MX2014007933A - Tablets and dry-coated agents. - Google Patents

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

COMPRESSES AND AGENTS DRY RECU BIERTOS CAM PO 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 TECHNIQUE It is known that Valsartan (angiotensin receptor antagonist I I) is effective for the treatment of congestive heart failure and is capable of reducing blood pressure, regardless of age, gender or race. PCT Application Number W097 / 49394 (corresponding to document J P2000-506540 and U.S. Patent No. 62941 97), Japanese Unexamined Patent Publication Number 2003-231634 and Japanese Patent Publication Unexamined Number 2007 -238637, for example, disclose Valsartan or a pharmaceutically acceptable salt thereof, as well as a solid oral agent formed by compression.

In recent years, orally disintegrating tablets (also known as "OD tablets") have been widely used because of their ease of ingestion. As for the OD tablets, the Japanese Patent Publication not examined Hej 5-271054, for example, describes tablets of the type of oral disintegration that are produced by compressing a mixture containing a medicinally active ingredient, saccharides and water, in an amount sufficient to moisten the surfaces of the particles of the saccharides . PCT Application Number WO95 / 20380 discloses a molded compressed product of the oral disintegration type, which comprises a saccharide having a low molding capacity, and a saccharide having a high molding capacity and which is provided with fast disintegrability in the mouth.

However, when the present inventors conducted tests, it was found that if Valsartan were an active ingredient, known methods, including those in Japanese Unexamined Patent Publication Hei 5-271054 and PCT Application Number WO95 / 20380, would produce tablets. OD but that would be unsuitable for use.

Specifically, Valsartan is hydrophobic, low solubility, bulky and strongly adhesive. Due to these effects, if OD tablets with sufficient disintegrability are prepared, there will be a need to expand the size of the tablets in order to obtain adequate amounts of Valsartan, and therefore, their intake and handling would be difficult.

The preparation of OD tablets also requires that the disintegrability be sufficient to easily disintegrate the tablets in the mouth, just as it requires that the hardness be enough as a tablet, and both are obtained at the same time. According to prior art methods, there were difficulties in the production of OD tablets that comprised Valsartan as the active ingredient with those properties at the same time.

In addition, in recent years, orally disintegrating tablets (also known as "OD tablets") have been widely used, because the self-administration of the tablets is easy enough to improve the quality of life (QOL).

However, Valsartan is a medicine that exhibits a bitter taste. Therefore, there will be a problem of not sufficiently improving the quality of life, even if the conventional solid oral agents themselves are made into orally disintegrating tablets.

BRIEF DESCRIPTION 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, having sufficient disintegrability and hardness to be suitable for use as an orally disintegrating tablet ("OD"). In other words, the tablet is capable of being administered orally and disintegrates in the oral cavity upon exposure to a patient's saliva or a comparable amount of water - without having to be chewed.

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

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

Specifically, the tablet is suitable for use as an oral disintegration tablet, because it has the specific composition mentioned. Therefore, when the tablet is used in the application where the tablet is administered orally through disintegration in the mouth by saliva or by water in an amount similar to saliva, this facilitates the self-administration of the tablet that Valsartan is understood as the active ingredient, and the improvement of quality of life (QOL), compliance and, consequently, adherence can be achieved as intended.

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

The tablet thus mentioned has sufficient disintegrability and hardness and is suitable for use as an OD tablet. In addition, said tablet facilitates the self-administration of the tablet comprising Valsartan as the active ingredient and which can achieve the improvement of quality of life, compliance and, consequently, adhesion as intended.

For example, the OD tablets of the invention can serve as an alternative dosage form in patients experiencing dysphagia (difficulty swallowing). In addition, the OD tablets of the invention can improve compliance and adherence in populations where they present problems (for example, in elderly patients, children, developmentally disabled patients, or patients with persistent nausea, who travel, or who they have limited access to water). The OD tablets of the invention are easier to administer than conventional tablets that are designed 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 approximately 30 seconds. In another embodiment, the disintegration time is between 1 and 60 seconds approximately, between 1 and 30 seconds approximately, or between 15 and 30 seconds approximately, as measured as the time required for the tablet to disintegrate in the mouth by / with exposure to saliva or water in an amount similar to saliva. In certain embodiments, the hardness of the tablet is between about 36N and 97N as measured using a tablet hardness meter.

The outer layer is preferably a layer comprising crystalline cellulose, a disintegrating agent and a lubricant. The outer layer thus constructed can achieve a greater hardness of the tablet while maintaining sufficient disintegrability.

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

The disintegrating agent preferably comprises at least low substituted hydroxypropylcellulose and may comprise at least one member selected from the group consisting of crospovidone, croscarmellose sodium, and sodium carboxymethyl starch, and low substituted hydroxypropylcellulose.

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

The glidant also preferably comprises light anhydrous silicic acid 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 antihypertensive agents beyond Valsartan (or a pharmaceutically acceptable salt thereof), including: hydrochlorothiazide, or amlodipine (or a pharmaceutically acceptable salt thereof). the same).

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

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

The present invention also provides a dry coated agent that contains an amount therapeutically effective Valsartan or a pharmaceutically acceptable salt thereof as an active ingredient and that, when administered orally to a patient, reduces or prevents the bitter taste experience of Valsartan.

In one embodiment, the present invention provides a dry-coated agent comprising an internal core consisting of a pharmaceutical composition containing Valsartan or a pharmaceutically acceptable salt thereof, and an outer layer that coats the inner core and consists of a composition of coating that contains a pH adjuster that makes the inside of the mouth slightly acidic.

The dry-coated agent thus mentioned sufficiently prevents the bitter taste when it is allowed to disintegrate in the mouth and is then used to be administered orally. Therefore, it is possible to achieve the improvement of the quality of life, compliance with treatment and, consequently, adherence as intended.

In the dry coated agent, the coating composition constituting the outer layer contains a pH adjuster which makes the interior of the mouth slightly acidic. Therefore, the interior of the mouth is slightly acidified when the dry-coated agent is allowed to disintegrate in the mouth. In addition, since Valsartan (or one of its pharmaceutically acceptable salts) is an acidic drug, it is believed that the immediate solubility will be reduced to the extent that the acidity within the mouth becomes taller.

Specifically, it is believed that according to the dry-coated agent, the interior of the mouth is acidified by the outer layer that has disintegrated therein prior to Valsartan (or a pharmaceutically acceptable salt thereof) and the inner core is released and, therefore, that the dissolution of Valsartan (or one of its pharmaceutically acceptable salts) in the mouth is suppressed to avoid the bitter taste.

The above pH adjuster may contain at least one component selected from the group consisting of anhydrous citric acid, citric acid hydrate, and sodium diacid 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 into the mouth before releasing Valsartan (or a pharmaceutically acceptable salt thereof). In this way, the bitter taste of Valsartan can be prevented more, and then the quality of life can be improved more and more.

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

In the dry coated agent according to a 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 rapid-acting sweetening agent diffuses in the mouth before the Valsarian (or pharmaceutically acceptable salt thereof) is released, whereby the initial bitter taste can be prevented; the slow-acting sweetening agent, which is contained in the inner core, diffuses into the mouth after the dry-coated agent has completely disintegrated, whereby the remaining bitter taste after administration can be diminished.

