HK1220139B - Orally disintegrating tablet - Google Patents

Description

orally disintegrating tablets

Technical Field

The present invention relates to an orally disintegrating tablet.

Background Art

Among currently used dosage forms, tablets are particularly excellent in ease of administration and handling. However, tablets are not necessarily an ideal dosage form for patients with swallowing problems, such as the elderly and young children. Therefore, orally disintegrating tablets were invented as a dosage form to address this issue and help improve medication compliance in these patients.

Generally speaking, to achieve their characteristic rapid disintegration in the oral cavity, orally disintegrating tablets are sometimes designed with a very low density to allow saliva to flow quickly into the tablet. However, this makes the tablet very brittle, and tablets can sometimes break or break during transportation or handling, which can be problematic.

On the other hand, in recent years, as an orally disintegrating tablet that compensates for the above-mentioned drawback of brittle tablets, Patent Document 1 discloses a fast-disintegrating preparation obtained by compressing a wet powder into tablets using a tablet press equipped with a special device and then drying the wet tablets using a drying device.

As an example of an orally disintegrating tablet that does not use special manufacturing equipment as described above, Patent Document 2 discloses an orally disintegrating tablet containing an active ingredient, crystalline cellulose, and an inorganic excipient, wherein the crystalline cellulose and the inorganic excipient are contained in a predetermined ratio. Patent Documents 3 to 7 disclose orally disintegrating tablets obtained by granulating sugar alcohols and the like with water-insoluble hydrophilic excipients such as starch and then compression molding. Patent Document 8 discloses an orally disintegrating tablet containing an active ingredient and granulated particles, wherein the granulated particles are formed by uniformly dispersing an inorganic substance and a disintegrant in composite particles of two or more sugars. Patent Documents 9 to 10 disclose orally disintegrating tablets containing (1) an active ingredient, (2) an inorganic excipient, (3) crystalline cellulose, and (4) a natural starch. Patent Document 11 discloses an orally disintegrating tablet containing (1) a sugar alcohol and the like, (2) starch and the like, and (3) a lubricant. Patent Document 12 discloses an orally disintegrating tablet comprising (1) an active ingredient, (2) 15% by weight or less of calcium silicate, (3) a disintegrant, and (4) a diluent such as a sugar alcohol or crystalline cellulose. Patent Document 13 discloses a directly compressible composite material comprising a water-soluble excipient such as a sugar alcohol and calcium silicate. Patent Document 14 discloses an orally disintegrating tablet comprising (1) an active ingredient, (2) a water-insoluble portion such as crystalline cellulose, (3) a surfactant, and (4) a disintegrant. Patent Document 15 discloses an orally disintegrating tablet comprising (1) an active ingredient, (2) a super disintegrant such as cross-linked polyvinylpyrrolidone, (3) a dispersant containing calcium silicate, and (4) a dispersant such as a sugar alcohol.

For these orally disintegrating tablets that do not require specialized manufacturing equipment, crystalline cellulose (water-insoluble cellulose) or sugar alcohols are often used to obtain tablets with ideal tablet properties. Furthermore, there is a trend to increase the content of excipients such as disintegrants and molding agents to maintain oral disintegration and tablet strength.

Patent Document 1: Japanese Patent No. 4162405

Patent Document 2: Japanese Patent No. 3996626

Patent Document 3: Japanese Patent Application Laid-Open No. 2010-155865

Patent Document 4: Japanese Patent No. 4446177

Patent Document 5: Japanese Patent No. 5062871

Patent Document 6: Japanese Patent No. 4551627

Patent Document 7: Japanese Patent No. 5062872

Patent Document 8: Japanese Patent Application No. 2011-513194

Patent Document 9: International Publication No. 2010/134574

Patent Document 10: International Publication No. 2009/066773

Patent Document 11: Japanese Patent No. 4802436

Patent Document 12: Japanese Patent Application No. 2010-540588

Patent Document 13: Japanese Patent Application No. 2009-532343

Patent Document 14: Japanese Patent Application No. 2011-506279

Patent Document 15: Japanese Patent Application No. 2005-507397

Summary of the Invention

As mentioned above, for existing orally disintegrating tablet, in order to have disintegration and tablet strength concurrently, many realize this purpose by increasing the content of the excipient beyond the active ingredient.But, if increase the content of active ingredient, then there is the trend that the equilibrium of tablet strength and disintegration reduces.In fact, for the orally disintegrating tablet (267 kinds) circulated in the Japanese market, the average content of the active ingredient in the tablet is low, is about 7.2 quality %.Therefore, from one aspect, problem of the present invention is to provide a kind of physical property and the content influence that are not easily subject to active ingredient etc., have the orally disintegrating tablet of rapid disintegration and high tablet strength in the oral cavity concurrently.

In view of the above problems, the present inventors conducted in-depth research and found that the crystalline cellulose mainly used in existing orally disintegrating tablets is easily affected by the physical properties and content of the active ingredient, making it difficult to achieve the desired disintegration and tablet strength, and instead adversely affecting the tablet's physical properties as an orally disintegrating tablet. Therefore, the present inventors conceived of orally disintegrating tablets that are substantially free of crystalline cellulose and focused on starch as an excipient to ensure rapid disintegration in the oral cavity. It is known that starch, which has not been processed into a formulation, generally has poor compression moldability. Therefore, increasing the starch content tends to increase tablet wear and capping (Yakuji Nippo Sha, Revised Handbook of Pharmaceutical Additives, pp. 603-p. 610, 2007). However, the present inventors have discovered that by combining specific starches with specific inorganic excipients, the problems encountered when using unprocessed starch can be resolved, resulting in orally disintegrating tablets containing high levels of active ingredients while maintaining both rapid disintegration in the oral cavity and high tablet strength, leading to the completion of the present invention. The present inventors have further discovered that sugar alcohols, commonly used in existing orally disintegrating tablets, can adversely affect the tablet properties of orally disintegrating tablets, similar to the aforementioned crystalline cellulose.

That is, the main configuration of the present invention is as follows.

<1> An orally disintegrating tablet comprising: (a) an active ingredient; (b) starch having an amylose content of 20% to 30% by mass and a degree of alpha-synthesis of less than 10%; and (c) at least one inorganic excipient selected from the group consisting of magnesium silicate, calcium silicate, and synthetic hydrotalcite;

The orally disintegrating tablet is a single-layer tablet in which the (a) active ingredient, the (b) starch, and the (c) inorganic excipient are dispersed and mixed throughout the orally disintegrating tablet. The content of crystalline cellulose in the orally disintegrating tablet is from 0% by mass to 5% by mass of the orally disintegrating tablet as a whole.

<2> The orally disintegrating tablet according to <1>, wherein the content of the sugar alcohol in the orally disintegrating tablet is 0% by mass or more and 15% by mass or less of the entire orally disintegrating tablet.

<3> An orally disintegrating tablet comprising (a) an active ingredient, (b) starch (wherein the amylose content is from 20% to 30% by mass and the degree of gelatinization is less than 10%), and (c) at least one inorganic excipient selected from the group consisting of magnesium silicate, calcium silicate, and synthetic hydrotalcite.

The orally disintegrating tablet is a core tablet comprising an inner core and an outer layer portion, wherein the inner core contains the (a) active ingredient, the outer layer portion covers the inner core, the outer layer portion contains the (b) starch and the (c) inorganic excipient, and the content of crystalline cellulose in the outer layer portion is 0% by mass or more and 5% by mass or less of the entire outer layer portion.

<4> The orally disintegrating tablet according to <3>, wherein the content of the sugar alcohol in the outer layer portion is 0% by mass or more and 15% by mass or less of the entire outer layer portion.

<5> The orally disintegrating tablet according to any one of <1> to <4>, wherein the total amount of the (a) active ingredient, the (b) starch, and the (c) inorganic excipient is 80% by mass or more of the entire orally disintegrating tablet (hereinafter sometimes referred to as the "preparation" in this specification).

<6> The orally disintegrating tablet according to any one of <1> to <5>, wherein the content of the above-mentioned (a) active ingredient is from 0.1% by mass to 60% by mass of the entire preparation, the content of the above-mentioned (b) starch is from 20% by mass to 96% by mass (or from 20% by mass to 95% by mass) of the entire preparation, and the content of the above-mentioned (c) inorganic excipient is from 3% by mass to 60% by mass (or from 4% by mass to 45% by mass) of the entire preparation.

<7> The orally disintegrating tablet according to <6>, wherein the content of the active ingredient (a) is 2.5% to 55% by mass (or 20% to 55% by mass) of the entire preparation.

<8> The orally disintegrating tablet according to <6>, wherein the content of the starch (b) is 25% to 85% by mass (or 25% to 70% by mass) of the entire preparation.

<9> The orally disintegrating tablet according to <6>, wherein the content of the (c) inorganic excipient is 4% to 45% by mass (or 8% to 30% by mass) of the entire preparation.

<10> The orally disintegrating tablet according to any one of <1> to <9>, wherein the starch (b) comprises at least one selected from the group consisting of corn starch, potato starch, and wheat starch, or is at least one selected from the group.

