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.

[0023] 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.

[0024] 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. 50 ) may be, for example, 1 to 350 μm, preferably 5 to 250 μm, and more preferably 20 to 150 μm. 50 The thickness 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.

[0025] When a sugar alcohol and a silicic acid are combined, the proportion of the sugar alcohol relative to 100 parts by mass of the silicic acid 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. If the proportion of the sugar alcohol is too low, there is a risk of the mechanical properties being reduced, whereas if it is too high, there is a risk of the dissolution of the active pharmaceutical ingredient being reduced.

[0026] The proportion of the 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 relative to 100 parts by mass of the drug substance particles. The proportion of the 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 the excipient is too low, there is a risk of the mechanical properties being reduced, and conversely, if it is too high, there is a risk of the dissolution of the drug substance being reduced.

[0027] The granules may further contain a binder in addition to the drug substance 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 polymers, 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 may be used alone or in combination.

[0028] Among these, alkyl cellulose is preferred, and C such as EC 1-3 Alkyl cellulose is particularly preferred. The volume-based cumulative 50% particle diameter (D 50 ) may be, for example, 1 to 60 μm, preferably 3 to 45 μm, and more preferably 5 to 15 μm.

[0029] 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 relative to 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, and conversely, if it is too high, there is a risk of reduced dissolution of the drug substance.

[0030] 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 mass, preferably 10 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 the coating agent.

[0031] In addition to the drug substance particles, the granules may further contain conventional additives incorporated into oral preparations, such as disintegrants, lubricants, plasticizers, surfactants, pH adjusters, colorants, sweeteners or flavoring agents (aspartame, acesulfame potassium, sucralose, ascorbic acid, stevia, crude licorice extract, simple syrup, etc.), flavorings or refreshing agents (yogurt micron, peppermint micron, menthol, ginger oil, etc.), antioxidants (dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, citric acid, etc.), preservatives or preservatives (sodium benzoate, parahydroxybenzoic acid esters, etc.), wetting agents, antistatic agents, disintegration aids, etc.

[0032] Examples of disintegrants include 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.

[0033] Examples of lubricants include fatty acids or metal salts thereof such as stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sodium coconut oil fatty acid; 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.

[0034] Examples of the plasticizer 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.

[0035] Examples of surfactants include macrogols such as polyethylene glycol having 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.

[0036] 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 hydrogen carbonate; and organic bases such as amines.

[0037] 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.

[0038] 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.

[0039] The granules are preferably made of hydroxy C cellulose such as hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC) in order to improve the dissolution of the active pharmaceutical ingredient. 2-4 It is preferable that the cellulose ether is substantially free of alkyl group-containing cellulose ethers. 2-4The proportion of cellulose ether having an alkyl group in the granules may be 1% by mass or less, preferably 0.5% by mass or less, further preferably 0.1% by mass or less, and further preferably 0.01% by mass or less. 2-4 It is most preferred that the cellulose ether does not contain any alkyl group-containing cellulose ether.

[0040] The shape of the granules is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, powdery, etc., and is usually amorphous, powdery, etc. Furthermore, the shape of the granules may be hollow, but a solid shape is preferred from the viewpoint of the feeling of taking the granules.

[0041] The volume-based cumulative 50% particle diameter of the granules (D 50 ) is, for example, 50 to 1000 μm, preferably 70 to 800 μm, more preferably 80 to 700 μm, even 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.

[0042] The amount of water contained in the granules is, for example, preferably 1.5% by mass or less, and more preferably 1.0% by mass or less.

[0043] [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, oral disintegration properties can be highly improved. Furthermore, by combining the granules with specific rapidly disintegrating particles, in addition to oral disintegration properties, the feeling of taking the tablet can be improved, and mechanical properties such as hardness required for OD tablets can also be ensured.

[0044] (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.

[0045] 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, granular, or the like.

[0046] Cumulative 50% particle size (D 50 ) 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 taking the drug may be reduced.

[0047] 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, further preferably 60 to 85% by mass, 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 particles will be reduced, and conversely, if it is too high, there is a risk that the oral disintegration property will be reduced.

[0048] (Ethyl cellulose) The rapidly disintegrating particles preferably contain ethyl cellulose as a binder, which can improve oral disintegration properties.

[0049] The shape of ethyl cellulose is not particularly limited, and may be amorphous, fibrous, ellipsoidal, spherical, tabular, or granular, and is usually amorphous or granular.

[0050] The volume-based cumulative 50% particle size of ethyl cellulose (D 50 ) 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 particles may be reduced.

[0051] 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, relative to 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, and conversely, if it is too high, oral disintegrability may be reduced.

