EP2797580A2

EP2797580A2 - Tablets and dry-coated agents

Info

Publication number: EP2797580A2
Application number: EP12806509.1A
Authority: EP
Inventors: Masaki Ando; Takanori Ichihashi; Sayaka KOJIMA; Masato Sakurai; Rina TANAKA
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2011-12-26
Filing date: 2012-12-21
Publication date: 2014-11-05
Also published as: BR112014015620A2; WO2013098268A2; WO2013098268A3; MX2014007933A; JP2015504878A; KR20140108652A; BR112014015620A8; AU2012360935A1; RU2014130743A

Abstract

The present invention is related to the provision of a tablet that may easily be orally administered and has valsartan as active ingredient. Specifically, the present invention provides a tablet consisting of pharmaceutical composition comprising a valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, wherein the tablet is orally administrated through disintegration in the mouth by saliva or water in a similar amount to the saliva. The present invention is also related to the provision of a dry-coated agent that may prevent bitter taste, sufficiently improve QOL, and has valsartan as active ingredient. Specifically, the present invention provides a dry-coated agent comprising an inner core consisting of pharmaceutical composition containing valsartan or its pharmaceutically acceptable salt thereof, and an outer layer coating the inner core and consisting of coating composition containing pH adjuster which makes inside of the mouth mildly acidic.

Description

Specification

Tablets and Dry-coated agents

FIELD OF THE INVENTION

The present invention relates to a tablet comprising valsartan or a pharmaceutically acceptable salt thereof. The present invention also relates to a dry-coated agent comprising valsartan or a pharmaceutically acceptable salt thereof.

RELATED BACKGROUND ART

It is known that valsartan (angiotensin II receptor antagonist) is effective for the treatment of congestive heart failure and is able to lower blood pressure irrespective of age, gender or race. PCT Application No. W097/49394 (corresponding to JP2000-506540 and U.S. Patent No. 6,294, 197), Japanese Unexamined Patent Publication No. 2003-231634 and Japanese Unexamined Patent Publication No. 2007-238637, for example, disclose valsartan or a pharmaceutically acceptable salt thereof as well as a solid oral agent formed by compressing.

In recent years, orally disintegrating tablets (also referred to as "OD Tablets") have been widely spread in use because of the ease of their ingestion. As for OD tablets, Japanese Unexamined Patent Publication Hei 5-271054, for example, discloses tablets of the orally disintegrating type that are produced by tableting a blend containing a medicinally active ingredient, saccharides and water in a sufficient amount to wet the surfaces of particles of the saccharides. PCT Application No. WO95/20380 discloses a compressed, molded product of the orally disintegrating type that comprises a saccharide having low moldability and a saccharide having high moldability and that is provided with quick disintegrability in the mouth.

However, when the present inventors made examinations, it was found out that if valsartan was made an active ingredient, the known methods, including those in Japanese Unexamined Patent Publication Hei 5-271054 and PCT Application No. WO95/20380, would produce OD tablets but which were unsuitable for use.

Specifically, valsartan is hydrophobic, low in solubility, bulky and strongly adhesive. Because of these effects, if OD tablets having sufficient disintegrability are to be prepared, there will be a need to enlarge the sizes of the tablets in order to obtain adequate amounts of valsartan, and thus, their ingestion and handling will be difficult.

The preparation of OD tablets also requires the disintegrability that is sufficient to easily disintegrate the tablets in the mouth as well as requires the hardness that is sufficient as tablet, to be both obtained at the same time. According to the methods in the prior art, there were difficulties in producing OD tablets comprising valsartan as the active ingredient provided with those properties at the same time.

Further, in recent years, orally disintegrating tablets (also referred to as "OD Tablets") have been widely utilized, because the self-administration of tablets is easy enough to improve the quality of life (QOL).

However, valsartan is a medicament that displays bitterness. Thus, there will be a problem of not sufficiently improving QOL even if the conventional solid oral agents themselves are made into orally disintegrating tablets.

SUMMARY OF THE INVENTION

The present invention provides a tablet containing a therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, which tablet has sufficient disintegrability and hardness to be suitable for use as an orally disintegrating ("OD") tablet. In other words, the tablet is capable of being administered orally and disintegrating in the oral cavity upon exposure to a patient's salvia or a comparable amount of water— without having to be chewed.

In one embodiment, the present application provides a tablet consisting of pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, wherein the tablet is orally administered through disintegration in the mouth by saliva or water in a similar amount to the saliva.

The tablet thus mentioned has sufficient disintegrability and tablet hardness and is suitable for use as an OD tablet.

Specifically, the tablet is suited to its use as an orally disintegrating tablet because it has the aforementioned specific composition. Therefore, when the tablet is used in the application wherein the tablet is orally administered through disintegration in the mouth by saliva or water in a similar amount to the saliva, it facilitates the self-administration of the tablet comprising valsartan as the active ingredient and it can achieve the improvement of the quality of life (QOL), compliance and, consequently, adherence as intended.

In another embodiment, the present invention provides an orally disintegrating tablet comprising an inner core consisting of pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, and an outer layer coating the inner core.

The tablet thus mentioned has sufficient disintegrability and tablet hardness and is suitable for use as an OD tablet. Further, said tablet facilitates the self-administration of the tablet comprising valsartan as the active ingredient and it can achieve the improvement of QOL, compliance and, consequently, adherence as intended.

For example, the OD tablets of the invention can serve as an alternative dosage form for patients who experience dysphagia (difficulty in swallowing). In addition, the OD tablets of the invention can improve compliance and adherence in populations where these are an issue (for example in elderly patients, children, developmentally disable patients, or patients with persistent nausea, who are traveling, or who have limited access to water). The OD tablets of the invention are easier to administer than conventional tablets that are intended to be swallowed, which also helps to ensure that the medication is taken as prescribed.

In one embodiment, the disintegration time of the OD tablet is within about 30 seconds. In another embodiment, the disintegration time is from about 1 to about 60 seconds, from about 1 to about 30 seconds, or from about 15 to about 30 seconds as measured as the time required for the tablet to disintegrate in the mouth by/upon exposure to saliva or water in a similar amount to the saliva. In certain embodiments, the tablet hardness is between about 36N to about 97N as measured using a tablet hardness tester.

The outer layer is preferably a layer that comprises crystalline cellulose, a disintegrant and a lubricant. The outer layer so constructed can achieve higher tablet hardness, while maintaining sufficient disintegrability.

The disintegrant preferably comprises at least one member selected from the group consisting of low-substituted hydroxypropylcellulose (L-HPC), crospovidone, sodium croscarmellose, sodium carboxymethylstarch, carmellose, calcium carmellose, partially pregelatinised starch, starch, sodium carmellose, alginic acid, sodium alginate, and guar gum.

The disintegrant preferably comprises at least low-substituted hydroxypropylcellulose and may comprise at least one member selected from the group consisting of crospovidone, sodium croscarmellose, and sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose.

The glidant preferably comprises at least one component selected from the group consisting of silicic acid, silicic acid anhydrous, aluminum silicate, calcium silicate, magnesium aluminometasilicate, aluminum oxide, aluminum hydroxide, magnesium oxide and magnesium hydroxide.

The glidant also preferably comprises light silicic acid anhydrous and/or synthetic aluminum silicate.

The lubricant preferably comprises at least one component selected from the group consisting of magnesium stearate, aluminum stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil, poly(ethylene glycol) and talc.

The lubricant preferably comprises at least magnesium stearate.

In certain embodiments, the pharmaceutical composition present in the OD tablets of the invention may comprise one or more additional anti-hypertensives beyond valsartan (or a pharmaceutically acceptable thereof), including: hydrochlorothiazide, or amlodipine (or a pharmaceutically acceptable salt thereof).

The pharmaceutical composition preferably further comprises a hydrochlorothiazide and/or an amlodipine or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition preferably further comprises a aliskiren or a pharmaceutically acceptable salt thereof.

The present invention also provides a dry-coated agent containing a therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof as the active ingredient and which, when administered orally to a patient, reduces or prevents the bitter taste of valsartan from being experienced.

In one embodiment, the present invention provides a dry-coated agent comprising an inner core consisting of pharmaceutical composition containing valsartan or a pharmaceutically acceptable salt thereof, and an outer layer coating the inner core and consisting of coating composition containing pH adjuster which makes inside of the mouth mildly acidic.

The dry-coated agent thus mentioned sufficiently prevents bitterness when it is allowed to disintegrate in the mouth and then used to be orally administered. Therefore, it can achieve the improvement of QOL, compliance and, consequently, adherence as intended.

In the dry-coated agent, the coating composition constituting the outer layer contains a pH adjuster which makes inside of the mouth mildly acidic. Thus, the inside of the mouth is slightly acidified when the dry-coated agent is allowed to disintegrate in the mouth. Further, since valsartan (or a pharmaceutically acceptable salt thereof) is an acidic medicament, it is thought that the immediate solubility will be lowered as the acidity inside the mouth becomes higher.

Specifically, it is thought that according to the dry-coated agent, the inside of the mouth is acidified by the outer layer that has disintegrated therein before valsartan (or a pharmaceutically acceptable salt thereof) in the inner core is released and, therefore, that the dissolution of valsartan (or a pharmaceutically acceptable salt thereof) in the mouth is suppressed to prevent the bitterness.

The pH adjuster above may contain at least one component selected from the group consisting of anhydrous citric acid, citric acid hydrate, and sodium dihydrogen citrate.

In the dry-coated agent according to another embodiment, the coating composition may further comprise a sweetening agent. Said dry-coated agent causes the sweetening agent to diffuse in the mouth before valsartan (or a pharmaceutically acceptable salt thereof) is released. Thus, the bitterness of valsartan can be more prevented and then QOL can be increasingly improved.

The sweetening agent above may contain at least one component selected from the group consisting of saccharin, saccharin sodium, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia and thaumatin.

In the dry-coated agent according to a still further embodiment, the coating composition may contain a fast-acting sweetening agent and the pharmaceutical composition may contain a slow-acting sweetening agent. According to said dry-coated agent, the fast-acting sweetening agent diffuses in the mouth before valsartan (or as pharmaceutically acceptable salt thereof) is released, by which the initial bitterness can be prevented; the slow-acting sweetening agent, which is contained in the inner core, diffuses in the mouth after the dry-coated agent has completely disintegrated, by which the bitterness remaining after administration can be lessened.

The fast-acting sweetening agent above may contain at least one component selected from the group consisting of aspartame, sucralose and acesulfame potassium.

The slow-acting sweetening agent above may contain saccharin and/or saccharin sodium.