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

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

EFFECT OF THE INVENTION The present invention provides a tablet comprising Valsarian as the active ingredient, which has sufficient disintegrability and 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, an agent that can prevent the bitter taste, as well as adequately improve the quality of life.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 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 modality.

Figure 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 modality.

Figure 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 modality.

Figure 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 modality.

DETAILED DESCRIPTION OF THE INVENTION First General Modality of the Invention: As used herein, the term "disintegration in the mouth by saliva or water in an amount similar to saliva" means the disintegration of the tablet, for example, in the order of 1 to 60 seconds, and preferably 1 at 30 seconds or from 15 to 29 seconds, in contrast to the disintegration of common tablets (for example, conventional solid dosage forms or capsules such as DIOVAN®, manufactured by Novartis Pharma KK), although it can not be defined unconditionally due to the differences between the individuals where the tablet is left to the natural movement of the mouth , such as the movement of the tongue when it is kept in the mouth. The term "disintegration in the mouth by saliva or water in a quantity similar to saliva" also includes disintegration after 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. "Disintegration time" refers to the time required for the tablet to disintegrate in the mouth by / with exposure to saliva or water in an amount similar to saliva.

Also, the term "sufficient disintegrability" refers to the disintegrability in such a way that the tablet can disintegrate in the mouth by saliva or water in an amount similar to saliva. In particular, the tablet according to the present embodiment differs from the common tablet in that the common tablet does not disintegrate or dissolve easily unless it is chewed when it is kept in the mouth.

The phrase "effective amount", as used herein, refers to the amount of active ingredient that stops, reduces or reverses the progress of the condition being treated or that otherwise cures completely or partially or acts palliatively on the condition.

Such an amount can easily be determined by a person skilled in the art by routine experimentation and without undue burden. The dosage ranges described herein are non-limiting examples of "effective amounts" of the active ingredient which can be used in the O-Dcompounds 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 a pharmaceutical composition comprising Valsarian or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant and a lubricant, wherein the tablet is orally administered through disintegration in the mouth by saliva or water in an amount similar to saliva.

In a certain embodiment, the present invention provides an oral disintegration tablet comprising an internal core consisting of a pharmaceutical composition comprising Valsarian or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant and a lubricant, and an outer layer that covers the inner core.

The tablet according to the present embodiment is suitable for use as an oral disintegrating tablet, because it has the specific composition mentioned. Therefore, when the tablet is used in the application where the tablet is administered orally through disintegration in the mouth by saliva or water in an amount similar to saliva, this facilitates self-administration of the tablet that Valsartan comprises as the active ingredient and quality improvement can be achieved of life, compliance and, consequently, adherence as intended.

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

The dissolvability of Valsartan from the tablet according to the present embodiment is desirably at the same level or at a level similar to that of Valsartan from a common tablet containing Valsartan, such as the DIOVAN ® tablet (manufactured by Novartis Pharma KK) . According to an example of the test methods for knowing such dissolubility, although it is available in several types, 75 percent or more of Valsartan is It dissolves preferably at 120 minutes after the start of the test when the tablet is tested at 50 rpm using the paddle method of the Japanese Pharmacopoeia by using a buffer of pH 3.0 as a test solution, and more preferably, 80 percent or more than Valsarian dissolves in 120 minutes. When administered to a human, the tablet according to the present invention undergoes a solution that is biologically equal to a DIOVAN® tablet.

Preferred embodiments of the tablet that can be used in the aforementioned administration will be described below.

Figure 1 is a view showing the first embodiment of the tablet according to the present invention. The tablet 100 is an orally disintegrating tablet comprising an inner core 10 and an outer layer 20 that lines the inner core 10.

Other features of the invention are illustrated below with reference to Figure 1, which illustrates a preferred embodiment.

A. Internal core 10 1. Active ingredient Valsarian is an angiotensin II receptor antagonist, and the acyl compound that is used for the treatment of hypertension. Valsartan is described, for example, in patents JP2749458, US5399578, and is described by (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. Pat. U U No. 5399578. Valsartan can be used for the purposes of this invention in its free form, as well as in any form of pharmaceutically acceptable salt. The salt forms include acid addition salts. Compounds having at least one acid group (e.g., COOH or 5-tetrazolyl) can also form salts with bases. Salts with suitable bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example, sodium, potassium, calcium or magnesium salts, or salts with ammonia or an organic amine, such such as morpholine, thiomorpholine, piperidine, pyrrolidine, a lower mono-, di- or tri-alkylamine, for example, ethyl-, tert-butyl-, diethyl-, di-isopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or tri-hydroxy-lower alkylamine, for example, mono-, di- or tri-ethanolamine.

In addition, corresponding internal salts can be formed. In one embodiment, the salts are, for example, selected from the mono-sodium salt in amorphous form; and Valsartan disodium salt in amorphous or crystalline form, especially in the hydrate form, thereof.

In one embodiment, the salts are, for example, selected from the calcium salt of Valsartan in crystalline form, especially in the form of hydrate, mainly tetrahydrate thereof; magnesium salt of Valsartan in crystalline form, especially in the hydrate form, mainly hexahydrate thereof; calcium / magnesium mixed salt of Valsartan in crystalline form, especially in the form of a hydrate; Valsartan bis-diethylammonium salt in crystalline form, especially in the form of a hydrate; bis-dipropylammonium salt of Valsartan in crystalline form, especially in the form of a hydrate; bis-dibutyl ammonium salt of Valsartan in crystalline form, especially in the form of a hydrate, especially the hemihydrate thereof; Valsartan mono-L-arginine salt in amorphous form; salt of bis-L-arginine from Valsartan in amorphous form; Valsartan mono-L-lysine salt in amorphous form; salt of d / s-L-lysine from Valsartan in amorphous form.

In one embodiment, Valsartan is used as a free acid. Although Valsartan has a chiral carbon, the racemic form and / or the mono optically active form of Valsartan can be used in the modality. Valsartan has active optical form (1a) or (1b) below, and preferably includes at least (1a).

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 in this composite manner can be specifically 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 which can be administered orally through disintegration in the mouth by saliva or water in an amount similar to saliva.

The dose of Valsartan or a pharmaceutically acceptable salt thereof is generally from 1 to 250 milligrams as Valsartan, and preferably from 40 to 1 60 milligrams. Therefore, the ratio of Valsartan or a pharmaceutically acceptable salt thereof in the inner core 10 is preferably from 1 to 250 milligrams as Valsartan, and more preferably from 40 to 1 milligrams.

The proportion of Valsarian or a pharmaceutically acceptable salt thereof (proportion of the mixture as Valsarian) is preferably 30 to 70 per hundred by mass, and more preferably 40 to 60 per cent by mass, based on the tolal of the composition. pharmaceutics that involves the internal nucleus 10.

