Intraoral rapidly disintegrating tablet

The present invention relates to tablets that rapidly disintegrate in the oral cavity.

Oral dosage forms of pharmaceuticals include, for example, tablets, capsules, granules, powders, syrups and the like. However, there are some problems with these oral preparations. For example, tablets and capsules are difficult to swallow for the elderly and children with weak swallowing ability. Granules and powders may cause discomfort in the mouth after administration, may enter the respiratory tract and lungs as powder, and require water when taken, so they may not be taken in places without water. Since the syrup is weighed at the time of administration, it takes time and effort, and accurate weighing cannot be expected for the elderly and children. On the other hand, a solid molded product that rapidly dissolves or disintegrates in the oral cavity can be easily taken by the elderly and children without the need for weighing. In addition, the solid molded product can be taken without water. There are several known formulations that rapidly dissolve or disintegrate in the oral cavity. For example, Japanese Patent Publication No. 62-50445 describes a solid preparation obtained by freeze-drying an aqueous solution containing gelatin as a main component containing an active ingredient, and WO93 / 12769 describes a suspension containing agar. The solid preparation obtained by drying the liquid is described. However, these formulations have problems such as weak solid strength, difficulty in pushing out from PTP (Press Through Pack) packaging, special formulation technology, and enormous capital investment. Has a point. Further, Japanese Patent Application Laid-Open No. 5-271054 or WO 93-15724 describes a method for preparing a tablet to be dried after being compression-molded at a low pressure by giving an appropriate amount of water to a mixture containing saccharides. However, this method also requires a special formulation technique, and may cause powder adhesion to the molding die surface during compression in a wet state, which makes it difficult to apply to industrial production.

<p> The present inventors have investigated an orally rapidly disintegrating tablet that can be easily and easily prepared with general equipment without requiring a special formulation technique. As a result, it is difficult to prepare with a conventional compression molding machine by compression-molding a mixture containing a sugar alcohol or sugar such as D-mannitol or lactose having an average particle size of 30 μm or less as a main component and containing an active ingredient and a disintegrant. It was found that within 1 minute, which was thought to be, a fast-disintegrating orally disintegrating tablet that disintegrates in the oral cavity and has a practically acceptable hardness can be obtained.</p>

<p> That is, the present invention describes (1) a tablet containing a sugar alcohol or sugar having an average particle size of 30 μm or less, an active ingredient and a disintegrant. (2) The tablet according to (1), which contains 1 to 30 mg of a disintegrant per dose. (3) The tablet according to (1) or (2), wherein the sugar alcohol is D-mannitol. (4) The tablet according to (1) or (2), wherein the sugar is lactose. (5) The tablets according to (1) to (4), wherein the disintegrant is crospovidone, croscarmellose sodium or low-substituted hydroxypropyl cellulose. The present invention also comprises (6) a method for producing a tablet, which comprises compression-molding a mixture containing a sugar alcohol or sugar having an average particle diameter of 30 μm or less, an active ingredient and a disintegrant. (7) The method for producing a tablet according to (6), which comprises applying a lubricant to the mortar and pestle of a tableting machine in advance during compression molding and then compression forming. (8) It is characterized in that a sugar alcohol or a mixture containing a sugar alcohol having an average particle size of 30 μm or less, an active ingredient and a disintegrating tablet is compression-formed in the presence of a disintegrating aid that volatilizes easily, and then the disintegrating aid is volatilized. The present invention relates to the method for producing tablets according to (6).</p>

<p> According to the present invention, in a conventional compression molding machine, a mixture containing a sugar alcohol such as D-mannitol or lactose having an average particle diameter of 30 μm or less or a sugar as a main component and containing an active ingredient and a disintegrant is compression-molded. It is possible to provide an orally rapidly disintegrating tablet having a hardness that disintegrates in the oral cavity within 1 minute, which is considered difficult to prepare, and has no practical problem. According to the method of the present invention, an orally rapidly disintegrating tablet can be easily and easily prepared with general equipment without requiring a special formulation technique.</p>

Examples of sugar alcohols include D-mannitol, sorbitol, etc., which are widely used in pharmaceuticals and foods, and examples of sugars include lactose, glucose, etc., which are widely used in pharmaceuticals and foods, and at least one type of sugar. Alcohol or sugar is used. Examples of the active ingredient include those described below, but the active ingredient is not particularly limited as long as it is intended for oral administration.