EFFECT OF THE INVENTION

The present invention provides a tablet comprising valsartan as the active ingredient, which tablet has sufficient disintegrability and tablet hardness and is suitable for use as an OD tablet.

The present invention also provides a dry-coated agent comprising valsartan or a pharmaceutically acceptable salt thereof as the active ingredient, which agent is capable of preventing bitterness as well as is capable of improving QOL adequately.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 : (a) is a perspective view showing a first embodiment of the tablet according to the present invention; and (b) is a cross-sectional view of the embodiment.

Fig. 2: (a) is a perspective view showing a second embodiment of the tablet according to the present invention; and (b) is a cross-sectional view of the embodiment.

Fig. 3 : (a) is a perspective view showing a first embodiment of the dry-coated agent according to the present invention; and (b) is a cross-sectional view of the embodiment.

Fig. 4: (a) is a perspective view showing a second embodiment of the dry-coated agent according to the present invention; and (b) is a cross-sectional view of the embodiment.

DETALED DESCRIPTION OF THE INVENTION

First General Embodiment of the Invention:

As used in the present Specification, the term "disintegration in the mouth by saliva or water in a similar amount to the saliva" means disintegration of the tablet, for example, on the order of from 1 to 60 seconds, and preferably from 1 to 30 seconds or from 15 to 29 seconds in contrast to the disintegration of common tablets (e.g., conventional solid dosage forms or capsules such as DIOVAN®, manufactured by Novartis Pharma KK), although it cannot unconditionally be defined because of the differences among individuals where the tablet is left to the natural movement of the mouth such as the movement of the tongue when it is held in the mouth. The term "disintegration in the mouth by saliva or water in a similar amount to the saliva" also includes the disintegration upon exposure to saliva or a comparative amount of water.

Methods for determining disintegration time are known in the art, and illustrative methods are described in the Examples. By "disintegration time" is meant the time required for the tablet to disintegrate in the mouth by/upon exposure to saliva or water in a similar amount to the saliva.

Also, the term "sufficient disintegrability" means the disintegrability such that the tablet can be disintegrated in the mouth by saliva or water in a similar amount to the saliva. Specifically, the tablet according to the present embodiment differs from the common tablet in that the common tablet will neither disintegrate nor dissolve easily unless it is chewed when held in the mouth.

The phrase "effective amount," as used herein, refers to the amount of active ingredient which arrests, reduces or reverses the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. Such an amount can be easily determined by a person skilled in the art by routine experimentation and with no undue burden. The dosage ranges disclosed herein are non-limiting examples of "effective amounts" of the active ingredient that can be used in the OD tablets of the invention.

Detailed Description The embodiments of the present invention will be described below.

The tablet according to the present embodiment is a tablet consisting of pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, wherein the tablet is orally administrated through disintegration in the mouth by saliva or water in a similar amount to the saliva.

In certain embodiment, the present invention provides an orally disintegrating tablet comprising an inner core consisting of pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, and an outer layer coating the inner core.

The tablet according to the present embodiment is suited to the use as an orally disintegrating tablet because it has the aforementioned specific composition. Therefore, when the tablet is used in the application wherein the tablet is orally administered through disintegration in the mouth by saliva or water in a similar amount to the saliva, it facilitates the self-administration of the tablet comprising valsartan as the active ingredient and it can achieve the improvement of QOL, compliance and, consequently, adherence as intended.

The tablet according to the present embodiment is useful in lowering blood pressure at the systolic phase, the diastolic phase or both. The tablet according to the present embodiment is also useful for the disease conditions, including hypertension (malignant, essential, renovascular, diabetic, isolated systolic or other secondary types), congestive heart failure, angina (stable or unstable), myocardial infarction, arteriosclerosis, atherosclerosis, diabetic nephropathy, diabetic myocardial disease, renal failure, peripheral arterial disease, left ventricular disease, cognitive function failure (such as Alzheimer disease), stroke and others.

The dissolvability of valsartan from the tablet according to the present embodiment is desirably at the same or similar level as that of valsartan from a common tablet containing valsartan such as DIOVAN® tablet (manufactured by Novartis Pharma Κ.Κ.)· According to one example of the test methods for ascertaining said dissolvability, although available in several types, 75% or more of valsartan is preferably dissolved in 120 minutes after the start of the test when the tablet is tested at 50 rpm using the paddle method of the Japanese Pharmacopeia by employing a buffer of pH 3.0 as testing solution, and more preferably, 80% or more of valsartan is dissolved in 120 minutes. When administered to a human, the tablet according to the present invention undergoes dissolution that is biologically equal to a DIOVAN® tablet.

The preferred embodiments of the tablet that can be used in the above-mentioned administration will be described below.

Fig. 1 is a view showing the first embodiment of the tablet according to the present invention. Tablet 100 is an orally disintegrating tablet comprising an inner core 10 and an outer layer 20 coating the inner core 10.

Other features of the invention are illustrated below with reference to Fig.l, which illustrates a preferred embodiment.

A. Inner Core 10

1. Active Ingredient

Valsartan is angiotensin II receptor antagonist, and acyl compound that is used for treatment of hypertension. Valsartan is disclosed, for example, in the patent,JP2749458, (1) below.

Valsartan suitable for use in the present invention is commercially available from Novartis or can be prepared according to known methods. For example, the preparation of valsartan is described in U.S. Patent No. 5399578. Valsartan may be used for purposes of this invention in its free form as well as in any pharmaceutically acceptable salt form. Salts forms include acid addition salts. The compounds having at least one acid group (e.g., COOH or 5-tetrazolyl) can also form salts with bases. Suitable salts with bases are, e.g., metal salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, calcium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, e.g., ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, e.g., mono-, di- or tri-ethanolamine. Corresponding internal salts may furthermore be formed. In one embodiment, salts are, e.g., selected from the mono-sodium salt in amorphous form; di-sodium salt of Valsartan in amorphous or crystalline form, especially in hydrate form, thereof.

In one embodiment, salts are, e.g., selected from the calcium salt of Valsartan in crystalline form, especially in hydrate form, primarily the tetrahydrate thereof; magnesium salt of Valsartan in crystalline form, especially in hydrate form, primarily the hexahydrate thereof; calcium/magnesium mixed salt of Valsartan in crystalline form, especially in hydrate form; bis-diethylammonium salt of Valsartan in crystalline form, especially in hydrate form; bis-dipropylammonium salt of Valsartan in crystalline form, especially in hydrate form; bis-dibutylammonium salt of Valsartan in crystalline form, especially in hydrate form, primarily the hemihydrate thereof; mono-L-arginine salt of Valsartan in amorphous form; bis-L-arginine salt of Valsartan in amorphous form; mono-L-lysine salt of Valsartan in amorphous form; d/s-L-lysine salt of Valsartan in amorphous form.

In one embodiment, Valsartan is used as the free acid.

Although Valsartan has a chiral carbon, racemic form and/or mono optical active form of valsartan may be used in the embodiment. Valsartan has optical active form (la) or (lb) below, and preferably includes at least (la).

The inner core 10 comprises a pharmaceutical composition containing valsartan or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant and a lubricant. The pharmaceutical composition thus specifically composed can be molded into the inner core 10 having sufficient disintegrability. Because the inner core 10 has acquired sufficient disintegrability, the tablet 100 can preferably be used as an orally disintegrating tablet that may be orally administered through disintegration in the mouth by saliva or water in a similar amount to the saliva.

The dosage of valsartan or a pharmaceutically acceptable salt thereof is usually from 10 to 250 mg as valsartan, and preferably from 40 to 160 mg. Therefore, the proportion of valsartan or a pharmaceutically acceptable salt thereof in the inner core 10 is preferably from 10 to 250 mg as valsartan, and more preferably from 40 to 160 mg.

The proportion of valsartan or a pharmaceutically acceptable salt thereof (blending proportion as valsartan) is preferably from 30 to 70 mass %, and more preferably from 40 to 60 mass % based on the total of the pharmaceutical composition constituting the inner core 10.

The pharmaceutical composition constituting the inner core 10 may comprise ingredients other than the aforementioned ingredient. Specifically, the pharmaceutical composition constituting the inner core 10 may further comprise hydrochlorothiazide (HCTZ), amlodipine, aliskiren or the like, or a pharmaceutically acceptable salt thereof. The tablet comprising said inner core 10 is effectively used for the treatment of hypertension. When hydrochlorothiazide, amlodipine or aliskiren is administered in combination with valsartan or a pharmaceutically acceptable salt thereof, it produces more effective antihypertensive activity.

Hydrochlorothiazide (HCTZ) is known as a diuretic, amlodipine is known as a calcium channel blocker, and aliskiren is known as a renin inhibitor. A pharmaceutically acceptable salt of HCTZ, amlodipine or aliskiren may be selected or obtained easily using a known method by those skilled in the art.

Hydrochlorothiazide may be combined in an amount of from 6 to 60 mg to from 10 to 250 mg of valsartan. It may also be combined in an amount of from 5 to 25 mg to from 50 to 160 mg of valsartan. Amlodipine may be combined in an amount of from 2.5 to 10 mg to from 40 to 320 mg of valsartan. In addition, aliskiren may be combined in an amount of from 100 to 350 mg to from 50 to 350 mg of valsartan. Aliskiren may be combined in an amount of from 150 to 300 mg to from 2.5 to 10 mg of amlodipine. All of hydrochlorothiazide, valsartan and amlodipine may also be combined in an amount of, respectively, from 10 to 250 mg (preferably from 10 to 25 mg), from 40 to 320 mg, and from 5 to 10 mg. Within the dosage ranges, the effect of lowering high blood pressure to a normal level is far more markedly manifested.

Compounding examples include combinations of about 80 mg of valsartan and about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide, combinations of about 160 mg of valsartan and about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide, combinations of about 80 mg of valsartan and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, and combinations of about 160 mg of valsartan and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 320 mg of valsartan and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 80 mg of valsartan, about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 160 mg of valsartan, about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide and about 2.5 mg, about 5 mg or about l O.mg of amlodipine, combinations of about 320 mg of valsartan, about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 80 mg of valsartan and about 150 mg or about 300 mg of aliskiren, combinations of about 160 mg of valsartan and about 150 mg or about 300 mg of aliskiren, and combinations of about ,320 mg of valsartan and about 150 mg or about 300 mg of aliskiren. Compounding examples also include combinations of about 150 mg of aliskiren and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, and combinations of about 300 mg of aliskiren and about 5 mg or about 10 mg of amlodipine.