The pharmaceutical composition constituting the infernal core 10 may comprise ingredients other than the aforementioned ingredient. Specifically, the pharmaceutical composition constituting the inner core 10 may further comprise hydrochloride amide (HCTZ), amlodipine, aliskirene or the like, or one of its pharmaceutically acceptable salts. The tablet comprising said inner core 10 is used effectively for the treatment of hyperphoresis. When hydrochloroiazide, amlodipine or aliskiren is administered in combination with Valsarian or with a pharmaceutically acceptable salt thereof, it produces the most effective antimicrobial 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 easily selected or made using a method known to those skilled in the art.

Hydrochlorothiazide can be combined in a range of 6 to 60 milligrams with 10 to 250 milligrams of Valsarian. I also know You can combine in an amount of 5 to 25 milligrams with 50 to 160 milligrams of Valsartan. Amlodipine can be combined in an amount of 2.5 to 10 milligrams with 40 to 320 milligrams of Valsartan. In addition, aliskiren can be combined in an amount of 100 to 350 milligrams with 40 to 350 milligrams of Valsartan. The aliskiren can be combined in an amount of 150 to 300 milligrams with 2.5 to 10 milligrams of amlodipine. All hydrochlorothiazide, valsartan and amlodipine may also be combined in an amount, respectively, of 10 to 250 milligrams (preferably 10 to 25 milligrams), 40 to 320 milligrams, and 5 to 10 milligrams. Within the dose ranges, the effect of reducing blood pressure to a normal level manifests much more clearly.

Examples of the formation of the compounds include combinations of about 80 milligrams of Valsartan and about 6.25 milligrams, about 12.5 milligrams or about 25 milligrams of hydrochlorothiazide, combinations of about 160 milligrams of Valsartan and about 6.25 milligrams, about 12.5 milligrams or about 25 milligrams of hydrochlorothiazide, combinations of approximately 80 milligrams of Valsartan and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, and combinations of approximately 160 milligrams of Valsartan and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of approximately 320 milligrams of Valsartan and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of approximately 80 milligrams of Valsartan, approximately 6.25 milligrams, approximately 12.5 milligrams or approximately 25 milligrams of hydrochlorothiazide and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of approximately 160 milligrams of Valsartan, approximately 6.25 milligrams, approximately 12.5 milligrams or approximately 25 milligrams of hydrochlorothiazide and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of about 320 milligrams of Valsartan, approximately 6.25 milligrams, approximately 12.5 milligrams or approximately 25 milligrams of hydrochlorothiazide and approximately 2.5 milligrams, about 5 milligrams or about 10 milligrams of amlodipine, combinations of about 80 milligrams of Valsartan and about 150 milligrams or about 300 milligrams of aliskiren, combinations of about 160 milligrams of Valsartan and about 150 milligrams or about 300 milligrams of aliskiren, and combinations of approximately 320 milligrams of Valsartan and approximately 150 milligrams or approximately 300 milligrams of aliskiren. The examples of compounding also include combinations of about 150 milligrams of aliskirene and about 2.5 milligrams, about 5 milligrams or about 10 milligrams of amlodipine, and combinations of about 300 milligrams of aliskiren and about 5 milligrams or about 10 milligrams of amlodipine. 2. Disintegrating agent.

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

Disintegrating agents include low substitution hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, carmellose, calcium carmellose, partially pregelatinized starch, starch, sodium carmellose, alginic acid, sodium alginate, guar gum and others. Among these disintegrating agents, a component can be used alone or two or more components can be used in combination.

The inner core 10 preferably comprises at least low substituted hydroxypropylcellulose as a disintegrating agent. The disintegrating agent also comprises at least one component selected from the group consisting of crospovidone, croscarmellose sodium, and carboxymethyl starch. sodium, and low substitution hydroxypropylcellulose.

Preferred blending examples of the disintegrating agents include low-substituted hydroxypropylcellulose, alone, a combination of low-substituted hydroxypropylcellulose and crospovidone, a combination of low-substituted hydroxypropylcellulose and croscarmellose sodium, a combination of low-substituted hydroxypropylcellulose and carboxymethyl-starch. of sodium, and others.

As used herein, the term "low substituted hydroxypropylcellulose" means hydroxypropylcellulose wherein the molar number of substitution of hydroxypropyl groups per glucose unit is from 5 to 16 percent, preferably from 7 to 13 percent.

The proportion of disintegrating agent in the inner core 10 is preferably 15 to 60 mass percent, and more preferably 20 to 40 mass percent, based on the total of the pharmaceutical composition constituting the inner core 10. When using two or more disintegrating agents in combination, the use is preferably such that the total disintegrating agents are within the ranges of the above proportions.

In the case when the disintegrating agent is added by the above proportion, if the outer layer 20 is made after the inner core 10 is made independently, the inner core 10 can be broken in the transport process of the inner core 10. or in the process of making the outer layer 20 on the inner core 10, because the inner core is very brittle. However, when using the OSDrC® rotary compression machine, the tablet including the disintegrating agent in the inner core 10 as the above ratio is easily obtained without breaking the inner core 10. 3. Sliding The glidant suppresses the adhesion of Valsartan (or one of its pharmaceutically acceptable salts). Specifically, the combination of the disintegrating agent and the glidant in the inner core 10 ensures sufficient disintegrability although Valsartan (or a pharmaceutically acceptable salt thereof) is the active ingredient.

Glidants include compounds of inorganic silicic acid, aluminum oxide, aluminum hydroxide, magnesium oxide, magnesium hydroxide and others. Inorganic silicic acid compounds include silicic acid, anhydrous silicic acid, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminometasilicate, and others. Among these sliding agents, a component can be used alone or two or more components can be used in combination.

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

The proportion of the slip agent in the inner core 10 is preferably from 1 to 10 percent by mass, and more preferably from 1 to 6 percent by mass, based on the total of the pharmaceutical composition constituting the inner core 10. When two or more sliding agents are used in combination, the use it is preferably such that the total of the sliding agents is within the ranges of the above proportions. 4. Lubricant Additionally, in the inner core 10 the lubricant ensures the dispersibility 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 to 8000, talc and others. Among these lubricants, a component can be used alone or two or more components can be used in combination.

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

The proportion of the lubricant in the inner core 10 is preferably 1 to 7 percent by mass, and more preferably 2 to 5 percent by mass, based on the total of the pharmaceutical composition that constitutes the inner core 10. When used two or more lubricants in combination, the use is preferably such that the total of the lubricants is within the ranges of the previous proportions. 5. Other ingredients The pharmaceutical composition constituting the inner core 10 may also comprise excipients, sweetening agents, flavor masking agents, coloring agents, pH adjusters, or binders other than the ingredients mentioned above. The crystalline cellulose or the microcrystalline cellulose may be contained in the pharmaceutical composition that constitutes the inner core 10.

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

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

The pH adjusters that may be used in the present invention may 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 above.

The 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, yellow food coloring No. 5, yellow coloring No. 4 for food, aluminum chelate, titanium oxide, or talcum.

