HK1167324B - Dry-coated orally-disintegrating tablet - Google Patents

Description

Compression coated orally disintegrating tablets

Technical Field

The present invention relates to a press-coated formulation (hereinafter, also referred to as a press-coated orally disintegrating tablet), wherein the core thereof is a powder/granular material having poor formability (formability); an outer layer of which surrounds the inner core; and its compressed tablet has suitable hardness and excellent disintegrability in the oral cavity.

Specifically, the present invention relates to a press-coated orally disintegrating tablet characterized in that its outer layer is rapidly disintegrated even when the tablet is taken with a small amount of water or without water, and then the granules or powder in its inner core are dispersed in the oral cavity.

Background

With the advent of an aging society, the development of orally disintegrating tablets which can be easily taken by elderly people who have difficulty or difficulty swallowing tablets has been progressing. For this development, there is an increasing demand for the development of orally disintegrating tablets containing various active ingredients. In the case where the active ingredient has a bitter taste, masking of the bitter taste will be necessary for formulating it into an orally disintegrating tablet or the like. Furthermore, controlled release of the active ingredient may be necessary to improve the bioavailability of the active ingredient. However, many of the above-mentioned functional particles tend to bring some adverse effects to tablet formulations (for example, they lack sufficient hardness when uniformly distributed in a tablet), and therefore, a large amount of additives such as excipients and binders must be added to avoid the adverse effects, which makes the tablet inconveniently large in size.

Patent reference 1 discloses a press-coated rapidly disintegrating tablet in a unique form not previously known. Compression-coated tablets have a double-layered structure consisting of an inner core and an outer layer, and are attracting attention as a new technique for formulating tablets. However, the press-coated formulation disclosed in patent reference 1 is designed to focus on the solubility and degradability of the inner core, and the ingredients of both the inner core and the outer layer contain ingredients having formability (for example, the ingredients of the inner core in patent reference 1 seem to have formability and a certain hardness, as recognized in the results of example 2, in which only the ingredients of the inner core are pressed into tablets). Therefore, no application route using a powder/particle material having poor formability has been attempted, and therefore, patent reference 1 discloses only a limited range of core ingredients. Moreover, the outer layer of the compression-coated tablet disclosed in patent reference 1 mainly contains erythritol as a sugar alcohol, and the combination of essential components of the outer layer of the present invention is not disclosed.

Patent reference 2 discloses an experiment in which microcapsule-like particles are applied to the inner core component of the formulation in the above-mentioned patent reference 1. That is, patent reference 2 discloses studies on application of microcapsule-like granules to the inner core of a press-coated tablet, and some successful examples of press-coated formulations containing microcapsule-like granules in their inner core, which are prepared according to a certain method using an outer layer comprising lactose and microcrystalline cellulose. However, patent reference 2 discloses only an invention of a compression-coated tablet containing microcapsule-like particles in its inner core, and it does not disclose or suggest any study of applying the compression-coated tablet to an orally disintegrating tablet. In addition, in patent reference 2, there is no study on applicable ingredients of the outer layer in a press-coated formulation containing microcapsule-like granules in their inner core, except lactose and microcrystalline cellulose. Of course, patent reference 2 does not disclose the combination of the essential components of the outer layer of the present invention.

The orally disintegrating tablet in patent reference 3 is characterized by containing an active ingredient, microcrystalline cellulose and an inorganic excipient, without any disintegrant. Also, as described therein, the orally disintegrating tablet of patent reference 3 has higher hardness and more excellent degradability shortly after compression as compared with those of the orally disintegrating tablet containing crospovidone and low-substituted hydroxypropylcellulose (for example, example 5 and comparative examples 5 to 9). Moreover, patent reference 3 describes "because the disintegrant has the following side effects: the present invention, which does not contain any disintegrant, is advantageous in that it reduces the tablet quality by reducing the tablet hardness, causes roughness on the tablet surface due to their moisture absorption, and aggravates the dry mouth feeling of the tablet in the oral cavity due to their absorption of saliva. Patent reference 3 is also lacking in disclosure and suggestion regarding the press-coated formulations disclosed in the above patent references 1 and 2.

Patent reference 4 discloses an orally disintegrating tablet containing an inorganic excipient, but does not describe specific disclosure regarding a press-coated formulation.

[ patent reference 1] WO2003/028706

[ patent reference 2] WO2005/097041

[ patent reference 3] WO2005/123040

[ patent reference 4] WO 2007/018192.

Disclosure of Invention

(problems to be solved by the invention)

As described above, in order to develop an orally disintegrating tablet, various functional ingredients/particles are generally used in a tablet. However, when the functional ingredient/particles used have an adverse effect on the tablet formability, some improvement must be made because additional additives are required to minimize the adverse effect, thereby enlarging the tablet.

On the other hand, the compression-coated tablets disclosed in patent references 1 and 2 are of interest as a new tablet technology, and in particular, patent reference 2 discloses an example of a formulation containing microcapsule-like particles in an inner core, and thus the formulation is expected to be applied to some functional formulations such as orally disintegrating tablets. However, the compression-coated tablets, the outer layer of which is similar to that of the formulation disclosed in patent reference 2, have significantly poor oral disintegration (see, comparative examples 1 to 3 of the present invention). We have also found that when a press-coated tablet containing particles having no formability is produced using the outer layer disclosed in patent reference 1, which relates to a press-coated tablet subjected to rapid disintegration, a sufficient hardness cannot be obtained (see, comparative examples 1 to 4 of the present invention).

As described above, in order to produce a press-coated tablet having a two-layer structure comprising an inner core and an outer layer, particularly a tablet comprising particles having no formability in the inner core thereof, it is necessary to maintain the tablet hardness using only the outer layer thereof, and thus the outer layer of the tablet needs to be harder than a normal tablet. On the other hand, in order to prepare an orally disintegrating tablet, it is necessary to reduce the hardness thereof to obtain rapid degradability thereof. Thus, it is difficult to maintain such a strong hardness for a compression-coated tablet having orally disintegrating properties.

An object of the present invention is to newly develop a press-coated formulation characterized in that its inner core contains a powder/granular material having poor formability and to provide a press-coated orally disintegrating tablet having excellent disintegration properties and suitable hardness as a whole tablet.

(means for solving the problems)

In general, it is difficult to make a tablet containing a large amount of particles (e.g., functional particles) having poor formability or active ingredient powder, and therefore, the present inventors tried to prepare a tablet in which an inner core thereof contains such particles or such powder and an outer layer thereof surrounds the inner core. In preparing such press-coated tablets containing the powder/granular material having poor formability as described above, it is very difficult to obtain a suitable hardness of the whole tablet while maintaining oral disintegratability. However, the present inventors have conducted extensive studies and, thereafter, have found that the above-mentioned problems can be solved by using a combination of specific ingredients in the outer layer. That is, the present inventors have found that a press-coated orally disintegrating tablet can be prepared having an outer layer surrounding an inner core thereof, wherein the inner core comprises a powder/particle material having poor formability; the outer layer comprises microcrystalline cellulose, inorganic excipients, and specific ingredients as described below; and the compressed tablet has suitable hardness and disintegration as a whole tablet. In more detail, the present invention provides a press-coated orally disintegrating tablet, wherein the thickness of the inner core is 10 to 90% of the entire thickness of the tablet, and the outer layer comprises (a) microcrystalline cellulose, (b) inorganic excipients, and (c) one or more specific ingredients selected from crospovidone, starch, low-substituted hydroxypropylcellulose, and carboxymethylcellulose (carmellose), and the compressed tablet has sufficient hardness and excellent disintegration in the oral cavity, even when the inner core has poor formability.

The present invention provides inventions of various embodiments described below.

First, the 1 Item(s)

A press-coated orally disintegrating tablet having an outer layer surrounding an inner core, wherein

The inner core has a thickness of 10 to 90% of the thickness of the entire sheet, and

the outer layer comprises (a) microcrystalline cellulose, (b) inorganic excipients, and (c) one or more specific ingredients selected from the group consisting of crospovidone, starch, low-substituted hydroxypropyl cellulose, and carboxymethylcellulose.