&lt;Drugs for the central nervous system&gt; Sleep sedatives, anxiolytics ... Amobarbital, alprazolam, flurazepam hydrochloride, diazepam, etc. Antiepileptic agents: sodium valproate, nitrazepam, phenytoin, etc. Analgesic, antipyretic and anti-inflammatory agents: aspirin, acetaminophen, ibuprofen, diclofenac sodium, ethenzamide, indomethacin, etc. Antiparkinson's agent: levodopa, amantadine hydrochloride, trihexyphenidyl hydrochloride, pyroheptin hydrochloride, etc. Psychiatric agents: etizolam, amitriptyline hydrochloride, sulpiride, etc.

&lt;Peripheral nervous system drug&gt; Skeletal muscle relaxant: chlorphenesin carbamate, chlormezanone, etc. Autonomic nerve agent Baletamate bromide, tofisopam, etc. Antispasmodic ... Afroqualol, etc.

&lt;Drugs for circulatory organs&gt; Cardiac stimulants: ubidecalenone, aminophylline, etilefrine hydrochloride, etc. Arrhythmia agents: atenolol, pindolol, etc. Diuretics: spironolactone, trichlormethiazide, furosemide, etc. Blood pressure lowering agent: todrarazine hydrochloride, nicardipine hydrochloride, hydralazine hydrochloride, etc. Vasoconstrictor: dihydroergotamine mesylate, etc. Vasodilators: benidipine hydrochloride, diltiazem hydrochloride, isosorbide dinitrate, etc. Hyperlipidemia agents: clinofibrate, Nicomol, etc. Others: Flunalidine hydrochloride, meclofenoxate hydrochloride, cinnaridine, etc.

&lt;Respiratory medicine&gt; Antistatic agent: loperamide hydrochloride, dimethicone, etc. Peptic ulcer agent: azulene, L-glutamine, aceglutamide aluminum, cetraxate hydrochloride, cimetidine, etc. Biliary agent: anethole trithione, chenodeoxycholic acid, etc. Others: domperidone, tothymebutin mailate, metoclopramide, cisupide, etc.

&lt;Metabolic drugs&gt; Vitamin preparations: alfacalcidol, thiamine hydrochloride, covamid, vitaroxin, riboflavin butyrate, ascorbic acid, phytonadione, etc. Diabetic agents: glybsol, tributamide, etc.

&lt;Allergy medicine&gt; Anti-histamine: Homochlorcyclizine hydrochloride, clemastine fumarate, chlorpheniramine maleate, etc. Others: oxatomide, ketotifen fumarate, azelastine hydrochloride, etc.

&lt;Tumor drug&gt; Antimetabolite: fluorouracil, decafur, etc.

&lt;Antibiotic preparation&gt; Paromomycin sulfate, amoxicillin, cefaclor, cephalexin, acetylspiramycin, minocycline hydrochloride, etc.

Examples of the disintegrant include crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose and the like, which are widely used in pharmaceuticals and foods, and at least one disintegrant is used.

Next, a method for producing a tablet of the present invention will be described. The tablet of the present invention can be obtained by granulating and then compression-molding a sugar alcohol or a mixture containing a sugar, an active ingredient and a disintegrant having an average particle size of 30 μm or less using a hammer mill, a jet mill or the like. .. Further, the tablet of the present invention contains a sugar alcohol or sugar having an average particle size of 30 μm or less using a hammer mill, a jet mill or the like, an active ingredient and a disintegrant in the presence of a disintegrating aid that easily volatilizes. It can also be obtained by granulating and compression molding the mixture and then volatilizing the disintegration aid.