B. Outer Coat 20 The outer layer 20 is provided to coat the inner core 10 and imparts sufficient tablet hardness to the tablet 100. The composition of the outer layer 20 is not particularly limited and the composition may be such that ingredients known for use in tablets are they combine appropriately so long as the composition is that which is capable of producing fast disintegration suitable for oral disintegrating tablets, such as rapid disintegration, after exposure to saliva or a comparable amount of water, and possesses the required hardness.

The outer layer 20 can, for example, be formed by molding a coating composition comprising the disintegrant, the lubricant and the crystalline cellulose (preferably, microcrystalline cellulose). The coating composition formed in this way can easily acquire sufficient fast densibility and hardness of the tablet at the same time.

The coating composition constituting the outer layer 20 preferably comprises crospovidone as a disintegrant. The coating composition constituting the outer layer 20 also preferably comprises a stearate as a slip agent 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 slip agent and a foaming agent, additives, such as a flavoring agent, a sweetening agent and a pH adjuster, and others as separate ingredients of those mentioned above. One or more components of these ingredients may be added in appropriate amounts and may be added in the powder, liquid or granule forms, as necessary, during the tablet manufacturing process which will be described below.

Foaming agents, for example, include sodium hydrogen carbonate. Flavoring agents, for example, include menthol, lemon, lime-lemon and orange. PH adjusters, for example, include citric acid, tartaric acid and malic acid. Sweetening agents, for example, include saccharin, sodium saccharin, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia, thaumatin, sucralose and others. Sweetening agents, for example, include a quick-acting sweetening agent such as aspartame, sucralose, acesulfame potassium.

C. Other Characteristics and Attributes The hardness of the OD tablets of the present invention is preferably one which is sufficient to allow easy and convenient storage, disposal of the packages, 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 package as conventional non-OD tablets.

The hardness of the orally disintegrating tablet of the present invention may vary depending on factors such as tablet form, size and weight. In one embodiment, the hardness of a round tablet with a diameter of about 6.0 to 10.0 millimeters, thickness of about 3.0 to 6.0 millimeters, and a weight of about 70 to 320 milligrams (20 milligrams to 80 milligrams of Valsartan) is, for example, 30N to 55N approximately, as measured using a tablet hardness measuring device such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan). In another embodiment, the hardness of an oval tablet with a dimension of approximately 15.0 and 8.0 millimeters, thickness of approximately 5.0 to 10.0 millimeters and a weight of approximately 500 to 600 milligrams (160 milligrams of Valsartan) is, for example, 50N to 100N approximately, as measured using a tablet hardness measuring device such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan).

The OD tablet of the present invention may take various forms, for example, round, oval, capsule, donut-shaped, but is not limited to any particular form.

The size of the OD tablets of the invention may 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 such that the tablet disintegrates in the oral cavity of a patient after exposure to saliva or a comparable amount of water. For example, an OD tablet of the invention may have a weight of about 70 milligrams to about 600 milligrams.

D. Manufacturing 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 external compression layer powder and internal core powder with an OSDrC® rotary compression machine having double structure punches.

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

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

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

Thus, the aforementioned manufacturing method allows the inner core to be coated by the outer layer without being forced 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 indicated above, the tablet 100 is a multilayer tablet. However, even if a tablet which can be provided as a single layer with an inner core 10 and an outer layer 20 provided on its surface, these alone can not be formed into an oral disintegrating tablet. When the tablet that can be provided as a single layer has oral disintegrability, it is not necessary to make a multilayer to form an oral disintegration tablet. Therefore, the tablet 100 according to the present embodiment is characterized in that the formation of multiple layers imparts oral disintegrability to the ingredient, which can practically not form an oral disintegration tablet as a single layer, due to its tablet hardness and property. shape retention Specifically, when a single-layer tablet is to be formed from the same ingredients as the inner core 10, for example, if the disintegrant is applied as the preferable pre-tablet interval, it is impossible to make the tablet because the hardness of the tablet It is not enough to be formed. This has an advantageous effect of being able to form an orally disintegrating tablet with multiple layers of the same ingredient of a non-oral disintegrating tablet with a single layer.

The tablet of the present invention can be a tablet having two inner cores, for example. Figure 2 is a view showing the second embodiment of the tablet according to the present invention. The tablet 110 shown in Figure 2 comprises two internal cores 11 and one outer layer 21 covering the two inner cores 11. The tablet 110 is provided with a slot 30 so that it can be easily divided into two separate tablets, each comprising an inner core 11 covered by an outer layer 21. The tablet 110 can be administer as is or can be divided into two, one of which will be administered, depending on the dose required.

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

Preferred embodiments of the present invention have been described above; however, the present invention should not be limited to the modalities mentioned above.

Second General Modality of the Invention: As used herein, the term "disintegration in the mouth by saliva or water in an amount similar to saliva" means the disintegration of the tablet, for example, in the order of 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 (eg, conventional solid dosage forms or capsules such as DIOVAN®, manufactured by Novartis Pharma KK), although they can not be defined unconditionally due to the differences between the individuals where the tablet is left to the natural movement of the mouth, such as the movement of the tongue when it is kept in the mouth. The term "disintegration in the mouth by saliva or water in a quantity similar to saliva" also includes disintegration after 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. "Disintegration time" refers to the time required for the tablet to disintegrate in the mouth by / with exposure to saliva or water in an amount similar to saliva.

As used herein, the term "sufficient disintegrability" means the disintegration of the tablet, for example, in the order of 1 to 60 seconds, and preferably 1 to 30 seconds or 15 to 29 seconds in contrast to the disintegration of common tablets (for example, conventional solid dosage forms or capsules such as DIOVAN®, manufactured by Novartis Pharma KK), although they can not be defined unconditionally due to the differences between the individuals where the tablet is left to the natural movement of the tablet. mouth, such as the movement of the tongue when it is kept in the mouth. In other words, the phrase "sufficient disintegrability" as used herein refers to the disintegrability in such a way that the dry-coated agent can be disintegrated in the mouth by / in the exposure to saliva or water in an amount similar to saliva. In particular, the dry-coated agent of the present invention differs from the common tablet in that the common tablet does not disintegrate or 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 that stops, reduces or reverses the progress of the condition being treated or that otherwise cures completely or partially or acts palliatively on the condition. Such an amount can easily be determined by a person skilled in the art by routine experimentation and without undue burden. The dosage ranges described herein are non-limiting examples of the "effective amounts" of active ingredient that can be used in the OD tablets of the invention.

Detailed description Preferred embodiments of the dry-coated agents according to the present invention will be described below.

Figure 3 is a view showing the first embodiment of the dry coated agent according to the present invention. The dry-coated agent 100 is a dry-coated agent comprising an internal core 10 which consists of a pharmaceutical composition which confers an effective amount of Valsartan or a pharmaceutically acceptable sai thereof, and an outer layer 20 covering the inner core 10.

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

The Valsarían is hydrophobic, of low solubility, voluminous and very adhesive; Therefore, it will be difficult to prepare oral disintegration tablets that have sufficient disinfection capacity. However, the internal nucleus that consists of the pharmaceutical composition allows to achieve sufficient disinfection. For this reason, the dry-coated organizer comprising the inner core 10 is particularly suitable as an oral disinfection tablet which is allowed to disinfect itself in the mouth and is administered orally. The respective ingredients that are included in the pharmaceutical composition will be described here in detail. 1. Active ingredient Valsarian is an angiotensin II receptor antagonist and is an acyl compound that can be used for the treatment of hyperlensions; is the compound described, for example, in Japanese Patent Number 2749458 and in the United States.