<11> The orally disintegrating tablet according to any one of <1> to <10>, further comprising (d) crospovidone.

<12> The orally disintegrating tablet according to <11>, wherein the content of the (d) crospovidone is 0.1% by mass or more and 20% by mass or less of the entire preparation.

<13> The orally disintegrating tablet according to any one of <1> to <12>, wherein the (a) active ingredient contains a water-soluble active ingredient or is a water-soluble active ingredient.

<14> The orally disintegrating tablet according to <13>, wherein the water-soluble active ingredient contains an α-glucosidase inhibitor or is an α-glucosidase inhibitor.

<15> The orally disintegrating tablet according to <14>, wherein the α-glucosidase inhibitor comprises or is miglitol.

According to the present invention, an orally disintegrating tablet can be provided that is not easily affected by the physical properties and content of the active ingredient and that exhibits both rapid disintegration in the oral cavity and high tablet strength. In particular, even when a water-soluble active ingredient is contained, and furthermore, even when the content thereof is high, the aforementioned desired tablet properties can be achieved, thereby providing an excellent orally disintegrating tablet.

BRIEF DESCRIPTION OF THE DRAWINGS

[ Fig. 1 ] is a cross-sectional view showing one embodiment of an orally disintegrating tablet (single-layer tablet).

FIG2 is a cross-sectional view showing one embodiment of an orally disintegrating tablet (core-containing tablet).

DETAILED DESCRIPTION

Hereinafter, embodiments of the present invention will be described in more detail. However, the present invention is not limited to the following embodiments.

The orally disintegrating tablet involved in this embodiment contains active ingredients, etc., and also contains specific starch and specific inorganic excipients described later. Figures 1 and 2 are cross-sectional views of an embodiment of the orally disintegrating tablet. The orally disintegrating tablet 1 of Figure 1 is a single-layer tablet containing active ingredients, starch and inorganic excipients, and is composed only of a single mixed layer 10 (in which the above ingredients are dispersed and mixed). In the case of this embodiment, the content of each component relative to the orally disintegrating tablet (preparation) 1 as a whole is consistent with the content of each component relative to the mixed layer 10. The orally disintegrating tablet 1 of Figure 2 is composed of a core 11 and an outer layer 20 covering the core 11. The active ingredient is usually mainly contained in the core 11, but the outer layer 20 may sometimes also contain a part of the active ingredient.

The orally disintegrating tablet 1 (mixed layer 10) or the outer layer 20 of this embodiment does not substantially contain the crystalline cellulose (or water-insoluble cellulose) commonly used in conventional orally disintegrating tablets. Specifically, the crystalline cellulose content can be from 0% to 5% by mass of the entire preparation or outer layer. In other words, the content of crystalline cellulose mixed with the specific starch and specific inorganic excipients described below is from 0% to 5% by mass of the entire mixed portion (mixed layer 10 or outer layer 20).

The (b) specific starch that may be contained in the orally disintegrating tablets involved in this embodiment refers to a starch having an amylose content of 20% to 30% by mass when measured by iodine colorimetry and a degree of alpha-ization of less than 10% when measured by glucoamylase. Such starch has low solubility in water and is therefore preferred. Orally disintegrating tablets containing starch having an amylose content of 20% to 30% by mass tend to disintegrate rapidly in the oral cavity. Orally disintegrating tablets containing starch having an alpha-ization of more than 10% are sometimes difficult to obtain ideal disintegration properties. Starches having an amylose content of 20% to 30% by mass and a degree of alpha-ization of less than 10% include, for example, corn starch, potato starch, and wheat starch. From the perspective of tablet physical properties, in particular, a starch selected from corn starch and potato starch can be used, or corn starch can be used. One of these can be used alone, or two or more can be used in combination.

The starch content can be 20% to 96% by mass, 25% to 85% by mass, or 30% to 75% by mass of the entire preparation. Starch contributes to rapid disintegration in the oral cavity. When the starch content is 20% by mass or more, or within the above numerical range, oral disintegration tends to be particularly excellent.

There is no particular restriction on the particle size of starch. However, when a mixture of water/95% ethanol/glycerol (volume ratio 1:1:1) is added to the starch and examined under an optical microscope, the particle diameter of the starch can be 100 μm or less. If the particle size of the starch is too large, there is a tendency for the oral cavity to feel rough when taken. It is generally believed that the compression moldability of starch that has not been processed by a formulation is not very good, but in the manufacture of the orally disintegrating tablets involved in this embodiment, starch that has not been processed by a formulation such as granulation can be used. This can achieve faster disintegration in the oral cavity.

The (c) specific inorganic excipient that may be contained in the orally disintegrating tablet according to this embodiment is at least one inorganic excipient selected from the group consisting of magnesium silicate, calcium silicate, and synthetic hydrotalcite. These inorganic excipients can impart high tablet strength, have low solubility in water, and are non-hygroscopic.

The particle size of the inorganic excipient is not particularly limited, but the average particle size of the inorganic excipient as measured by laser diffraction scattering can be 1 to 50 μm.

The content of at least one inorganic excipient selected from the group consisting of magnesium silicate, calcium silicate, and synthetic hydrotalcite may be 3% to 60% by mass, 3% to 50% by mass, 4% to 45% by mass, or 7% to 40% by mass of the overall formulation. Inorganic excipients contribute to high tablet strength. If the content of inorganic excipients in the overall formulation is appropriately high, specifically within the above-mentioned numerical range, the compression moldability problem of starch can be more easily improved.

For the orally disintegrating tablets involved in the present embodiment, inorganic excipients other than those mentioned above may be further contained, but are not necessarily contained. As inorganic excipients other than those mentioned above, inorganic excipients having a solubility of 0.1 g/L or less in water at 20 ± 5 ° C can be used. Specifically, as inorganic excipients other than those mentioned above, kaolin, hydrated silicon dioxide, hydrated amorphous silicon oxide, dried aluminum hydroxide gel, magnesium aluminosilicate, magnesium aluminum silicate, light silicic anhydride, synthetic aluminum silicate, titanium oxide, magnesium oxide, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide sodium bicarbonate coprecipitate, aluminum hydroxide magnesium bicarbonate calcium carbonate coprecipitate, magnesium hydroxide, tribasic calcium phosphate (tribasic calcium phosphate), calcium carbonate, precipitated calcium carbonate, magnesium carbonate, silicon dioxide, bentonite, silicic anhydride hydrate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, monocalcium phosphate, calcium hydrogen phosphate hydrate, and calcium hydrogen phosphate granules etc. can be cited. When the orally disintegrating tablet further contains the above-mentioned other inorganic excipients, in order to obtain ideal tablet strength, at least 50% by mass of the total inorganic excipients can be (c) at least one or more inorganic excipients selected from the group consisting of magnesium silicate, calcium silicate, and synthetic hydrotalcite. If the above-mentioned other inorganic excipients are used in large quantities, there is a possibility of increased adhesion to the die and punch, and there is a possibility of wear on the tablet press and the generation of metallic foreign matter.

Next, the (a) active ingredient that can be used in the orally disintegrating tablets involved in this embodiment is described. There are no particular restrictions on the powder properties and shape of the active ingredient, and active ingredients of all powder properties and shapes can be used. For example, the raw material of the powdered or crystalline active ingredient can be directly mixed with part or all of the other ingredients according to the purpose. The raw material can be used directly, or the active ingredient with a particle size adjusted by sieving the raw material can be used.

With regard to the active ingredient, it can be contained in the orally disintegrating tablet in its independent form, or in the form of particles containing the active ingredient (particles containing the active ingredient). For the particles containing the active ingredient, without departing from the scope of the present invention, for the purposes of controlled release, masking bitterness, or solubilization, additives allowed in the medicine can be used, the active ingredient is implemented to be processed by formulations such as granulation and obtained. As particles containing the active ingredient, for example, granulated particles, microcapsules and coated particles can be enumerated. In addition to containing the active ingredient, the particles containing the active ingredient can also contain excipients that are the same or different from the above-mentioned inorganic excipients. The content of the active ingredient in the particles containing the active ingredient is not particularly limited, for example, relative to the entirety of the particles containing the active ingredient, it can be 0.001% by mass or less than 100% by mass. The particles containing the active ingredient can be manufactured according to methods known to those skilled in the art (such as conventional methods such as stirring granulation, fluidized bed granulation, and dry granulation) using solvents or purified water allowed in the medicine.