[0052] (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.

[0053] 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 unit constituting cellulose, and the maximum value is 1.

[0054] The shape of carmellose (raw material carmellose) is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, granular, or the like, and is usually amorphous, granular, or the like.

[0055] Cumulative 50% particle size (D 50 ) 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, there is a risk that oral disintegration will be reduced, and conversely, if it is too large, there is a risk that the feeling of taking the tablet will be reduced.

[0056] The bulk density of carmellose is, for example, 100 to 800 g / liter, preferably 200 to 500 g / liter, and more preferably 300 to 400 g / liter.

[0057] The proportion of carmellose can be selected from the range of about 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, 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, and conversely, if it is too high, the feeling when taken may be reduced.

[0058] (silicic acids) The rapidly disintegrating particles may further contain silicic acids as binders and / or disintegrants in addition to sugar alcohols and carmellose. Silicic acids are generally used as excipients, but when combined with sugar alcohols 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 greatly improve oral disintegration and a comfortable feeling when taken, possibly due to improved water conductivity.

[0059] Examples of silicic acids include those exemplified as excipients in the section on granules. The silicic acids can be used alone or in combination of two or more. Among these, silicic anhydride is preferred, and light silicic anhydride is particularly preferred.

[0060] The shape of the silicic acids (raw silicic acids) is not particularly limited, and may be amorphous, fibrous, ellipsoidal, spherical, tabular, granular, or the like, and is usually amorphous, granular, or the like.

[0061] The cumulative 50% particle size (D) of silicic acid (especially anhydrous silicic acid) based on the volume 50 ) 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 compound is too small, there is a risk that the oral disintegration property will decrease, and conversely, if it is too large, there is a risk that the feeling of taking the compound will decrease.

[0062] The BET specific surface area of ​​silicic acid (raw silicic acid) is, for example, 50 to 1000 m 2 / g, preferably 100 to 500m 2 / g, more preferably 150 to 450m 2 / g, most preferably 200-400m 2 If the BET specific surface area is too small, there is a risk that the hardness will decrease, and conversely, if it is too large, there is a risk that the oral disintegrability will decrease.

[0063] In this specification and claims, the BET specific surface area of ​​silicic acids can be measured by a conventional method, for example, a nitrogen adsorption method.

[0064] The proportion of silicic acids (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, relative to 100 parts by mass of sugar alcohol. The proportion of silicic acids (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 acids is too low, the effect of improving hardness and oral disintegrability may be reduced, while if it is too high, the feeling of taking the tablet may be reduced.

[0065] (crospovidone) The rapidly disintegrating particles may contain crospovidone as a disintegrant.

[0066] The shape of crospovidone (raw crospovidone) is not particularly limited and may be amorphous, fibrous, ellipsoidal, spherical, flat, granular, or the like, and is usually amorphous, granular, or the like.

[0067] The cumulative 50% particle size (D 50 ) 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 disintegration may decrease, whereas if it is too large, the feeling of taking the tablet may decrease.

[0068] 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, relative to 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, while if it is too high, the mechanical properties of the particles may be reduced.

[0069] (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.

[0070] These additives can be used alone or in combination of two or more. 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).

[0071] The rapidly disintegrating particles may contain zonisamide active ingredient, but from the viewpoint of formulation design etc., particles that do not substantially contain zonisamide active ingredient are preferred, and it is more preferred that they do not contain zonisamide active ingredient.

[0072] (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.

[0073] The volume-based cumulative 50% particle diameter (D 50 ) 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 size of the rapidly disintegrating particles is too small, there is a risk that the oral disintegration property will decrease, and conversely, if it is too large, there is a risk that the feeling of taking the drug will decrease.

[0074] The volume-based cumulative 10% particle diameter of the rapidly disintegrating particles (D 10) is, for example, 1 μm or more (for example, 1 to 75 μm), preferably 5 μm or more (for example, 5 to 50 μm), further preferably 10 μm or more (for example, 10 to 40 μm), more preferably 20 μm or more (for example, 20 to 35 μm), and most preferably 25 μm or more (for example, 25 to 30 μm). 10 If the particle size is too small, there is a risk that the oral disintegration property will decrease.

[0075] The volume-based cumulative 90% particle diameter (D 90 ) 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). 90 If the value is too large, the feeling of taking the medicine may be reduced.

[0076] In the orally disintegrating tablet (OD tablet), the proportion of rapidly disintegrating particles relative to 100 parts by mass of granules is, for example, 10 to 1000 parts by mass, preferably 30 to 500 parts by mass, further 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. If the proportion of rapidly disintegrating particles is too low, there is a risk that oral disintegration and intake sensation will be reduced, and conversely, if it is too high, there is a risk that formulation designability will be reduced.