No. 5399578, and is described by (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. Pat. U U Number 5399578. Valsartan can be used for the purposes of this invention in its free form, as well as in any form of pharmaceutically acceptable salt. The salt forms include acid addition salts. Compounds having at least one acid group (e.g., COOH or 5-tetrazolyl) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example, sodium, potassium, calcium or magnesium salts, or salts with ammonia or an organic amine, such such as morpholine, thiomorpholine, piperidine, pyrrolidine, a lower mono-, di- or tri-alkylamine, for example, ethyl-, tert-butyl-, diethyl-, di-isopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or tri-hydroxy-lower alkylamine, for example, mono-, di- or tri-ethanolamine.

In addition, the corresponding internal salts can be formed. In one embodiment, the salts are, for example, selected from the mono-sodium salt in amorphous form; disodium salt of Valsartan in amorphous or crystalline form, especially in the form of hydrate, thereof.

In one embodiment, the salts are, for example, selected from the calcium salt of Valsartan in crystalline form, especially in the form of a hydrate, mainly the tetrahydrate thereof; magnesium salt of Valsartan in crystalline form, especially in the hydrate form, mainly the hexahydrate thereof; calcium / magnesium mixed salt of Valsartan in crystalline form, especially in the form of a hydrate; Valsartan bis-diethylammonium salt in crystalline form, especially in the form of a hydrate; bis-dipropylammonium salt of Valsartan in crystalline form, especially in the form of a hydrate; bis-dibutyl ammonium salt of Valsartan in crystalline form, especially in the form of a hydrate, especially the hemihydrate thereof; Valsartan mono-L-arginine salt in amorphous form; salt of bis-L-arginine from Valsartan in amorphous form; Valsartan mono-L-lysine salt in amorphous form; salt of d / s-L-lysine from Valsartan in amorphous form.

In one embodiment, Valsartan is used as the free acid. Although Valsartan has a chiral carbon, the racemic form of and / or the mono optically active form of Valsartan can be used in the modality. Valsartan has active optical form (1a) or (1b) below, and preferably includes at least (1a).

The dose of Valsartan or a pharmaceutically acceptable salt thereof is generally from 10 to 250 milligrams as Valsartan, and preferably from 40 to 160 milligrams. Therefore, the ratio of Valsartan or a pharmaceutically acceptable salt thereof in inner core 10 is preferably from 1 to 250 milligrams as Valsartan, and more preferably from 40 to 1 milligrams.

The ratio of Valsartan or a pharmaceutically acceptable salt thereof, focusing on the proportion of the mixture as Valsartan, is preferably 30 to 70 percent by mass, and more preferably 40 to 60 percent by mass, based on the total of the pharmaceutical composition that constitutes the internal core 10.

The pharmaceutical composition that constitutes the inner core 1 0 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. He dry coated agent 100 comprises said inner core 10 which is used effectively for the treatment of hypertension. When hydrochlorothiazide, amlodipine or aliskiren is administered in combination with Valsarian or with a pharmaceutically acceptable salt thereof, it produces the most 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 can be selected or easily obtained using a method known to those skilled in the art.

Hydrochlorothiazide can be combined in an amount of 6 to 60 milligrams with 10 to 250 milligrams of Valsartan. It can also be combined in an amount of 5 to 25 milligrams with 50 to 160 milligrams of Valsartan. Amlodipine can be combined in an amount of 2.5 to 10 milligrams with 40 to 320 milligrams of Valsartan. In addition, aliskiren can be combined in an amount of 100 to 350 milligrams with 40 to 350 milligrams of Valsartan. The aliskiren can be combined in an amount of 150 to 300 milligrams with 2.5 to 10 milligrams of amlodipine. All hydrochlorothiazide, valsartan and amlodipine may also be combined in an amount, respectively, of 10 to 250 milligrams (preferably 10 to 25 milligrams), 40 to 320 milligrams, and 5 to 10 milligrams. Within these dose ranges, the effect Reduction of blood pressure to a normal level manifests much more clearly.

Examples of the formation of the compounds include combinations of about 80 milligrams of Valsartan and about 6.25 milligrams, about 12.5 milligrams or about 25 milligrams of hydrochlorothiazide, combinations of about 160 milligrams of Valsartan and about 6.25 milligrams, about 12.5 milligrams or about 25 milligrams of hydrochlorothiazide, combinations of approximately 80 milligrams of Valsartan and approximately 2.5 milligrams or approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of approximately 160 milligrams of Valsartan and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of approximately 320 milligrams of Valsartan and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of approximately 80 milligrams of Valsartan, approx. approximately 6.25 milligrams, approximately 12.5 milligrams or approximately 25 milligrams of hydrochlorothiazide and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of approximately 160 milligrams of Valsartan, approximately 6.25 milligrams, approximately 12.5 milligrams or approximately 25 milligrams of hydrochlorothiazide and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine, combinations of about 320 milligrams of Valsartan, approximately 6.25 milligrams, approximately 12.5 milligrams or approximately 25 milligrams of hydrochlorothiazide and approximately 2.5 milligrams, approximately 5 milligrams or approximately 10 milligrams of amlodipine , combinations of approximately 80 milligrams of Valsartan and approximately 150 milligrams or approximately 300 milligrams of aliskirene, combinations of approximately 160 milligrams of Valsartan and approximately 150 milligrams or approximately 300 milligrams of aliskiren, and combinations of approximately 320 milligrams of Valsartan and approximately 150 milligrams or approximately 300 milligrams of alskyrene. Examples of compound formation also include combinations of about 150 milligrams of aliskirene and about 2.5 milligrams, about 5 milligrams or about 10 milligrams of amlodipine, and combinations of about 300 milligrams of aliskirene and about 5 milligrams or about 10 milligrams of amlodipine. 2. Disintegrating agent The disintegrating agent imparts to the inner core 10, the disintegrability which is sufficient to disintegrate easily in the mouth. Specifically, the disintegrating agent imparts to the inner core 10 a disintegrability that is sufficient for the active ingredient (particularly Valsartan in its free or salt form) disintegrates easily in the mouth, for example, after exposure to saliva or a comparable amount of water.

Disintegrating agents include low substitution hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, carmellose, calcium carmellose, partially pregelatinized starch, starch, sodium carmellose, alginic acid, sodium alginate, guar gum and others. Among these disintegrating agents, a component can be used alone or two or more components can be used in combination.

The inner core 10 preferably comprises at least low substituted hydroxypropylcellulose as a disintegrating agent. The disintegrating agent also comprises at least one component selected from the group consisting of crospovidone, croscarmellose sodium, and sodium carboxymethyl starch, and low substituted hydroxypropyl cellulose.