As the (a) active ingredient that can be used in the orally disintegrating tablets involved in the present embodiment, as long as it is an active ingredient that can be orally administered, there is no particular limitation on its efficacy. As an active ingredient, for example, gastrointestinal drugs, chemotherapeutics, bronchodilators, cardiotonic agents, antihypertensive drugs, vasodilators, vasoconstrictors, vascular enhancers, antipyretic, analgesic and anti-inflammatory drugs, hyperlipidemia drugs, antipsychotics, antibiotics, antiepileptics, antiparkinsonian drugs, antihistamines, anxiolytics, osteoporosis drugs, skeletal muscle relaxants, hypnotic sedatives, antidiarrheal drugs, peptic ulcer drugs, autonomic nervous system drugs, psychoneurological drugs, antacids, intestinal drugs, antitussive and expectorant drugs, antispasmodics, gout therapeutic drugs, diabetes drugs, arrhythmia drugs, hormone drugs, and diuretics can be mentioned. As bronchodilators, PDE inhibitors can be mentioned, as vasodilators, dihydropyridine calcium antagonists can be mentioned, and as diabetes drugs, α-glucosidase inhibitors can be mentioned. These drugs may be used alone or in combination of two or more. Supplements or nutrients such as vitamins and amino acids may also be used as active ingredients.

Among these active ingredients, water-soluble active ingredients may be used in some embodiments. A water-soluble active ingredient is one for which the amount of water required to dissolve 1 g or 1 mL of the active ingredient at 20±5°C is less than 1,000 mL. Water-soluble active ingredients may also require less than 100 mL, less than 30 mL, or less than 10 mL of water.

Examples of the active ingredient in which the amount of water is less than 10 mL include levetiracetam, chlorpromazine hydrochloride, loxoprofen sodium, sodium valproate, selegiline hydrochloride, siopride hydrochloride, milnacipran hydrochloride, pramipexole hydrochloride hydrate, dothiopine hydrochloride, dimethazine mesylate, amantadine hydrochloride, clomipramine hydrochloride, imipramine hydrochloride, ethosuximide, sultopride hydrochloride, emofacone, Tatirelin hydrate, pentazocine hydrochloride, thiazolamide hydrochloride, tramadol hydrochloride, amitriptyline hydrochloride, talipexol hydrochloride, amfenac sodium hydrate, amide hydrochloride, flurazepam hydrochloride, chlordiazepoxide dipotassium, methylphenidate hydrochloride, ropinirole hydrochloride and nalfuraphine hydrochloride; as peripheral nerve drugs, aclacholine naphthylidene disulfonate, disopyramide bromide, N-methylscopolamine methylsulfate, butylscopolamine bromide, Propantheline bromide, pyridostigmine bromide, neostigmine bromide, eperisone hydrochloride, tolperisone hydrochloride, and ambenium chloride; betahistine mesylate and DL-isoproterenol hydrochloride as sensory organ medications; etilefrine hydrochloride, aprindine hydrochloride, procainamide hydrochloride, bisoprolol fumarate, oxprenolol hydrochloride, isosorbide, betaxolol hydrochloride, metoprolol tartrate, and tilisolol hydrochloride as circulatory organ medications , Losartan Potassium, Leconol, Trimetazidine Hydrochloride, Prophylline, Propranolol Hydrochloride, Acebutolol Hydrochloride, Bufuran Hydrochloride, Pilicarbone Hydrochloride Hydrate, Alprenolol Hydrochloride, Mexiletine Hydrochloride, Disopyramide Phosphate, Quinapril Hydrochloride, Perindopril, Celiprolol Hydrochloride, Benazepril Hydrochloride, Aliskiren Fumarate, Sumatriptan Succinate, Diltiazem Hydrochloride, Dextran Sulfate Sodium Sulfur 18 18), pravastatin sodium, γ-aminobutyric acid, beraprost sodium and meclofenoxate hydrochloride; as respiratory drugs, fudosteine, L-methylcysteine hydrochloride, L-ethylcysteine hydrochloride, cloperastine hydrochloride, salbutamol sulfate, pentoxyverine citrate, terbutaline sulfate, tulobuterol hydrochloride; as digestive drugs, roxatidine acetate hydrochloride, methylthioamino chloride, ranitidine hydrochloride, rabeprazole sodium, sodium picosulfate hydrate, itopride hydrochloride, cevimeline hydrochloride hydrate, epothilone sodium hydrate, pirenzepine hydrochloride anhydrate, tetracycline hydrochloride, ramosetron hydrochloride, domiphene bromide, granisetron hydrochloride, pilocarpine hydrochloride, indisetron hydrochloride, cetylpyridine chloride hydrate, azasetron hydrochloride, tropisetron hydrochloride; as hormone drugs, Kallikrein, conjugated estrogens, and methimazole; ritodrine hydrochloride, oxybutynin hydrochloride, fesoterodine fumarate, and solifenacin succinate for genitourinary and anal use; fursultiamine hydrochloride, sodium flavin adenine dinucleotide, ascorbic acid, calcium pantothenate, pyridoxine hydrochloride, dextromethionine hydrochloride hydrate, and vitamin B12 acetate for vitamins; potassium iodide, potassium L-aspartate, potassium aspartate, magnesium aspartate, sodium dihydrogen phosphate monohydrate, calcium chloride hydrate, calcium L-aspartate hydrate, glucose, potassium chloride, dried ferric sulfate, and anhydrous disodium hydrogen phosphate for nourishing and strengthening drugs; warfarin potassium and adrenochrome monoaminoguanidine methanesulfonate for blood and body fluid use. mesilate) hydrate, limaprost alpha-cyclodextrin, sodium citrate, tranexamic acid and clopidogrel sulfate; metabolic drugs: potassium citrate, L-carnitine chloride (levocarnitine chloride), alagliptin, sapropterin hydrochloride, protoporphyrin disodium, voglibose, lactitol hydrate, diisopropylamine dichloroacetate, adenosine triphosphate disodium hydrate, acarbose, lysozyme hydrochloride, L-arginine hydrochloride, L-arginine, isoprinosine, fingolimod hydrochloride, sodium citrate hydrate, vildagliptin, L-cysteine, metformin hydrochloride, monoammonium glycyrrhizate, glutathione, buformin hydrochloride, metformin as tumor drugs: imatinib mesylate, estramustine sodium phosphate hydrate, cytarabine octadecyl phosphate hydrate, hydroxyurea, procarbazine hydrochloride; as tissue cell function drugs: suplatast tosilate, D-chlorpheniramine maleate, cetirizine hydrochloride, chlorcyclizine hydrochloride, promethazine hydrochloride; as antibiotic preparations: clavulanate potassium, cefotiam hydrochloride, chlorpheniramine ... hydrochloride), kanamycin sulfate, colistin sodium methanesulfonate, clindamycin hydrochloride, vancomycin hydrochloride, cloxacillin sodium hydrate, doxycycline hydrochloride hydrate, faropenem sodium hydrate, pivmecillinam hydrochloride, lincomycin hydrochloride hydrate, and polymyxin B sulfate; ethambutol hydrochloride, indinavir sulfate ethanolate, raltegravir potassium, isoniazid, emtricitabine, ribavirin, oseltamivir phosphate, isoniazid methanesulfonate as chemotherapeutic agents Sodium sulfonate hydrate, valganciclovir hydrochloride, and valacyclovir hydrochloride; diethylcarbamazine citrate as a parasitic drug; tartaric acid and urea as diagnostic drugs; cocaine hydrochloride, ethylmorphine hydrochloride hydrate, oxycodone hydrochloride hydrate, codeine phosphate hydrate, dihydrocodeine phosphate, and opium alkaloid hydrochloride as alkaloid anesthetics; meperidine hydrochloride as a non-alkaloid anesthetic; and varenicline tartrate as another non-therapeutic pharmaceutical product.

Examples of the active ingredient in the amount of water less than 30 mL (10 mL or more) include donepezil hydrochloride, trazodone hydrochloride, lobenzalide disodium, gabapentin, methixol hydrochloride, memantine hydrochloride, and rimazafen hydrochloride hydrate as central nervous system drugs; tizanidine hydrochloride as peripheral nerve drugs; aminophylline hydrate, carteolol hydrochloride, pirmenol hydrochloride hydrate, lisinopril hydrate, hydralazine hydrochloride, captopril, imidapril hydrochloride, clonidine hydrochloride, midodrine hydrochloride, rizatriptan benzoate, dilazepoxide hydrochloride hydrate, and fluvastatin sodium as circulatory organ drugs; fenoterol hydrobromide, procaterol hydrochloride hydrate, clenbuterol hydrochloride, and benproperine as respiratory organ drugs; and benexamate β-cyclodextrin hydrochloride as a digestive organ drug. betadex); desmopressin acetate hydrate as a hormonal drug; propiverine hydrochloride and vardenafil hydrochloride hydrate as urogenital and anal medications; adenosylcobalamin as a vitamin preparation; calcium gluconate hydrate and calcium glycerophosphate as tonics; ticlopidine hydrochloride as a blood and body fluid medication; risedronate sodium hydrate, pronase, sitagliptin phosphate hydrate, DL-methionine, and taurine as metabolic drugs; cyclophosphamide hydrate and doxifluridine as oncology medications; cycloserine, bacampicillin hydrochloride, and demeclocycline hydrochloride as antibiotic preparations; lamivudine, abacavir sulfate, sertraline, and famciclovir as chemotherapy agents; sodium bicarbonate as a diagnostic drug; morphine sulfate hydrate and morphine hydrochloride hydrate as alkaloid anesthetics; and methadone hydrochloride as a non-alkaloid anesthetic.