2. Disintegrant

The disintegrant imparts to the inner core 10, the disintegrability that is sufficient to easily disintegrate in the mouth. Specifically, the disintegrant imparts to the inner core 10 a disintegrability that is sufficient for the tablet to easily disintegrate in the mouth, e.g., upon exposure to saliva or a comparable amount of water.

The disintegrants include low-substituted hydroxypropylcellulose, crospovidone, sodium croscarmellose, sodium carboxymethylstarch, carmellose, calcium carmellose, partially pregelatinised starch, starch, sodium carmellose, alginic acid, sodium alginate, guar gum and others. Among these disintegrants, one component may be used alone or two or more components may be used in combination.

The inner core 10 preferably comprises at least low-substituted hydroxypropylcellulose as disintegrant. The disintegrant also comprises at least one component selected from the group consisting crospovidone, sodium croscarmellose, and sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose.

The preferred blend examples of the disintegrants include low-substituted hydroxypropylcellulose alone, a combination of low-substituted hydroxypropylcellulose and crospovidone, a combination of low-substituted hydroxypropylcellulose and sodium croscarmellose, a combination of low-substituted hydroxypropylcellulose and sodium carboxymethylstarch, and others.

As used in the present Specification, the term "low-substituted hydroxypropylcellulose" means hydroxypropylcellulose wherein the molar number of substituting hydroxypropyl groups per glucose unit is from 5 to 16%, preferably from 7 to 13%.

The proportion of disintegrant in the inner core 10 is preferably from 15 to 60 mass %, and more preferably from 20 to 40 mass % based on the total of the pharmaceutical composition constituting the inner core 10. When two or more disintegrants are used in combination, the use is preferably such that the total of the disintegrants is within the ranges of the above proportions.

In the case when disintegrant is added by the proportion above, if the outer layer 20 is made after the inner core 10 is made independently, the inner core 10 may be broken in the process of transport of the inner core 10 or in the process of making the outer layer 20 on the inner core 10, because inner core is fragile very much. However, when OSDrC® rotary tableting machine is used, tablet that includes the disintegrant in the inner core 10 as the proportion above is obtained easily without being broken of the inner core 10.

3. Glidant

The glidant suppresses the adhesion of valsartan (or a pharmaceutically acceptable salt thereof). Specifically, the combination of the disintegrant and the glidant in the inner core 10 affords sufficient disintegrability although valsartan (or a pharmaceutically acceptable salt thereof) is made the active ingredient.

The glidants include inorganic silicic acid compounds, aluminum oxide, aluminum hydroxide, magnesium oxide, magnesium hydroxide and others. The inorganic silicic acid compounds include silicic acid, silicic acid anhydrous, light silicic acid anhydrous, aluminum silicate, calcium silicate, magnesium aluminometasilicate, and others. Among these glidants, one component may be used alone or two or more components may be used in combination.

The inner core 10 preferably comprises as the glidant, light silicic acid anhydrous and/or synthetic aluminum silicate.

The proportion of glidant in the inner core 10 is preferably from 1 to 10 mass %, and more preferably from 1 to 6 mass % based on the total of the pharmaceutical composition constituting the inner core 10. When two or more glidants are used in combination, the use is preferably such that the total of the glidants is within the ranges of the above proportions.

4. Lubricant

Additionally, in the inner core 10 the lubricant insures the dispersability of valsartan (or a pharmaceutically acceptable salt thereof) in the mouth.

The lubricants include magnesium stearate, aluminum stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil, poly(ethylene glycol) such as PEG 4000-8000, talc and others. Among these lubricants, one component may be used alone or two or more components may be used in combination.

The inner core 10 comprises at least a stearate preferably and comprises at least magnesium stearate more preferably.

The proportion of lubricant in the inner core 10 is preferably from 1 to 7 mass %, and more preferably from 2 to 5 mass % based on the total of the pharmaceutical composition constituting the inner core 10. When two or more lubricants are used in combination, the use is preferably such that the total of the lubricants is within the ranges of the above proportions.

5. Other ingredients

The pharmaceutical composition constituting the inner core 10 may also comprise excipients, sweetening agents, taste-masking agents, coloring agents, pH adjuster, or binders other than those ingredients mentioned above. Crystalline cellulose or microcrystalline cellulose may be contained in the pharmaceutical composition constituting the inner core 10. The sweetening agents include, for example, saccharin sodium, dipotassium glycyrrhizate, aspartame, acesulfame potassium, stevia, thaumatin, sucralose and others.

The binders, for example, include water-soluble polymers (such as hydroxypropylcellulose, and hydroxypropylmethylcellulose), gum arabic powder, gelatin and pullulan.

pH adjuster that can be used in the present invention can comprise or consist of one or more of the following: citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, an amino acid, succinic acid, lactic acid, or a salt form of any of the foregoing.

Coloring agents that can be used in the present invention comprise or consist of one or more of the following: iron sesquioxide, yellow iron sesquioxide, Food Yellow No. 5, Food Yellow No. 4, aluminum chelate, titanium oxide, or talc.

B. Outer Layer 20

The outer layer 20 is provided to coat the inner core 10 and imparts sufficient hardness of tablet to the tablet 100. The composition of the outer layer 20 is not particularly limited and the composition may be such that known ingredients for use in tablets are appropriately combined as long as the composition is that which is capable of producing quick disintegrability suited to orally disintegrating tablets, such as quick disintegrability upon exposure to salvia or a comparable amount of water, and possesses the requisite hardness.

The outer layer 20 may, for example, be formed by molding a coating composition comprising the disintegrant, the lubricant and crystalline cellulose (preferably, microcrystalline cellulose). The coating composition thus composed can easily acquire sufficient quick disintegrability and tablet hardness at the same time.

The coating composition constituting the outer layer 20 preferably comprises crospovidone as disintegrant. The coating composition constituting the outer layer 20 also preferably comprises a stearate as glidant and more preferably comprises magnesium stearate.

In addition, the coating composition constituting the outer layer 20 may comprise excipients (e.g., lactose monohydrate), including the binder, the glidant and a foaming agent, additives, such as a flavoring agent, a sweetening agent and a pH adjuster, and others as ingredients other than those mentioned above. One or more components of these ingredients may be added in appropriate amounts and they may be added in the forms of powder, liquid or granule, as necessary, during the tablet manufacturing process that will be described later.

The foaming agents, for example, include sodium hydrogencarbonate. The flavoring agents, for example, include menthol, lemon, lemon lime and orange. The pH adjusters, for example, include citric acid, tartaric acid and malic acid. The sweetening agents, for example, include saccharin, saccharin sodium, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia, thaumatin, sucralose and others. The sweetening agents, for example, include a fast-acting sweetening agent such as aspartame, sucralose, acesulfame potassium.

C. Other Features and Attributes

The hardness of the OD tablets of the present invention is preferably one that is sufficient to allow easy and convenient storage, removal from the packaging, and subsequent handling without breaking the tablet. In one embodiment, the orally disintegrating tablets of the invention are hard enough to be handled and can be packaged like conventional non-OD tablets.

The hardness of the orally disintegrating tablet of the present invention can vary depending on factors including the tablet's shape, size, and weight. In one embodiment, the hardness of a round tablet with diameter of about 6.0 to 10.0 mm, thickness of about 3.0 to 6.0 mm and weight of about 70 to 320 mg (20 mg to 80 mg of valsartan) is, for example, about 30N to about 55N, as measured using a tablet hardness measuring apparatus such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan). In another embodiment, the hardness of a oval tablet with dimension of about 15.0 and 8.0 mm, thickness of about 5.0 to 10.0 mm and weight of about 500 to 600 mg (160 mg of valsartan) is, for example, about 5 ON to about 100N as measured using a tablet hardness measuring apparatus such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan).

The OD tablet of the present invention can take various shapes, for example, round, oval, caplet, doughnut shape, but is not limited to any particular shape.

The size of the OD tablets of the invention can vary but is within an acceptable size so that the tablet is compatible with oral administration and can disintegrate in the oral cavity of a patient.

The weight of the OD tablets of the invention can also vary depending on the amount of active and non-active ingredients present, but is within an acceptable weight range so that the tablet can disintegrate in the oral cavity of a patient upon exposure to salvia or a comparable amount of water. For example, an OD tablet of the invention can have a weight of about 70 mg to about 600 mg.

D. Manufacture

The OD tablet of the invention can be produced by any method known in the art. The tablet 100 can be manufactured, for example, by tableting outer layer powder and inner core powder with an OSDrC® rotary tableting machine having double-structure punches.

Specifically, the outer layer powder is supplied to a space surrounded by a lower center punch and a lower outer punch in the state where the lower center punch is lowered relative to the lower outer punch, and excess powder is removed by rubbing the powder off on the lower outer punch face (mortar face). The upper center punch and the lower center punch are next allowed to move in the direction of mutual approach; and the bottom face part of an outer layer is temporarily molded at a predetermined compression pressure.

Subsequently, inner core powder is supplied to a space surrounded by the lower outer punch and over the bottom face part of an outer layer that has been temporarily molded, in the state where the lower center punch remains lowered. The upper center punch and the lower center punch are allowed to move in the direction of mutual approach; and an inner core is temporarily molded at a predetermined compression pressure.

Finally, the remaining outer layer powder is supplied to a space over the temporarily molded product that has been molded before and during prior steps and around the peripheries within the mortar, in the state where the lower punches (the lower center punch and the lower outer punch) are lowered. This leads to the state where the temporarily molded inner core is completely covered by the temporarily molded bottom face part of an outer layer as well as by the supplied outer layer powder. The upper and lower punches are allowed to move in the direction of mutual approach and molding is carried out at a predetermined pressure.

The manufacturing method thus mentioned permits the inner core to be coated by the outer layer without being forced to move out of the punch. Therefore, even if the inner core 10 has high disintegrability, it will be possible to mold the tablet 100 with ease and reliability.

As stated above, the tablet 100 is a multilayer tablet. However, even if a tablet that can be provided as a single layer is made an inner core 10 and an outer layer 20 is provided on its surface, they alone cannot be formed into an orally disintegrating tablet. When the tablet that can be provided as a single layer has oral disintegrability, there is no need to make it a multilayer to form an orally disintegrating tablet. Thus, the tablet 100 according to the present embodiment is characterized in that the formation of multilayer imparts oral disintegrability to the ingredient, which cannot practically form an orally disintegrating tablet as the single layer because of its tablet hardness and shape-retaining property.

Specifically, when a single layer tablet is to be formed of the same ingredients as the inner core 10, for example, if disintegrant is applied as the preferable range above to the table, it is impossible to make tablet because hardness of the tablet is not enough to be shaped. This produces an advantageous effect of being able to form an orally disintegrating tablet with multilayers from the same ingredient as a non-orally disintegrating tablet with a single layer.