Preferred blending examples of the disintegrating agents include low substitution hydroxypropylcellulose alone, a combination of low substitution hydroxypropylcellulose and crospovidone, a combination of low substitution hydroxypropylcellulose and croscarmellose sodium, a combination of low substitution hydroxypropylcellulose and carboxymethylstarch of sodium, and others.

As used herein, the term "low substituted hydroxypropylcellulose" means hydroxypropyl cellulose wherein the molar number of substitution of hydroxypropyl groups per glucose unit is from 5 to 16 percent, preferably from 7 to 13 percent.

The proportion of disintegrating agent in the inner core 10 is preferably 15 to 60 mass percent, and more preferably 20 to 40 mass percent, based on the total of the pharmaceutical composition constituting the inner core 10. When using two or more disintegrating agents in combination, the use is preferably such that the total disintegrating agents are within the ranges of the above proportions.

In the case when the disintegrating agent is added by the above proportion, if the outer layer 20 is made after the inner core 10 is made independently, the inner core 10 can be broken in the transport process of the inner core 10. or in the process of making the outer layer 20 on the inner core 10, because the inner core is very brittle. However, when the OSDrC® rotary compression machine is used, the tablet that includes the disintegrating agent in the inner core 10 as the above ratio is easily obtained without breaking the inner core 10. 3. Sliding The glidant suppresses the adhesion of Valsartan or one of its pharmaceutically acceptable salts. Specifically, the combination of the disintegrating agent and the slider in the core internal 10 ensures high disintegrability although Valsartan (or a pharmaceutically acceptable salt thereof) is the active ingredient.

Glidants include compounds of inorganic silicic acid, aluminum oxide, aluminum hydroxide, magnesium oxide, magnesium hydroxide and others. Inorganic silicic acid compounds include silicic acid, anhydrous silicic acid, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminometasilicate, and others. Among these sliding agents, a component can be used alone or two or more components can be used in combination.

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

The proportion of the slip agent in the inner core 10 is preferably 1 to 10 mass percent, and more preferably 1 to 6 mass percent, based on the total of the pharmaceutical composition constituting the inner core 10. When using two or more sliding agents in combination, the use is preferably such that the total of the sliding agents is within the ranges of the above proportions. 4. Lubricant The lubricant ensures the dispersibility of Valsartan (or a pharmaceutically acceptable salt thereof) in the mouth.

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

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

The proportion of the lubricant in the inner core 10 is preferably 1 to 7 mass percent, and more preferably 2 to 5 mass percent, based on the total of the pharmaceutical composition constituting the inner core 10. When used two or more lubricants in combination, the use is preferably such that the total of the lubricants is within the ranges of the above proportions. 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 rapid-acting sweetening agent, the rapid-acting sweetening agent diffuses into the mouth before the medicament is released, whereby the initial bitter taste can be prevented; the slow-acting sweetening agent, which is contained in the inner core, diffuses into the mouth after the dry-coated agent has completely disintegrated, whereby the Bitter taste remaining after administration can be decreased.

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

The proportion of slow-acting sweetening agent can be adjustable according to its sweetness and is the amount to be as sweet as preferably from 100 to 5,000 mass parts of sucrose, and more preferably from 500 to 2,000 mass parts of sucrose per 100 mass parts of Valsarian in the pharmaceutical composition constituting the internal core 10. Saccharin has 300 times of sweetness and sucralose has 500 times of sweetness in comparison with the sweetness of sucrose.

In the case when sodium saccharin is used as the slow-acting sweetening agent, the proportion of sodium saccharin is preferably 0.5 to 5.0 mass parts of sodium saccharin, and more preferably 1.5 to 2.5 mass parts of sodium saccharin per 100 mass parts of Valsarían in the pharmaceutical composition that constitutes the internal nucleus 10. 6. Other ingredients The pharmaceutical composition constituting the inner core 10 may also comprise excipients, sweetening agents, flavor masking agents, coloring agents, agents pH adjusters, or binders other than the ingredients mentioned above. Crystalline cellulose or microcrystalline cellulose may be contained in the pharmaceutical composition that constitutes the inner core 10.

Binders, for example, include water soluble polymers (such as hydroxypropylcellulose and hydroxypropylmethylcellulose), Arabian gum powder, gelatin and pullulan.

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

The pH adjusting agents that may be used in the present invention may 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, acid lactic, or a salt form of any of the above.

The 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 talcum powder.

B. Outer Coat 20 The outer layer 20 consists of a coating composition containing a pH adjuster that makes the interior of the mouth slightly acidic (i.e., in the pH range of 2.0 to 5. 0, and more preferably in the pH range of 3.0 to 4.0) and coat the inner core 10 to impart sufficient hardness for 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 the bitter taste and achieve the improvement of the quality of life as intended when the dry coated agent is allowed to disintegrate in the mouth and Then it is used to be administered orally.

The interior of the mouth is slightly acidified when the dry coated agent 100 is allowed to disintegrate in the mouth. In addition, since Valsartan is an acid medicine, it is believed that the immediate solubility will be reduced as the acidity inside the mouth becomes higher. Specifically, it is believed that the interior of the mouth is acidified by the outer layer 20 that has disintegrated therein before the Valsartan in the inner core 10 is released and, therefore, that the dissolution of Valsartan in the mouth It is suppressed to avoid the bitter taste.

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

The amount of pH regulator is preferably determined by the amount that changes the pM of 5 milliliters of purified water to the slightly acidic pH range, ie from 2.0 to 5.0, and more preferably in the pH range of 3.0 to 4.0.

In the case when anhydrous citric acid is used as the pH adjuster, the proportion of the anhydrous citric acid is preferably from 0.5 to 10 mass parts of anhydrous citric acid, and more preferably from 0.5 to 5 mass parts of anhydrous citric acid per 100 mass parts of Valsarían in the pharmaceutical composition that constitutes the internal 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 the Valsartan. The inclusion of the sweetening agent in the outer layer 20, therefore, allows the sweetening agent to diffuse into the mouth before the Valsartan is released, whereby the bitter taste exhibited by the Valsartan can be prevented further.

Sweetening agents include, for example, saccharin, sodium saccharin, 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 between the aforementioned sweetening agents. previously. The fast acting agent can produce the effects of bitter taste prevention by the aforementioned sweetening agents more effectively.

Based on the combination of the inner core 10 containing the slow-acting sweetening agent (for example saccharin and / or sodium saccharin) and the outer layer 20 containing the fast-acting sweetening agent, the rapid-acting sweetening agent diffuses in the mouth before the medication is released, so the initial bitter taste can be prevented; the slow-acting sweetening agent, which is contained in the inner core, diffuses into the mouth after the dry-coated agent has completely disintegrated, whereby the bitter taste remaining after administration may be decreased.

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

The proportion of sweetening agent in the outer layer can be adjustable according to its sweetness and is the amount to be as sweet as preferably from 100 to 5,000 mass parts of sucrose, and more preferably from 1,000 to 3,000 mass parts of sucrose per 100 parts. Valsartan masses in the pharmaceutical composition that makes up the inner core 10. Aspartame and acesulfame potassium have 200 times the sweetness and sucralose has 600 times the sweetness compared to the sweetness of sucrose.