Examples of the active ingredient in the amount of water less than 100 mL (30 mL or more) include acetaminophen, diclofenac sodium, mosapramine hydrochloride, clocarbamine hydrochloride hydrate, tetrabenazine, duloxetine hydrochloride, atomoxetine hydrochloride, zolpidem tartrate, mianserin hydrochloride, fluvoxamine maleate, pilohepidine hydrochloride, nortriptyline hydrochloride, mazatidine hydrochloride hydrate, epiriazole, pentobarbital calcium, lithium carbonate, pregabalin, and oxalic acid, which are drugs for the central nervous system. Escitalopram; thioperidone bromide, peridol hydrochloride, pridinol mesylate and methocarbamol as peripheral nerve drugs; diphenidol hydrochloride as sensory organ drugs; cibenzoline succinate, flecainide acetate, mozavaptan hydrochloride, labetalol hydrochloride, delapril hydrochloride, enalapril maleate, terazosin hydrochloride hydrate, amosulalol hydrochloride, nicorandil, verapamil hydrochloride and ametazimium mesylate as circulatory organ drugs; sodium azulenesulfonate hydrate, hydrobromide Dextromethorphan hydrochloride, dimethorphan phosphate, ambroxol hydrochloride, temequinol hydrochloride hydrate, chlorpheniramine hydrochloride, and eprazone hydrochloride; nizatidine and cetraxate hydrochloride as digestive tract medications; tamsulosin hydrochloride and tolterodine tartrate as genitourinary and anal medications; vitamin B12, thiamine mononitrate, niacin, and methylcobalamin as vitamin preparations; sodium carbazoline sulfonate hydrate as a blood and body fluid medication; camostat mesylate and alendronate as metabolic drugs. Sodium phosphite hydrate, colchicine, alogliptin benzoate, pirfenidone and calcium folinate; fluorouracil and capecitabine as oncology drugs; olopatadine hydrochloride and bepotastine besylate as tissue cell function drugs; cephalexin, cefaclor, ampicillin hydrate and minocycline hydrochloride as antibiotic preparations; flucytosine, zidovudine, linezolid, ciprofloxacin hydrochloride, tenofovir disoproxil fumarate and didanosine as chemotherapy agents; and metyrapone as a diagnostic drug.

Examples of the active ingredient in the amount of water less than 1,000 mL (100 mL or more) include central nervous system drugs such as trihexyphenidyl hydrochloride, biperiden hydrochloride, actarit, levodopa, carbidopa hydrate, quetiapine fumarate, maprotiline hydrochloride, sertraline hydrochloride, trimipramine maleate, tandospirone citrate, septiline maleate, carapipramine hydrochloride hydrate, topiramate, droxidopa, propranolol hydrochloride, and paroxetine hydrochloride. hydrate, perphenazine maleate, fluphenazine maleate, pergolide mesylate and perospirone hydrochloride; as peripheral nerve drugs, mepenzolate bromide, oxadiazolium iodide, baclofen, tiotropium bromide, chlorpheniramine carbamate and tiquidionium bromide; as sensory organ drugs, dimenhydrinate; as circulatory organ drugs, arotinolol hydrochloride, atenolol, disopyramide, propafenone hydrochloride, nadolol, bepridil hydrochloride hydrate, amlodipine besylate, alacepril, methyldopa hydrate Drugs, doxazosin mesylate, nicardipine hydrochloride, cilazapril hydrate, bevantolol hydrochloride, cilazapril, bunazosin hydrochloride, barnidipine hydrochloride, guanabenzyl acetate, dihydroergotamine mesylate, eletriptan hydrobromide, isoxsuprine hydrochloride, rosuvastatin calcium, ifenprodil tartrate, dihydroergotamine mesylate, lomerizine hydrochloride and sildenafil citrate; theophylline and bromhexine hydrochloride as drugs for respiratory organs; loperamide hydrochloride, qu Cipitide, cimetidine, ecabet sodium hydrate, caprolactam, trimebutine maleate and mesalazine; clomiphene citrate as a hormone drug; flavoxate hydrochloride and methylergonovine maleate as drugs for genitourinary organs and anus; benfotiamine and pyridoxal phosphate hydrate as vitamin preparations; sodium ferrous citrate as a tonic drug; aspirin, sarpogrelate hydrochloride and edoxaban tosilate hydrate as drugs for blood and body fluids. hydrate); mitiglinide calcium hydrate, propagermanium, and cinacalcet hydrochloride as metabolic drugs; melphalan, sunitinib malate, tamoxifen citrate, temozolomide, fludarabine phosphate, ubenimex, and uracil as tumor drugs; azelastine hydrochloride, fexofenadine hydrochloride, ketotifen fumarate, cyproheptadine hydrochloride hydrate, and bucillamine as tissue cell function drugs; rifampicin, amoxicillin hydrate, and ceftriaxone as antibiotic preparations. hydrate, chloramphenicol, cefcapene pivoxil hydrochloride hydrate, fosfomycin calcium hydrate and rifabutin as chemotherapy agents; acyclovir, moxifloxacin hydrochloride, ofloxacin, terbinafine hydrochloride, garenoxacin mesylate hydrate, fluconazole, entecavir hydrate, pyrazinamide, atazanavir sulfate, levofloxacin hydrate and lomefloxacin hydrochloride as parasitic drugs; metronidazole and mefloquine hydrochloride as parasitic drugs; and oximethebanol as an alkaloid anesthetic.

It is generally believed that when the active ingredient is water-soluble, it is difficult to design an orally disintegrating tablet with both rapid disintegration and high tablet strength in the oral cavity. Therefore, there has always been a trend: by reducing the content of the water-soluble active ingredient in each preparation and incorporating a large amount of excipients such as disintegrants and forming agents, an orally disintegrating tablet showing ideal physical properties is obtained. According to the present embodiment, even when the active ingredient is water-soluble and the content of the active ingredient is large, an orally disintegrating tablet with both rapid disintegration and strong tablet strength can be obtained. Even when using an active ingredient that is considered to be difficult to design for an orally disintegrating tablet, ideal physical properties are also shown, which means that more ideal physical properties can be shown when using an active ingredient that is easy to design for a formulation.

The content of above-mentioned (a) active ingredient or the particle containing active ingredient depends on its powder characteristics, but can be more than 60 mass % below 0.1 mass %, more than 55 mass % below 2.5 mass % or more than 50 mass % below 50 mass % of the overall preparation.According to the orally disintegrating tablet of the present embodiment, even when the content of active ingredient or the particle containing active ingredient is high, excellent characteristics as orally disintegrating tablet can be obtained.Therefore, even if the content of active ingredient or the particle containing active ingredient is higher, for example, more than 60 mass % below 20 mass % or more than 60 mass % below 25 mass % can also obtain excellent orally disintegrating tablet.When orally disintegrating tablet comprises the particle containing active ingredient and the active ingredient being dispersed individually in orally disintegrating tablet, the total content of the particle containing active ingredient and the active ingredient dispersed individually can be made within the above-mentioned numerical range.

The total content of (a) the active ingredient, (b) the specific starch, and (c) the specific inorganic excipient may be 80% by mass or more of the entire preparation. If a large amount of ingredients other than the above excipients are contained, it may be difficult to obtain an orally disintegrating tablet having rapid oral disintegration and high tablet strength.

The content of crystalline cellulose in orally disintegrating tablet or outer portion can be less than 5 mass %, less than 3 mass %, less than 1 mass % or less than 0.1 mass % of the entirety of orally disintegrating tablet or outer portion. Although crystalline cellulose is often used in existing orally disintegrating tablet, in the orally disintegrating tablet of the present embodiment, not only the amount of the excipient contained is increased in vain, but also there is the possibility of producing the problem that tablet strength is reduced according to circumstances. Therefore, orally disintegrating tablet or outer portion can be substantially free of crystalline cellulose, the content of crystalline cellulose can also be set within the scope of the tablet characteristics that do not significantly damage orally disintegrating tablet. Specifically, the content of crystalline cellulose can be made to be roughly less than 5 mass % or below the above-mentioned upper limit value of the entirety of preparation or outer portion.

Orally disintegrating tablets can be substantially free of the water-insoluble cellulose comprising the above-mentioned crystalline cellulose, and the content of the water-insoluble cellulose in orally disintegrating tablets or outer layer portion can also be below 5 mass %, below 3 mass %, below 1 mass % or below 0.1 mass % of the entirety of orally disintegrating tablets or outer layer portion. As water-insoluble cellulose, ethyl cellulose, ethyl cellulose aqueous dispersion, carboxymethyl ethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, crosslinked sodium carboxymethyl cellulose, crystalline cellulose, crystalline cellulose sodium carboxymethyl cellulose, crystalline cellulose (microparticles), crystalline cellulose (grain), synthetic aluminum silicate hydroxypropyl starch crystalline cellulose, cellulose acetate, low-substituted hydroxypropyl cellulose, lactose crystalline cellulose spherical particles, microcrystalline cellulose, hypromellose acetate succinate, powdered cellulose etc. Water-insoluble cellulose is owing to its structure having certain water absorption capacity, and when therefore coordinating water-insoluble cellulose in a large amount, there is the saliva in the oral cavity to be excessively absorbed, thus causing the trend that the taking property such as feeling roughness in the oral cavity declines.