First, the 2 Item(s)

The press-coated orally disintegrating tablet of item 1, wherein said inner core is a powder/granular material having poor formability.

First, the 3 Item(s)

The press-coated orally disintegrating tablet of item 1 or 2, wherein said microcrystalline cellulose (a) accounts for 5 to 80 wt% based on 100 wt% of said outer layer.

First, the 4 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 3, wherein said inorganic excipient (b) accounts for 10 to 80 wt% based on 100 wt% of said outer layer.

First, the 5 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 4, wherein the total amount of the specific ingredient (c) is 1 to 40 wt% based on 100 wt% of the outer layer.

First, the 6 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 5, wherein the specific ingredient (c) is one or more selected from crospovidone, starch and low-substituted hydroxypropylcellulose.

First, the 7 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 6, wherein said starch is corn starch.

First, the 8 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 7, wherein said inner core has a thickness of 20 to 80% of the thickness of the entire tablet.

First, the 9 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 8, wherein the porosity in the outer layer is from 1 to 40%.

First, the 10 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 9, wherein the inner core comprises an active ingredient.

First, the 11 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 10, wherein said microcrystalline cellulose (a) accounts for 10 to 70 wt% based on 100 wt% of said outer layer.

First, the 12 Item(s)

The press-coated orally disintegrating tablet of any one of items 1 to 11, wherein the inner core comprises a powder, a granular material (granulated material) or a powder/granular material (powder/granulated material) having poor formability in addition to microcapsule-like functional particles.

(effect of the invention)

The present invention can provide a press-coated orally disintegrating tablet containing a large amount of powder/granular material having poor formability in its core, which has excellent disintegration properties and suitable hardness as a whole tablet.

Detailed Description

The press-coated orally disintegrating tablet of the present invention is composed of an "inner core" containing a powder/granular material having poor formability such as microcapsule-like functional particles and an "outer layer" surrounding the inner core to impart suitable hardness and disintegratability to the formed tablet. Also, the present invention may apply a powder, a granular material or a powder/granular material having poor formability in the inner core thereof in addition to the microcapsule-like functional particles to provide a tablet having sufficient hardness and disintegration.

In the present invention, the "outer layer" comprises (a) microcrystalline cellulose, (b) inorganic excipients, and (c) one or more specific ingredients selected from crospovidone, starch, low-substituted hydroxypropylcellulose, and carboxymethylcellulose. With the combination of these ingredients, it becomes possible to prepare a press-coated orally disintegrating tablet having sufficient hardness and excellent disintegratability even when the inner core therein has poor formability.

The term "orally disintegrating tablet" refers to a tablet that rapidly disintegrates in the oral cavity in the absence of water. In detail, it refers to a tablet whose inner core and outer layer disintegrate or disperse within 60 seconds, preferably within 45 seconds, or even more preferably within 30 seconds, when the actual disintegration test is performed in the human mouth or in a device. Devices for disintegration testing include, for example, ODT-101 (manufactured by toyama sangyo co., ltd.). In an actual disintegration test in the human oral cavity, the time from putting a tablet into the oral cavity to completion of oral disintegration was measured as an oral disintegration time. After the test, the recipient removes the test sample from their mouth and rinses their mouth with clear water.

The hardness of the tablet of the present invention was given by measuring the force required to crush the tablet in the diametrical direction using a tablet hardness meter (PORTABLE CHECKER PC-30, manufactured by Okada Seiko co. The "absolute hardness" was calculated according to the following formula using the obtained tablet hardness. The "absolute hardness" is a value obtained by dividing the hardness measured with a tablet hardness meter by the longitudinal sectional area (tablet diameter (mm) × tablet thickness (mm)).

Absolute hardness (N/mm)²) Hardness (N)/longitudinal cross-sectional area (mm)²)

In the present invention, the term "having suitable hardness and disintegratability" as used herein means that the balance of absolute hardness and oral disintegration time is good. The term "HDBI" as used herein is an abbreviation for hardness and disintegration balance index, and is calculated as an index of the balance of absolute hardness and oral disintegration time according to the following formula. The larger the value is, the more excellent the balance between hardness and disintegratability is. In detail, the orally disintegrating tablet of the present invention has an HDBI value of 0.15 or more, preferably 0.2 or more, more preferably 0.25 or more, and even more preferably 0.3 or more.

HDBI(N/mm²Sec) = absolute hardness (N/mm)²) Oral disintegration time (sec)

In the present invention, the "wide acceptable compression force range" means that the range of compression force is wide during tabletting (tableting) in preparing an orally disintegrating tablet having suitable hardness and disintegratability, i.e., it is possible to cause extremely small variations in hardness and disintegratability at different compression forces. If the range of compression forces is narrow in preparing an orally disintegrating tablet, it may be necessary to change the compression force of each tablet, or to change the compression force again during the compression process. In addition, there is a fear that the product cannot achieve a good balance of hardness and disintegratability. Therefore, in view of industrial production of tablets, it is important to design a formulation having a wide acceptable compression force, that is, little variation in hardness and disintegration even when the compression force is changed.

In a press-coated orally disintegrating tablet comprising a poorly formable inner core, the hardness and the disintegration are dependent only on the formulation of the outer layer, and thus it is difficult to achieve a good balance of hardness and disintegration as compared with a single-layered orally disintegrating tablet (a general orally disintegrating tablet) or a press-coated orally disintegrating tablet comprising a formable inner core. Even if a good balance between hardness and disintegration is achieved, it is quite difficult to control the compression force within a wide acceptable range.

In general, the porosity ratio can be calculated according to the following formula

Porosity (%) of tablet = (1-Wt/(ρ × V)) × 100

ρ true density of tablet (mg/mm)³),

V volume of tablet (mm)³),

Wt: weight of tablet (mg).

In the present invention, the porosity of the outer layer can be calculated according to the following formula

Porosity (%) of outer layer = (1-Wt/(ρ × 3.14.14 3.14 × D)²×T))×100

ρ true density of the outer layer (mg/mm)³),

D, the radius (mm) of the outer layer (lower part),

t is the thickness (mm) of the outer layer (lower part),

wt: weight of outer layer (lower) (mg).

In the present invention, the thickness of the inner core is calculated as follows. The thickness of the entire sheet was measured by a digital caliper (Mitutoyo co., ltd. The press-coated tablets were divided diametrically, the cross-sectional surface was analyzed using a digital microscope (VHX-500, manufactured by Keyence co., ltd.), and the thicknesses of the upper and lower portions of the outer layer were measured.

Thickness of inner core (mm) = thickness of entire sheet (mm) -sum of thicknesses of upper and lower portions of outer layer (mm)

In the present invention, the term "proportion of the thickness of the inner core" refers to the proportion of the thickness of the inner core to the thickness of the entire tablet, i.e., the proportion of the thickness of the inner core in the cross-sectional area parallel to the side faces of the tablet. In the case where the proportion of the core thickness depends on the separation position, the highest proportion in the entire cross-sectional surface is defined as "proportion of the core thickness".

Ratio of core thickness (%) = thickness of core (mm)/thickness of entire sheet (mm) × 100

In the present invention, it is preferable to decrease the porosity of the outer layer to increase the hardness, compared to a general tablet without the inner core. The porosity of the outer core is generally from 1 to 40%, preferably from 1 to 30%.

The invention is further elucidated below.

(1) Outer layer

(a) Microcrystalline cellulose

The microcrystalline cellulose used herein as an essential component of the outer layer is not limited to any particular microcrystalline cellulose as long as it can be orally administered. From the viewpoint of oral sensation, the preferable average particle size of the microcrystalline cellulose used as a starting material is 150 μm or less, more preferably 130 μm or less, even more preferably 120 μm or less, because a preparation prepared by using microcrystalline cellulose having a large average particle size is orally disintegrated after the oral cavityA feeling of sand is produced in the cavity. The content of microcrystalline cellulose used herein is generally 5 to 80 wt%, preferably 9 to 70 wt%, more preferably 20 to 50 wt% of the total weight of the outer layer in terms of hardness, disintegration time and acceptable compression force range. Examples of microcrystalline cellulose for use herein include CEOLUS^TM(PH-101, PH-102, PH-301, PH-302, PH-F20J, KG-800, KG-1000, ST-02: manufactured by Asahi Kasei Chemicals Co., Ltd.), and AVICEL^TM(PH-101, PH-102, PH-301, PH-302, FD-101, FD-301, FD-F20: manufactured by FMC BioPolymer Co., Ltd.). The microcrystalline cellulose used herein may be any one of them or a combination of two or more of them.