In the case where aspartame is used as an agent fast-acting sweetener, the proportion of aspartame is preferably from 1 to 20 mass parts of sucrose, and more preferably from 5 to 10 mass parts of aspartame per 100 mass parts of Valsarian 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 ingredients known for use in tablets are properly combined. It is further preferred that the composition be a composition capable of providing adequate rapid disintegrability for an oral 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, microcrystalline cellulose) as ingredients other than those mentioned previously, for example. The coating composition formed in this way can easily acquire sufficient fast densibility and the strength of the agent at the same time.

The coating composition constituting the outer layer 20 preferably comprises crospovidone as disintegrating 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 may be added in the powder, liquid or granule forms, as necessary, during the tablet manufacturing process which will be described below.

Foaming agents, for example, include sodium hydrogen carbonate. Flavoring agents, for example, include menthol, lemon, lime-lemon and orange.

C. Other Characteristics and Properties The hardness of the dry-coated agents of the present invention can be adjusted such that it is sufficient to allow easy and convenient storage, disposal of packages, and subsequent handling of the coating agents without breaking the dry-coated agent. In one embodiment, the dry-coated agent is hard enough to be handled and can be packaged as conventional non-OD tablets.

The hardness of the dry coated agent of the present invention may vary depending on factors such as shape, dimensions and weight. In one embodiment, the hardness of a round tablet with a diameter of about 6.0 to 10.0 millimeters, a thickness of about 3.0 to 6.0 millimeters and a weight of about 70 to 320 milligrams (20 milligrams to 80 milligrams of Valsartan) is, for example , from 30N to 55N approximately, as measured using a tablet hardness measuring device such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan). In another embodiment, the hardness of an oval tablet with a dimension of approximately 15.0 and 8.0 millimeters, a thickness of approximately 5.0 to 10.0 millimeters and a weight of approximately 500 to 600 milligrams (160 milligrams of Valsartan) is, for example, 50N a 100N approximately, as measured using a tablet hardness measuring device such as Portable Checker (PC-30, Okada Seiko Co., Ltd., Japan).

The dry-coated agent of the present invention can take various forms, for example, round, oval, compressed, donut-shaped, but is not limited to any particular form.

The size of the dry coated agent of the invention may vary, but it must 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 a patient's oral cavity. For example, a dry-coated agent of the invention may have a weight of about 70 milligrams to about 600 milligrams.

The dissolvability of Valsartan from the dry-coated agent according to the present embodiment is preferably the same level or a level similar to that of Valsartan from a common Valsartan-containing tablet such as the DIOVAN ® tablet (manufactured by Novartis Pharma KK). According to an example of the test methods for knowing such dissolubility, although available in various types, 75 percent 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 method of palettes of the Japanese Pharmacopoeia by employing a buffer of pH 3.0 as a test solution, and more preferably, 80 percent or more of Valsartan dissolves in 120 minutes. When administered to a human, the tablet according to the present invention undergoes a solution that is biologically equal to a DIOVAN® tablet.

D. Manufacturing 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 outer layer powder Compression and internal core powder with an OSDrC® rotary compression machine that has double-structure punches.

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

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

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

Thus, the aforementioned manufacturing method allows the inner core to be coated by the outer layer without being forced out of the punch. Therefore, even if the inner core 10 has a 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 can be a dry-coated agent having two cores, for example. Figure 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 Figure 4 comprises two inner cores 11 and an outer layer 21 covering 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. different dry coated agents, each comprising an inner core 11 covered by an outer layer 21. The dry coated agent 110 can be administered as is or can be divided into two, one of which is to be administered, depending on the required dose.

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

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

Preferred embodiments of the present invention have been described above; however, the present invention should not be limited to the modalities mentioned above.

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 following were mixed: 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 mixed material was passed through a screen and mixed further for a certain period of time. The mixed material was compacted using a roll compactor. Then, the compacted material was pulverized to the target particle size, and then mixed after 7.0 parts by weight of crospovidone and 1.0 parts by weight of sodium saccharin were added. The mixed material was compacted again by the roll compactor. The compacted material was granulated to the target particle size and, therefore, the granulated powder was obtained. The compaction and granulation are repeated as necessary, and the obtained granulated powder was mixed to be prepared as the 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 were mixed. anhydrous and 0.5 parts by weight of light anhydrous silicic acid. Then 0.3 parts by weight of magnesium stearate was added, and after further mixing, the powder of outer layer 20-A was prepared.

Through the OSDrC® rotary compression machine that employing a double layer punch having an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-A and the powder of the outer layer 20-A were compressed. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (143.5 milligrams) formed by compressing the inner core powder 10-A as the inner core, and a coating composition (176.5 milligrams) was produced. formed by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE I-2 The following were mixed: 55.5 parts by weight of Valsarian, 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 mixed material was passed through a screen and mixed further for a certain period of time. The mixed material was compacted using a roll compactor. Next, the compacted material was pulverized to the target particle size, and then mixed after 6.9 parts by weight of crospovidone, 1.0 parts by weight of sodium saccharin and 0.5 parts by weight of sodium saccharin were added. The mixed material was compacted again by the roll compactor. The compacted material was granulated to the target particle size and, therefore, the granulated powder was obtained. The compaction and granulation are repeated as necessary, and the The obtained granulated powder was mixed to be prepared as the inner core powder 10-B.

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

By means of the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 9.5 mm F and a punch of 7.5 mm F, the internal core powder 10-B and the powder of the outer layer 20- were compressed TO. Therefore, a dry coated tablet (320.0 milligrams) having a pharmaceutical composition (144.2 milligrams) formed by compressing the inner core powder 10-B as the inner core, and a coating composition (175.8 milligrams) was produced. formed by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE I-3 The following were mixed: 60.0 parts by weight of Valsarian, 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 mixed material was passed through a screen and mixed further for a certain period of time. The mixed material was compacted using a roll compactor. Next, the compacted material was pulverized to the target particle size, and then mixed after 7.5 parts by weight of crospovidone, 1.1 parts were added. by weight of sodium saccharin and 0.5 parts by weight of magnesium stearate. The mixed material was compacted again by the roll compactor. The compacted material was granulated to the target particle size and, therefore, the granulated powder was obtained. The compaction and granulation are repeated as necessary, and the obtained granulated powder was mixed to be prepared as the inner core powder 10-C.

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

Using the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 9.5 mm F and a punch of 7.5 mm F, the internal core powder 10-C and the powder of the outer layer 20-A were compressed. Therefore, a dry-coated tablet (308.3 milligrams) having a pharmaceutical composition (133.3 milligrams) formed by compressing the inner core powder 10-C as the inner core, and a coating composition (175.0 milligrams) was produced. formed by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE I-4 The following were mixed: 60.0 parts by weight of Valsarian, 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 mixed material is It passed through a sieve and was mixed further during a certain period of time. The mixed material was compacted using a roll compactor. Next, the compacted material was pulverized to the target particle size, and then mixed 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 were added. by weight of crystalline cellulose. The mixed material was compacted again by the roll compactor. The compacted material was granulated to the target particle size and, therefore, the granulated powder was obtained. The compaction and granulation are repeated as necessary, and the granulated powder obtained was mixed to be prepared as the 10-D core powder.