In orally disintegrating tablet, can not contain water-soluble excipient in fact, perhaps, the content of the water-soluble excipient in orally disintegrating tablet or outer layer portion is below 15 mass %, below 10 mass %, below 5 mass % or below 1 mass % of preparation or outer layer portion as a whole.In the case of all excipients being water-insoluble and low water-absorbing excipient, have nothing to do with the physical properties of active ingredient etc., have the advantage of being easy to obtain good disintegrating property in oral cavity.It should be noted that, as water-soluble excipient, can enumerate saccharide and sugar alcohol etc.

In water-soluble excipients, for sugar alcohol, the content in the orally disintegrating tablet or the outer layer can be more than 0 mass % and less than 15 mass %, less than 10 mass %, less than 5 mass % or less than 1 mass % of the orally disintegrating tablet or the outer layer as a whole. As sugar alcohol, for example, erythritol, D-mannitol, D-sorbitol, xylitol, maltitol, anhydrous maltose, hydrous maltose, anhydrous lactitol, hydrous lactitol, and reduced maltose starch syrup can be mentioned. Sugar alcohol has the property of high water solubility and low formability. In particular, when these sugar alcohols are matched in the case of known preparation processing such as granulation, there is a trend that is difficult to obtain ideal tablet strength or difficult to carry out appropriately tableting. The allowable content of sugar alcohol in the orally disintegrating tablet can be below the above-mentioned upper limit value, but also considering the influence of the content of other components, it can also be set to a value exceeding the upper limit value.

Saccharide is also identical with sugar alcohol.The sum of the content of the saccharide in orally disintegrating tablet or outer layer portion and sugar alcohol can be more than 15 mass %, less than 10 mass %, less than 5 mass % or less than 1 mass % of orally disintegrating tablet or outer layer portion as a whole.As saccharide, water-soluble monosaccharides and disaccharides such as glucose, xylose, lactose, sucrose and maltose can be enumerated.Contain sugar and/or sugar alcohol as sweetener etc. for orally disintegrating tablet, as long as in the scope (such as above-mentioned numerical range) without departing from the purpose of the present invention then it is OK.

The orally disintegrating tablet may be substantially free of water-soluble celluloses, and the content of water-soluble celluloses in the orally disintegrating tablet or the outer layer may be 5% by mass or less, or 3% by mass or less of the entire orally disintegrating tablet or the outer layer. Examples of water-soluble celluloses include hydroxypropyl cellulose and hypromellose.

The above description describes the orally disintegrating tablet of the present embodiment, which may not substantially contain ingredients such as crystalline cellulose. However, any ingredient may be used within a range that does not significantly affect the tablet properties (disintegration and tablet strength) of the orally disintegrating tablet. The permissible content of these ingredients may be the content relative to the entire mixed layer or outer layer when mixed with the above-mentioned (b) starch and (c) inorganic excipients. This is because ingredients such as crystalline cellulose affect the tablet properties when mixed with the above-mentioned (b) starch and (c) inorganic excipients. For example, in the case of a core-type orally disintegrating tablet (core-type tablet) consisting of an inner core and an outer layer covering the inner core, if the outer layer contains (b) starch and (c) inorganic excipients and the inner core contains ingredients such as crystalline cellulose, even if the content of ingredients such as crystalline cellulose is high, it is not easy to affect the tablet properties. In this core-type form, the so-called mixed part as a whole refers to the outer layer as a whole. In the case of a single-layer tablet (ordinary tablet), the so-called mixed part as a whole refers to the tablet as a whole (the entire preparation, the entire orally disintegrating tablet). Therefore, when describing crystalline cellulose, the content of crystalline cellulose mixed with the above-mentioned (b) starch and (c) inorganic excipients may be 0% by mass or more and 5% by mass or less relative to the entire mixed portion (outer layer). Similarly, the content of sugar alcohol mixed with the above-mentioned (b) starch and (c) inorganic excipients may be 0% by mass or more and 15% by mass or less relative to the entire mixed portion (outer layer).

Core-type orally disintegrating tablets can be manufactured, for example, according to the manufacturing method for core-type tablets described in WO01/98067 (particularly the manufacturing method shown in FIG1 ). Core-type fast-dissolving and disintegrating molded products based on the manufacturing method for core-type tablets described in WO01/98067 are also described in WO03/028706. However, the core-type fast-disintegrating and disintegrating molded products in WO03/028706 have an outer layer containing a component with high formability and high disintegratability, and an inner core containing a component with low formability, such as an active ingredient. Similar core-type orally disintegrating tablets are also described in WO2010/134540 and WO2011/071139.

The orally disintegrating tablet of this embodiment achieves sufficient formability by using the (b) starch and (c) inorganic excipients. Therefore, even when the formability of the active ingredient (a) is low, a core tablet having a core containing the active ingredient (a) can be obtained, for example, by using the core tablet manufacturing method of WO01/98067. In such a core-type orally disintegrating tablet of this embodiment, as long as the core contains the active ingredient (a) and the outer layer contains the (b) starch and (c) inorganic excipients, the active ingredient (a) can be contained solely in the core, that is, the core can contain the entire amount of the active ingredient (a). Alternatively, the (b) starch and (c) inorganic excipients can be contained solely in the outer layer. To adjust the disintegration properties of the core, the core can also contain a portion of the (b) starch and/or (c) inorganic excipients in addition to the active ingredient (a).

In the orally disintegrating tablet of core tablet, there is no particular limitation on the size of kernel and the thickness of outer layer. For example, when the active ingredient is only contained in the kernel and the moldability of the kernel is insufficient, in order to maintain the moldability by the outer layer (which mainly contains the above-mentioned (b) starch and (c) inorganic excipient), it is sufficient to set it as follows, that is, the size of the kernel is determined based on the content of the above-mentioned (a) active ingredient, so that the thickness of the outer layer is such that the moldability of the entire molded product, i.e., the tablet strength, can be maintained. From these viewpoints, for example, the maximum diameter of the kernel can be 1 mm or more and 11 mm or less, and the thickness of the outer layer can be 0.3 mm or more and 10.5 mm or less. The ratio of kernel to outer layer is also arbitrary, but the ratio of the kernel in the orally disintegrating tablet as a whole can be, for example, 1 to 90% by mass.

The orally disintegrating tablet of this embodiment may further contain (d) crospovidone as needed. Orally disintegrating tablets further containing crospovidone tend to further improve tablet strength without compromising rapid disintegration in the oral cavity. To achieve this effect, the content of crospovidone may be from 0.1% to 20% by mass, or from 5% to 15% by mass, relative to the overall formulation.

In the orally disintegrating tablet of the core-containing tablet, the above-mentioned (d) crospovidone may be contained in any part of the outer layer portion or the inner core in order to improve the strength and disintegration properties.

The orally disintegrating tablet of the present embodiment, in addition to the above-mentioned ingredients, can contain additives that can be used as pharmaceutical additives. As these additives, for example, other inorganic excipients, sweeteners, flavorings, spices, lubricants, fluidizing agents, coloring agents, stabilizers, antioxidants, solubilizers, disintegrants, deodorants, antistatic agents, adsorbents, preservatives, wetting agents, and pH adjusting agents can be enumerated. The content of these additives can be 0% by mass or less than 20% by mass or 0% by mass or less than 10% by mass relative to the entire preparation.

If the active ingredient is unstable to light, the photostability of the active ingredient can be improved by incorporating light-absorbing substances such as various pigments into the outer layer of the cored tablet. Examples of light-absorbing substances that can be included in the outer layer include Food Red No. 2, Food Red No. 3, Food Yellow No. 4, ferric oxide, yellow ferric oxide, and black iron oxide. This is described in detail in WO2010/087462, so reference is made thereto.

The orally disintegrating tablet of this embodiment exhibits both rapid oral disintegration and high tablet strength. "Rapid oral disintegration" refers to a short oral disintegration time (the time from tablet placement to complete disintegration or dissolution in the mouth of a healthy adult, in the absence of water). The oral disintegration time is typically 5 to 60 seconds, but can be 5 to 45 seconds, or 5 to 30 seconds.