(b) Inorganic excipient

Inorganic excipients useful herein as an essential component of the outer layer include dibasic calcium phosphate, magnesium carbonate, magnesium silicate, magnesium hydroxide, dry aluminum hydroxide gel, magnesium oxide, synthetic aluminum silicate, synthetic hydrotalcite, sodium bicarbonate, magnesium aluminum metasilicate (magnesium metasilicate), magnesium aluminum silicate, calcium carbonate, precipitated calcium carbonate, talc, magnesium aluminum oxide hydrate (magnesium hydroxide), calcium silicate, mixed gels of dry aluminum hydroxide and magnesium carbonate, coprecipitates of aluminum hydroxide and sodium bicarbonate, aluminum hydroxide, coprecipitates of calcium carbonate and magnesium carbonate, and coprecipitates of aluminum hydroxide and potassium aluminum sulfate. Preferably, the inorganic excipients used herein include dibasic calcium phosphate, magnesium carbonate, magnesium silicate, magnesium hydroxide, dry aluminum hydroxide gel, magnesium oxide, synthetic aluminum silicate, synthetic hydrotalcite and sodium bicarbonate, more preferably dibasic calcium phosphate, magnesium carbonate, magnesium silicate, magnesium hydroxide, dry aluminum hydroxide gel, magnesium oxide and synthetic aluminum silicate, even more preferably dibasic calcium phosphate, magnesium silicate, dry aluminum hydroxide gel, magnesium oxide, synthetic aluminum silicate. The most preferred inorganic excipients among the above are calcium hydrogenphosphates, particularly calcium hydrogenphosphate (dicalcium phosphate), anhydrous calcium hydrogenphosphate (dicalcium phosphate anhydrous) and monocalcium phosphate (monocalcium phosphate). The inorganic excipient used herein may be any one or a combination of two or more thereof. The amount of the inorganic excipient used herein is generally 10 to 80 wt%, preferably 20 to 80 wt%, more preferably 30 to 60 wt% of the total weight of the outer layer in terms of hardness, disintegration time and an acceptable range of compressive force.

(c) Specific component

The specific ingredient, which is an essential ingredient of the outer layer of the present invention, is characterized by using at least one ingredient selected from the group consisting of crospovidone, starch, low-substituted hydroxypropylcellulose, and carboxymethylcellulose. A press-coated orally disintegrating tablet not containing the specific ingredient (described below) or a press-coated orally disintegrating tablet containing an ingredient that increases the disintegratability different from the specific ingredient described above cannot have the desired effect because the porosity of the outer layer of the press-coated orally disintegrating tablet needs to be reduced in order to increase the hardness of the outer layer as compared with a normal tablet having no inner core. Instead, we have found that the desired effect can be achieved when the outer layer comprises the specified ingredients in combination with microcrystalline cellulose and inorganic excipients.

(c-1) Crospovidone

Crospovidone used herein is not particularly limited, but in general crospovidone conforming to the japanese pharmacopoeia (japanese pharmacopoeia) may be used herein. From the aspect of oral sensation, the preferred average particle size of crospovidone used as the starting material is, but not limited to, preferably 10 to 200 μm, more preferably 10 to 150 μm, and even more preferably 10 to 100 μm, because a formulation prepared by using crospovidone having a large average particle size produces a feeling of sand in the oral cavity after oral disintegration. To obtain the desired particle size, the crospovidone may optionally be milled using, for example, a jet mill or hammer mill. The content of crospovidone used in the outer layer is generally 1 to 40 wt%, preferably 1 to 30 wt%, more preferably 1 to 20 wt%, even more preferably 1 to 10 wt%, most preferably 1 to 5 wt% of the total weight of the outer layer in terms of hardness, disintegration time and acceptable compression force range.

(c-2) Starch

Starch as used herein may include corn starch, potato starch, rice starch, wheat starch, sweet potato starch, mung bean starch, tapioca starch, and partially pregelatinized starch, preferably corn starch. In the present invention, fully pregelatinized starch cannot be used due to its poor disintegration. These starches used herein may be any one of them or a combination of two or more of them. From the viewpoint of oral sensation, the average particle size of the starch is, but not limited to, preferably 10 to 200 μm, more preferably 10 to 100 μm, and even more preferably 10 to 50 μm, because a formulation prepared by using starch of large average particle size produces a sandy feeling in the cavity after oral disintegration. To obtain the desired particle size, the starch may optionally be milled, for example, with a jet mill or hammer mill. The content of starch is 1 to 40 wt% of the total weight of the outer layer in terms of hardness, disintegration time and acceptable compression force range. Too high a starch content results in reduced flowability and poor press productivity. Thus, the starch is typically present in an amount of 1 to 40 wt%, preferably 1 to 30 wt%, more preferably 1 to 20 wt%, even more preferably 1 to 10 wt%, most preferably 1 to 5 wt% of the total weight of the outer layer.

(c-3) Low-substituted hydroxypropyl cellulose (L-HPC)

The degree of substitution in the low-substituted hydroxypropylcellulose of the invention is not limited as long as it conforms to the japanese pharmacopoeia, and generally the degree of substitution is 7.0 to 12.9%. From the viewpoint of oral sensation, the average particle size of the low-substituted hydroxypropylcellulose used as a starting material is, but not limited to, preferably 10 to 200 μm, more preferably 10 to 150 μm, even more preferably 10 to 100 μm, because a formulation prepared by using a low-substituted hydroxypropylcellulose having a large average particle size produces a sandy granular sensation in the oral cavity after oral disintegration. To obtain the desired particle size, the low-substituted hydroxypropylcellulose can be optionally milled using, for example, a jet mill or a hammer mill. The content of the low-substituted hydroxypropylcellulose used in the outer layer is usually 1 to 40 wt%, preferably 1 to 30 wt%, more preferably 1 to 20 wt%, even more preferably 1 to 10 wt%, most preferably 1 to 5 wt% of the total weight of the outer layer in terms of hardness, disintegration time, and acceptable compression force range.

(c-4) Carboxymethyl cellulose (CMC)

The carmellose used herein is not particularly limited, but carmellose conforming to the japanese pharmacopoeia may be used herein. From the viewpoint of oral sensation, the average particle size of carboxymethylcellulose used as a starting material is, but not limited to, preferably 10 to 200 μm, more preferably 10 to 150 μm, even more preferably 10 to 100 μm, because a formulation prepared by using carboxymethylcellulose of a large average particle size produces a sandy granular sensation in the oral cavity after oral disintegration. To obtain the desired particle size, the carboxymethylcellulose can optionally be milled using, for example, a jet mill or hammer mill. The content of carboxymethylcellulose used in the outer layer is 1 to 40 wt%, preferably 1 to 30 wt%, more preferably 1 to 20 wt%, even more preferably 1 to 10 wt%, most preferably 1 to 5 wt% of the total weight of the outer layer in terms of hardness, disintegration time and acceptable compression force range.

Among the above specific ingredients, preferred examples thereof include crospovidone, starch, and low-substituted hydroxypropylcellulose; more preferably crospovidone and starch; and even more preferably crospovidone and corn starch. The most preferable example of the specific ingredient is crospovidone in terms of balance of hardness and disintegratability. The amount of the specific ingredient or the total amount of the specific ingredient used herein is generally 2 to 40 wt%, preferably 2 to 30 wt%, more preferably 2 to 20 wt%, even more preferably 2 to 10 wt%, most preferably 2 to 5 wt% of the total weight of the outer layer in terms of hardness, disintegration time and acceptable compression force range.

