WO2013100705A1

WO2013100705A1 - Fast-disintegrating tablet suitable for environmentally sensitive drug and process for manufacturing the same

Info

Publication number: WO2013100705A1
Application number: PCT/KR2012/011753
Authority: WO
Inventors: Sang Yeob Park; Kyung Hee Kim
Original assignee: Samyang Biopharmaceuticals Corporation
Priority date: 2011-12-28
Filing date: 2012-12-28
Publication date: 2013-07-04
Also published as: KR101494180B1; KR20130076511A

Abstract

Disclosed are an oral formulation which disintegrates quickly in the oral cavity; a fast-disintegrating tablet having fast disintegrability and high hardness, and a process for manufacturing the same, more specifically, a fast-disintegrating tablet comprising slightly wetted granules comprising a spray-dried mannitol and a sucrose binder, and sufficiently dried granules; and a process for manufacturing the same.

Description

FAST-DISINTEGRATING TABLET SUITABLE FOR ENVIRONMENTALLY SENSITIVE DRUG AND PROCESS FOR MANUFACTURING THE SAME

The present invention relates to an oral formulation which disintegrates quickly in the oral cavity; a fast-disintegrating tablet having fast disintegrability and high hardness, and a process for manufacturing the same. More specifically, the present invention relates to a fast-disintegrating tablet comprising slightly wetted granules and sufficiently dried granules, each comprising a spray-dried mannitol and a sucrose binder, and a process for manufacturing the same. The fast-disintegrating tablet has fast disintegrability and high hardness; is particularly suitable for drugs sensitive to the environment, such as light, temperature, moisture, etc.; is also suitable for drugs with trace contents in tablets; and can be manufactured by a conventional tableting machine and manufacturing process without any problems even if active ingredients, excipients, additives, etc. could cause troubles in tableting.

Pill or tablet formulation has been conveniently and practically used for a long time in order to administer a drug to the body. However, it has been known that a surprising number of people have trouble in swallowing pills. In addition, the tablet formulation type is inconvenient for old people who have hand tremors or dysphagia; infants and young children who cannot swallow pills, and thus need to take pills in syrup form or take pills by crushing and mixing them with water; people in a situation in which drinking water is difficult to get, such as while traveling; water-restricted patients (for example, nephropathy patients); patients who lie down continuously, and thus have difficulty in sitting up to take medicine; and the like.

Fast-disintegrating tablets have been developed to improve the above problems. Fast-disintegrating tablet is one type of tablet which disintegrates in the oral cavity in several seconds to several tens of seconds by saliva upon putting the tablet in the mouth, and thus may be taken without water. Fast-disintegrating tablet is known by several names, such as “orally disintegrating tablet,” “rapidly melting tablet,” “orodispersible tablet,” “fast-dissolving tablet,” “rapidly eroding tablet,” etc. Fast-disintegrating tablet is useful for some mental patients other than the subjects mentioned above; there are cases in which they pretend to eat in front of a nurse, hiding a tablet under his/her tongue, and then spitting out the tablet when the nurse is absent, so fast-disintegrating tablet is a useful dosage form to ensure the administration of medicine.

Ideal fast-disintegrating tablets disintegrate quickly and softly in the oral cavity and have physical properties suitable for production, transportation, packaging, storage, etc.―for example, high hardness and low friability. Unfortunately, fast-disintegrating tablets generally have poor physical properties; on the other hand, tablets with good physical properties generally have poor disintegration. Most commercially available fast-disintegrating tablets find a balance or compromise among these needs; or they focus on one aspect, while the shortages are attributed to consumers―for example, by issuing precautions; or they are supplemented in another way, such as specialty packaging.

The known methods for manufacturing fast-disintegrating tablets include a method using freeze-drying; a method similar to a cotton-candy-making process; a method to contain an appropriate amount of foaming agent in tablets; a method using a large amount of disintegrating agent; a method using an appropriate combination of highly soluble saccharide and highly moldable saccharide; a method for improving the physical properties by humidifying or heating the tablet obtained by low-pressure tableting; a method for tableting a mixture which contains little lubricant without problems by using an improved tableting machine in which a lubricant is sprayed into a mold where a tablet is formed; etc.

However, many of the above manufacturing methods require special equipment or high-priced facilities; or general pharmaceutical equipment cannot be used as it is, and thus has to be modified, and which may cause a rise in the production cost or restrict various applications. In addition, the tablets which need a specific humidity and temperature conditions at or after tableting may be exposed to harsh conditions or require unnecessary investments in equipment, which may limit applications.

The chemical name of ramosetron is (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole. Tetrahydrobenzimidazole derivatives including ramosetron and pharmaceutically acceptable salts thereof have an antagonistic action to serotonin 5-HT3 receptors. On the basis of such an action, there has been suggested a possibility of suppression of emesis caused by anti-cancer drugs such as cisplatin and radioactive rays, and prevention and treatment of migraine, complex headache, trigeminal neuralgia, anxiety symptom, gastrointestinal motility abnormalities, peptic ulcer, irritable bowel syndrome, etc. (European Patent No. 381422). Ramosetron was originally developed in Japan. Ramosetron hydrochloride for suppression of digestive-organ symptoms such as nausea, emesis, etc. caused by administration of an anti-malignant-tumor agent is commercially available and its usual clinical dose per day for adults is 0.1 mg q.d. by oral administration or 0.3 mg by intravenous injection which is administered once daily. In Korea, it is sold under the trademark name Nasea^® OD tablet 0.1 mg and Nasea^® injection 0.3 mg by Astellas Pharma Korea, Inc. Ramosetron hydrochloride for treatment of male diarrhea-type irritable bowel syndrome is commercially available, and its usual clinical dose per day for adults is 2.5 μg or 5 μg q.d. by oral administration. In Korea, it is sold under the trademark name Irribow^® tablet 2.5 and 5 μg by Astellas Pharma Korea, Inc. Nasea^® OD tablet as an anti-emetic agent is a fast-disintegrating tablet that can be taken without water. It is very helpful to take a fast-disintegrating tablet instead of a conventional tablet at the time of converting to oral administration after injection administration for patients who have nausea or emesis even from drinking water. In addition, since drugs are generally sensitive to light many ways to include a stabilizing agent have been proposed, but if the stabilizing agent contains iron oxide, it tends to stick to a punch when tableting, and thus there can be problems in manufacturing fast-disintegrating tablets. Furthermore, there can be problems in securing content uniformity of the 0.1 mg tablet.