"High tablet strength" refers to a tablet that can be handled with the same level of care as a standard tablet during transportation, dispensing by automated packaging machines at pharmacies, or when administered to patients. Tablet strength can be used as an indicator of such handling and can be calculated from tablet hardness and tablet fracture area. It has been reported that tablet strengths of 1 to 2 N/mm² are sufficient to withstand PTP packaging, ^while tablet strengths of 2 N/mm² or ^greater can be handled with the same level of care as standard tablets (Ochiai Yasushi, Development of New Amlodipine OD Tablets, pp. 51-57, New Drugs and Clinical Practice, Vol. 58 (2009)). For example, ^when the tablet strength of a tablet with a fracture area of 20.0 ^mm2 is 0.5, 1.0, 1.5, and 2.0 N/mm2, the tablet hardness is approximately 10.0 N, 20.0 N, 30.0 N, and 40.0 N, respectively. When a difference of 0.5 N/ ^mm2 occurs in tablet strength, a difference of approximately 10 N occurs in tablet hardness.

Regarding tablet size, for round tablets, a diameter of 7 to 9 mm is considered to be easier to take and easier to handle. In one embodiment, even if the content of active ingredients in the entire preparation is relatively high, an orally disintegrating tablet with a diameter of 7 to 9 mm can be provided. For example, in the case of a preparation where the single administration amount of active ingredients is relatively high and the tablet diameter is larger than 9 mm when formulated using conventional methods, the excipient content can be reduced to increase the content ratio of active ingredients per tablet. Therefore, the tablet mass can be reduced to a tablet diameter of 9 mm or less. As a result, the burden on patients can be reduced when taking the tablet.

The orally disintegrating tablet of the present embodiment can be manufactured, for example, by a method comprising the following steps. The manufacturing method of the orally disintegrating tablet involved in one embodiment includes the following steps: at least the above-mentioned (a) active ingredient, etc., the above-mentioned (b) specific starch and the above-mentioned (c) specific inorganic excipient are mixed (mixed in a dry state as needed) to obtain a mixture; and then the (dry) mixture is subjected to a compression molding step. In the step of obtaining the mixture, (d) cross-linked polyvinylpyrrolidone or the other additives mentioned above can be further mixed as needed. In the compression molding step, the mixture can be compression molded to a desired formulation density.

In the process of obtaining the mixture, at least the above-mentioned (b) starch and the above-mentioned (c) inorganic excipient can be directly mixed when the known preparation processes such as granulation are not implemented. If so, the orally disintegrating tablet having both rapid disintegration in the oral cavity and high tablet strength can be manufactured using a simplified manufacturing process. During mixing, a W-type mixer, a V-type mixer, a container mixer (Container Mixer) etc. can be used. During compression molding, a single punch tablet press, a rotary tablet press etc. can be used, and the mixture can be directly compressed (direct tableting).

The so-called formulation density refers to the mass per tablet volume. The formulation density of orally disintegrating tablets can be 0.5-2.0 mg/ ^mm³ , 1.0-1.5 mg/ ^mm³ , or 1.1-1.3 mg/ ^mm³ . To achieve such a formulation density, those skilled in the art can appropriately set the tableting pressure within the range of 3.0-20.0 kN. The formulation of this embodiment, particularly within the above-mentioned formulation density range, can provide an orally disintegrating tablet that exhibits both rapid oral disintegration and high tablet strength.

Example

The present invention is described in detail below with reference to Examples, Comparative Examples, and Reference Examples, but these examples do not limit the present invention in any way. The tablets obtained in the Examples, Comparative Examples, and Reference Examples were tested for disintegration time, tablet strength, and formulation density using the following test methods (1) to (3).

(1) Disintegration (disintegration time)

The disintegration time of 6 tablets was measured according to the disintegration test method of the 16th revised edition of the Japanese Pharmacopoeia, and the average value was calculated. The standard for disintegration time was set to within 120 seconds, more preferably within 90 seconds.

(2) Tablet strength

Tablet hardness was measured for each of ten tablets using a tablet hardness tester (PC-30, manufactured by Okada Seiko Co., Ltd.). Tablet diameter and thickness were measured using a thickness gauge (SM-528, manufactured by TECLOCK Corporation). The tablet strength was calculated from the average of these values using the following formula. The benchmark for tablet strength was set at 1.8 N/mm² or ^higher , and more preferably at 2.0 N/mm² or ^higher .

Tablet strength (N/mm ² ) = average hardness (N) / fracture area (mm ² )

(3) Preparation density

The tablet mass of each of the ten tablets was measured using an electronic balance (XS-204, manufactured by METTLER TOLEDO), and the tablet diameter and thickness were measured using a thickness gauge (SM-528, manufactured by TECLOCK Corporation). The average value was used to calculate the formulation density using the following formula.

Formulation density (mg/mm ³ ) = average mass (mg) / average tablet volume (mm ³ )

(4) Oral disintegration test

The time from tablet placement to complete tablet disintegration or dissolution was measured in the mouths of healthy adult males without water, and the average value was calculated. The standard for oral disintegration time was set at 45 seconds or less.

Table 1

The tablets of Examples and Comparative Examples were prepared by the following method, with adjustment of the tableting pressure and other parameters, to obtain tablets having a formulation density of 1.1 to 1.3 mg/mm ³ .

(Example 1)

Each component was weighed according to the content in Table 1, sieved with a sieve, mixed with a V-type mixer (manufactured by Tokuju Works), and made into tablets of 200 mg per tablet using a tablet press (VIRG, manufactured by Kikusui Manufacturing Co., Ltd.). At this time, a round punch with a diameter of 8.5 mm was used. The shape of the tablet corresponds to the shape of the punch. It should be noted that miglitol was used as the active ingredient. Miglitol is a water-soluble drug that is generally difficult to design into an orally disintegrating tablet with both rapid disintegration in the oral cavity and high tablet strength. The amount of water required to dissolve 1 g of miglitol is less than 10 mL. As described later, the amylose content of the corn starch used in Example 1 is 25 to 30% by mass, and its alpha degree is less than 10%.

(Example 2)

The tablets of Example 2 were prepared using the same conditions as in Example 1, except that another excipient (crospovidone) was used in addition to the inorganic excipient (synthetic hydrotalcite) of Example 1, and the contents were as shown in Table 1.

(Comparative Example 1)

The tablets of Comparative Example 1 were prepared by replacing the inorganic excipients of Example 1 with other excipients (crospovidone) according to the contents shown in Table 1 under the same conditions as in Example 1.

(Comparative Example 2)

The tablets of Comparative Example 2 were prepared by removing the inorganic excipients from Example 1 and using the same conditions as in Example 1 according to the contents shown in Table 1.

(Comparative Example 3)

The tablets of Comparative Example 3 were prepared by replacing the starch in Example 1 with inorganic excipients and other excipients (crospovidone) according to the contents in Table 1 under the same conditions as in Example 1.

(Comparative Examples 4 to 6)

The tablets of Comparative Examples 4 to 6 were prepared under the same conditions as in Example 1, except that the starch in Example 2 was replaced with sugar alcohol, according to the contents shown in Table 1.

(Comparative Examples 7-8)

The tablets of Comparative Examples 7 and 8 were prepared using the same conditions as in Example 1, with the contents shown in Table 1, by adding crystalline cellulose (which is often used in the prior art) to the formulation of the present invention.

(Comparative Examples 9-10)

For the tablets of Comparative Examples 9-10, a formulation in which sugar alcohol (which is often used in the prior art) is added to the formulation of the present invention was used, and the preparation was carried out according to the contents in Table 1 under the same conditions as in Example 1.

Table 2

Tablet evaluation results for Examples 1-2 and Comparative Examples 1-10 are shown in Table 2. Example 1, comprising an active ingredient, a specific starch, and a specific inorganic excipient, exhibited a tablet strength of 2.0 N/ ^mm² or greater and a disintegration time of 90 seconds or less, both excellent. Example 2, in which crospovidone was further added, also exhibited a tablet strength of 2.0 N/ ^mm² or greater and a disintegration time of 90 seconds or less, similar to Example 1. Comparative Examples 1 and 3, in which synthetic hydrotalcite or corn starch was removed from the formulation of Example 1 and replaced with crospovidone, exhibited good tablet strength of 2.0 N/ ^mm² or greater, but exhibited prolonged disintegration times. Comparative Example 2, in which synthetic hydrotalcite was removed from the formulation of Example 1, exhibited a good disintegration time but a low tablet strength of 0.64 N/ ^mm² . In Comparative Examples 4 to 6, in which the starch in the formulation of Example 2 was replaced with a sugar alcohol, significant tableting problems (capping) were observed during the tableting process, making tablet production difficult in Comparative Example 6. Furthermore, tablet strength was low in Comparative Examples 4 and 5, at approximately 1.7 N/ ^mm² . On the other hand, in Comparative Examples 7 and 8, in which the crystalline cellulose content was 10% by mass, the expected tablet strength was not achieved.

As can be seen from the above results, in orally disintegrating tablets, the combination of the specific starch of (b) and the specific inorganic excipient of (c) is particularly important, and compared with the situation where any one of them is replaced by other excipients, excellent physical property values can be obtained. In addition, it is known that when excessively adding crystalline cellulose in such a combination, the physical properties of the tablet as an orally disintegrating tablet will be adversely affected. It should be noted that, since high tablet strength can be obtained in the embodiment in which the content of crystalline cellulose is 0 mass %, it can be considered that if the content of crystalline cellulose is approximately below 5 mass %, the physical properties of the tablet as an orally disintegrating tablet will not be substantially affected.