Additional formulation ingredients

In addition to the above-mentioned ingredients, additional formulation ingredients may be added to the outer layer of the orally disintegrating tablet of the present invention. With respect to the "additional formulation ingredients" in the present invention, any formulation ingredients may be used herein as long as the ingredients have no or little influence on the hardness and disintegration time of the tablet and do not cause any problem to the formulation. Examples of additional ingredients used herein include other fillers, disintegrants, binders, sweeteners, taste/odor correctors, stabilizers, surfactants, fluidizing agents (fluidizing agents), antistatic agents, coating agents, lubricants, colorants, flavors, and the like. The content of said "additional formulation ingredients" is 0.01 to 25 wt% of the total weight of the outer layer, and the content of each of the above-mentioned essential ingredients is reduced corresponding to the amount of these additional ingredients in the tablet.

Lubricant agent

In the present invention, it is preferable that the tablet contains the lubricant among the above-mentioned additional formulation components in its outer layer. Examples of lubricants include stearic acid, metal stearates, sodium stearyl fumarate, sucrose esters of fatty acids, talc, hydrogenated oils, and macrogols. Examples of the metal stearate include magnesium stearate, calcium stearate, aluminum stearate and the like, and among the lubricants, stearic acid, metal stearate, particularly magnesium stearate, are preferable. The average particle size of the lubricant prior to the formulation process is 0.5 to 50 μm, preferably 1 to 30 μm. The amount of lubricant is generally from 0.01 to 2.5 wt%, preferably from 0.01 to 2 wt%, even more preferably from 0.01 to 1 wt%, of the total weight of the outer layer. In the present invention, the lubricant may be added to the formulation by an external lubrication method or an internal lubrication method.

(2) Inner core

In the present invention, the inner core is not particularly limited as long as the inner core has good oral disintegration and dispersibility. The outer layer of the present invention can impart sufficient hardness to the entire tablet even when the inner core of the tablet is poorly formable, and thus, the present invention is effective for a tablet comprising an inner core containing "powder/granular material with poor formability". "powder/granular material with poor formability" means a powder/granular material containing a powder and/or a granular material with poor formability, which also means that it is impossible to obtain a pressed substance, or a pressed substance with extremely low hardness is obtained, even if pressing succeeds. In detail, it means that when a substance (50 mg) is compressed into a tablet (diameter 6 mm) at a pressure of 4 kN, it is impossible to obtain a compressed substance, or a compressed substance having an extremely low hardness (10N or less) is obtained, even if the compression is successful. The average particle size of the "powder/particulate material having poor formability" used herein is, but not limited to, generally 3 mm or less, preferably 1 mm or less, even more preferably 300 μm or less, most preferably 150 μm or less, in terms of oral sensation. In the present invention, it is preferred that the inner core comprises an active ingredient, for example comprising functional particles (such as caplets and coated granules) comprising an active ingredient; an active ingredient powder; or mixed powders or granular materials prepared by adding additives to the functional particles (such as caplets and coated granules) containing the active ingredient or active ingredient powder to improve flowability, dispersibility and adhesiveness.

The granular material may be prepared by fluid bed granulation, extrusion, dry compression and granulation, roto-granulation (roto-granulation method), rotary fluid bed granulation, high speed mixer granulation, and crushing granulation (crushing granulation method).

Functional particles comprising an active ingredient can be prepared according to the methods described in, for example, JP 3(1991) -130214A, JP 2007-63263A, WO 2005/055989 and JP 2002-332226A. In detail, the small capsules among the functional particles include, for example, microcapsules in a broad sense of the term, such as microcapsules, seamless capsules (seamlesscapsules), mini soft capsules, and microspheres.

The coated particles in the functional particles include, for example, polymer-coated particles, wax-coated particles, and sugar-coated particles. It also includes particles that may be inactivated by high pressure tableting, such as enzyme-containing granulates. The above-mentioned various coated particles include, for example, granules prepared by coating granular particles with a coating layer, granules containing a core in their granular particles, and granules obtained by coating granules containing a core in their granular particles; it is designed to improve sustained release, enteric solubility, gastric solubility, heat resistance, light resistance, stability or bitterness. In the present invention, the term "coated" or "coating" includes coating the entire surface or a part of the surface of the active ingredient with a coating material. As the apparatus for the coating, there can be mentioned a general fluid bed granulator (including a rotary fluid bed granulator, Wurster fluid bed granulator, etc.); in order to suppress the particle enlargement (coarsening) in the step, a modified Wurster fluidized bed granulator (e.g., SPC, manufactured by POWREX CORPORATION, etc.) equipped with a device for forced circulation from the side is preferable, a hybrid fluidized bed granulator (e.g., ultrafine particle coating and granulating processor SFP-01, manufactured by POWREX CORPORATION, etc.) equipped with a grinding mechanism (screen impeller type, vane stator type, cross-screws, lump crushers, etc.), and a rotary fluidized bed granulator (e.g., omnitec, manufactured by NARA senior CORPORATION, ltd., etc.). As the means for spray drying, a general spray dryer (manufactured by OKAWARACORPORATION, manufactured by OHKAWARA KAKOKI co.

The core material for preparing the above-mentioned functional particles includes, for example, commercially available microcrystalline cellulose spheres, sucrose-starch spherical granules, purified sucrose spherical granules, lactose-crystalline cellulose spherical granules, D-mannitol, anhydrous dibasic calcium phosphate, magnesium oxide, magnesium hydroxide, and the like.

Active ingredient

The active ingredient used in the orally disintegrating tablet of the present invention is not particularly limited as long as the active ingredient functions as a pharmaceutical active ingredient for treating and preventing diseases and is orally administrable. The active ingredients include, for example, nutritional tonics (alimentaryorbents); antipyretic analgesic anti-inflammatory drugs (antipyrotic analgesic antiphlogitics); psychotherapeutic agents (psychotropic agents); hypnotics (hypnotics); antispasmodics (antinispassmodics); central nervous system acting drugs (centrainnervous system acting drugs); brain metabolism improving agents (cerebellometalalism improving agents); brain circulation improving agents (cerebellation improving agents); antiepileptics (antiepileptics); sympathomimetic agents (sympathomimics); digestants (digestants); antiulcer agents (antiulcer agents); prokinetic agents (prokinetic); antacids (antacids); antitussives (antitussives); anti-motility agents (anti-motility agents); antiemetics (antiemetics); respiratory stimulants (respiratory stimulants); bronchodilators (bronchodilators); anti-allergic agents (antiallergic agents); cardiotonic agents (cardioacs); antiarrhythmic agents (antiarrhythmics); diuretics (diuretics); vasoconstrictors (vasoconstrictors); coronary vasodilators (coronary vasodilators); vasodilators (vasodialators); peripheral vasodilators (peripheral vasodialators); antihyperlipidemic drugs (antihyperlipidemic drugs); choleretic drugs (choleogues); chemotherapeutic agents (chemotherapeutics); drugs for diabetic complications (drugs for diabetes compositions); osteoporosis treating drugs (osteoporotric treating drugs); antirheumatics (antirheumatics); skeletal muscle relaxants (skelestal muscle relaxants); gout suppressors (gout supressants); anticoagulants (anticoaglents); antitumor agents (antineoplastic agents), and the like. The active ingredient used herein may be in the form of a salt or a free form thereof, as long as it is pharmaceutically acceptable. Furthermore, it may be in the form of solvates such as alcoholates and hydrates. Further, the above active ingredients may be used alone or in combination of two or more kinds thereof.

When the inner core of the present invention contains an active ingredient, the content of the active ingredient in the inner core is, but not particularly limited to, 0.1 to 100 wt%, preferably 1 to 95 wt% of the total weight of the inner core. The "content of the active ingredient in the inner core" in the present invention is based on the form of the "pharmaceutically active ingredient" which is generally used as a drug, that is, in the case where the drug is in the form of a salt, it is based on the amount of the salt. Furthermore, the above active ingredients may be incorporated into the outer layer to the extent that they have no or minimal effect on the hardness and oral disintegration time of the final formulation.

(3) Preparation of compression coated orally disintegrating tablets

The press-coated orally disintegrating tablets of the present invention can be prepared using a known tablet press capable of preparing a press-coated formulation. A press-coated orally disintegrating tablet comprising a plurality of microcapsule-like functional particles in its inner core may be prepared using a tablet press for press-coating formulations disclosed in WO2005/097041 et al, or using a similar tablet press or method for preparing press-coated formulations having a poorly formable inner core.