Korean Patent No. 0642976 discloses a method for manufacturing a fast-disintegrating tablet, comprising tableting after granulating a drug, diluent and saccharide having a relatively low melting point; heating over the melting temperature at which the saccharide having a low melting point is melted; and cooling. However, the method includes a heating step, wherein the formed tablet is placed in a 120-160℃ oven for several minutes, and thus has a limitation in that it cannot be used for drugs unstable to high temperature.

Korean Patent No. 0655627 discloses a fast-disintegrating tablet which comprises saccharide and amorphous saccharide, and is manufactured by humidifying and drying after tableting. According to the examples of the above patent, a formed tablet was placed in a 35℃, 85% RH thermohygrostat for 20 minutes and then dried in a 50℃ oven for several tens of minutes; or was placed in a 25℃, 70-80% RH thermohygrostat for 12-24 hours and then dried at 25 to 40℃ for several hours. Consequently, this method is difficult to apply to drugs unstable to moisture and requires cumbersome processes after tableting.

US Patent No. 5,466,464 discloses a fast-disintegrating tablet comprising lactose, mannitol and agar (0.1-1.2 w/w% based on the sugar) and a method for manufacturing the same. In this patent, the fast-disintegrating tablet is manufactured by a process which comprises suspending an active ingredient and an excipient, filling the suspension in a mold (mainly a sheet for Press Through Pack (blister packaging)) to solidify it into a jelly-like form, and then drying. The obtained fast-disintegrating tablet shows a high hardness and fast disintegration. However, the manufacturing process is complicated; the tablet shape may be irregular; and its edge is liable to break.

Therefore, there has been a continuous need to develop a fast-disintegrating tablet having fast disintegrability as well as high hardness which can be manufactured without modifying the tableting machine or forming machine conventionally used in a pharmaceutical manufacturing process and without using additional equipment; and a process for manufacturing the same not requiring cumbersome post-treatment processes under harsh conditions after the tableting or forming step.

Furthermore, there is an urgent need to develop a fast-disintegrating tablet which can be produced by a conventional manufacturing process and a tableting machine without problems even though active ingredients sensitive to the environment, such as light, temperature, moisture, etc.; or active ingredients, excipients, additives that could cause troubles in tableting.

The present invention is intended to provide a fast-disintegrating tablet having high hardness and fast disintegrability which can be manufactured by a process employing a conventionally used tableting machine or forming machine; not requiring cumbersome post-treatment processes under harsh conditions after a tableting or forming step. Furthermore, the object of the present invention is to provide a fast-disintegrating tablet which can be produced by a conventional manufacturing process and a tableting machine without problems even though the tablet comprises active ingredients sensitive to the environment, such as light, temperature, moisture, etc.; or active ingredients, excipients and additives could cause troubles in tableting.

In order to solve the technical problems, the present invention provides a fast-disintegrating tablet comprising 50 to 99% by weight of slightly wetted granules comprising a spray-dried mannitol and a sucrose binder, and 1 to 50% by weight of sufficiently dried granules comprising a spray-dried mannitol and a sucrose binder.

According to another aspect of the present invention, the present invention provides a process for manufacturing a fast-disintegrating tablet comprising the steps of: preparing slightly wetted granules comprising a spray-dried mannitol and sucrose binder, and sufficiently dried granules comprising a spray-dried mannitol and a sucrose binder, respectively; forming a post-granulation mixture for tableting comprising the slightly wetted granules and the sufficiently dried granules; compressing the post-granulation mixture for tableting to obtain a tablet; and drying the tablet.

The fast-disintegrating tablet according to the present invention can be manufactured by employing a tableting machine or forming machine conventionally used in the pharmaceutical art. In addition, the fast-disintegrating tablet having high hardness and fast disintegrability can be obtained by a process that does not require cumbersome post-treatment processes under harsh conditions after a tableting or forming step. Accordingly, the production cost is low; additional investment in equipment need not be made; packaging, transport and storage are easy; and patients can easily take their medication. Furthermore, the fast-disintegrating tablet can be produced by a conventional manufacturing process and a tableting machine without problems even if the tablet comprises an active ingredient sensitive to the environment, such as light, temperature, moisture, etc., or active ingredients, excipients and additives could cause troubles in tableting. Particularly, even if the amount of active ingredient is small―for example, 0.1 mg―the content uniformity can be secured and tablets can be effectively manufactured without troubles in tableting.

Unless specified otherwise, the terms and expressions used herein are defined as follows:

The term “loss-on-drying” stated herein refers to an evaporated amount of water, solvent and volatile materials in a sample, expressed as a percentage (%) based on the weight before drying when the sample is dried under heating condition. An exemplary measuring method is as follows: about 2 g or more of sample is taken and evenly spread onto an aluminum plate, and the weight of the sample (“weight after drying”) is measured at 105℃ for several to several tens of minutes until there is no change in the value by using an MA100 LOD meter (Sartorius). The loss-on-drying (%) is calculated as follows: after subtracting the weight after drying from the weight before drying, the difference is divided by the weight before drying, and then multiplying by 100. For example, when 2.00 g of sample is taken and 1.95 g is left after the solvent or moisture was evaporated by drying, the loss-on-drying is 2.5%. For accuracy, after one measurement, the next measurement is conducted after a sample inlet is cooled below 35℃, and the three measurements are performed and their average value is determined as the loss-on-drying.

The term “sufficiently dried granules” stated herein refers to granules which are obtained by drying after the wet-granulation step and its loss-on-drying is in an unchanged state even after additional drying. For example, it refers to granules wherein the loss-on-drying of the granules after agglomeration by using a binder solution in a wet-granulation step and drying in a 50℃ convection oven for 4 hours, is equivalent to that of the granules additionally dried for 2 hours in the same way. More specifically, for example, it refers to granules wherein the loss-on-drying values of the following two granules are the same: granules prepared by a process comprising the steps of passing 500 g of the wetted mass agglomerated by using a binder solution in a wet-granulation step through a 30-mesh sieve; drying in a 50℃ convection oven (FO600M, Jeio-Tech) for 2 hours after evenly spreading onto a stainless-steel plate to be about 0.1-2 cm thick; passing by the dried resultant through a 30-mesh sieve; drying for 2 hours again (total drying time is 4 hours); and sieving the dried resultant again with a 30-mesh sieve; and granules additionally dried for 2 hours in the same way as before. The term “the same loss-on-drying value” means that the difference in the loss-on-drying value is within ±0.3%, preferably ±0.2% in light of measurement error. For instance, the loss-on-drying value of the sufficiently dried granules is usually within 3% or 2%, but depending on materials comprised in the granule, it may be within 1% or 0.5%.