The tablet of the present invention may be a tablet having two inner cores, for example. Fig. 2 is a view showing the second embodiment of the tablet according to the present invention. The tablet 110 shown in Fig. 2 comprises two inner cores 11 and an outer layer 21 coating the two inner cores 11. The tablet 110 is provided with a groove 30 so that it can be easily divided into two distinct tablets, each comprising an inner core 11 coated by an outer layer 21. The tablet 110 may be administered as is or may be divided into two, one of which is to be administered, depending on the required dosage.

The inner core 11 and the outer layer 21 can both be composed of compositions that are the same in composition as the pharmaceutical composition constituting the inner core 10 or the coating composition constituting the outer layer 20.

The preferred embodiments of the present invention have been described above; however, the present invention should not be limited to the above-mentioned embodiments.

Second General Embodiment of the Invention:

As used in the present Specification, the term "sufficient disintegrability" means disintegration of the tablet, for example, on the order of from 1 to 60 seconds, and preferably from 1 to 30 seconds or from 15 to 29 seconds in contrast to the disintegration of common tablets (e.g., conventional solid dosage forms or capsules such as DIOVAN®, manufactured by Novartis Pharma KK), although it cannot unconditionally be defined because of the differences among individuals where the tablet is left to the natural movement of the mouth such as the movement of the tongue when it is held in the mouth. In other words, the phrase "sufficient disintegrability" as used herein means disintegrability such that the dry-coated agent can be disintegrated in the mouth by/upon exposure to saliva or water in a similar amount to the saliva. Specifically, the dry-coated agent of the present invention differs from the common tablet in that the common tablet will neither disintegrate nor dissolve easily unless it is chewed when held in the mouth.

The phrase "effective amount," as used herein, refers to the amount of active ingredient which arrests, reduces or reverses the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. Such an amount can be easily determined by a person skilled in the art by routine experimentation and with no undue burden. The dosage ranges disclosed herein are non-limiting examples of "effective amounts" of the active ingredient that can be used in the OD tablets of the invention. Detailed Description

The preferred embodiments of the dry-coated agent according to the present invention will be described below.

Fig. 3 is a view showing the first embodiment of the dry-coated agent according to the present invention. Dry-coated agent 100 is a dry-coated agent comprising an inner core 10 consisting of pharmaceutical composition containing an effective amount of valsartan or a pharmaceutically acceptable salt thereof, and an outer layer 20 coating the inner core 10.

A. Inner Core

The inner core 10 may, for example, comprise a pharmaceutical composition containing valsartan or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant and a lubricant. The dray-coated agent is capable of being orally administered and disintegrated in the mouth upon exposure to saliva or a comparable amount of water.

Valsartan is hydrophobic, low in solubility, bulky and strongly adhesive; therefore, it will be difficult to prepare orally disintegrating tablets that possess sufficient disintegrability. However, the inner core 10 consisting of the pharmaceutical composition allows the sufficient disintegrability to be obtained. For this reason, the dry-coated agent comprising the inner core 10 is particularly suited as an orally disintegrating tablet that is allowed to disintegrate in the mouth and is orally administered. The respective ingredients that are included in the pharmaceutical composition will be described herein in detail.

1. Active Ingredient

Valsartan is an angiotensin II receptor antagonist and is an acyl compound that may be used for the treatment of hypertension; it is the compound disclosed, for example, in Japanese Patent No. 2749458 and US Patent No. 5399578, and described by (1) below..

In one embodiment, Valsartan is used as the free acid.

Although Valsartan has a chiral carbon, racemic form and/or mono optical active form of valsartan may be used in the embodiment. Valsartan has optical active form (la) or (lb) below, and preferably includes at least (l a).

Proportion of valsartan or a pharmaceutically acceptable salt thereof, focusing on the blending proportion as valsartan, is preferably from 30 to 70 mass %, and more preferably from 40 to 60 mass % based on the total of the pharmaceutical composition constituting the inner core 10.

The pharmaceutical composition constituting the inner core 10 may comprise ingredients other than the aforementioned ingredient. Specifically, the pharmaceutical composition constituting the inner core 10 may further comprise hydrochlorothiazide (HCTZ), amlodipine, aliskiren or the like, or a pharmaceutically acceptable salt thereof. The dry-coated agent 100 comprising said inner core 10 is effectively used for the treatment of hypertension. When hydrochlorothiazide, amlodipine or aliskiren is administered in combination with valsartan or a pharmaceutically acceptable salt thereof, it produces more effective antihypertensive activity.

Hydrochlorothiazide may be combined in an amount of from 6 to 60 mg to from 10 to 250 mg of valsartan. It may also be combined in an amount of from 5 to 25 mg to from 50 to 160 mg of valsartan. Amlodipine may be combined in an amount of from 2.5 to 10 mg to from 40 to 320 mg of valsartan. In addition, aliskiren may be combined in an amount of from 100 to 350 mg to from 50 to 350 mg of valsartan. Aliskiren may be combined in an amount of from 150 to 300 mg to from 2.5 to 10 mg of amlodipine. All of hydrochlorothiazide, valsartan and amlodipine may also be combined in an amount of, respectively, from 10 to 250 mg (preferably from 10 to 25 mg), from 40 to 320 mg, and from 5 to 10 mg. Within these dosage ranges, the effect of lowering high blood pressure to a normal level is far more markedly manifested.

Compounding examples include combinations of about 80 mg of valsartan and about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide, combinations of about 160 mg of valsartan and about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide, combinations of about 80 mg of valsartan and about 2.5 mg or about 5 mg or about 10 mg of amlodipine, combinations of about 160 mg of valsartan and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 320 mg of valsartan and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 80 mg of valsartan, about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 160 mg of valsartan, about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 320 mg of valsartan, about 6.25 mg, about 12.5 mg or about 25 mg of hydrochlorothiazide and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, combinations of about 80 mg of valsartan and about 150 mg or about 300 mg of aliskiren, combinations of about 160 mg of valsartan and about 150 mg or about 300 mg of aliskiren, and combinations of about 320 mg of valsartan and about 150 mg or about 300 mg of aliskiren. Compounding examples also include combinations of about 150 mg of aliskiren and about 2.5 mg, about 5 mg or about 10 mg of amlodipine, and combinations of about 300 mg of aliskiren and about 5 mg or about 10 mg of amlodipine.

2. Disintegrant

The disintegrant imparts to the inner core 10, the disintegrability that is sufficient to easily disintegrate in the mouth. Specifically, the disintegrant imparts to the inner core 10 a disintegrability that is sufficient for the active ingredient (particularly valsartan in either its free or salt form) to easily disintegrate in the mouth, e.g., upon exposure to saliva or a comparable amount of water.

The inner core 10 preferably comprises at least low-substituted hydroxypropylcellulose as disintegrant. The disintegrant also comprises at least one component selected from the group consisting of crospovidone, sodium croscarmellose, and sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose. The preferred blend examples of the disintegrants include low-substituted hydroxypropylcellulose alone, a combination of low-substituted hydroxypropylcellulose and crospovidone, a combination of low-substituted hydroxypropylcellulose and sodium croscarmellose, a combination of low-substituted hydroxypropylcellulose and sodium carboxymethylstarch, and others.

3. Glidant

The glidant suppresses the adhesion of valsartan or a pharmaceutically acceptable salt thereof. Specifically, the combination of the disintegrant and the glidant in the inner core 10 affords high disintegrability although valsartan (or a pharmaceutically acceptable salt thereof) is made the active ingredient.

The glidants include inorganic silicic acid compounds, aluminum oxide, aluminum hydroxide, magnesium oxide, magnesium hydroxide and others. The inorganic silicic acid , compounds include silicic acid, silicic acid anhydrous, light silicic acid anhydrous, aluminum silicate, calcium silicate, magnesium aluminometasilicate, and others. Among these glidants, one component may be used alone or two or more components may be used in combination.

The inner core 10 preferably comprises light silicic acid anhydrous and/or synthetic aluminum silicate.

4. Lubricant

The lubricant insures the dispersability of valsartan (or a pharmaceutically acceptable salt thereof) in the mouth.

5. Sweetening Agent

The pharmaceutical composition constituting the inner core 10 may comprise a slow-acting sweetening agent. Based on the combination of the inner core 10 comprising the slow-acting sweetening agent and the outer layer 20 comprising the fast-acting sweetening agent, the fast-acting sweetening agent diffuses in the mouth before the medicament is released, by which the initial bitterness can be prevented; the slow-acting sweetening agent, which is contained in the inner core, diffuses in the mouth after the dry-coated agent has completely disintegrated, by which the bitterness remaining after administration can be lessened.

The slow-acting sweetening agents include saccharin, saccharin sodium and others, among which saccharin sodium is preferable. One component of the slow-acting sweetening agents may be used alone or two or more components may be used in combination.

The proportion of slow-acting sweetening agent may be adjustable depending on its sweetness and is the amount to be as sweet as preferably from 100 to 5000 mass part of sucrose, and more preferably from 500 to 2000 mass part of sucrose for 100 mass part of valsartan in the pharmaceutical composition constituting the inner core 10. Saccharin has 300 times of sweetness and sucralose has 500 times of sweetness compared to sweetness of sucrose.

In the case when saccharin sodium is used as the slow-acting sweetening agent, the proportion of saccharin sodium is preferably from 0.5 to 5.0 mass part of saccharin sodium, and more preferably from 1.5 to 2.5 mass part of saccharin sodium for 100 mass part of valsartan in the pharmaceutical composition constituting the inner core 10.

6. Other ingredients

The pharmaceutical composition constituting the inner core 10 may also comprise excipients, some other sweetening agents, taste-making agents, coloring agents, pH adjusting agents or binders other than those ingredients mentioned above. Crystalline cellulose or microcrystalline cellulose may be contained in the pharmaceutical composition constituting the inner core 10.

The binders, for example, include water-soluble polymers (such as hydroxypropylcellulose and hydroxypropylmethylcellulose), gum arabic powder, gelatin and pullulan. The sweetening agents include, for example, saccharin sodium, dipotassium glycyrrhizate, aspartame, acesulfame potassium, stevia, thaumatin, sucralose and others.

pH adjusting agents that can be used in the present invention can comprise or consist of one or more of the following: citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, an amino acid, succinic acid, lactic acid, or a salt form of any of the foregoing.