The laboratory process of the present invention comprises the following:

the mixture of the above components (a) - (c) is placed in a die (die) whose diameter corresponds to the diameter of the desired inner core and the die is shaken gently to smooth the powder surface, which is the lower part of the outer layer. On this mixture, an appropriate amount of powder/granular material with poor formability as a core component was put, and the layered material was temporarily pressed at a relatively low pressure using a hand press machine. The temporarily compressed mass is placed concentrically on a punch (punch) with the lower part of the outer layer down, the diameter of the punch corresponding to the diameter of the final formulation. The die was placed over it and an appropriate amount of additional mixture of the above-described outer layer ingredients (for the side portions and upper portion of the outer layer) was placed over the temporarily pressed mass. Finally compressing the composition between the die and punch into tablets to produce a press-coated orally disintegrating tablet.

Another example of the process includes the following:

the mixture of ingredients (a) - (c) above is placed in a die having a diameter corresponding to the desired tablet diameter and temporarily compressed using a hand press machine at relatively low pressure. In addition, a powder/particle material having poor formability as a component of the inner core is placed in a die having a diameter corresponding to that of the inner core and temporarily pressed at a relatively low pressure using a hand press machine. The temporarily compressed mass for the inner core is placed concentrically on the temporarily compressed material for the outer layer. The die was covered and an appropriate amount of additional mixture of the above outer layer ingredients was placed on the temporarily pressed mass. Finally compressing the composition between the die and punch into tablets to produce a press-coated orally disintegrating tablet.

The material of the outer layer may be prepared into granules prior to tableting according to methods known in the art. For example, a press-coated formulation can be prepared according to the above-described method using a homogeneous mixture of the above-described ingredients (a) - (c). Also, each of the above (a) to (c) ingredients is granulated before tableting, a lubricant is added to the mixture of the granulated ingredients, and then the resulting mixture may be used to prepare a press-coated formulation according to the above method. Further, before tableting, a part of each of the above (a) to (c) ingredients is granulated, the rest of the ingredients (a) to (c) and a lubricant are added to the granulated ingredient mixture, and then a press-coated formulation may be prepared using the obtained mixture according to the above-described method. Such granulation methods include, for example, fluid bed granulation, extrusion, dry compression and granulation, rotor fluid bed granulation, high speed mixing/granulation, and crushing granulation.

(4) Compression coated orally disintegrating tablets

The press-coated orally disintegrating tablet prepared as described above means a formulation which can be administered without water and shows rapid disintegration in the oral cavity. In detail, the orally disintegrating tablet of the present invention means a formulation which can be orally disintegrated mainly by saliva within about 60 seconds, usually 45 seconds, preferably 30 seconds.

Furthermore, the orally disintegrating tablet of the present invention has sufficient hardness without being broken or cracked during the preparation process or during transportation. In detail, the absolute hardness of the orally disintegrating tablet of the present invention is 1.5N/mm²Above, preferably 2.0N/mm²The above.

The shape of the orally disintegrating tablet as a press-coating of the final formulation of the present invention may be, but is not particularly limited to, round tablets, round-shaped R-tablets (round-shaped R-tablets), angular round tablets (round-shaped tablets with irregular cores), various irregular shaped tablets, and the like. The diameter of the circular sheet, the circular R-sheet, and the circular chamfered edge sheet (rounded-shaped measured edge sheet) of the present invention is usually 5 to 16 mm, preferably 7 to 10 mm.

In the present invention, the "percentage of the thickness of the inner core" is usually 10 to 90%, preferably 20 to 80%, more preferably 30 to 80%. Further, in the present invention, the thickness of the outer layer is usually 0.3 to 1.5mm, preferably 0.4 to 1.0 mm.

In the present invention, the volume of the inner core is 10 to 80%, preferably 20 to 70%, based on the total volume of the final formulation.

The press-coated orally disintegrating tablet of the present invention should satisfy oral disintegratability and hardness sufficient to maintain its form as a formulation during the manufacturing process, the distribution process, the medical practice setting process, and the like. It is desirable that the outer layer has sufficient hardness because the present invention is characterized in that the formulation of the present invention contains a powder/particle material having poor formability as its inner core. In addition, a higher hardness of the outer layer is required compared to the hardness of the conventional orally disintegrating tablet without the core. A lower porosity of the outer layer compared to conventional tablets is preferred so that sufficient hardness can be obtained. The porosity of the outer layer of the tablet of the invention is preferably 1-40%, more preferably 1 to 30%.

Examples

Hereinafter, the present invention is further illustrated by the following examples, but it should not be construed that the present invention is limited to the examples.

Unless otherwise indicated, the calcium hydrogen phosphate, corn starch, magnesium stearate, carboxymethylcellulose, low-substituted hydroxypropylcellulose (L-HPC), microcrystalline cellulose spheres, microcrystalline cellulose, crospovidone and talc used in the examples were the materials calcium hydrogen phosphate anhydrous (GS: manufactured by Kyowa Chemical Co., Ltd.), corn starch ((XX16) W: manufactured by Nihon Shokuhin Kako Co., Ltd.), magnesium stearate (light and vegetitive: manufactured by Taihei Chemical Industrial Co., Ltd.), carboxymethylcellulose (NS-300: manufactured by Gotoku Chemical Co., Ltd.), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), microcrystalline cellulose spheres (CELERE CP-203: manufactured by Ashi KACo., Ltd.), microcrystalline cellulose (CEL CP-301 US: SEI, SEI 101, or SEI: Asph SEI, Ltd., SEI, ltd., manufactured), crospovidone (Kollidon CL: manufactured by basf Japan ltd., or Polyplasdone XL-10: manufactured by ISP Japan ltd., manufactured), talc (manufactured by Hayashi-kaseico., ltd., manufactured), erythritol (fine powder: manufactured by Nikken Chemical co., ltd., manufactured).

Examples 1-1 To 1-4 Study of the specific ingredients

< preparation of compression-coated orally disintegrating tablet >

Four formulations having different outer layers containing each specific ingredient shown in the table were prepared according to the formulations shown in table 1-1. First, the ingredients of each outer layer are mixed. A portion (40mg) of each composition was placed in a die (6 mm diameter) which was gently shaken to smooth the powder surface (which is the lower part of the outer layer). On the mixture, 50 mg of microcrystalline cellulose spheres (CELPHERECP-203) as an inner core component were placed, and then the layered material was temporarily pressed at a low pressure (3 kN) using a hand press machine (oil press system, manufactured by RIKEN). The temporarily pressed mass was placed concentrically on a punch (diameter 8 mm) in such a manner that the lower part of the outer layer was placed downward. A die (8 mm diameter) was placed over it and an additional mixture of the above-described outer layer ingredients (140 mg for the side and upper portions of the outer layer) was placed over the temporarily compressed mass. Finally the composition between the die and punch was compressed at a pressure of 10 kN to produce the desired press coated orally disintegrating tablet. Furthermore, the hardness of a compressed tablet (50 mg) prepared by compressing only the microcrystalline cellulose spheres (CELPHERE CP-203) used herein in a punch/die (diameter 6 mm) at a pressure of 4 kN was less than 10N.

TABLE 1-1 formulation (mg)

Tables 1-2 formulation proportions (wt%) in the outer layer

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness, HDBI and porosity were calculated. The results are tabulated in tables 1-3 to show the physical properties of the product tablets. As described in examples 1-1 to 1-4, in the case where the tablet outer layer contains any one of carboxymethylcellulose, corn starch, L-HPC or crospovidone, an oral disintegration time of 30 seconds or less and 1.5N/mm are obtained²The above absolute hardness results in high HDBI, which is an index of the balance of hardness and disintegratability. Furthermore, in each formulation, the mouth feel was satisfactory and no dry mouth was felt. HDBI is highest when crospovidone is used as the specific ingredient. The porosity in each outer layer is less than 30%.

Tables 1-3 physical Properties of the tablets

Comparative examples 1-1 To 1-2 Tablets not containing the specific component (1)

According to the formulation shown in table 2-1, a formulation (comparative example 1-1) containing no specific ingredient in the outer layer thereof and a formulation (comparative example 1-2) containing croscarmellose sodium instead of the specific ingredient in the outer layer thereof were prepared as described in example 1-1. Ac-Di-Sol (manufactured by DSPGokyo Food and Chemical Co., Ltd.) was used as croscarmellose sodium.