(Study on Starch 1)

The differences in effect due to the amylose content of starch were investigated.

Table 3

(Example 3)

The ingredients were weighed according to the contents in Table 3, and the tablets of Example 3 were prepared under the same conditions as in Example 1.

(Example 4)

The tablets of Example 4 were prepared by replacing the corn starch of Example 3 with potato starch according to the contents in Table 3 under the same conditions as in Example 3.

(Comparative Example 11)

The tablets of Comparative Example 11 were prepared by replacing the corn starch of Example 3 with rice starch according to the contents shown in Table 3 under the same conditions as in Example 3.

Table 4

Tablet evaluation results for Examples 3-4 and Comparative Example 11 are shown in Table 4. In Examples 3-4, which used starches with an amylose content of 20-30% by mass, the tablet strengths were all 1.8 N/ ^mm² or greater, and the disintegration times were all within 90 seconds, indicating good results. In Comparative Example 11, which used starches with an amylose content of 15-20% by mass, the tablet strength was good, but the disintegration time was significantly delayed. This confirms that starches with an amylose content of 20-30% by mass can achieve both high tablet strength and rapid disintegration.

(Study on Starch 2)

The difference in effect caused by the degree of starch alpha-glucose was studied.

Table 5

(Example 5)

The tablets of Example 5 were prepared by weighing the respective ingredients according to the contents in Table 5 under the same conditions as in Example 1.

(Comparative Examples 12-13)

The tablets of Comparative Examples 12 and 13 were prepared under the same conditions as in Example 5, except that the corn starch in Example 5 was partially replaced with α-starch or α-starch, according to the contents shown in Table 5.

Table 6

Tablet evaluation results for Example 5 and Comparative Examples 12-13 are shown in Table 6. It was confirmed that disintegration time significantly increased with increasing starch gelatinization. Furthermore, it was confirmed that increasing starch gelatinization significantly increased the compression pressure during the tableting process, even under the same tableting conditions. This confirms that rapid oral disintegration is achieved when starch has a gelatinization degree of less than 10%.

(Study on Inorganic Excipients 1)

The differences in effects caused by the types of inorganic excipients were studied.

Table 7

(Example 6)

The tablets of Example 6 were prepared by weighing the components according to the contents in Table 7 under the same conditions as in Example 1.

(Example 7)

The tablets of Example 7 were prepared under the same conditions as in Example 6, except that the synthetic hydrotalcite as the inorganic excipient in Example 6 was replaced with magnesium silicate, and the contents were as shown in Table 7.

(Example 8)

The tablets of Example 8 were prepared under the same conditions as in Example 6, except that the synthetic hydrotalcite as the inorganic excipient in Example 6 was replaced with calcium silicate, and the contents in Table 7 were used.

(Comparative Example 14)

The tablets of Comparative Example 14 were prepared under the same conditions as in Example 6, except that the synthetic hydrotalcite as the inorganic excipient in Example 6 was replaced with anhydrous calcium hydrogen phosphate, and the contents were as shown in Table 7.

Table 8

Tablet evaluation results for Examples 6-8 and Comparative Example 14 are shown in Table 8. In Examples 6-8, which used synthetic hydrotalcite, magnesium silicate, or calcium silicate as inorganic excipients, the tablet strengths were 2.0 N/ ^mm² or greater, and the disintegration times were within 90 seconds, indicating excellent tablet properties. In Comparative Example 14, which used anhydrous calcium hydrogen phosphate as an inorganic excipient, disintegration was good but the tablet strength was low, at 1.45 N/ ^mm² . This indicates that synthetic hydrotalcite, magnesium silicate, and calcium silicate are particularly preferred inorganic excipients.

(Study on Inorganic Excipients 2)

The differences in effects caused by the content of inorganic excipients were studied.

Table 9

(Example 5)

As described above, each component was weighed according to the content in Table 9, and the tablets of Example 5 were prepared under the same conditions as in Example 1.

(Examples 9-10)

The tablets of Examples 9 and 10 were prepared under the same conditions as in Example 5, except that the contents of the inorganic excipients in Example 5 were changed and the contents in Table 9 were followed.

(Reference Examples 1-2)

Tablets of Reference Examples 1 and 2 were prepared under the same conditions as in Example 5, except that the active ingredient and a portion of the synthetic hydrotalcite in Example 5 were replaced with corn starch, using the contents shown in Table 9. These Reference Examples 1 and 2 were prepared to minimize the effects of the active ingredient and explore the lower limit of synthetic hydrotalcite. These examples can be considered examples of cases where the active ingredient content is minimal.

Table 10

Tablet evaluation results are shown in Table 10. In Examples 5, 9, and 10, where the inorganic excipient content was 15 to 40% by mass, the tablet strength was 2.0 N/ ^mm² or greater, the disintegration time was within 90 seconds, and the tablet properties were good. Furthermore, in Reference Examples 1 and 2, where the inorganic excipient content was 5% and 10% by mass, similarly to Example 1, the tablet strength was 2.0 N/ ^mm² or greater, the disintegration time was within 90 seconds, and the tablet properties were good. This demonstrates that when the inorganic excipient content is approximately 3% by mass or greater, the desired tablet properties can be achieved.

When discussing the range of the content of the inorganic excipient, although the content of the inorganic excipient in Example 10 is 40% by mass, it is believed that even if miglitol as an active ingredient is removed from this Example 10, the properties of the orally disintegrating tablet will not be lost. Therefore, if the content of the inorganic excipient is approximately 60% by mass or less, 55% by mass or less, or 50% by mass or less, particularly excellent tablet properties can be obtained. It should be noted that, as can be seen from the results of Reference Examples 1 and 2, in order to obtain the properties of an orally disintegrating tablet, an active ingredient is not essential. Therefore, it can be seen that even a core-type orally disintegrating tablet consisting of a core (which contains an active ingredient) and an outer layer (which contains a specific starch and a specific inorganic excipient) can have good tablet properties.

(Study on starch and its active ingredients)

The differences in effects caused by the content of starch and active ingredients were studied.

Table 11

(Example 2)

As described above, each component was weighed according to the content in Table 11, and the tablets of Example 2 were prepared under the same conditions as in Example 1.

(Examples 11-12)

The tablets of Examples 11 and 12 were prepared under the same conditions as in Example 2, except that the contents of the active ingredient and starch in Example 2 were changed and the contents were as shown in Table 11.

(Reference Example 1)

As described above, tablets of Reference Example 1 were prepared under the same conditions as in Example 2 according to the contents shown in Table 11. This can be considered to be the case where the active ingredient, crospovidone, and part of the synthetic hydrotalcite in Example 2 were replaced with corn starch.

Table 12

Tablet evaluation results for Examples 2, 11-12, and Reference Example 1 are shown in Table 12. In Examples 2 and 11, where the active ingredient content was 5-25% by mass and the starch content was 49-69% by mass, the tablet strength was 2.0 N/ ^mm² or greater, and the disintegration time was within 90 seconds, both considered good. In Example 12, where the active ingredient content was 50% by mass and the starch content was 24% by mass, the tablet strength was 2.0 N/ ^mm² or greater, considered good, and the disintegration time was within 120 seconds, also within the acceptable range. In Reference Example 1, where the active ingredient content was 0% by mass and the starch content was 94% by mass, the tablet strength was 2.0 N/ ^mm² or greater, and the disintegration time was within 90 seconds, both considered good. This indicates that orally disintegrating tablets exhibit particularly good physical properties when the active ingredient content is 60% or less of the total formulation, and when the starch content is adjusted to 20-95% by mass based on the active ingredient content.

(Confirmation of other active ingredients)

Studies were conducted to change the type of active ingredient.

Table 13

(Example 13)

The tablets of Example 13 were prepared using the same conditions as in Example 1, except that the active ingredient was replaced with theophylline, according to the contents shown in Table 13. The amount of water required to dissolve 1 g of theophylline was less than 1,000 mL.

(Example 14)

The tablets of Example 14 were prepared under the same conditions as in Example 1, except that the active ingredient was replaced with nifedipine, according to the contents shown in Table 13. The amount of water required to dissolve 1 g of nifedipine was 10,000 mL or more.

(Example 15)

A coating solution consisting of 5.3% by mass of triethyl citrate (trade name: CITROFLEX, manufactured by Morimura Shoji Co., Ltd.), 15.8% by mass of talc (trade name: Nippon Pharmacopoeia Talc, manufactured by Matsumura Sangyo Co., Ltd.), and 52.6% by mass (solids basis) of methacrylic acid copolymer LD (trade name: Eudragit L30D-55, manufactured by EVONIC INDUSTRIES) was sprayed onto 26.3% by mass of crystalline cellulose granules (trade name: Celphere CP-203, manufactured by Asahi Kasei Chemicals Corporation) as core particles using a fluidized bed granulation dry coater FLO-5 (manufactured by Freund Corporation). The coating solution was then dried, and tablets of Example 15 were prepared using the same conditions as in Example 1, using the contents shown in Table 13. Although the tablets of Example 15 do not contain an active ingredient, the coated granules can be regarded as particles containing the active ingredient obtained by subjecting the crystalline cellulose particles, which are the supposed active ingredient, to formulation processing for controlled release and bitterness masking.