B. Outer Layer 20

The outer layer 20 consists of a coating composition containing a pH adjuster which makes the inside of the mouth mildly acidic ( i.e., pH range from 2.0 to 5.0, and more preferably pH range from 3.0 to 4.0) and coats the inner core 10 to impart sufficient hardness to the dry-coated agent 100.

1. pH Adjuster

The inclusion of the pH adjuster in the coating composition constituting the outer layer 20 can adequately prevent bitterness and achieve the improvement of QOL as intended when the dry-coated agent is allowed to disintegrate in the mouth and then used to be orally administered.

The inside of the mouth is slightly acidified when the dry-coated agent 100 is allowed to disintegrate in the mouth. Further, since valsartan is an acidic medicament, it is thought that the immediate solubility will be lowered as the acidity inside the mouth becomes higher. Specifically, it is thought that the inside of the mouth is acidified by the outer layer 20 that has disintegrated therein before valsartan in the inner core 10 is released and, therefore, that the dissolution of valsartan in the mouth is suppressed to prevent the bitterness.

The pH adjusters include anhydrous citric acid, citric acid hydrate, a citrate such as sodium dihydrogen citrate and a phosphate such as sodium dihydrogen phosphate. Among these, anhydrous citric acid and citric acid hydrate are preferable. One component of the pH adjusters may be used alone or two or more components may be used in combination.

The amount of pH adjuster is preferably determined by the amount that changes pH of 5ml purified water to the mildly acidic pH range, i.e., from 2.0 to 5.0, and more preferably the pH range from 3.0 to 4.0.

In the case when anhydrous citric acid is used as the pH adjuster, the proportion of anhydrous citric acid is preferably from 0.5 to 10 mass part of anhydrous citric acid, and more preferably from 0.5 to 5 mass part of anhydrous citric acid for 100 mass part of valsartan in the pharmaceutical composition constituting the inner core 10.

2. Sweetening Agent

The coating composition constituting the outer layer 20 preferably comprises a sweetening agent. The outer layer 20 disintegrates in the mouth before the inner core 10 disintegrates to release valsartan. The inclusion of the sweetening agent in the outer layer 20, therefore, allows the sweetening agent to be diffused in the mouth before valsartan is released, by which the bitterness exhibited by valsartan can be more prevented.

The sweetening agents include, for example, saccharin, saccharin sodium, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia, thaumatin and others.

The coating composition constituting the outer layer 20 preferably comprises a fast-acting sweetening agent among the aforementioned sweetening agents. The fast-acting agent can produce the bitterness prevention effects by the aforementioned sweetening agents more effectively.

Based on the combination of the inner core 10 containing the slow-acting sweetening agent (e.g., saccharin and/or saccharin sodium) and the outer layer 20 containing the fast-acting sweetening agent, the fast-acting sweetening agent diffuses in the mouth before the medicament is released, by which the initial bitterness can be prevented; the slow-acting sweetening agent, which is contained in the inner core, diffuses in the mouth after the dry-coated agent has completely disintegrated, by which the bitterness remaining after administration can be lessened.

The fast-acting sweetening agents include aspartame, sucralose, acesulfame potassium and others.

The proportion of sweetening agent in the outer layer may be adjustable depending on its sweetness and is the amount to be as sweet as preferably from 100 to 5000 mass part of sucrose, and more preferably from 1000 to 3000 mass part of sucrose for 100 mass part of valsartan in the pharmaceutical composition constituting the inner core 10. Aspartame and acesulfame potassium have 200 times of sweetness and sucralose has 600 times of sweetness compared to sweetness of sucrose.

In the case when aspartame is used as the fast-acting sweetening agent, the proportion of aspartame is preferably from 1 to 20 mass part of aspartame, and more preferably from 5 to 10 mass part of aspartame for 100 mass part of valsartan in the pharmaceutical composition constituting the inner core 10.

3. Other ingredients

The ingredients of the coating composition constituting the outer layer 20 other than those mentioned above are not particularly limited and the composition may be such that known ingredients for use in tablets are appropriately combined. The composition is further preferred to be a composition capable of providing quick disintegrability suited to an orally disintegrating tablet.

The coating composition constituting the outer layer 20 may comprise the disintegrant (e.g., crospovidone), the lubricant (e.g., a stearate such as magnesium stearate) and crystalline cellulose (preferably, macrocrystalline cellulose) as ingredients other than those mentioned above, for example. The coating composition thus composed can easily acquire sufficient quick disintegrability and the strength of agent at the same time.

The coating composition constituting the outer layer 20 preferably comprises crospovidone as disintegrant. The coating composition constituting the outer layer 20 also preferably comprises a stearate and more preferably comprises magnesium stearate.

In addition, the coating composition constituting the outer layer 20 may comprise excipients (e.g., lactose monohydrate), including the binder, the glidant and a foaming agent, additives, such as a flavoring agent and a pH adjuster, and others as ingredients other than those mentioned above. One or more components of these ingredients may be added in appropriate amounts and they may be added in the forms of powder, liquid or granule, as necessary, during the tablet manufacturing process that will be described below.

The foaming agents, for example, include sodium hydrogencarbonate. The flavoring agents, for example, include menthol, lemon, lemon lime and orange.

C. Other Features and Properties

The hardness of the dry-coated agent of the present invention can be adjusted so that it is sufficient to allow easy and convenient storage, removal from packaging, and subsequent handling of the coating agent without breaking the dry-coated agent. In one embodiment, the dry-coated agent is hard enough to be handled and packaged like conventional non-OD tablets.

The hardness of the dry-coated agent of the present invention can vary depending upon factors including its shape, dimensions and weight. In one embodiment, the hardness of a round tablet with diameter of about 6.0 to 10.0 mm, thickness of about 3.0 to 6.0 mm and weight of about 70 to 320 mg (20 mg to 80 mg of valsartan) is, for example, about 30N to about 55N, as measured using a tablet hardness measuring apparatus such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan). In another embodiment, the hardness of a oval tablet with dimension of about 15.0 and 8.0 mm, thickness of about 5.0 to 10.0 mm and weight of about 500 to 600 mg (160 mg of valsartan) is, for example, about 50N to 100N as measured using a tablet hardness measuring apparatus such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan). The dry-coated agent of the present invention can take various shapes, for example, round, oval, caplet, doughnut shape, but is not limited to any particular shape.

The size of the dry-coated agent of the invention can vary but should be within the acceptable size for oral administration of the dry-coated agent and its disintegration in the oral cavity of a patient.

The weight of the dry-coated agent of the invention can also vary depending on the amount of active and non-active ingredients, but is within the acceptable weight range for disintegration in the oral cavity of a patient. For example, a dry-coated agent of the invention can have a weight of about 70 mg to about 600 mg.

The dissolvability of valsartan from the dry-coated agent according to the present embodiment is preferably at the same or similar level as that of valsartan from a common tablet containing valsartan such as DIOVAN® tablet (manufactured by Novartis Pharma K.K.). According to one example of the test methods for ascertaining said dissolvability, although available in several types, 75% or more of valsartan is preferably dissolved in 120 minutes after the start of the test when the tablet is tested at 50 rpm using the paddle method of the Japanese Pharmacopeia by employing a buffer of pH 3.0 as testing solution, and more preferably, 80% or more of valsartan is dissolved in 120 minutes. When administered to a human, the tablet according to the present invention undergoes dissolution that is biologically equal to a DIOVAN® tablet.

D. Manufacture

The OD tablet of the invention can be produced by any method known in the art. The dry-coated agent 100 can be manufactured, for example, by tableting outer layer powder and inner core powder with an OSDrC® rotary tableting machine having double-structure punches.

Specifically, outer layer powder is supplied to a space surrounded by a lower center punch and a lower outer punch in the state where the lower center punch is lowered relative to the lower outer punch, and excess powder is removed by rubbing the powder off on the lower outer punch face (mortar face). The upper center punch and the lower center punch are next allowed to move in the direction of mutual approach; and the bottom face part of an outer layer is temporarily molded at a predetermined compression pressure.

Subsequently, inner core powder is supplied to a space surrounded by a lower outer punch and over the bottom face part of an outer layer that has been temporarily molded, in the state where the lower center punch remains lowered. The upper center punch and the lower center punch are allowed to move in the direction of mutual approach; and an inner core is temporarily molded at a predetermined compression pressure.

Finally, the remaining outer layer powder is supplied to a space over the temporarily molded product that has been molded before and during the prior steps and around the peripheries within the mortar, in the state where the lower punches (the lower center punch and lower outer punch) are lowered. This leads to the state where the temporarily molded inner core is completely covered by the temporarily molded bottom face part of an outer layer as well as by the supplied outer layer powder. The upper and lower punches are allowed to move in the direction of mutual approach and molding is carried out at a predetermined pressure.

The manufacturing method thus mentioned permits the inner core to be coated by the outer layer without being forced to move out of the punch. Therefore, even if the inner core 10 has high disintegrability, it will be possible to mold the dry-coated agent 100 with ease and reliability.

The dry-coated agent of the present invention may be a dry-coated agent having two cores, for example. Fig. 4 is a view showing the second embodiment of the dry-coated agent according to the present invention. The dry-coated agent 110 shown in Fig. 4 comprises two inner cores 11 and an outer layer 21 coating the two inner cores 11. The dry-coated agent 110 is provided with a groove 30 so that it can be easily divided into two distinct dry-coated agents, each comprising an inner core 11 coated by an outer layer 21. The dry-coated agent 110 may be administered as is or may be divided into two, one of which is to be administered, depending on the required dosage.

The dry-coated agent of the present embodiment is useful in lowering blood pressure at the systolic phase, the diastolic phase or both. The dry-coated agent of the present embodiment is also useful for the disease conditions, including hypertension (malignant, essential, renovascular, diabetic, isolated systolic or other secondary types), congestive heart failure, angina (stable or unstable), myocardial infarction, arteriosclerosis, atherosclerosis, diabetic nephropathy, diabetic myocardial disease, renal failure, peripheral arterial disease, left ventricular disease, cognitive function failure (such as Alzheimer disease), stroke and others.

EXAMPLES

The present invention will be described in more detail by way of examples; however, the present invention should not be limited to the examples.

EXAMPLE 1-1

The followings were blended: 55.7 parts by weight of valsartan, 5.1 parts by weight of light anhydrous silicic acid, 29.1 parts by weight of low-substituted hydroxypropylcellulose and 2.0 parts by weight of magnesium stearate. The blended material was passed through a sieve and further blended for a certain period of time. The blended material was compacted using a roller compactor. Next, the compacted material was pulverized to target particle size and then blended after 7.0 parts by weight of crospovidone and 1.0 parts by weight of sodium saccharin were added. The blended material was compacted again by roller compactor. The compacted material was granulated to target particle size and thus, the granulated powder was obtained. The compacting and granulation were repeated as necessary, and the obtained granulated powder was blended to be prepared as inner core powder 10-A.