[0077] (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.

[0078] Although conventional methods can be used for fluidized bed granulation, when the rapidly disintegrating granules contain a sugar alcohol, carmellose, ethyl cellulose, silicic acid, and crospovidone, a preferred method is to previously mix the ingredients other than crospovidone in a fluidized bed granulator, and then spray an aqueous dispersion (granulation liquid) containing crospovidone onto the mixture to granulate. By mixing a solid sugar alcohol with a solid carmellose, it becomes easier to prepare rapidly disintegrating granules that have both good oral disintegrability and a pleasant feeling when taken.

[0079] The solvent contained in the granulation liquid is not particularly limited, but may be water or a lower alcohol (e.g., C ethanol, isopropanol, etc. 1-4 Generally, solvents such as crospovidone, ethanol, aliphatic ketones (e.g., acetone), or mixtures thereof are used, and from the viewpoint of safety, water and / or ethanol are preferred, with water being particularly preferred. The proportion of the solvent 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 per 100 parts by mass of crospovidone.

[0080] [Oru-disintegrating tablet] The orally disintegrating tablet (OD tablet) of the present invention may be any 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.

[0081] (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.

[0082] The excipient may further contain the excipients and binders exemplified in the section on granules. The excipients may be used alone or in combination of two or more. Among these, alkylcellulose is preferred, and C such as EC is also preferred. 1-3 Alkyl cellulose is particularly preferred. The volume-based cumulative 50% particle diameter (D 50The particle size 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, relative to 100 parts by mass of the granules.

[0083] Examples of lubricants include the lubricants exemplified in the section on granules, as well as silicic acids exemplified as excipients in the section on granules. The lubricants can be used alone or in combination of two or more. Among the lubricants, fatty acid metal salts such as magnesium stearate and silicic acids such as light anhydrous silicic acid are preferred. The cumulative 50% particle diameter (D) of the lubricant based on volume is 50 ) 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 mass, preferably 1 to 7 parts by mass, and more preferably 2 to 5 parts by mass, relative to 100 parts by mass of the granules.

[0084] Examples of sweeteners or flavoring agents include those exemplified in the section on granules. The ratio of the sweetener or flavoring agent to 100 parts by mass of the granules is, for example, 1 to 30 parts by mass, preferably 5 to 20 parts by mass, and more preferably 10 to 15 parts by mass.

[0085] Examples of the flavoring agent or refreshing agent include those exemplified in the section on granules above. The proportion of the flavoring agent or refreshing agent is, for example, 0.01 to 3 parts by mass, preferably 0.05 to 1 part by mass, and more preferably 0.1 to 0.5 parts by mass, relative to 100 parts by mass of the granules.

[0086] In order to achieve both oral disintegration and a comfortable feeling when taken, the OD tablet preferably does not substantially contain 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 most preferably does not contain crystalline cellulose. If OD tablets contain crystalline cellulose, both oral disintegration and a comfortable feeling when taken will be reduced.

[0087] The OD tablets are made of hydroxy C such as hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC) in order to achieve both oral disintegration and a comfortable feeling when taken. 2-4 It is preferable that the cellulose ether is substantially free of alkyl group-containing cellulose ethers. 2-4 The proportion of cellulose ether having an alkyl group in the OD tablet may be 1% by mass or less, preferably 0.5% by mass or less, further preferably 0.1% by mass or less, and further preferably 0.01% by mass or less. 2-4 It is most preferred that the cellulose ether does not contain any alkyl group-containing cellulose ether.

[0088] In order to achieve both oral disintegrability and a comfortable feeling when taken, the OD tablet preferably contains substantially no starches, and particularly preferably does not contain substantially any starch.

[0089] Examples of 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.

[0090] In the OD tablet, the proportion of starches (particularly starches such as corn starch) 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 most preferably no starches are contained. When starches (particularly starch) are contained in the OD tablet, both oral disintegration property and swallowing sensation are reduced.

[0091] The tablet diameter (average diameter) of the OD tablet 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.

[0092] The water content in 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.

[0093] The hardness of the OD tablet of the present invention is, for example, preferably 55N or more, more preferably 65N or more.

[0094] In this specification and claims, the hardness of OD tablets can be measured by the method described in the Examples below.

[0095] 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 a composition for OD tablets. [Example]

[0096] 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. The weights of the raw materials used are all solid weights.

[0097] [Particle size distribution] Particle size distribution (D 10 , D 50 , D 90 ) was measured on a volume basis using a laser diffraction particle size distribution analyzer (manufactured by Malvern Instruments, trade name "Mastersizer 3000").