The term “slightly wetted granules” stated herein refers to granules having 1.05- to 5-times, preferably 1.1- to 3-times, and most preferably 1.2- to 2.5-times greater loss-on-drying value than that of the sufficiently dried granules, when measuring the loss-on-drying of the granules obtained by a wet-granulation and drying process.

The slightly wetted granules show property having no problem in manufacturing a tablet with a conventionally used amount of a commonly used lubricant by a general tablet-manufacturing process.

The phrase “general tablet-manufacturing process” refers to a process which utilizes a tableting machine or forming machine generally used in pharmaceutics, and employs general humidity and temperature conditions inside a tableting room.

The term “general tableting machine and forming machine” may be a single-punch or multiple-punch tableting machine and refers to machines in which no special modifications are made, such as preventing a tablet from sticking to a punch when tableting by using a special film; or spraying a lubricant into the mold.

The phrase “general humidity and temperature conditions inside a tableting room” refers to within the conventionally controlled humidity and temperature range of the inner-space air where the tableting machine or forming machine is placed―for example, the conditions of 20-30℃ of temperature and 40% or less RH of humidity.

The phrase “conventionally used lubricant” refers to a lubricant that is conventionally used for forming tablets, and any suitable agent may be employed.

The phrase “a conventionally used amount of lubricant” refers to not using excessive lubricant, which means the amount employed in conventional tablet manufacturing―i.e., 3% or less (based on tablet weight), preferably 2% or less, and more preferably 1.5% or less.

The phrase “has no problem in forming a tablet” means that there are no troubles in tableting―for example, during the tableting or forming process, a part or all of the tablet sticks to a punch or mold, or is crushed; or when taking the produced tablet in a container or transferring it to another container, a part or all of the tablet is crushed. In addition, it means that a mixture for tableting has sufficient flowability to produce tablets without variations in weight.

Hereinafter, the present invention will be described more specifically.

Slightly wetted granules and process for manufacturing the same

The slightly wetted granules which are contained in the fast-disintegrating tablet of the present invention comprise a spray-dried mannitol and a sucrose binder.

According to one embodiment of the present invention, the slightly wetted granules may further comprise an active ingredient and/or various additional components other than the spray-dried mannitol and the sucrose binder for the purpose―such as effectiveness in granule manufacturing, stability of active ingredients, appearance, color, protection, binding, performance improvement, manufacturing process improvement, etc.

Mannitol dissolves well in water (1 part per 5.5 parts of water at 20℃); is chemically stable and non-hygroscopic; does not undergo the Maillard reaction with amino group; and has a good taste when it disintegrates in the oral cavity.

Spray-dried mannitol has advantages other than the above properties, such as fast disintegration in water due to its porosity; good flowability; and good compressibility. Examples of such spray-dried mannitol include commercially available Mannogen™ EZ (SPI Pharma), Pearlitol^® SD (Roquette), etc., but are not limited thereto. Spray-dried mannitol has various applications in the pharmaceutical art due to said properties and is mainly used as a diluent in direct tableting without manufacturing granules. Unconventionally, the present invention uses spray-dried mannitol for wet granulation, thereby making the granules have more micropores than when mannitol powder is used for wet granulation; confers enhanced compressibility and flowability, which make tablets disintegrate faster and have better hardness and friability.

Preferably, the slightly wetted granules of the present invention may comprise the spray-dried mannitol in an amount of 20 to 98% by weight, more preferably 30 to 95% by weight, and even more preferably 50 to 90% by weight based on total weight of the slightly wetted granules. If the amount of spray-dried mannitol is less than 20% by weight or greater than 98% by weight based on total weight of the slightly wetted granules, tablet hardness may be lowered or disintegration time may be prolonged.

Preferably, the sucrose binder may be used by dissolving it in water, non-aqueous solvent or a mixed solvent thereof, more preferably a mixed solvent of water and ethanol. The concentration of sucrose may be 1 to 60% (w/w), preferably 5 to 50% (w/w) based on such solvents.

Preferably, the slightly wetted granules of the present invention may comprise the sucrose binder in a dried amount of 1 to 50 parts by weight, more preferably 2 to 30 parts by weight, and even more preferably 3 to 15 parts by weight based on 100 parts by weight of said spray-dried mannitol. If the amount of dried sucrose binder is less than 1 part by weight based on 100 parts by weight of the spray-dried mannitol, the tablet hardness may be lowered, and if it is greater than 50 parts by weight, the disintegration time may be prolonged.

The slightly wetted granules of the present invention may or may not comprise an active ingredient. If the slightly wetted granules comprises an active ingredient, it may be mixed in a solid state with the spray-dried mannitol before adding a binder solution for wet granulation, and its state may be a powdered state; crystalline state; granular state; fine-powdered state; or nanoparticle state. Alternatively, the active ingredient may be dissolved or dispersed in a solvent when the sucrose binder solution is prepared.

The slightly wetted granules of the present invention may further comprise additional ingredients for manufacturing said granule. Exemplary additional ingredients for manufacture of the granule include dry binder, coloring agent, flavor, sweetening agent, stabilizing agent, antioxidant, etc., which may be added in a solid state along with the spray-dried mannitol.

Preferably, the slightly wetted granules of the present invention may comprise the dry binder among the above additional ingredients for manufacture of the granule in an amount of 50 parts by weight or less (e.g., 0.1 to 50 parts by weight), more preferably 30 parts by weight or less, and even more preferably 15 parts by weight or less based on 100 parts by weight of the spray-dried mannitol.