Table 14

The tablet evaluation results of Examples 13 to 15 are shown in Table 14. In Examples 13 to 14 in which theophylline or nifedipine was used as the active ingredient, the tablet strength was 2.0 N/mm ² or more, the disintegration time was within 90 seconds, and the tablet physical properties were good. As an example of particles containing an active ingredient, in Example 15 in which coated crystalline cellulose particles (coated particles) were used, the tablet strength was 2.0 N/mm ² or more, the disintegration time was within 90 seconds, and the tablet physical properties were good. As can be seen from the above results, the combination of a specific starch and a specific inorganic excipient not only shows ideal physical properties when containing a water-soluble active ingredient (which is generally considered difficult to design as an orally disintegrating tablet), but also shows more ideal physical properties when containing a water-insoluble active ingredient. Therefore, it is believed that with respect to the orally disintegrating tablet of the present invention, regardless of the properties of the active ingredient or the particles containing the active ingredient, good physical properties are all shown.

(Study on core-type orally disintegrating tablets)

Based on the discussion of Reference Examples 1 and 2, it was investigated whether or not an orally disintegrating tablet could actually be made into a core-type orally disintegrating tablet.

Table 15

(Example 16)

According to the content of table 16, after taking the kernel component by weighing, mix and obtain kernel powder. In addition, after taking the outer layer component by weighing, mix and obtain outer layer portion powder. Then, use the extrudable circular punch with dual structure that inner diameter is 6.0mm, outer diameter is 8.0mm, utilize the manufacture method of the core tablet of recording in Fig. 1 of WO01/98067, with the first outer layer portion being 20 mass %, kernel being 12.5 mass %, the second outer layer portion being 67.5 mass % to arrange each powder, then, carry out temporary compression, finally use automatic plotter (Autograph) (AG-1, Shimadzu Corporation system) to carry out tabletting under the compression pressure of about 10kN/ sheet, prepare the core type orally disintegrating tablet that every 1 sheet is 200mg. It should be noted that, about the ratio of kernel and outer layer portion, relative to kernel 12.5 mass %, outer layer portion is 87.5 mass %.

(Example 17)

The tablets of Example 17 were prepared under the same conditions as in Example 16, except that the inorganic excipient in the outer layer components of Example 16 was replaced with calcium silicate, and the contents were shown in Table 16.

(Example 18)

The tablets of Example 18 were prepared by replacing part of the starch in the outer layer component of Example 16 with another excipient (crospovidone) according to the contents in Table 16 under the same conditions as in Example 16.

Table 16

Tablet evaluation results for Examples 16 to 18 are shown in Table 17. For the orally disintegrating tablets of Examples 16 to 18, which are core tablets composed of an active ingredient, starch, and an inorganic excipient, the tablet strength was 2.0 N/ ^mm² or greater and the disintegration time was within 90 seconds, which were excellent. Furthermore, even in Example 18, in which a portion of the starch in the outer layer was replaced with crospovidone, similar to Examples 16 and 17, the tablet strength was 2.0 N/ ^mm² or greater and the disintegration time was within 90 seconds, indicating excellent tablet properties. These results demonstrate that the orally disintegrating tablets of the present invention can achieve properties suitable for orally disintegrating tablets by combining a specific starch and a specific inorganic excipient. Therefore, even in core tablets comprising an outer layer composed of a specific starch and a specific inorganic excipient and an inner core containing the entire amount of the active ingredient or the entire amount of particles containing the active ingredient, ideal physical properties for an orally disintegrating tablet can be achieved. It should be noted that the mixture of anhydrous caffeine, corn starch and magnesium stearate in Examples 16 to 18 (which is a powder or granule for the core) is a powder or granule with extremely low moldability. These Examples are actually core-type orally disintegrating tablets described in WO03/028706, WO2010/134540 and WO2011/071139, in which the core is formed of an incompletely molded product, or a core-type orally disintegrating tablet with a powder or granule with low moldability.

(Correlation between the disintegration test method of the 16th revised edition of the Japanese Pharmacopoeia and the oral disintegration test)

Regarding a part of the above-mentioned Examples and Comparative Examples, the disintegration time in the oral cavity was measured on 6 healthy adult males (25 to 39 years old).

Table 17

Example 1 Example 2 Example 11 Example 12 Comparative Example 1 Comparative Example 2 Comparative Example 3 Disintegration time (seconds) 42 88 45 105 134 65 128 Oral disintegration time (seconds) 24.0 24.0 8.5 43.0 50.5 18.5 47.3

The evaluation results of Examples 1, 2, 11, 12 and Comparative Examples 1 to 3 are shown in Table 15. In Examples 1, 2, 11, 12 and Comparative Example 2, the disintegration time measured by the disintegration test method of the Japanese Pharmacopoeia 16th Revised Edition was within 120 seconds, and the intraoral disintegration time was within 45 seconds, which is a good result. On the other hand, in Comparative Examples 1 and 3, the disintegration time measured by the same method was 120 seconds or more, and the intraoral disintegration time was 45 seconds or more. It can be seen from this that there is the following correlation: if the disintegration time measured by the disintegration test method of the Japanese Pharmacopoeia 16th Revised Edition is within 120 seconds, the intraoral disintegration time is within 45 seconds.

Description of Reference Numerals

1: orally disintegrating tablet, 10: mixed layer, 11: inner core, 20: outer layer.

Claims (13)

1. An orally disintegrating tablet, comprising: (a) Active ingredients; (b) Starch, with an amylose content of 20% to 30% by mass and an α-degree of oxidization of less than 10%; and (c) Inorganic excipients, selected from one or more of the group consisting of magnesium silicate, calcium silicate, and synthetic hydrotalcite; The orally disintegrating tablet is selected from any of the orally disintegrating tablets described in (i) and (ii) below. (i) A single-layer tablet, wherein (a) the active ingredient, (b) the starch, and (c) the inorganic excipient are dispersed and mixed within the orally disintegrating tablet as a whole. (ii) A cored sheet having a core and an outer layer, the core containing the active ingredient (a), the outer layer covering the core, and the outer layer containing the starch (b) and the inorganic excipient (c). The content of crystalline cellulose in the orally disintegrating tablet or the outer layer is more than 0% by mass and less than 5% by mass of the whole orally disintegrating tablet or the whole outer layer; the content of sugar alcohol is more than 0% by mass and less than 1% by mass of the whole orally disintegrating tablet or the whole outer layer; and the total content of sugars and sugar alcohols is more than 0% by mass and less than 15% by mass of the whole orally disintegrating tablet or the whole outer layer. 2. The orally disintegrating tablet as claimed in claim 1, wherein the content of sugar alcohol in the orally disintegrating tablet or the outer layer is 0% by mass of the entire orally disintegrating tablet or the entire outer layer. 3. The orally disintegrating tablet as described in claim 1 or 2, wherein the total content of (a) the active ingredient, (b) the starch, and (c) the inorganic excipient is more than 80% by mass of the whole orally disintegrating tablet. 4. The orally disintegrating tablet as described in claim 1 or 2, wherein, The content of the active ingredient in (a) is more than 0.1% by mass and less than 60% by mass of the total orally disintegrating tablet. The starch content of (b) is more than 20% by mass and less than 96% by mass of the total orally disintegrating tablet. The content of the inorganic excipient (c) is more than 3% by mass and less than 60% by mass of the whole orally disintegrating tablet. 5. The orally disintegrating tablet as described in claim 4, wherein the content of the active ingredient (a) is more than 2.5% by mass and less than 55% by mass of the whole orally disintegrating tablet. 6. The orally disintegrating tablet as claimed in claim 4, wherein the starch content of (b) is more than 25% by mass and less than 85% by mass of the total orally disintegrating tablet. 7. The orally disintegrating tablet as claimed in claim 4, wherein the content of the inorganic excipient (c) is more than 4% by mass and less than 45% by mass of the total orally disintegrating tablet. 8. The orally disintegrating tablet as claimed in claim 1 or 2, wherein the starch (b) comprises at least one selected from the group consisting of corn starch, potato starch, and wheat starch. 9. The orally disintegrating tablet of claim 1 or 2, further comprising (d) crospovidone. 10. The orally disintegrating tablet of claim 9, wherein the content of (d) crosslinked povidone is more than 0.1% by mass and less than 20% by mass of the total orally disintegrating tablet. 11. The orally disintegrating tablet as claimed in claim 1 or 2, wherein the active ingredient (a) comprises a water-soluble active ingredient. 12. The orally disintegrating tablet of claim 11, wherein the water-soluble active ingredient is an α-glucosidase inhibitor. 13. The orally disintegrating tablet of claim 12, wherein the α-glucosidase inhibitor is miglitol.