[0098] [Average dissolution rate 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.

[0099] The test was started by taking 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.

[0100] 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.

[0101] The sample solution and the standard solution were tested by ultraviolet-visible absorbance measurement, and the absorbance of each solution at a wavelength of 285 nm was measured.

[0102] [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.

[0103] [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 to measure the time it took for the tablets to completely disintegrate.

[0104] Comparative Example 1 The particle size distribution of unground zonisamide was measured, and the cumulative 50% particle size (D 50 ) is 19.8 μm, and the volume-based cumulative 10% particle diameter (D 10 ) is 3.6 μm, and the volume-based cumulative 90% particle diameter (D 90 ) was 116.0 μm.

[0105] Example 1 Uncrushed zonisamide was crushed at 6000 rpm using an impact crusher to obtain zonisamide drug substance particles. The particle size distribution was measured, and the cumulative 50% particle size (D 50 ) is 11.7 μm, and the volume-based cumulative 10% particle diameter (D 10 ) is 2.5 μm, and the volume-based cumulative 90% particle diameter (D 90 ) was 38.1 μm.

[0106] Example 2 Uncrushed zonisamide was crushed at 10,000 rpm using an impact crusher to obtain zonisamide drug substance particles. The particle size distribution was measured, and the cumulative 50% particle size (D 50 ) is 8.7 μm, and the volume-based cumulative 10% particle diameter (D 10 ) is 2.1 μm, and the cumulative 90% particle diameter (D 90 ) was 22.3 μm.

[0107] Example 3 Uncrushed zonisamide was crushed at 14,000 rpm using an impact crusher to obtain zonisamide drug substance particles. The particle size distribution was measured, and the cumulative 50% particle size (D 50 ) is 7.0 μm, and the volume-based cumulative 10% particle diameter (D 10 ) is 1.9 μm, and the cumulative 90% particle diameter (D 90 ) was 18.1 μm.

[0108] Example 4 Uncrushed zonisamide was crushed at 18,000 rpm using an impact crusher to obtain zonisamide drug substance particles. The particle size distribution was measured, and the cumulative 50% particle size (D 50 ) is 5.9 μm, and the volume-based cumulative 10% particle diameter (D 10 ) is 1.7 μm, and the cumulative 90% particle diameter (D 90 ) was 15.7 μm.

[0109] The average dissolution rates of the drug substance particles of Comparative Example 1 and Examples 1 to 4 were measured and the results are shown in Table 1.

[0110] [Table 1]

[0111] As is clear from the results in Table 1, compared to Comparative Example 1, the drug substance particles of Examples 1 to 4 had higher dissolution rates.

[0112] 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 liquid.

[0113] 2) Zonisamide drug substance particles (D 50 :6.35μm, D 10 :1.76μm, D 90 :15.1μm) 25mg, D-mannitol (D 50 : 55 μm) 2.8 mg and light anhydrous silicic acid (D 50 1.2 mg of PEG (2.75 μm) was added and mixed, and the dispersion was sprayed and dried.

[0114] 3) The granules were sized using a 30M sieve (mesh opening: 500 μm) to obtain zonisamide granules.

[0115] (Preparation of Rapidly Disintegrating Particles) 1) Crospovidone (D 50 5.115 mg of granules (15.6 μm) were dispersed in purified water, and this dispersion was used as a granulation liquid.

[0116] 2) Add D-mannitol (D) to the fluidized bed granulator dryer. 50 : 55 μm) 60.5275 mg, ethyl cellulose (D 50 :10.3μm) 1.705mg, light anhydrous silicic acid (D 50 :2.75μm) 0.8525mg, carmellose (D 50 The mixture was mixed with 17.05 mg of 54.2 μm granules, sprayed with the granulation liquid, dried and sized to obtain rapidly disintegrating particles.

[0117] (Mixing, tableting, packaging) 1) Zonisamide granules 40.25 mg, fast-disintegrating particles 85.25 mg, ethyl cellulose (D 50 :10.3μm) 3mg, aspartame 5mg, light anhydrous silicic acid (D 50 0.75 mg of the powder (2.75 μm) was placed in a diffusion mixer and mixed to obtain a mixed powder.

[0118] 2) 0.75 mg of magnesium stearate was added to the mixed powder and mixed to obtain a tablet powder.

[0119] 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 good results in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegration.

[0120] The average dissolution rate of the OD tablets of Example 5 was measured, and the results are shown in Table 2.

[0121] [Table 2]

[0122] As is clear from the results in Table 2, the OD tablet of Example 5 exhibited good dissolution properties.

[0123] 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 liquid.