Next, 44.0 parts by weight of lactose monohydrate, 40.0 parts by weight of crystalline cellulose, 10.0 parts by weight of crospovidone, 4.0 parts by weight of aspartame, 0.5 parts by weight of fragrance, 0.7 parts by weight of citric acid anhydrous and 0.5 parts by weight of light anhydrous silicic acid were blended, then 0.3 parts by weight of magnesium stearate was added, and after further blending, outer layer powder 20-A was prepared.

By OSDrC® rotary tableting machine employing a double-layered punch having an outer punch of 9.5 mmO and a center punch of 7.5 mm , inner core powder 10-A and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (320.0 mg) having a pharmaceutical composition (143.5 mg) formed by compressing inner core powder 10-A as the inner core and a coating composition (176.5 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-2

The followings were blended: 55.5 parts by weight of valsartan, 5.1 parts by weight of light anhydrous silicic acid, 29.0 parts by weight of low-substituted hydroxypropylcellulose and 2.0 parts by weight of magnesium stearate. The blended material was passed through a sieve and further blended for a certain period of time. The blended material was compacted using a roller compactor. Next, the compacted material was pulverized to target particle size and then blended after 6.9 parts by weight of crospovidone, 1.0 parts by weight of sodium saccharin and 0.5 parts by weight of magnesium stearate were added. The blended material was compacted again by roller compactor. The compacted material was granulated to target particle size and thus, the granulated powder was obtained. The compacting and granulation were repeated as necessary, and the obtained granulated powder was blended to be prepared as inner core powder 10-B.

Next, outer layer powder 20-A was obtained in the same manner as Example 1-1.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 mmO, inner core powder 10-B and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (320.0 mg) having a pharmaceutical composition (144.2 mg) formed by compressing inner core powder 10-B as the inner core and a coating composition (175.8 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-3

The followings were blended: 60.0 parts by weight of valsartan, 5.5 parts by weight of light anhydrous silicic acid, 23.2 parts by weight of low-substituted hydroxypropylcellulose and 2.2 parts by weight of magnesium stearate. The blended material was passed through a sieve and further blended for a certain period of time. The blended material was compacted using a roller compactor. Next, the compacted material was pulverized to target particle size and then blended after 7.5 parts by weight of crospovidone, 1.1 parts by weight of sodium saccharin and 0.5 parts by weight of magnesium stearate were added. The blended material was compacted again by roller compactor. The compacted material was granulated to target particle size and thus, the granulated powder was obtained. The compacting and granulation were repeated as necessary, and the obtained granulated powder was blended to be prepared as inner core powder 10-C.

Next, outer layer powder 20-A was obtained in the same manner as Example 1-1.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 mmO, inner core powder 10-C and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (308.3 mg) having a pharmaceutical composition (133.3 mg) formed by compressing inner core powder 10-C as the inner core and a coating composition (175.0 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-4

The followings were blended: 60.0 parts by weight of valsartan, 5.5 parts by weight of light anhydrous silicic acid, 18.8 parts by weight of low-substituted hydroxypropylcellulose and 2.2 parts by weight of magnesium stearate. The blended material was passed through a sieve and further blended for a certain period of time. The blended material was compacted using a roller compactor. Next, the compacted material was pulverized to target particle size and then blended after 7.5 parts by weight of crospovidone, 1.1 parts by weight of sodium saccharin, 1.1 parts by weight of magnesium stearate and 3.8 parts by weight of crystalline cellulose were added. The blended material was compacted again by roller compactor. The compacted material was granulated to target particle size and thus, the granulated powder was obtained. The compacting and granulation were repeated as necessary, and the obtained granulated powder was blended to be prepared as inner core powder 10-D.

Next, outer layer powder 20-A was obtained in the same manner as Example 1-1.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mm<t> and a center punch of 7.5 mmO, inner core powder 10-D and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (308.3 mg) having a pharmaceutical composition (133.3 mg) formed by compressing inner core powder 10-D as the inner core and a coating composition (175.0 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-5

Inner core powder 10-A and outer layer powder 20-A were obtained in the same manner as Example 1-1. By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 6.0 mmO and a center punch of 4.5 mmO, inner core powder 10-A and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (80.0 mg) having a pharmaceutical composition (35.9 mg) formed by compressing inner core powder 10-A as the inner core and a coating composition (44.1 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-6

Inner core powder 10-A and outer layer powder 20-A were obtained in the same manner as Example 1-1. By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 6.0 mmO and a center punch of 4.5 mmO, inner core powder 10-A and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (96.5 mg) having a pharmaceutical composition (35.9 mg) formed by compressing inner core powder 10-A as the inner core and a coating composition (60.6 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-7

Inner core powder 10-D and outer layer powder 20-A were obtained in the same manner as Example 1-4. By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 6.0 mmO and a center punch of 4.5 mmO, inner core powder 10-D and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (77.1 mg) having a pharmaceutical composition (33.3 mg) formed by compressing inner core powder 10-D as the inner core and a coating composition (43.8 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-8

Inner core powder 10-D and outer layer powder 20-A were obtained in the same manner as Example 1-4. By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 6.0 mmO and a center punch of 4.5 mmO, inner core powder 10-D and outer layer powder 20-A are tableted. Thus, a dry-coated tablet (96.0 mg) having a pharmaceutical composition (33.3 mg) formed by compressing inner core powder 10-D as the inner core and a coating composition (62.7 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-9

Inner core powder 10-A and outer layer powder 20-A were obtained in the same manner as Example 1-1. By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 8.0 mm and a center punch of 7.5 mmi>, inner core powder 10-A and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (160.0 mg) having a pharmaceutical composition (71.75 mg) formed by compressing inner core powder 10-A as the inner core and a coating composition (88.25 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE I- 10

Inner core powder 10-D and outer layer powder 20-A were obtained in the same manner as Example 1-4. By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 8.0 mmO and a center punch of 7.5 mmO, inner core powder 10-D and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (154.2 mg) having a pharmaceutical composition (66,65 mg) formed by compressing inner core powder 10-D as the inner core and a coating composition (87.55 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE I- 11

Inner core powder 10-A and outer layer powder 20-A were obtained in the same manner as Example 1-1. By OSDrC® rotary tableting machine employing a double-layered punch having atypical outer punch with longest diameter of 15 mm and shortest diameter of 8 mm and atypical center punch with longest diameter of 13 mm and shortest diameter of 6 mm, inner core powder 10-A and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (590.0 mg) having a pharmaceutical composition (287.0 mg) formed by compressing inner core powder 10-A as the inner core and a coating composition (303.0 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE 1-12

Inner core powder 10-D and outer layer powder 20-A were obtained in the same manner as Example 1-4. By OSDrC® rotary tableting machine employing a double-layered punch having atypical outer punch with longest diameter of 15 mm and shortest diameter of 8 mm and atypical center punch with longest diameter of 13 mm and shortest diameter of 6 mm, inner core powder 10-D and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (580.0 mg) having a pharmaceutical composition (266.6 mg) formed by compressing inner core powder 10-D as the inner core and a coating composition (313.4 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

Table 1-2 lists the compositions of inner core powder 10-A to 10D. Table 1-3 lists the composition of outer layer powder 20-A.

Table 1-2

Inner Core Powder

Table 1-3

Outer Layer Powder

Table 1-4 lists the compositions of the dry-coated tablets of Examples 1-1 to 1-12.

Table 1-4

The dry-coated tablets obtained in the examples were measured for their hardness in the diameter direction using a tablet hardness meter (PC-30, Okada Seiko Co., Ltd., Japan). The results obtained are as shown in Table 1-1. <Measurement of abrasive level>

The dry-coated tablets obtained in the examples were measured for their abrasive levels in accordance with Tablet Friability Test (Japanese Pharmacopeia Reference Information). The results obtained are as shown in Table 1-1.

The dry-coated tablets obtained in the examples were evaluated for the time spent on their oral disintegration in male adults. Detailed procedures are as follows. The dry-coated tablets were each taken into the oral cavity and allowed to disintegrate while being rolled by the tongue. The time required for complete disintegration was measured for each tablet. The results obtained are as shown in Table 1-1.

Table 1-1

EXAMPLES The present invention will be described in more detail by way of examples; however, the present invention should not be limited to the examples.

[Comparative Example II-l]

The followings were blended: 55.1 parts by weight of valsartan, 4.6 parts by weight of light anhydrous silicic acid, 23.3 parts by weight of low-substituted hydroxypropylcellulose and 3.0 parts by weight of magnesium stearate. The blended material was passed through a sieve and further blended for a certain period of time. The blended material was compacted using a roller compactor. Next, the compacted material was pulverized to target particle size and then blended after 4.0 parts by weight of sucralose and 10.0 parts by weight of crospovidone were added. The blended material was compacted again by roller compactor. The compacted material was granulated to target particle size and thus, the granulated powder was obtained. The compacting and granulation were repeated as necessary, and the obtained granulated powder was blended to be prepared as inner core powder 10-A.

Next, 46.9 parts by weight of lactose monohydrate, 40.0 parts by weight of crystalline cellulose, 10.0 parts by weight of crospovidone, 1.4 parts by weight of aspartame, 1.0 parts by weight of sodium saccharin and 0.5 parts by weight of fragrance were blended, then 0.2 parts by weight of magnesium stearate was added, and after further blending, outer layer powder 20-A was prepared.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 mmO, inner core powder 10-A and outer layer powder 20-A are tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-A as the inner core and a coating composition (174.8 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

EXAMPLE II- 1 Inner core powder 10-A was obtained in the same manner as Comparative Example II-l . Aside from adding 0.7 parts by weight of citric acid anhydrous together with magnesium stearate, outer layer powder 20-B was obtained in the same manner as Comparative Example II-l .

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mm<E> and a center punch of 7.5 mm<B, inner core powder 10-A and outer layer powder 20-B were tableted. Thus, a dry-coated tablet (321.3 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-A as the inner core and a coating composition (176.1 mg) formed by compressing outer layer powder 20-B as the outer layer, was produced.

(Bitter taste evaluation 1)

A sensory test was conducted for the dry-coated tablets of Comparative Example II-l and Example II-l . As a result, a dry-coated tablet of Example II-l had a lower degree of bitterness as compared to the dry-coated tablet of Comparative Example II-l .

Table II-3 shows the compositions of the dry-coated tablets of Comparative Example II-l and Example II-l .