The dry binder may be saccharide, sugar alcohol, starch, polysaccharide, cellulose derivative, or a mixture thereof―for example, one or more selected from: fructose, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, erythritol, xylitol, maltodextrin, isomalt, dextrin, dextrose, dextrate, starch, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, STARLAC^® (a spray-dried solid powder consisting of 15% corn starch and 85% α-lactose monohydrate, Roquette American Inc.), MICROCELAC^® (a spray-dried solid powder consisting of 75% α-lactose monohydrate and 25% microcrystalline cellulose, Meggle Excipients & Technology), CELLACTOSE^® (a spray-dried compound consisting of 75% α-lactose monohydrate and 25% cellulose powder, Meggle Excipients & Technology), etc., but are not limited thereto.

Other ingredients except for the dry binder among the additional ingredients for manufacture of the granule―i.e. coloring agent, flavor, sweetening agent, stabilizing agent, antioxidant, etc.―may be dissolved or dispersed during the preparation of the sucrose binder solution.

The slightly wetted granules of the present invention as mentioned above may be manufactured by a method comprising the steps of: forming a granule comprising a spray-dried mannitol and a sucrose binder; drying said granule to prepare a slightly wetted granules having 1.05- to 5-times greater loss-on-drying value than the sufficiently dried granules.

Preferably, the sucrose binder dissolved in water, non-aqueous solvent or mixed solvent thereof may be used in preparing a mixture for the formation of the granule comprising the spray-dried mannitol and the sucrose binder.

The granule comprising the spray-dried mannitol and the sucrose binder may further comprise an active ingredient and/or additional ingredients for the manufacture of the granule. The way to introduce them into said mixture is described above.

The slightly wetted granules of the present invention may be manufactured by the wet-granulation process conventionally used in the pharmaceutical art. According to one embodiment of the present invention, a mixture comprising a spray-dried mannitol; a sucrose binder; optional active ingredient; and/or optional additional ingredient for the manufacture of the granule may be prepared in a state of agglomerated particle mass by using a granulator, a mixer, a U-type mixer, a high-speed mixer, a fluidized bed granulator, etc., or manually The prepared agglomerated particle mass may directly undergo a drying step or may undergo a drying step after sieving. According to one embodiment of the present invention, the agglomerated particle mass may be granulated by passing through a 30-mesh sieve.

Conventional drying techniques―for example, convection-oven drying, vacuum-oven drying, drying by fluidized bed dryer, drying by dryer, natural drying at room temperature, etc.―may be used to prepare the slightly wetted granules. In addition, the slightly wetted granules of desired size may be obtained by additional sieving during or after drying.

Sufficiently dried granules and process for manufacturing the same

The sufficiently dried granules which are contained in the fast-disintegrating tablet of the present invention also comprise a spray-dried mannitol and a sucrose binder. The difference between it and the slightly wetted granules lies in their state of drying. Besides that, the components and the manufacturing process used for preparing the sufficiently dried granules are the same as described for the above slightly wetted granules.

According to one embodiment of the present invention, the sufficiently dried granules may comprise active ingredients sensitive to the external environment, such as temperature, light, moisture, etc., or active ingredients, excipients and additives that could cause troubles in tableting.

In one embodiment of the present invention, when the sufficiently dried granule comprises active ingredients sensitive to the external environment, such as temperature, moisture, etc., or active ingredients, excipients and additives that could cause troubles in tableting, it may be dried under a condition milder than that of ordinary drying. For example, drying may be carried out by using a convection oven, vacuum oven, fluidized bed dryer, dryer, etc. under mild conditions, such as a temperature of 40℃ or less; or by a natural drying process at room temperature.

Fast-disintegrating tablet

The fast-disintegrating tablet of the present invention comprises the slightly wetted granules and the sufficiently dried granules as explained above.

Preferably, the fast-disintegrating tablet of the present invention may comprise the slightly wetted granules in an amount of 50 to 99% by weight, more preferably 60 to 98% by weight and even more preferably 70 to 97% by weight based on total weight of the tablet. If the amount of slightly wetted granules is less than 50% by weight based on total weight of the tablet, the tablet may not exhibit the properties of the fast-disintegrating tablet―i.e., high hardness and fast disintegrability; and if greater than 99% by weight, troubles in tableting may occur or disintegration in water may be poor.

Preferably, the fast-disintegrating tablet of the present invention may comprise the sufficiently dried granules in an amount of 1 to 50% by weight, more preferably 2 to 35% by weight and even more preferably 3 to 25% by weight based on total weight of the tablet. If the amount of sufficiently dried granules is less than 1% by weight based on total weight of the tablet, there may be a problem in content uniformity when comprising active ingredients; and if greater than 50% by weight, the tablet hardness or friability may be deteriorated.

If the amount is within the above range, the fast-disintegrating tablet can be manufactured without problems. In addition, in the case that the fast-disintegrating tablet comprises components such as iron oxide, etc. that could cause troubles in tableting, if such components are comprised in the sufficiently dried granules, troubles in tableting may not occur or may be significantly decreased.

The fast-disintegrating tablet of the present invention may further comprise an active ingredient and/or additional ingredients for the manufacture of tablet other than the spray-dried mannitol and the sucrose binder comprised in the slightly wetted granules and the sufficiently dried granules. Such an active ingredient and/or additional ingredients for the manufacture of tablet may be introduced to the slightly wetted granules, or alternatively, during the formation of post-granulation mixture for tableting. The active ingredient introduced during the preparation step of the post-granulation mixture may be in a powdered state, a crystalline state, a granular state, a fine-powdered state, a nanoparticular state, the state of taste-masked particle or sustained-release coated particle for delivery control, etc. Additional ingredients for the manufacture of tablet may be introduced to achieve additional objects―such as improving efficiency of tableting; prompting disintegration; stabilizing active ingredient; improving appearance, color, protection, binding and performance; improving manufacturing process; and the like. Examples of the additional ingredients for the manufacture of tablet include a disintegrating agent, a lubricant, surfactant, a dry binder, a coloring agent, a flavor, a sweetening agent, a stabilizing agent, an antioxidant, a souring agent, etc., but they are not limited thereto.

The specific type and usage of the above additional ingredients and the way to introduce such ingredients into the tablet of the present invention would be well known to a person having ordinary skill in the art, and can variously be modified.

Specifically, the disintegrating agent may be one or more selected from the group consisting of sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, starch and the like. The amount of disintegrating agent may suitably be 7% by weight or less, preferably 5% by weight or less, and more preferably 3% by weight or less, based on total weight of the tablet.