TABLE 2-1 formulation (mg)

TABLE 2-2 formulation ratio in the outer layer (wt%)

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness, HDBI and porosity were calculated. The results are tabulated in tables 2-3 to show the physical properties of the product tablets. As shown by the results in which examples 1-1 and 1-2 were compared, in the case where the outer layer of the tablet does not contain the specific ingredient of the present invention, its oral disintegration time exceeded 30 seconds, although the porosity in the outer layer was similar to that of example 1. HDBI, an index of balance of hardness and disintegratability, is low (not more than 0.15).

Tables 2-3 physical Properties of the tablets

Comparative examples 1-3: Tablets not containing said specific ingredients (2)( Patent reference 2 Outer layer of )

As described in example 1-1 of the present application, a preparation free of the specific ingredient of the present application and other ingredients was prepared according to the formulations shown in tables 2-4 similarly to the examples in patent reference 2. Note that the dies and punches used herein have a small amount of magnesium stearate applied. Cellactose80 (manufactured by MEGGLE co., ltd.) was used.

TABLE 2-4 formulation (mg)

Tables 2-5 formulation proportions (wt%) in the outer layer

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 2-6 to show the physical properties of the product tablets. The product tablet does not disintegrate in oral cavity.

Tables 2-6 physical Properties of the tablets

Comparative examples 1-4: Tablets not containing said specific ingredients (3)( Patent reference 1 Outer layer of )

According to the formulations shown in tables 2 to 7, preparations not containing the specific ingredients in the outer layer were prepared as described in example 1-1. The formulation of the outer layer was the same as that described in example 6 of patent reference 6 (60 mg of erythritol, 19.5 mg of microcrystalline cellulose, and 0.5 mg of magnesium stearate).

TABLE 2-7 formulation (mg)

Tables 2-8 formulation proportions (wt%) in the outer layer

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and H were calculatedAnd (4) DBI. The results are tabulated in tables 2-9 to show the physical properties of the product tablets. When a press-coated tablet containing non-formable particles is prepared according to the outer layer described in example 6 of patent reference 1, its oral disintegration time is short, but its absolute hardness is insufficient and low (less than 1N/mm)²). Therefore, it was concluded that when a compression-coated tablet containing non-formable particles was prepared, sufficient hardness of the entire tablet could not be obtained by using the ingredients disclosed in patent reference 1 in the outer layer.

Tables 2-9 physical Properties of the tablets

Examples 2-1 To 2-5 Study of microcrystalline cellulose ratio (1)

Five formulations containing varying amounts of microcrystalline cellulose in the outer layer were prepared according to the formulations shown in table 3-1, as described in example 1-1 herein. The final compression into tablets was carried out under the following pressures: the pressure was 8 kN in examples 2-2, 15kN in examples 2-4 and 10 kN in other examples.

TABLE 3-1 formulation (mg)

TABLE 3-2 formulation ratio in the outer layer (wt%)

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 3-3 to show the physical properties of the product tablets. The thickness of the inner core accounts for the percentage of the whole thickness of each tablet: 38% in example 2-1, 34% in example 2-2, 44% in examples 2-4, and 39% in examples 2-5.

In the case where the percentage of microcrystalline cellulose in the outer layer is in the range of 5 to 80% as described in examples 2-1 to 2-5, an oral disintegration time of 30 seconds or less and 1.5N/mm are obtained²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability.

TABLE 3-3 physical Properties of the tablets

Examples 2-6 Study of microcrystalline cellulose ratio (2)

Formulations containing 59.2% microcrystalline cellulose and 30% inorganic excipients in the outer layer thereof were prepared according to the formulations shown in tables 3-4, as described in example 1-1. The final compression into tablets is carried out under a pressure of 10 kN.

TABLE 3-4 formulation (mg)

Tables 3-5 formulation proportions (wt%) in the outer layer

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 3-6 to show the physical properties of the product tablets. The thickness of the inner core accounts for 31 percent of the thickness of the whole sheet.

An oral disintegration time of 30 seconds or less and 1.5N/mm are obtained²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability.

Tables 3-6 physical Properties of the tablets

Examples 3-1 To 3-3 Study of Lubricant ratio

Formulations containing varying amounts of lubricant in the outer layer were prepared according to the formulations shown in table 4-1, as described in example 1-1 herein. The final compression into tablets was carried out under the following pressures: the pressure was 15kN in example 3-1, and 10 kN in other examples.

TABLE 4-1 formulation (mg)

TABLE 4-2 formulation ratio in the outer layer (wt%)

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 4-3 to show the physical properties of the product tablets. In all the tablets shown in tables 4 to 3, an oral disintegration time of 30 seconds or less and 1.5N/mm were obtained²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability.

TABLE 4-3 physical Properties of the tablets

Examples 4-1 To 4-4 Specific components ( Corn starch ) Investigation of the proportions

Formulations containing varying amounts of corn starch in the outer layer were prepared according to the formulations shown in table 5-1, as described in example 1-1 herein. The final compression into tablets is carried out under a pressure of 10 kN.

TABLE 5-1 formulation (mg)

TABLE 5-2 formulation ratio in the outer layer (wt%)

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 5-3 to show the physical properties of the product tablets. The thickness of the inner core accounts for the percentage of the whole thickness of each tablet: 40% in example 4-1, 39% in example 4-3 and 38% in example 4-4.

As shown in comparative example 1-1, the tablet having the outer layer without any corn starch did not disintegrate in the oral cavity within 30 seconds, whereas the tablet having the outer layer containing 1% to 40% corn starch as described in examples 4-1 to 4-4 achieved an oral disintegration time of 30 seconds or less and 1.5N/mm²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability. Thus, these results indicate that when the outer layer comprises 1 to 40% corn starch, an excellent press-coated orally disintegrating tablet can be provided.

TABLE 5-3 physical Properties of the tablets

Examples 5-1 To 5-4 Specific components ( Crospovidone ) Investigation of the proportions

Formulations containing varying amounts of crospovidone in the outer layer were prepared according to the formulations shown in table 6-1, as described in example 1-1 herein. The final compression into tablets is carried out under a pressure of 10 kN.

TABLE 6-1 formulation (mg)

TABLE 6-2 formulation ratio in the outer layer (wt%)

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 6-3 to show the physical properties of the product tablets. The thickness of the inner core accounts for the percentage of the whole thickness of each tablet: 44% in example 5-1, 38% in example 5-2, 38% in example 5-3, and 34% in example 5-4.

As shown in comparative example 1-1, the tablet having an outer layer without any crospovidone did not disintegrate in the oral cavity within 30 seconds, whereas the outer layer contained 1% to 5% as described in examples 5-1 to 5-4Tablets of 30% crospovidone achieved an oral disintegration time of less than 30 seconds and 1.5N/mm²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability. Notably, lower crospovidone content resulted in higher HDBI.

TABLE 6-3 physical Properties of the tablets

Examples 6-1 To 6-3 Study of inner core thickness (1)

Formulations having different core thicknesses from each other were prepared according to the formulations shown in Table 7-1. First, the ingredients of the outer layer are mixed. The amount of the outer layer mixture shown in each column of "outer layer weight (lower part)" in table 7-1 was placed in a die having the diameter shown in each column of "inner core" in table 7-1. The die was gently shaken to smooth the powder surface. On this mixture, microcrystalline cellulose spheres (CELPHERECP-203) were placed in the amounts shown in the table, and the layered material was temporarily pressed at a low pressure of 3 kN using a hand press machine (oil press system, manufactured by RIKEN). The temporarily pressed mass was placed concentrically on a punch (diameter 8 mm) in such a manner that the lower part of the outer layer was placed downward. A die (diameter 8 mm) was placed thereon, and an additional mixture of the above-mentioned outer layer components was added thereto in the amounts shown in each column of "outer layer weight (side part and upper part)" of Table 7-1. The composition between the punch and die is finally compressed to produce a press-coated orally disintegrating tablet. The final compression into tablets is carried out under a pressure of 15 kN.