The amount of sugar alcohol or sugar used is preferably 60 to 95%, more preferably 80 to 95% in the tablet.

The amount of the active ingredient used varies depending on the type of active ingredient, the dose, etc., but is preferably 0.01 to 30%, more preferably 0.01 to 10% in the tablet.

The amount of the disintegrant used is preferably 1 to 30 mg per dose, preferably 1 to 10% in a tablet.

Examples of the easily volatilizing disintegrant aid include camphor, urethane, urea, ammonium bicarbonate, benzoic acid and the like having sublimation properties, and camphor is particularly preferable. Easy to volatilize The amount of the disintegrating aid to be emitted is preferably 1 to 20%, more preferably 1 to 10% in the tablet.

As a granulation method, wet granulation using purified water, ethanol or the like is preferable, and for example, a general fluidized bed granulator, a rolling stirring granulator, an extrusion granulator or the like is used for granulation. After drying the product, add a lubricant, mix and compression mold. At this time, as an additive, a binder, an acidulant, a foaming agent, a sweetening agent, a flavoring agent, a coloring agent, or the like can be added. Examples of the lubricant include magnesium stearate, stearic acid, stearyl alcohol, sucrose fatty acid ester, talc, and light anhydrous citric acid, and examples of the binder include hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and partial saponification. Polyvinyl alcohol, methyl cellulose, purulan and the like can be mentioned, citric acid, malic acid, adipic acid, ascorbic acid and the like can be mentioned as acidulants, and sodium hydrogen carbonate, sodium carbonate, calcium carbonate and the like can be mentioned as foaming agents. , Sweeteners include aspartame (registered trademark), saccharin, glycyrrhizin, etc., fragrances include lemon, orange, pine, mint, menthol, etc. Examples include iron dioxide and tar-based pigments. The amount of the lubricant used is preferably 0.01 to 1%, more preferably 0.01 to 0.5% in the tablet.

The compression molding method is not particularly limited, but it is preferable to use a rotary lock machine, a hydraulic press machine, or a single-shot lock machine having excellent productivity. When a disintegrant aid that volatilizes easily is used, it is dried by heating or the like after compression molding. Further, during compression molding, the lubricant can be applied to the mortar and pestle of the tableting machine in advance without containing the lubricant in the granulated product, and then compression molding can be performed, which further enhances the effect of the present invention. To do. The compression molding pressure is preferably 300 kg or more when a rotary locking machine is used.

The shape of the tablet obtained in the present invention may be a round tablet or various deformed tablets having a surface shape such as a normal R surface, a sugar-coated R surface, a Sumikaku plane, a Sumimal plane, and a two-stage R surface. Further, the tablet may be used as a divided tablet having a score line.

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples.

[Comparative example 1] 1890 g of D-mannitol (Towa Kasei: average particle size of about 60 μm) and 100 g of crospoviton (Polyplusdon XL-10: GAF) are charged in a fluidized bed granulator (Grat, WSG-5 type) for purification. Water was sprayed, and a granulated product was obtained through a granulation and drying process. After adding 10 g of magnesium stearate to the granulated product and mixing it, compression molding was performed using a rotary type tableting machine (Kikusui Seisakusho, Clean Press Collect 12 type). The molding conditions were a tablet weight of 200 mg, a mold with a diameter of 8 mm and a flat mold, and the compression molding pressure was changed to 150, 300, 450, 600 and 800 kg for tableting.