Specifically, the lubricant may be one or more selected from the group consisting of stearic acid, glyceryl behenate, glyceryl monostearate, magnesium stearate, calcium stearate, silicon dioxide, talc, sugar ester, sodium stearyl fumarate, magnesium silicate, sodium stearate, poly(ethylene glycol), polyoxypropylene-polyoxyethylene block copolymer, colloidal silicon dioxide and sucrose esters of fatty acids. The amount of lubricant may suitably be 3% by weight or less, preferably 2% by weight or less, and more preferably 1.5% by weight or less, based on total weight of the tablet.

Preferably, the fast-disintegrating tablet has one or more, more preferably two or more, even more preferably three or more, even more preferably four or more, and most preferably all of the following five properties:

- Hardness: 2.5 Kp or more (for example, 2.5 to 20 Kp), preferably 3.0 Kp or more, and more preferably 4.0 Kp or more

- Friability: 1.0% or less (for example, 0.001 to 1.0%), preferably 0.8% or less, and more preferably 0.5% or less

- Disintegration time in water: 2 minutes or less (for example, 1 second to 2 minutes), preferably 1 minute or less, and more preferably 40 seconds or less

- Disintegration time in oral cavity: 40 seconds or less (for example, 1 second to 40 seconds), preferably 30 seconds or less, and more preferably 25 seconds or less.

- Content uniformity: Tablets have a uniform content of active ingredient (preferably 95 to 105% based on the labeled content) even when a trace amount of active ingredient is contained.

Method for manufacturing the fast-disintegrating tablet

The fast-disintegrating tablet of the present invention may be manufactured by a method comprising the steps of: preparing slightly wetted granules and sufficiently dried granules, respectively; forming a post-granulation mixture for tableting comprising the slightly wetted granules and the sufficiently dried granules; compressing the post-granulation mixture for tableting to obtain a tablet; and drying the tablet.

The fast-disintegrating tablet of the present invention may be manufactured by using a tableting machine or forming machine conventionally used in the pharmaceutical art. In addition, a low-pressure compressing process may be used for tableting, and tablet may be dried under a mild condition.

The compressing pressure in the step of compressing the post-granulation mixture for tableting to obtain a tablet is generally low―that is, about 150 MPa or less (for example, 1 Pa to 150 MPa), preferably about 35 MPa or less and more preferably about 10 MPa or less.

In order for the tablet to disintegrate quickly in the oral cavity, water has to be rapidly absorbed into the inner core thereof and the ingredients also need to dissolve quickly. Therefore, it is important for the compressed tablet to maintain high porosity. The low-pressure tableting process is usually employed to maintain high porosity of the compressed tablet; but if the tablet is processed under low pressure, its hardness and friability cannot but be worsen. However, by using the slightly wetted granules of the present invention, the tablet can be produced even by low-pressure tableting without any such trouble in tableting; and after the drying step, the tablet has not only good physical properties of high hardness and low friability but also fast disintegrability.

The mild condition for drying tablet may be conditions of room temperature and humidity which is not too high―for example, 20 to 30℃ of temperature and 40% RH or less of humidity. In order to dry faster and completely, a 20 to 50℃ low-temperature convection oven may be used; and a method of providing dry air, a method using a dehumidifier, a method using a dehumidifying agent, etc. may be used.

Active ingredient

The active ingredient may be mixed into a solid in the process of manufacturing the slightly wetted granules; added during the preparation of the sucrose binder solution; or introduced in the step of forming post-granulation mixture. Such an active ingredient may be in a solution state, paste state, powder state, crystalline state, granular state, fine-powdered state, nanoparticular state, state of taste-masked particle or sustained-release coated particle for delivery control, etc.

In addition, the active ingredient may be used alone, or two or more active ingredients may be used as a combined formulation.

Active ingredients useful in the present invention are too many to mention one by one herein. Representative examples of the drug which can be formulated as the fast-disintegrating tablet of the present invention include the following, but are not limited to:

anti-migraine drugs, such as almotriptan, ergotamine tatrate, frovatriptan, methysergide maleate, sumatriptan succinate, zolmitriptan, etc.;

ADHD (Attention Deficit Hyperactivity Disorder) drugs, such as methylphenidate, atomoxetine, etc.;

erectile dysfunction drugs, such as sildenafil, vardenafil, alprostadil, tadalafil, mirodenafil, udenafil, etc.;

anti-rheumatic drugs, such as auranofin, azathioprine, cyclosporine, hydroxychloroquine sulfate, lefunomide, methotrexate, penicillamine, sulfasalazine, etc.;

nonsteroidal anti-inflammatory drugs, such as acetaminophen, aspirin, diclofenac, etodolac, fenoprofen, ibuprofen, ketoprofen, naproxen, indomethacin, ketorolac, sulindac, tolmetin, meclofenamate, mefenamic acid, nabumetone, meloxicam, piroxicam, celecoxib, rofecoxib, etc.;

opioids, such as buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, morphine, oxycodone, pentazocine, propoxyphene, tramadol, etc.;

anti-mycobacterial drugs, such as aminosalicylic acid salts, clofazimine, cycloserine, ethionamide, rifabutin, etc.;

anti-parasitic drugs, such as albendazol, ivermectin, mebendazol, praziquantel, etc.;

anti-viral drugs, such as valacyclovir, didanosine, famciclovir, valganciclovir, indinavir, lamivudine, nelfinavir mesylate, nevirapine, ritonavir, stavudine, oseltamivir phosphate, etc.;

beta-lactam, such as amoxicillin, amoxicillin and potassium clavulanate, ampicillin, cefuroxime sodium, cefuroxime axetil, penicillin G and Y salts, cefditoren, cefixime, cloxacillin sodium, dicloxacillin sodium, etc.;

macrolide antibiotics, such as erythromycin estolate, erythromycin ethylsuccinate, erythromycin stearate, etc.;

fluoroquinolones, such as ciprofloxacin, enoxacin, etc.;

tetracyclines, such as demeclocycline hydrochloride, doxycycline calcium, tetracycline, tetracycline hydrochloride, etc.;

alkylating agents, such as altretamine, busulfan, chlorambucil, melphalan, cyclophosphamide, procarbazine hydrochloride, temozolomide, etc.;

antimetabolites, such as methotrexate, mercaptopurine, thioguanine, etc.;

hormonal drugs and antagonists, such as bicalutamide, flutamide, nirutamide, aminoglutethimide, anastrozole, exemestane, letrozole, tamoxifen citrate, toremifene citrate, etc.;