TABLE 7-1 formulation (mg)

TABLE 7-2 formulation proportions (wt%) in the outer layer

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 7-3 to show the physical properties of the product tablets. As described in examples 6-1 to 6-3, in the case where the percentage of the thickness of the inner core is 32 to 76%, the tablet attains an oral disintegration time of 30 seconds or less and 1.5N/mm²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability.

TABLE 7-3 physical Properties of the tablets

Examples 6-4 To 6-5 Study of inner core thickness (2)

Formulations in which the inner core thicknesses were different from each other were prepared according to the formulations shown in tables 7 to 4. First, the ingredients of the outer layer are mixed. The amount of the outer layer mixture shown in each column of "outer layer weight (lower part)" in tables 7 to 4 was placed in a die (diameter 8 mm). The die was gently shaken to smooth the powder surface. On this mixture, microcrystalline cellulose spheres CELPHERE CP-203 were placed in the amounts shown in the table, and the layered material was temporarily pressed at low pressure using a hand press machine (oil press system, manufactured by RIKEN). The temporarily pressed mass was concentrically placed on a punch (diameter 10 mm) in such a manner that the lower part of the outer layer was placed downward. A die (diameter 10 mm) was placed thereon, and an additional mixture of the above-described outer layer components was added thereto in the amounts shown in each column of "outer layer weight (side part and upper part)" in tables 7 to 4. Finally, the composition between the punch and die is compressed to produce a press-coated orally disintegrating tablet. The final compression into tablets was carried out under the following pressures: the pressure was 8 kN in examples 6-4 and 15kN in examples 6-5.

TABLE 7-4 formulation (mg)

TABLE 7-5 formulation proportions (wt%) in the outer layer

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 7-6 to show the physical properties of the product tablets. As described in examples 6-4 to 6-5, in the case where the percentage of the thickness of the inner core was 32 to 76%, the tablets obtained an oral disintegration time of 30 seconds or less and 1.5N/mm²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability.

TABLE 7-6 physical Properties of the tablets

Comparative examples 2 Comparison with physical Properties of conventional tablet

A general tablet in which non-formable particles are uniformly distributed was prepared. First, the ingredients shown in tables 7 to 7 were uniformly mixed in the proportions shown in the tables. The mixture was compressed under a pressure of 8 kN into tablets (diameter 10 mm) to prepare ordinary tablets. Note that the ordinary tablets were prepared under the same conditions as the compression-coated tablets of examples 6 to 4, such as the amount of each ingredient in each tablet, the tablet weight, the tablet diameter and the compression force, except for the different distribution of the non-formable granules.

TABLE 7-7 formulation (mg)

Tables 7-8 formulation proportions (wt%)

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. As shown in tables 7 to 9, the conventional tablets had lower absolute hardness and longer oral disintegration time than those of the compression-coated tablets.

Thus, for an orally disintegrating tablet comprising a large number of non-formable particles, it was found that a compression-coated tablet comprising non-formable particles in the inner core can obtain more preferable physical properties than a conventional tablet in which non-formable particles are uniformly distributed.

Tables 7-9 physical Properties of the tablets

Examples 7-1 To 7-3 Study of porosity in outer layer

According to the formulation shown in Table 8-1, preparations having porosities different from each other in the outer layer were prepared as described in example 1-1. The final compression into tablets was carried out under a pressure of 6 kN, 10 kN and 15 kN.

TABLE 8-1 formulation (mg)

TABLE 8-2 formulation ratio in the outer layer (wt%)

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness, HDBI and porosity were calculated. The results are tabulated in tables 8-3 to show the physical properties of the product tablets. The tablet realizes oral cavity disintegration time below 30s and 1.5N/mm²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability. Tablets compressed at pressures of 6 kN to 15kN had suitable hardness and disintegration, indicating a wide acceptable range of compression pressures.

TABLE 8-3 physical Properties of the tablets

Examples 8 A press-coated orally disintegrating tablet containing an active ingredient

(8-1) Comprises paracetamol (acetaminophen) A compression-coated tablet of the particles of

1) Contains paracetamol ( By Asahi Kasei Chemicals Co., Ltd. Manufacture of ) Preparation of the particles of

Paracetamol was coated to prepare paracetamol containing particles having a coating rate of 10 wt%. The coating material used herein comprises Aquacoat in a ratio of 100: 25: 50 (wt%), respectively^TM(manufactured by asahi kasei Chemical co., Ltd.), triacetin, and mannitol.

2) Preparation of compression coated tablets

As described in example 1-1, a preparation comprising paracetamol-containing particles was prepared according to the formulation shown in Table 9-1. The final compression into tablets is carried out under a pressure of 8 kN.

TABLE 9-1 formulation (mg)

TABLE 9-2 formulation ratio in outer layer (wt%)

3) Results

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 9-3 to show the physical properties of the product tablets. An oral disintegration time of 30 seconds or less and 1.5N/mm are obtained²The above absolute hardness gives a high HDBI, which is an index of the balance between hardness and disintegratability. Thus, it has also been shown that preferred press-coated orally disintegrating tablets can be prepared in the case where they contain an active ingredient.

TABLE 9-3 physical Properties of the tablets

(8-2) Comprises famotidine (famotidine) A compression-coated tablet of the particles of

1) Preparation of particles comprising famotidine

To 567 g of purified water was added 31.5g of polysorbate 80 (japanese pharmacopoeia polysorbate 80 (HX): manufactured by NOF co., ltd.) and the mixture was thoroughly mixed. Then, 73.5 g of talc (manufactured by Hayashi Kasei co., ltd.) and 52.5 g of croscarmellose sodium (Ac-Di-Sol: manufactured by FMC BioPolymer co., ltd.) were added thereto, and the solution ("solution I") was sufficiently stirred.

In addition, another solution of sodium hydroxide (2.85 g) in purified water (67.65 g) was slowly added to 705 g of methacrylic acid copolymer LD (POLYQUID PA-30S: manufactured by Sanyo chemical industries Ltd.), and the solution was stirred ("solution II"). To solution I, solution II was added for suspension. The suspension was sieved through a mesh (177 μm) to obtain a coating dispersion.

346.5 g of famotidine and 3.5 g of light anhydrous silicic acid (Aerosil 200: manufactured by Nippon Aerosil Co. Ltd.) were separately sieved through a mesh (500 μm), and thoroughly mixed in a polyethylene bag to prepare a composition containing the drug. The composition was then sprayed with the coating dispersion prepared above in a Wurster-fluid bed granulator (modified Wurster-fluid bed granulator, MP-01 SPC, manufactured by Powrex co., inc.) equipped with a forced circulation device. Spraying is carried out at an inlet air temperature of 80 to 90 ℃ and an outlet air temperature of 26 to 30 ℃, the spraying liquid being sprayed from a bottom sprayer at a flow rate of 10-12g/min, the spraying air flow rate being 80L/min, the spraying air pressure being 0.2-0.3MPa, the side air pressure being 0.2-0.25MPa, and the inlet air flow rate being about 0.30-0.55 m³At/min, the preparation was carried out. The coating was completed when the amount of coating dispersion was about 1306 g and the resulting particles were dried until the outlet air temperature reached 42 ℃. The resulting particles were sieved through a 32 mesh (500 μm) sieve to prepare famotidine-containing particles having an average diameter of about 165 μm.

2) Preparation of compression coated tablets

Formulations containing particles containing the active ingredient in the inner core were prepared according to the formulations shown in tables 9-4. Particles comprising famotidine and mixed particles of crospovidone and talc particles are used in the inner core. First, the ingredients of the outer layer are mixed. A portion (40mg) of the mixture was placed in a die (diameter 6 mm) which was gently shaken to smooth the powder surface, which is the lower part of the outer layer. On this mixture, 50 mg of the mixed particles of the inner core were put, and then, the layered material was temporarily pressed at a low pressure (3 kN) using a hand press machine (oil press system, manufactured by RIKEN). The temporarily pressed mass was placed concentrically on a punch (diameter 8 mm) in such a manner that the lower part of the outer layer was placed downward. A die (8 mm diameter) was placed over it and an additional mixture of the above-described outer layer ingredients (140 mg for the side and upper portions of the outer layer) was placed over the temporarily compressed mass. Finally the composition between the punch and die was compressed at a pressure of 8 kN to prepare the desired press coated orally disintegrating tablet.