<p> D-mannitol (Towa Kasei: average particle size about 60 μm) is crushed in advance using a jet mill (manufactured by Nippon Pneumatic Co., Ltd .: PJM-1-1.5 type) to obtain D-mannitol with an average particle size of about 20 μm. It was. 1890 g of this crushed D-mannitol product and 100 g of crospovidone (Polyplusdon XL-10: GAF) are charged in a fluidized bed granulator (WSG-5 type, manufactured by Grat), sprayed with purified water, and granulated. , A granulated product was obtained through a drying step. After adding 10 g of magnesium stearate to the granulated product and mixing it, compression molding was performed using a rotary type tableting machine (Kikusui Seisakusho, Clean Press Collect 12 type). The molding conditions were the same as in Comparative Example 1.</p><p>[Comparative example 2] Gastrointestinal motility improver Domperidone 100g, lactose (DMV: average particle size about 80μm) 1790g and crospovidone (Polyplusdon XL-10: GAF) 100g fluidized bed granulator / dryer (Grat, WSG- It was charged into type 5), sprayed with purified water, and granulated and dried to obtain granulated products. After adding 10 g of magnesium stearate to the granulated product and mixing it, compression molding was performed using a rotary type tableting machine (Kikusui Seisakusho, Clean Press Collect 12 type). The molding conditions were the same as in Comparative Example 1.</p>

<p> Lactose (DMV: average particle size of about 80 μm) was pulverized in advance using a jet mill (Nippon Pneumatic Co., Ltd .: PJM-1-1.5 type) to obtain lactose with an average particle size of about 15 μm. 1790 g of this crushed lactose product, 100 g of domperidone and 100 g of crospovidone (Polyplusdon XL-10: GAF) were charged into a fluidized bed granulator (WSG-5 type, manufactured by Grat), and purified water was sprayed. A granulated product was obtained through a granulation and drying process. After adding 10 g of magnesium stearate to the granulated product and mixing it, compression molding was performed using a rotary type tableting machine (Kikusui Seisakusho, Clean Press Collect 12 type). The molding conditions were the same as in Comparative Example 1.</p>

<p> Using the granules obtained in Example 1, apply a very small amount of magnesium stearate to the mold (8 mm diameter flat mold) and mortar of a hydraulic press machine (manufactured by Riken Seiki Co., Ltd .: P-1B type). Tablets were obtained at a tablet weight of 200 mg and a pressure molding pressure of 50 kg / cm2.</p>

<p> 140 g of crushed D-mannitol used in Example 1, 10 g of donperidone, 10 g of crospovidone (Polyplusdon XL-10: GAF) and kanfa-40 g are put in a plastic bag and mixed, and then the tablet weight is 200 mg and the mold is used. Tablets were obtained at a compression molding pressure of about 1500 kg / cm2 using a single-shot tableting machine (N-20E type double pressure type powder tablet machine manufactured by Okada Seiko Co., Ltd.) with a diameter of 9 mm. The tablets were dried in a vacuum dryer at 80 ° C. under vacuum for 10 minutes.</p><p> Next, the tablet hardness and disintegration time of the tablets of the present invention will be described with reference to Test Examples. [Test example] The tablet hardness and disintegration time of the tablets obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were measured. The tablet hardness was measured using a tablet breaking strength measuring machine (manufactured by Toyama Sangyo: TH-203CP type). did. Regarding the disintegration time of the tablet, the tablet was placed on the No. 10 wire mesh, water was dropped from the top at a rate of 4 ml / min, and the time until the tablet was removed from the wire mesh was measured, and that time was defined as the disintegration time. did.</p><p> The evaluation results are shown in Table 1.<tables num="1"><img file="JP2012167105A_D0001.tif" /></tables></p><p> In Comparative Examples 1 and 2, it was difficult to mold up to a compression molding pressure of 450 kg, and it was finally possible to mold from about 600 kg. However, the hardness of the molded product was weak and unsatisfactory. In Examples 1 and 2, sufficient tablet hardness was obtained at a compression formation pressure of 300 kg or more, and the disintegration time was also very fast. When the tablets obtained at the compression molding pressure of 450 kg of Example 1 were actually taken, they disintegrated in the oral cavity in 10 seconds.</p><p> For each tablet obtained in Examples 3 and 4, the tablet hardness and disintegration time were measured in the same manner as described above. As a result, the tablet obtained in Example 3 had a hardness of about 6.5 kgf, which was sufficient, and the disintegration time was about 10 seconds. The tablet obtained in Example 4 had a hardness of about 4 kgf and a very fast disintegration time in the oral cavity of about 2 seconds.</p>

The present invention provides tablets that rapidly disintegrate in the oral cavity.