mitotic inhibitors, such as etoposide phosphate, etc.;

immunosuppressive drugs, azathioprine, cyclosporine, mycophenolate mofetil, sirolimus, tacrolimus, etc.;

antiarrhythmics drugs, such as amiodarone hydrochloride, digoxin, disopyramide phosphate, dofetilide, flecainide acetate, mexiletine hydrochloride, moricizine hydrochloride, procainamide hydrochloride, propafenone hydrochloride, quinidine sulfate, quinidine gluconate, sotalol hydrochloride, tocainide, etc.;

antihypertensive drugs, such as doxazosin mesylate, prazosin hydrochloride, terazosin hydrochloride, benazepril, captopril, clonidine hydrochloride, enalapril, hydralazine hydrochloride, labetalol hydrochloride, losartan potassium, methyldopate hydrochloride, minoxidil, moexipril, trandolapril, candesartan, irbesartan, losartan, telmisartan, valsartan, guanabenz acetate, guanadrel sulfate, guanfacine hydrochloride, reserpine, etc.;

beta-adrenergic blocking drugs, such as acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol, etc.;

calcium channel blockers, such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil, etc.;

lipid-lowering drugs, such as fenofibrate, gemfibrozil, niacin, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, etc.;

nitrates, such as isosorbide dinitrate, nitroglycerin, nitroprusside sodium, etc.;

antiseizure drugs, such as carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, divalproex sodium, zonisamide, etc.;

antidepressants, such as mirtazapine, bupropion, amoxapine, phenelzine, tranylcypromine, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, maprotiline, trazodone, nefazodone, amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, etc.;

antipsychotic drugs, such as chlorpromazine, thioridazine, loxapine, molindone, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, fluphenazine, haloperidol, perphenazine, trifluoperazine, thiothixene, paliperidone, etc.;

anxiolytics, sedatives and hypnotics, such as alprazolam, lorazepam, oxazepam, chlordiazepoxide, clorazepate, diazepam, halazepam, midazolam, triazolam, zaleplon, zolpidem, estazolam, temazepam, flurazepam, quazepam, meprobamate, phenobarbital, chloral hydrate, ethchlorvynol, glutethimide, pentobarbital, secobarbital, etc.;

neurodegenerative disease drugs, such as amantadine, benztropine mesylate, carbidopa and levodopa, donepezil, bromocriptine, pergolid, pramipexole, ropinirole, etc.;

anti-glaucoma drugs, such as acetazolamide, dichlorphenamide, methazolamide, etc.;

acid-peptic disease drugs, such as aluminum carbonate, aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, calcium carbonate, magaldrate, bismuth salts, cimetidine, famotidine, nizatidine, ranitidine, misoprostol, lansoprazole, omeprazole, pantoprazole, rabeprazole, sucralfate, etc.;

antiemetics, such as buclizine, cyclizine, dimenhydrinate, diphenhydramine, meclizine, dronabinol, chlorpromazine, perphenazine, prochlorperazine, promethazine, thiethylperazine, triflupromazine, dolasetron, granisetron, ondansetron, dexamethasone, lorazepam, granisetron, ramosetron, aprepitant, etc.;

gastrointestinal motility drugs, such as bisacodyl, diphenoxylate hydrochloride and atropine sulfate, docusate salts, loperamide, magnesium salts, metoclopramide, ursodiol, etc.;

coagulants and anticoagulants, such as clopidogrel bisulfate, phytonadione, ticlopidine, warfarin sodium, etc.;

hematopoiesis stimulants, such as iron salts, etc.;

adrenal hormones, such as cortisone, hydrocortisone, methylprednisolone, prednisone, triamcinolone, betamethasone, dexamethasone, fludrocortisone, etc.;

anti-diabetic drugs, such as acarbose, metformin, nateglinide, repaglinide, acetohexamide, chlorpropamide, tolazamide, tolbutamide, glimepiride, glipizide, glyburide, pioglitazone, rosiglitazone, etc.;

contraceptives, such as norethindrone, norgestrel, levonorgestrel, etc.;

female sex hormones, such as estradiol and esters thereof, estrogen, estropipate, medroxyprogesterone, mifepristone, norethindrone acetate, progesterone, raloxifene, etc.;

thyroid and anti-thyroid hormones, such as iodide, levothyroxine sodium, liothyronine sodium, liotrix, methimazole, propylthiouracil, etc.;

diuretics, such as amyloid hydrochloride, bumetanide, ethacrynic acid, furosemide, torasemide, hydrochlorothiazide, chlorthiazide, chlorthalidone, indapamide, metolazone, polythiazide, quinthazone, trichomethiazide, spironolactone, triamterene, etc.;

electrolytes, such as chelated magnesium, magnesium chloride, magnesium hydroxide, magnesium oxide, potassium salts, etc.;

gout drugs, such as allopurinol, colchicine, probenecid, sulfinpyrazone, etc.;

asthma drugs, such as albuterol sulfate, montelukast sodium, theophylline, zileuton, etc.;

antihistamines, such as acrivastine, azatadine, brompheniramine maleate, carbinoxamine maleate, cetirizine hydrochloride, chlorpheniramine maleate, diphenhydramine hydrochloride, clemastine fumarate, cyproheptadine hydrochloride, fexofenadine, hydroxyzine, loratidine, desloratadine, etc.;

drugs for cough and cold, such as dextromethorhpan hydrobromide, guaifenesin, pseudoephedrine hydrochloride, etc.; and

health functional foods.

According to a preferred embodiment, the fast-disintegrating tablet of the present invention is particularly suitable, in the case that the active ingredient is sensitive to the environment, such as light, temperature, moisture, etc.; there is a trace amount of the active ingredient in the tablet; or the active ingredient itself or the excipients or additives added for improving stability or medicinal effect can cause troubles in tableting. In one example of the present invention, the active ingredient is ramosetron or pharmaceutically acceptable salts thereof but is not limited thereto. In this case, preferably the fast-disintegrating tablet of the present invention may comprise the active ingredient in the sufficiently dried granules. The phrase “there is a trace amount of the active ingredient in the tablet” means that the amount of the active ingredient is 5% by weight or less, preferably 3% by weight or less, more preferably 1% by weight or less and most preferably 0.5% by weight or less based on total weight of the tablet.