TABLE 9-4 formulation (mg)

TABLE 9-5 formulation ratio in outer layer (wt%)

(8-3) Comprises mosapride (mosapride) A compression-coated tablet of the particles of

1) Preparation of particles comprising mosapride

Particles containing mosapride were prepared as described in example 8-2 using mosapride citrate instead of famotidine.

2) Preparation of compression coated tablets

According to the formulations shown in tables 9 to 6, preparations containing particles containing mosapride in the inner core were prepared. Particles comprising mosapride and mixed particles of crospovidone and talc particles are used in the inner core.

First, the ingredients of the outer layer are mixed. A portion (40mg) of the mixture was placed in a die (diameter 6 mm) which was gently shaken to smooth the powder surface, which is the lower part of the outer layer. On the mixture, 50 mg of the mixed particles of the inner core were put, and then, the layered material was temporarily pressed at a low pressure (3 kN) using a hand press machine (oil press system, manufactured by RIKEN). The temporarily pressed mass was placed concentrically on a punch (diameter 8 mm) in such a manner that the lower part of the outer layer was placed downward. A die (8 mm diameter) was placed over it and an additional mixture of the above-described outer layer ingredients (140 mg for the side and upper portions of the outer layer) was placed over the temporarily compressed mass. Finally the composition between the punch and die was compressed at a pressure of 8 kN to prepare the desired press coated orally disintegrating tablet.

TABLE 9-6 formulation (mg)

TABLE 9-7 formulation proportions (wt%) in the outer layer

3) Results

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 9-8 to show the physical properties of the product tablets. An oral disintegration time of 30 seconds or less and 1.5N/mm are obtained²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability. The taste from mosapride was masked and the oral sensation was good.

TABLE 9-8 physical Properties of the tablets

(8-4) Comprises enteric-coated particles ( enteric particle ) The press-coated tablet of

1) Particles comprising enteric particles

Red granules in a contrac 600ST capsule (Glaxo Smith Kline) were used as enteric particles.

2) Preparation of compression coated tablets

According to the formulations shown in tables 9 to 9, preparations containing enteric particles in the inner core were prepared. First, the ingredients of the outer layer are mixed. A portion (40mg) of the mixture was placed in a die (diameter 6 mm) which was gently shaken to smooth the powder surface, which is the lower part of the outer layer. 50 mg of Contac 600ST particles (50 mg) were placed on the powder and the die was gently shaken to smooth the surface of the layered material. Then, 20 mg of another mixture of the above-mentioned outer layer ingredients (for the upper part of the outer layer) was placed on the layered material, and the die was gently shaken to smooth the surface of the layered mixture. The layered mixture was temporarily pressed at a low pressure (1 kN) using a hand press machine (oil press system, manufactured by RIKEN). The temporarily pressed mass was placed concentrically on a punch (diameter 8 mm) in such a manner that the lower part of the outer layer was placed downward. A die (8 mm diameter) was placed over it and an additional mixture of the above-described outer layer ingredients (for the outer layer side part and upper part, 120 mg) was placed over the temporarily compressed mass. Finally the composition between the punch and die was compressed at a pressure of 6 kN to prepare the desired press coated orally disintegrating tablet.

TABLE 9-9 formulation (mg)

Tables 9-10 formulation proportions (wt%) in the outer layer

3) Results

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 9-11 to show the physical properties of the product tablets. An oral disintegration time of 30 seconds or less and 1.5N/mm are obtained²The above absolute hardness results in a high HDBI, which is an index of the balance of hardness and disintegratability.

TABLE 9-11 physical Properties of the tablets

(8-5) Compression coated tablets containing famotidine microcapsules

1) Famotidine microcapsule

As used herein, famotidine microcapsules are agar beads containing 70% famotidine, supplied by Riken Vitamin co.

2) Preparation of compression coated tablets

Formulations containing the microcapsules in the inner core were prepared according to the formulations shown in tables 9-12. A mixed particle of the microcapsule and erythritol particles (fine powder: manufactured by Nikken Chemical Laboratory co., ltd.) was used as an inner core.

First, the ingredients of the outer layer are mixed. A portion (40mg) of the mixture was placed in a die (diameter 6 mm) which was gently shaken to smooth the powder surface, which is the lower part of the outer layer. On the mixture, 57.2 mg of the mixed particles of the inner core were put, and then, the layered material was temporarily pressed at a low pressure (3 kN) using a hand press machine (oil press system, manufactured by RIKEN). The temporarily pressed mass was placed concentrically on a punch (diameter 8 mm) in such a manner that the lower part of the outer layer was placed downward. A die (8 mm diameter) was placed over it and an additional mixture of the above-described outer layer ingredients (140 mg for the side and upper portions of the outer layer) was placed over the temporarily compressed mass. Finally the composition between the punch and die was compressed at a pressure of 6 kN to prepare the desired press coated orally disintegrating tablet.

TABLE 9-12 formulation (mg)

Tables 9-13 formulation proportions (wt%) in the outer layer

3) Results

The oral disintegration time, hardness and thickness of the product tablets were measured and their absolute hardness and HDBI calculated. The results are tabulated in tables 9-14 to show the physical properties of the product tablets. An oral disintegration time of 30 seconds or less and 1.5N/mm are obtained²The above absolute hardness results in a high HDBI, which represents an index of the balance between hardness and disintegratability.

Tables 9-14 physical Properties of the tablets

As shown above, press-coated tablets comprising various inner cores, such as spherical particles (e.g., CELPHERE), particles coated with microparticles, enteric particles, and microcapsules, can be prepared to provide a press-coated orally disintegrating tablet having a better balance between hardness and disintegratability.

Industrial applicability

The present invention can provide a press-coated orally disintegrating tablet in which the inner core thereof has poor formability and which has a better balance between hardness and disintegratability.

Claims (8)

1. A press-coated orally disintegrating tablet having an inner core which is a powder/granular material having poor formability and an outer layer surrounding the inner core, wherein

The thickness of the inner core accounts for 20 to 80% of the thickness of the whole sheet, and

the outer layer is composed of (a) microcrystalline cellulose, (b) inorganic excipients, (c) one or more specific ingredients selected from the group consisting of crospovidone, starch, and low-substituted hydroxypropylcellulose, and (d) one or more additional formulation ingredients,

wherein the microcrystalline cellulose (a) is 5 to 80 wt% based on 100 wt% of the outer layer,

the inorganic excipient (b) accounts for 10 to 80 wt% of the outer layer of 100 wt%,

the total content of the specific component (c) is 1 to 40 wt% based on 100 wt% of the outer layer,

the total content of the further formulation component (d) is from 0.01 to 25% by weight, based on 100% by weight of the outer layer, and

the porosity in the outer layer is from 1 to 30%.

2. The press-coated orally disintegrating tablet of claim 1, wherein said inner core comprises microcapsule-like functional particles.

3. The press-coated orally disintegrating tablet of claim 1, wherein said inner core is a powder, a granular material or a powder/granular material having poor formability, other than the microcapsule-like functional particles.

4. The press-coated orally disintegrating tablet of any one of claims 1 to 3, wherein said microcrystalline cellulose (a) is 9 to 70% by weight based on 100% by weight of said outer layer, said inorganic excipient (b) is 20 to 80% by weight based on 100% by weight of said outer layer, and said specific ingredient (c) is contained in total in an amount of 1 to 30% by weight based on 100% by weight of said outer layer.

5. The press-coated orally disintegrating tablet of any of claims 1 to 3, wherein said starch is corn starch.

6. The press-coated orally disintegrating tablet of any one of claims 1 to 3, wherein said specific ingredient (c) is one or two selected from the group consisting of crospovidone and corn starch.

7. The press-coated orally disintegrating tablet of any one of claims 1 to 3, wherein said specific ingredient (c) is crospovidone.

8. The press-coated orally disintegrating tablet of any of claims 1 to 3, wherein said inner core comprises an active ingredient.