Table II-3

comparative

Examples li 11-1

example IH

Inner Core Powder 10-A 10-A

Valsartan 55.1 55.1

Low-substituted hydroxypropylcellulose 23.3 23.3

Crospovidone 10.0 10.0

Light anhydrous silicic acid 4.6 4.6

Magnesium stearate 3.0 3.0

Sodium saccharin

Sucralose 4.0 4.0

Crystalline cellulose

Total (part) 100.0 100.0

Pharmaceutical composition (mg) 145.2 145.2

Outer Layer Powder 20-A 20-B

Lactose monohydrate 46.9 46.9

Crystalline cellulose 40.0 40.0

Crospovidone 10.0 10.0

Aspartame 1.4 1.4

Sodium saccharin 1.0 1.0

Citric acid anhydrous 0.7

Light anhydrous silicic acid

Fragrance 0.5 0.5

Magnesium stearate 0.2 0.2

Total (part) 100.0 100.7

Coating composition (mg) 174.8 176.1

Dry -coated agent (mg) 320.0 321.3

Outer punch (mm) 9.5 9.5

Center punch (mm) 7.5 7.5

EXAMPLE II-2

The followings were blended: 55.2 parts by weight of valsartan, 4.6 parts by weight of light anhydrous silicic acid, 27.2 parts by weight of low-substituted hydroxypropylcellulose and 3.0 parts by weight of magnesium stearate. The blended material was passed through a sieve and further blended for a certain period of time. The blended material was compacted using a roller compactor. Next, the compacted material was pulverized to target particle size and then blended after 10.0 parts by weight of crospovidone was added. The blended material was compacted again by roller compactor. The compacted material was granulated to target particle size and thus, the granulated powder was obtained. The compacting and granulation were repeated as necessary, and the obtained granulated powder was blended to be prepared as inner core powder 10-B.

Next, outer layer powder 20-B was obtained in the same manner as Example II- 1.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 ηιηιΦ and a center punch of 7.5 mmO, inner core powder 10-B and outer layer powder 20-B were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-B as the inner core and a coating composition (174.8 mg) formed by compressing outer layer powder 20-B as the outer layer, was produced.

EXAMPLE II-3

Aside from adding crospovidone in the amount of 9.0 parts by weight and further adding 1.0 parts by weight of sodium saccharin, the inner core powder was prepared in the same manner as Example II-2 to obtain Inner core powder 10-C. Next, outer layer powder 20-B was obtained in the same manner as Example II- 1.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mm and a center punch of 7.5 ηπηΦ, inner core powder 10-C and outer layer powder 20-B were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-C as the inner core and a coating composition (174.8 mg) formed by compressing outer layer powder 20-B as the outer layer, was produced.

(Comparative Example II-2)

Aside from adding crospovidone in the amount of 8.0 parts by weight and further adding 2.0 parts by weight of sodium saccharin, the inner core powder was prepared in the same manner as Example II-2 to obtain Inner core powder 10-D. Next, outer layer powder 20-A was obtained in the same manner as Comparative Example II- 1.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 mmO, inner core powder 10-D and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-D as the inner core and a coating composition ( 174.8 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

(Comparative Example II-3)

Aside from adding crospovidone in the amount of 6.9 parts by weight and further adding 3.1 parts by weight of sodium saccharin, the inner core powder was prepared in the same manner as Example II-2 to obtain Inner core powder 10-E. Next, outer layer powder 20-A was obtained in the same manner as Comparative Example II- 1.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 mmO, inner core powder 10-E and outer layer powder 20-A were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-E as the inner core and a coating composition ( 174.8 mg) formed by compressing outer layer powder 20-A as the outer layer, was produced.

(Bitter taste evaluation 2)

With four participants, a sensory test was conducted for the dry-coated tablets of Examples II-2 and II-3, and the dry-coated tablets of Comparative Examples II-2 and II-3. The bitterness was ranked from low degree and evaluated with the rank sum of the four participants. The result is as shown in Table II-l .

Table II- 1

Table II-4 shows the eompositions of the dry-coated tablets of Examples II-2 and II-3 and the dry-coated tablets of Comparative Examples II-2 and II-3.

Table II-4 comparative comparative

Examples II 11-2 II-3

example II-2 example II— 3

Inner Core Powder 10-B 10-C 10-D 10-E

Valsartan 55.2 55.2 55.2 55.2

Low-substituted hydroxypropylcellulose 27.2 27.2 27.2 27.2

Crospovidone 10.0 9.0 8.0 6.9

Light anhydrous silicic acid 4.6 4.6 4.6 4.6

Magnesium stearate 3.0 3.0 3.0 3.0

Sodium saccharin 1.0 2.0 3.1

Sucralose

Crystalline cellulose

Total (part) 100.0 100.0 100.0 100.0

Pharmaceutical composition (mg) 145.2 145.2 145.2 145.2

Outer Layer Powder 20-B 20-B 20-A 20-A

Lactose monohydrate 46.9 46.9 46.9 46.9

Crystalline cellulose 40.0 40.0 40.0 40.0

Crospovidone 10.0 10.0 10.0 10.0

Aspartame 1.4 1.4 1.4 1.4

Sodium saccharin 1.0 1.0 1.0 1.0

Citric acid anhydrous 0.7 0.7

Light anhydrous silicic acid

Fragrance 0.5 0.5 0.5 0.5

Magnesium stearate 0.2 0.2 0.2 0.2

Total (part) 100.7 100.7 100.0 100.0

Coating composition (mg) 174.8 174.8 174.8 174.8

Dry-coated agent (mg) 320.0 320.0 320.0 320.0

Outer punch (mm) 9.5 9.5 9.5 9.5

Center punch (mm) 7.5 7.5 7.5 7.5

EXAMPLE II-4

The followings were blended: 55.2 parts by weight of valsartan, 5.0 parts by weight of light anhydrous silicic acid, 28.8 parts by weight of low-substituted hydroxypropylcellulose and 3.0 parts by weight of magnesium stearate. The blended material was passed through a sieve and further blended for a certain period of time. The blended material was compacted using a roller compactor. Next, the compacted material was pulverized to target particle size and then blended after 6.9 parts by weight of crospovidone and 1.0 parts by weight of sodium saccharin were added. The blended material was compacted again by roller compactor. The compacted material was granulated to target particle size and thus, the granulated powder was obtained. The compacting and granulation were repeated as necessary, and the obtained granulated powder was blended to be prepared as inner core powder 10-G.

Next, 46.9 parts by weight of lactose monohydrate, 40.0 parts by weight of crystalline cellulose, 10.0 parts by weight of crospovidone, 1.4 parts by weight of aspartame, 1.0 parts by weight of sodium saccharin, 0.7 parts by weight of citric acid anhydrous and 0.5 parts by weight of fragrance were blended, then 0.2 parts by weight of magnesium stearate was added, and after further blending, outer layer powder 20-C was prepared.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 ιηιηΦ, inner core powder 10-G and outer layer powder 20-C were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-G as the inner core and a coating composition (174.8 mg) formed by compressing outer layer powder 20-C as the outer layer, was produced.

EXAMPLE II-5

Inner core powder 10-G was obtained in the same manner as Example II-4. Aside from adding lactose monohydrate in the amount of 46.3 parts by weight and aspartame in the amount of 2.0 parts by weight, outer layer powder 20-D was obtained in the same manner as Example II-4.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 mmO, inner core powder 10-G and outer layer powder 20-D were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-G as the inner core and a coating composition (174.8 mg) formed by compressing outer layer powder 20-D as the outer layer, was produced.

EXAMPLE II-6

Inner core powder 10-G was obtained in the same manner as Example Π-4. Aside from adding lactose monohydrate in the amount of 44.3 parts by weight and aspartame in the amount of 4.0 parts by weight, outer layer powder 20-E was obtained in the same manner as Example II-4.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mm<I> and a center punch of 7.5 mmO, inner core powder 10-G and outer layer powder 20-E were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-G as the inner core and a coating composition (174.8 mg) formed by compressing outer layer powder 20-E as the outer layer, was produced.

EXAMPLE II-7

Inner core powder 10-G was obtained in the same manner as Example II-4. Aside from adding lactose monohydrate in the amount of 42.3 parts by weight and aspartame in the amount of 6.0 parts by weight, outer layer powder 20-F was obtained in the same manner as Example II-4.

By OSDrC® rotary tableting machine employing a double-layered punch having outer punch of 9.5 mmO and a center punch of 7.5 mmO, inner core powder 10-G and outer layer powder 20-F were tableted. Thus, a dry-coated tablet (320.0 mg), which has a pharmaceutical composition (145.2 mg) formed by compressing inner core powder 10-G as the inner core and a coating composition (174.8 mg) formed by compressing outer layer powder 20-F as the outer layer, was produced.

(Bitter taste evaluation 2)

With four participants, a sensory test was conducted for the dry-coated tablets of Examples II-4-7. The bitterness was ranked from low degree and evaluated with the rank sum of the four participants. The result is as shown in

Table II-2.

Table II-2

Table II-5 shows the compositions of the dry-coated tablets Examples II-4 to II-7.

Table II-5

Examples II 11-4 II-5 II-6 II-7

Inner Core Powder 10-G 10-G 10-G 10-G

Valsartan 55.2 55.2 55.2 55.2

Low-substituted hydroxypropylcellulose 28.8 28.8 28.8 28.8

Crospovidone 6.9 6.9 6.9 6.9

Light anhydrous silicic acid 5.0 5.0 5.0 5.0

Magnesium stearate 3.0 3.0 3.0 3.0

Sodium saccharin 1.0 1.0 1.0 1.0

Sucralose

Crystalline cellulose

Total (part) 100 100 100 100

Pharmaceutical composition (mg) 145.2 145.2 145.2 145.2

Outer Layer Powder 20-C 20-D 20-E 20-F

Lactose monohydrate 46.9 46.3 44.3 42.3

Crystalline cellulose 40.0 40.0 40.0 40.0

Crospovidone 10.0 10.0 10.0 10.0

Aspartame 1.4 2.0 4.0 6.0

Sodium saccharin 1.0 1.0 1.0 1.0

Citric acid anhydrous 0.7 0.7 0.7 0.7

Light anhydrous silicic acid

Fragrance 0.5 0.5 0.5 0.5

Magnesium stearate 0.2 0.2 0.2 0.2

Total (part) 100.7 100.7 100.7 100.7

Coating composition (mg) 174.8 174.8 174.8 174.8

Dry -coated agent (mg) 320.0 320.0 320.0 320.0

Outer punch (mm) 9.5 9.5 9.5 9.5

Center punch (mm) 7.5 7.5 7.5 7.5

EXAMPLE III The dry-coated tablets PTl and PT2 having the composition as shown e III were produced.