The following examples illustrate the present invention and are not intended as a means of defining the limits and scope of the present invention.

Examples

The following methods were used for analyzing properties of the Examples and Comparative Examples:

Hardness Measurement

The tablet hardness was measured by using a hardness tester 8M (Dr. Schleuniger, Switzerland). At least 6 specimens were measured, and their average values were recorded.

Friability Measurement

The friability test method was performed according to the method described in the Tablet Friability of the General Chapters of USP (US Pharmacopoeia) 25 describing general tests and assays.

Disintegration Test in Water

The disintegration test was performed according to a disintegration test method among general test methods described in the 8^th edition of the Korean Pharmacopoeia. Water was used as test liquid, 6 specimens were subjected to the test at 37℃, and their average values were recorded.

Disintegration Test in the Oral Cavity

For a fast-disintegrating tablet, disintegration tests were performed in the oral cavity with applicants. Applicants were randomly selected and had their mouths washed out with water. Disintegration time began by measuring with a stopwatch which was started immediately after the tablet was placed on the tongue. The applicants were permitted to move the fast-disintegrating tablet to the roof of mouth using their tongue; roll it gently without biting the tablet; and roll it from side to side. The stopwatch was stopped right after the tablet could be swallowed with saliva as it was disintegrated, and the time was recorded.

Loss-on-drying Value

For loss-on-drying value of powder, granule, etc., about 2 g of sample was taken and evenly spread onto an aluminum plate, and the loss-on-drying was measured for several to several tens of minutes by using an MA100 LOD meter (Sartorius). When there was no change in value, the test was set to be automatically over.

For loss-on-drying value of tablet, a sample corresponding to about 2 g was taken and placed on an aluminum plate, and its loss-on-drying was measured with the same method as for powder or granule.

For loss-on-drying value of crushed tablet, a tablet corresponding to about 2 g was taken and then crushed in a mortar. Its loss-on-drying was then measured with the same method as for powder or granule.

Content Uniformity

The tablets obtained in the following Examples and Comparative Examples were tested according to a content uniformity test method described in the chapter “Uniformity of Dosage Units” of the Korean Pharmacopoeia. One tablet of medicine being tested was admixed into 5 ml of a mobile phase to complete disintegration, and then the resulting liquid was centrifuged and the supernatant was filtered with a membrane filter having a pore size of 0.45 μm. About 2 ml of the first filtrate was discarded and the next filtrate was taken as a test liquid. 10 μl of the test liquid was tested according to a liquid chromatography test method among general test methods described in the Korean Pharmacopoeia by using an appropriate column and flow rate, and detected at a wavelength of 254 nm. The mobile phase was prepared as follows: a diluted phosphoric acid was added to 0.05 mol/L of potassium dihydrogen phosphate to adjust pH to 4.0, and 100 ml of ethanol and 100 ml of tetrahydrofuran were added to 800 ml of the liquid.

Example 1

(1) Preparation of slightly wetted granules

106.6 g of spray-dried mannitol (Mannogem™ EZ, SPI), 2.8 g of corn starch and 2.8 g of fructose were added to a 1 L container of a high-speed mixer, and 31.3 g of 50% (w/w) sucrose (Samyang Corporation) solution (ethanol:water = 4:6 (w:w)) was added thereto and kneaded with rotational mixing at an impeller speed of 150 rpm and a chopper speed of 1,700 rpm. After removal, the product was granulated by passing through a 30-mesh sieve (mesh size: 600 μm) and dried in a 50℃ oven for about 30 minutes. Drying time was appropriately controlled such that the final loss-on-drying of the final slightly wetted granules was about 1.5%. The final loss-on-drying of the dried slightly wetted granules was about 1.78%.

(2) Preparation of sufficiently dried granules

0.1 g of ramosetron HCl, 26.7 g of spray-dried mannitol (Mannogem™ EZ, SPI), 0.7 g of corn starch, 0.7 g of fructose, 0.85 g of red iron oxide and 0.85 g of yellow iron oxide were put into a plastic bag and then mixed well with shaking. 7.8 g of 50% (w/w) sucrose (Samyang Corporation) solution (ethanol:water = 4:6 (w:w)) was added thereto and manually kneaded. The product was granulated by passing through a 30-mesh sieve (mesh size: 600 μm), and dried in a 40℃ oven for about 2 hours, and dried again to obtain a sufficiently dried granules. The final loss-on-drying of the sufficiently dried granules was 0.90%.

(3) Preparation of fast-disintegrating tablet

128.3 g of the prepared slightly wetted granules, 33.8 g of the prepared sufficiently dried granules, 5.1 g of low-substituted hydroxypropyl cellulose (L-HPC) and 2.55 g of sodium stearyl fumarate (Pruv^®) were admixed, and then tableted by a single-punch tablet press (EK-0, Korsch) such that the fast-disintegrating tablet was 8.5 mm in diameter and weighed 170 mg. Immediately after tableting, tablet hardness was about 1.4 Kp. After completion of tableting, the product was held at room temperature (about 25℃, 10-30% RH) for 2 days and then packaged. Physical properties of the packaged tablet were as follows: hardness, 4.1 Kp; friability, 0.41%; disintegration time in water, 20.5 seconds; disintegration time in the oral cavity, 18 seconds; loss-on-drying value of the tablet, 0.88%; loss-on-drying value of the crushed tablet, 0.98%. The content uniformity of the tablet was 3.6% as determined in accordance with a content uniformity test method among general test methods described in the Korean Pharmacopoeia, and the value satisfied the criteria (determined as being uniform when the determination value is within 15%. Formula: determination value (%) = absolute value of [100-average content %] + 2.2 × standard deviation).

Example 2

(1) Preparation of slightly wetted granules

297 g of spray-dried mannitol (Mannogem™ EZ, SPI) and 15.5 g of lactose (Pharmatose 200M) were added to a 3 L high-speed mixer, and 57.3 g of 50% (w/w) sucrose (Samyang Corporation) solution (ethanol:water = 4:6 (w:w)) was added thereto and kneaded with rotational mixing at an impeller speed of 150 rpm and a chopper speed of 1,700 rpm. After removal, the product was granulated by passing through a 30-mesh sieve (mesh size: 600 μm) and dried in a 50℃ oven for about 50 minutes. Drying time was appropriately controlled such that the final loss-on-drying of the final slightly wetted granules was about 1.0%. The final loss-on-drying of the dried slightly wetted granules was about 1.01%.