[0124] 2) Zonisamide drug substance particles (D 50 :6.35μm, D 10 :1.76μm, D 90 50 mg of 15.1 μm silicate, 5.6 mg of D-mannitol, and 2.4 mg of light anhydrous silicic acid were mixed together, and the dispersion was sprayed and dried.

[0125] 3) The granules were sized using a 30M sieve (mesh opening: 500 μm) to obtain zonisamide granules.

[0126] (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.

[0127] 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.

[0128] (Mixing, tableting, packaging) 1) Zonisamide granules (80.5 mg), rapidly disintegrating particles (170.5 mg), ethyl cellulose (6 mg), aspartame (10 mg), and light anhydrous silicic acid (1.5 mg) were mixed in a diffusion mixer to obtain a mixed powder.

[0129] 2) 1.5 mg of magnesium stearate was added to the mixed powder and mixed to obtain a tablet powder.

[0130] 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). As a result of the sensory evaluation, good results were obtained in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegration.

[0131] The average dissolution rate of the OD tablets of Example 6 was measured, and the results are shown in Table 3.

[0132] [Table 3]

[0133] As is clear from the results in Table 3, the OD tablet of Example 6 exhibited good dissolution properties.

[0134] Example 7 Zonisamide drug substance particles with different particle sizes (D50 :3.3μm, D 10 :1.1μm, D 90 Except for using a granular material (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. The sensory evaluation showed good results in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegrability.

[0135] The average dissolution rate of the OD tablets of Example 7 was measured, and the results are shown in Table 4.

[0136] [Table 4]

[0137] As is clear from the results in Table 4, the OD tablet of Example 7 exhibited good dissolution properties.

[0138] Example 8 Zonisamide drug substance particles with different particle sizes (D 50 :3.3μm, D 10 :1.1μm, D 90 Except for using a granular material (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. The sensory evaluation showed good results in terms of ease of swallowing, taste upon disintegration, aftertaste after administration, roughness, and disintegrability.

[0139] The average dissolution rate of the OD tablets of Example 8 was measured, and the results are shown in Table 5.

[0140] [Table 5]

[0141] As is clear from the results in Table 5, the OD tablet of Example 8 exhibited good dissolution properties. [Industrial Applicability]

[0142] The zonisamide drug substance particles of the present invention can be effectively used as a benzisoxazole antiepileptic drug having anticonvulsant and antiparkinsonian effects.

Claims

1. A particle formed from zonisamide or its salt, having a volume-based cumulative 50% particle diameter (D ５０ ) is 3 to 12 μm, and the volume-based cumulative 10% particle diameter (D １０ ) is 1.5 to 3 μm, Hydroxy C ２－４ Solid granules that do not contain alkyl group-containing cellulose ethers.

2. An orally disintegrating tablet comprising the solid granules according to claim 1 and rapidly disintegrating particles.

3. 3. The orally disintegrating tablet according to claim 2, wherein the rapidly disintegrating particles contain ethyl cellulose.

4. 3. The orally disintegrating tablet according to claim 2, wherein the rapidly disintegrating particles contain a sugar alcohol, carmellose, silicic acid compounds and crospovidone.

5. 4. The orally disintegrating tablet according to claim 3, wherein the rapidly disintegrating particles further comprise a sugar alcohol, carmellose, silicic acid, and crospovidone.

6. 6. The orally disintegrating tablet according to claim 4, wherein the rapidly disintegrating particles do not contain crystalline cellulose.

7. The orally disintegrating tablet according to any one of claims 2 to 6, which does not contain crystalline cellulose.

8. Hydroxy C ２－４ The orally disintegrating tablet according to any one of claims 2 to 7, which does not contain alkyl group-containing cellulose ethers and starches.

9. A particle formed of zonisamide or a salt thereof and having a volume-based cumulative 50% particle diameter (D ５０ ) is 3 to 12 μm, ２－４ solid granules that do not contain alkyl group-containing cellulose ether; Contains ethyl cellulose, sugar alcohol, carmellose, silicic acid and crospovidone, and also contains crystalline cellulose, hydroxy C ２－４ An orally disintegrating tablet comprising a cellulose ether having an alkyl group and rapidly disintegrating particles not containing starches.

10. The volume-based cumulative 50% particle diameter (D ５０ ) is 3 to 12 μm, and the volume-based cumulative 10% particle diameter (D １０ ) is adjusted to 1.5 to 3 μm, Further, the drug substance particles are contained, and hydroxy C ２－４ A method for improving the dissolution rate of zonisamide or a salt thereof in water by preparing solid granules that do not contain alkyl group-containing cellulose ethers.

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