Table III

Explanation of reference numerals

100, 110: tablet; 10, 11 : inner core; 20, 21 : outer layer; 30: groove.

All patents, patent applications, publications and the like referenced in this application are incorporated herein by reference in their entirety. This invention includes the following embodiments:

[1] A tablet consisting of pharmaceutical composition comprising a valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, wherein the tablet is orally administrated through disintegration in the mouth by saliva or water in a similar amount to the saliva.

[2] An orally disintegrating tablet comprising an inner core consisting of pharmaceutical composition comprising a valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant, and a lubricant, and an outer layer coating the inner core.

[3] The tablet according to [2], wherein the outer layer comprises a crystalline cellulose, a disintegrant and a lubricant.

[4] The tablet according to any one of [l]-[3], wherein the disintegrant comprises at least one component selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, sodium croscarmellose, sodium carboxymethylstarch, carmellose, calcium carmellose, partially pregelatinised starch, starch, sodium carmellose, alginic acid, sodium alginate and guar gum.

[5] The tablet according to any one of [l]-[4], wherein the disintegrant comprises at least low-substituted hydroxypropylcellulose.

[6] The tablet according to any one of [l]-[5], wherein the disintegrant comprises at least one component selected from the group consisting of crospovidone, sodium croscarmellose and sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose.

[7] The tablet according to any one of [l]-[6], wherein the glidant comprises at least one component selected from the group consisting of silicic acid, silicic acid anhydrous, aluminum silicate, calcium silicate, magnesium aluminometasilicate, aluminum oxide, aluminum hydroxide, magnesium oxide and magnesium hydroxide.

[8] The tablet according to any one of [l]-[7], wherein the glidant comprises light anhydrous silicic acid and/or synthetic aluminum silicate.

[9] The tablet according to any one of [l]-[8], wherein the lubricant comprises at least one component selected from the group consisting of magnesium stearate, aluminum stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil, poly(ethylene glycol) and talc.

[10] The tablet according to any one of [l]-[9], wherein the lubricant comprises at least magnesium stearate.

[11] The tablet according to any one of [1]-[10], wherein the pharmaceutical composition further comprises a hydrochlorothiazide and/or an amlodipine or a pharmaceutically acceptable salt thereof.

[12] The tablet according to any one of [1 ]-[11], wherein the pharmaceutical composition further comprises a aliskiren or a pharmaceutically acceptable salt thereof.

[12-1] The tablet according to any one of [1]-[12], wherein the outer layer is consisting of coating composition containing pH adjuster which makes inside of the mouth mildly acidic.

[12-2] The tablet according to [12-1], wherein the pH adjuster contains at least one component selected from the group consisting of anhydrous citric acid, citric acid hydrate and sodium dihydrogen citrate.

[12-3] The tablet according to [12-1] or [12-2], wherein the coating composition further contains a sweetening agent.

[12-4] The tablet according to [12-3], wherein the sweetening agent contains at least one component selected from the group consisting of saccharin, saccharin sodium, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia and thaumatin.

[12-5] The tablet according to [12-3], wherein the sweetening agent is a fast-acting sweetening agent, and the pharmaceutical composition further contains a slow-acting sweetening agent.

[12-6] The tablet according to [12-5], wherein the fast-acting sweetening agent contains at least one component selected from the group consisting of aspartame, sucralose and acesulfame potassium.

[12-7] The tablet according to [12-5] or [12-6], wherein the slow-acting sweetening agent contains saccharin and/or saccharin sodium.

[13] A dry-coated agent comprising an inner core consisting of pharmaceutical composition containing valsartan or its pharmaceutically acceptable salt, and an outer layer coating the inner core and consisting of coating composition containing pH adjuster which makes inside of the mouth mildly acidic.

[14] The dry-coated agent according to [13], wherein the pH adjuster contains at least one component selected from the group consisting of anhydrous citric acid, citric acid hydrate and sodium dihydrogen citrate.

[15] The dry-coated agent according to [13] or [14], wherein the coating composition further contains a sweetening agent.

[16] The dry-coated agent according to [15], wherein the sweetening agent contains at least one component selected from the group consisting of saccharin, saccharin sodium, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia and thaumatin.

[17] The dry-coated agent according to [15], wherein the sweetening agent is a fast-acting sweetening agent, and the pharmaceutical composition further contains a slow-acting sweetening agent.

[18] The dry-coated agent according to [17], wherein the fast-acting sweetening agent contains at least one component selected from the group consisting of aspartame, sucralose and acesulfame potassium.

[19] The dry-coated agent according to [17] or [18], wherein the slow-acting sweetening agent contains saccharin and/or saccharin sodium.

[19-1] The dry-coated agent according to any one of [13-19], wherein the inner core consisting of pharmaceutical composition comprises a valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, wherein the dry-coated agent is orally administrated through disintegration in the mouth by saliva or water in a similar amount to the saliva.

[19-2] The dry-coated agent according to any one of [13-19], wherein the inner core consisting of pharmaceutical composition comprises a valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant, and a lubricant.

[19-3] The dry-coated agent according to [19-2], wherein the outer layer comprises a crystalline cellulose, a disintegrant and a lubricant.

[19-4] The dry-coated agent according to any one of [19-l]-[19-3], wherein the disintegrant comprises at least one component selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, sodium croscarmellose, sodium carboxymethylstarch, carmellose, calcium carmellose, partially pregelatinised starch, starch, sodium carmellose, alginic acid, sodium alginate and guar gum.

[19-5] The dry-coated agent according to any one of [19-l]-[19-4], wherein the disintegrant comprises at least low-substituted hydroxypropylcellulose.

[19-6] The dry-coated agent according to any one of [19-l]-[19-5], wherein the disintegrant comprises at least one component selected from the group consisting of crospovidone, sodium croscarmellose and sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose.

[19-7] The dry-coated agent according to any one of [19-l]-[19-6], wherein the glidant comprises at least one component selected from the group consisting of silicic acid, silicic acid anhydrous, aluminum silicate, calcium silicate, magnesium aluminometasilicate, aluminum oxide, aluminum hydroxide, magnesium oxide and magnesium hydroxide.

[19-8] The dry-coated agent according to any one of [19-l]-[19-7], wherein the glidant comprises light anhydrous silicic acid and/or synthetic aluminum silicate.

[19-9] The dry-coated agent according to any one of [ 19- 1 ]-[ 19-8], wherein the lubricant comprises at least one component selected from the group consisting of magnesium stearate, aluminum stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil, poly(ethylene glycol) and talc.

[19-10] The dry-coated agent according to any one of [19-l]-[19-9], wherein the lubricant comprises at least magnesium stearate.

[19-11] The dry-coated agent according to any one of [19-1 ]-[ 19-10], wherein the pharmaceutical composition further comprises a hydrochlorothiazide and/or an amlodipine or a pharmaceutically acceptable salt thereof.

[19-12] The dry-coated agent according to any one of [19-1]-[19-11], wherein the pharmaceutical composition further comprises a aliskiren or a pharmaceutically acceptable salt thereof.

Claims

1. A tablet consisting of pharmaceutical composition comprising a valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant and a lubricant, wherein the tablet is orally administrated through disintegration in the mouth by saliva or water in a similar amount to the saliva.

2. An orally disintegrating tablet comprising an inner core consisting of pharmaceutical composition comprising a valsartan or a pharmaceutically acceptable salt thereof, a disintegrant, a glidant, and a lubricant, and an outer layer coating the inner core.

3. The tablet according to Claim 2, wherein the outer layer comprises a crystalline cellulose, a disintegrant and a lubricant.

4. The tablet according to any one of Claims 1 -3, wherein the disintegrant comprises at least one component selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, sodium croscarmellose, sodium carboxymethylstarch, carmellose, calcium carmellose, partially pregelatinised starch, starch, sodium carmellose, alginic acid, sodium alginate and guar gum.

5. The tablet according to any one of Claims 1-4, wherein the disintegrant comprises at least low-substituted hydroxypropylcellulose.

6. The tablet according to any one of Claims 1-5, wherein the disintegrant comprises at least one component selected from the group consisting of crospovidone, sodium croscarmellose and sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose.

7. The tablet according to any one of Claims 1 -6, wherein the glidant comprises at least one component selected from the group consisting of silicic acid, silicic acid anhydrous, aluminum silicate, calcium silicate, magnesium aluminometasilicate, aluminum oxide, aluminum hydroxide, magnesium oxide and magnesium hydroxide.

8. The tablet according to any one of Claims 1 -7, wherein the glidant comprises light anhydrous silicic acid and/or synthetic aluminum silicate.

9. The tablet according to any one of Claims 1-8, wherein the lubricant comprises at least one component selected from the group consisting of magnesium stearate, aluminum stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil, poly(ethylene glycol) and talc.

10. The tablet according to any one of Claims 1 -9, wherein the lubricant comprises at least magnesium stearate.

11. The tablet according to any one of Claims 1 -10, wherein the pharmaceutical composition further comprises a hydrochlorothiazide and/or an amlodipine or a pharmaceutically acceptable salt thereof.

12. The tablet according to any one of Claims 1 -11, wherein the pharmaceutical composition further comprises a aliskiren or a pharmaceutically acceptable salt thereof.

13. A dry-coated agent comprising an inner core consisting of pharmaceutical composition containing valsartan or its pharmaceutically acceptable salt, and an outer layer coating the inner core and consisting of coating composition containing pH adjuster which makes inside of the mouth mildly acidic.

14. The dry-coated agent according to Claim 13, wherein the pH adjuster contains at least one component selected from the group consisting of anhydrous citric acid, citric acid hydrate and sodium dihydrogen citrate.

15. The dry-coated agent according to Claim 13 or 14, wherein the coating composition further contains a sweetening agent.

16. The dry-coated agent according to Claim 15, wherein the sweetening agent contains at least one component selected from the group consisting of saccharin, saccharin sodium, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia and thaumatin.

17. The dry-coated agent according to Claim 15, wherein the sweetening agent is a fast-acting sweetening agent, and the pharmaceutical composition further contains a slow-acting sweetening agent.

18. The dry-coated agent according to Claim 17, wherein the fast-acting sweetening agent contains at least one component selected from the group consisting of aspartame, sucralose and acesulfame potassium.

19. The dry-coated agent according to Claim 17 or 18, wherein the slow-acting sweetening agent contains saccharin and/or saccharin sodium.