(2) Preparation of sufficiently dried granules

0.235 g of ramosetron HCl, 66.2 g of spray-dried mannitol (Mannogem™ EZ, SPI) and 3.47 g of lactose were put into a plastic bag and then mixed well with shaking. 12.7 g of 50% (w/w) sucrose (Samyang Corporation) solution (ethanol:water = 4:6(w:w)) in which 0.5 g of red iron oxide, 0.5 g of yellow iron oxide and 0.76 g of acesulfame potassium were dissolved or dispersed, was added thereto and manually kneaded. The product was granulated by passing through a 30-mesh sieve (mesh size: 600 μm), and dried in a 40℃ oven for about 2 hours, and dried again to obtain a sufficiently dried granules. The final loss-on-drying of the sufficiently dried granules was 0.51%.

(3) Preparation of fast-disintegrating tablet

284.9 g of the prepared slightly wetted granules, 72.2 g of the prepared sufficiently dried granules, 11.2 g of low-substituted hydroxypropyl cellulose (L-HPC) and 5.61 g of calcium stearate were admixed, and then tableted by a single-punch tablet press (EK-0, Korsch) such that the fast-disintegrating tablet was 8.5 mm in diameter and weighed 170 mg. Immediately after tableting, tablet hardness was about 1.4 Kp. After completion of tableting, the product was held at room temperature (about 25℃, 10-30% RH) for 2 days and then packaged. Physical properties of the packaged tablet were as follows: hardness, 4.3 Kp; friability, 0.27%; disintegration time in water, 18 seconds; disintegration time in the oral cavity, 15 seconds; loss-on-drying value of the tablet, 0.21%; loss-on-drying value of the crushed tablet, 0.45%. The content uniformity of the tablet was 3.4% as determined in accordance with a content uniformity test method among general test methods described in the Korean Pharmacopoeia, and the value satisfied the criteria.

Comparative Example 1

0.08 g of ramosetron HCl, 104.4 g of spray-dried mannitol (Mannogem™ EZ, SPI), 2.74 g of corn starch and 2.74 g of fructose were added to a 1 L high-speed mixer, and 30.7 g of 50% (w/w) sucrose (Samyang Corporation) solution (ethanol:water = 4:6 (w:w)) was added thereto and kneaded with rotational mixing at an impeller speed of 150 rpm and a chopper speed of 1,700 rpm. After removal, the product was granulated by passing through a 30-mesh sieve (mesh size: 600 μm) and dried in a 50℃ oven for about 30 minutes. Drying time was appropriately controlled such that the final loss-on-drying value of the final slightly wetted granules was about 1.5%. The final loss-on-drying value of the dried slightly wetted granules was about 1.72%.

117 g of the prepared slightly wetted granules, 1.265 g of yellow iron oxide, 3.8 g of low-substituted hydroxypropyl cellulose (L-HPC) and 1.89 g of Pruv^® were admixed, and then tableted by a single-punch tablet press (EK-0, Korsch) such that the fast-disintegrating tablet was 8.5 mm in diameter and weighed 170 mg. Immediately after tableting, tablet hardness was about 1.4 Kp. After the tableting was partly performed, it was observed that the product stuck to the punch and its shape was not intact. Though tableting proceeded after wiping the punch, the phenomenon repeated after several tens of tablets were manufactured.

Claims

A fast-disintegrating tablet comprising:

50 to 99% by weight of slightly wetted granules comprising a spray-dried mannitol and a sucrose binder, and having 1.05- to 5-times greater loss-on-drying than sufficiently dried granules; and

1 to 50% by weight of sufficiently dried granules comprising a spray-dried mannitol and a sucrose binder.
The fast-disintegrating tablet according to Claim 1, wherein at least one of the slightly wetted granules and the sufficiently dried granules further comprise a dry binder.
The fast-disintegrating tablet according to Claim 2, wherein the dry binder is selected from the group consisting of saccharide, sugar alcohol, starch, polysaccharide, cellulose derivative and a mixture thereof.
The fast-disintegrating tablet according to Claim 1, wherein the slightly wetted granules comprise the spray-dried mannitol in an amount of 20 to 98% by weight, based on 100% by weight of the slightly wetted granules.
The fast-disintegrating tablet according to Claim 1, wherein the slightly wetted granules comprise the sucrose binder in an amount of 1 to 50 parts by weight as a dried sucrose, based on 100 parts by weight of spray-dried mannitol.
The fast-disintegrating tablet according to Claim 2, wherein the dry binder is comprised in an amount of 50 or less parts by weight, based on 100 parts by weight of spray-dried mannitol.
The fast-disintegrating tablet according to Claim 1, characterized in that the tablet has one or more of the following properties (1) to (5):

(1) Hardness: 2.5Kp or more

(2) Friability: 1.0% or less

(3) Disintegration time in water: 2 minutes or less

(4) Disintegration time in the oral cavity: 40 seconds or less

(5) Content uniformity: 95 to 105% based on the labeled content.
The fast-disintegrating tablet according to any one of Claims 1 to 7, which further comprises an active ingredient.
The fast-disintegrating tablet according to Claim 8, wherein the active ingredient is contained in the sufficiently dried granules.
A process for manufacturing a fast-disintegrating tablet comprising the steps of:

preparing slightly wetted granules comprising a spray-dried mannitol and a sucrose binder, and having 1.05- to 5-times greater loss-on-drying than sufficiently dried granules; and sufficiently dried granules comprising a spray-dried mannitol and a sucrose binder, respectively;

forming a post-granulation mixture for tableting comprising the slightly wetted granules and the sufficiently dried granules;

compressing the post-granulation mixture for tableting to obtain a tablet; and

drying the tablet.
The process for manufacturing a fast-disintegrating tablet according to Claim 10, wherein the post-granulation mixture for tableting is compressed under a pressure of 150 Mpa or less to obtain a tablet.
The process for manufacturing a fast-disintegrating tablet according to Claim 10, wherein the step of drying is conducted:

under the condition of temperature of 20℃ to 30℃ and relative humidity of 40% or less;

in a 20℃- to 50℃-convection oven;

by providing dry air; or

by using a dehumidifier or dehumidifying agent.