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

By means of the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-D and the powder of the outer layer 20- were compressed TO. Therefore, a dry-coated tablet (308.3 milligrams) having a pharmaceutical composition (133.3 milligrams) formed by compressing the inner core powder 10-D as the inner core, and a coating composition (175.0 milligrams) was produced. formed by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE 1-5 The powder of the inner core 10-A and the powder of the outer layer 20-A were obtained in the same manner as in Example 1-1. By means of the OSDrC® rotary compression machine that uses a double-layer punch that has an external punch of 6.0 millimeters F and a punch of 4.5 millimeters F, the internal core powder 10-A and the powder of the outer layer 20- were compressed TO. Therefore, a dry coated tablet (80.0 milligrams) having a pharmaceutical composition (35.9 milligrams) formed by compressing the inner core powder 10-A as the inner core, and a coating composition (44.1 milligrams) was produced. formed by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE I-6 The powder of the inner core 10-A and the powder of the outer layer 20-A were obtained in the same manner as in Example 1-1. By means of the OSDrC® rotary compression machine that uses a double-layer punch that has an external punch of 6.0 millimeters F and a punch of 4.5 millimeters F, the internal core powder 10-A and the powder of the outer layer 20- were compressed TO. Therefore, a dry coated tablet (96.5 milligrams) having a pharmaceutical composition (35.9 milligrams) formed by compressing the inner core powder 10-A as the inner core and a coating composition (60.6 milligrams) formed by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE 1-7 The powder of the inner core 10-D and the powder of the outer layer 20-A were obtained in the same manner as in Example I-4. By means of the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 6.0 millimeters F and a punch of 4.5 millimeters F, the internal core powder 10-D and the powder of the outer layer 20- were compressed TO. Therefore, a dry coated tablet (77.1 milligrams) having a pharmaceutical composition (33.3 milligrams) formed by compression of the inner core powder 10-D as the inner core and a coating composition (43.8 milligrams) formed was produced. by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE I-8 The powder of the internal core 10-D and the powder of the outer layer 20-A were obtained in the same manner as in Example I-4. By means of the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 6.0 millimeters F and a punch of 4.5 millimeters F, the internal core powder 10-D and the powder of the outer layer 20- were compressed TO. Therefore, it produced a dry coated tablet (96.0 milligrams) having a pharmaceutical composition (33.3 milligrams) formed by compressing the inner core powder 10-D as the inner core and a coating composition (62.7 milligrams) formed by compressing the powder of outer layer 20-A as the outer layer.

EXAMPLE I-9 The powder of the inner core 10-A and the powder of the outer layer 20-A were obtained in the same manner as in Example 1-1. By means of the OSDrC® rotary compression machine using a double-layer punch with an external punch of 8.0 mm F and a punch of 7.5 mm F, the internal core powder 10-A and the dust of the outer layer 20- were compressed TO. Therefore, a dry-coated tablet (160.0 milligrams) having a pharmaceutical composition (71.75 milligrams) formed by compressing the inner core powder 10-A as the inner core and a coating composition (88.25 milligrams) formed was produced. by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE 1-10 The powder of the inner core 10-D and the powder of the outer layer 20-A were obtained in the same manner as in Example I-4. Through the OSDrC® rotary compression machine that uses a Double-ply punch having an external punch of 8.0 mm F and a punch of 7.5 mm F, the inner core powder 10-D and the powder of the outer layer 20-A were compressed. Therefore, a dry-coated tablet (154.2 milligrams) having a pharmaceutical composition (66.65 milligrams) formed by compressing the inner core powder 10-D as the inner core and a coating composition (87.55 milligrams) formed was produced. by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE 1-11 The powder of the inner core 10-A and the powder of the outer layer 20-A were obtained in the same manner as in Example 1-1. Using an OSDrC® rotary compression machine that uses a double-layer punch with atypical exterior punch with a diameter greater than 15 millimeters and a diameter of less than 8 millimeters and an atypical punch with a diameter greater than 13 millimeters and a diameter of less than 6 millimeters, the internal core powder 10-A and outer layer powder 20-A. Therefore, a dry-coated tablet (590.0 milligrams) having a pharmaceutical composition (287.0 milligrams) formed by compressing the inner core powder 10-A as the inner core and a coating composition (303.0 milligrams) formed was produced. by compressing the outer layer powder 20-A as the outer layer.

EXAMPLE 1-12 The powder of the inner core 10-D and the powder of the outer layer 20-A were obtained in the same manner as in Example I-4. Using the OSDrC® rotary compression machine, which uses a double layer punch with atypical exterior punch with a diameter greater than 15 millimeters and a diameter of less than 8 millimeters and an atypical punch with a diameter greater than 13 millimeters and smaller than 6 millimeters in diameter, they were compressed 10-D internal core powder and outer layer powder 20-A. Therefore, a dry-coated tablet (580.0 milligrams) having a pharmaceutical composition (266.6 milligrams) formed by compressing the inner core powder 10-D as the inner core and a coating composition (313.4 milligrams) formed was produced. by compressing the outer layer powder 20-A as the outer layer.

Table I-2 lists the internal core powder compositions 10-A to 10-D. Table I-3 lists the outer layer powder compositions 20-A.

Table I-2 Internal Core Powder Table I-3 Outer Coat Powder Table I-4 lists the compositions of the dry-coated tablets of Examples 1-1 to 1-1 2.

Table I-4 Hardness measurements The dry-coated tablets obtained in the examples were measured for their hardness in the diameter direction using a com puter d u ction m eder (PC-30, Okada Seiko Co., Ltd., J apón). The results obtained are as shown in Table 1-1.

Abrasive level measurements The dry-coated tablets obtained in the examples were measured by their abrasive levels according to the Tablet Friability Test (Reference Information of the Japanese Pharmacopoeia). The results obtained are as shown in Table 1-1.

Measurement of the time consumed in oral disintegration The dry-coated tablets obtained in the examples were evaluated for the time devoted to their oral disintegration in male adults. The detailed procedures are as follows. The dry-coated tablets were each taken in the oral cavity and allowed to disintegrate when rolled up by the tongue. The time required for complete disintegration for each tablet was measured. The results obtained are as shown in Table 1-1.

Table 1-1 EXAM PLOS 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 11 Comparison 11-1 The following were mixed: 55.1 parts by weight of They would be worth, 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 mixed material was passed through a screen and mixed further for a certain period of time. The mixed material was compacted using a roll compactor. Next, the compacted material was pulverized to the target particle size and then mixed after 4.0 parts by weight of sucralose and 10.0 parts by weight of crospovidone were added. The mixed material was compacted again by the roll compactor. The compacted material was granulated to the target particle size and, therefore, the granulated powder was obtained. The compaction and granulation are repeated as necessary, and the obtained granulated powder was mixed to be prepared as the 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 the mixture were mixed. fragrance. Then 0.2 parts by weight of magnesium stearate was added, and after further mixing, the powder of outer layer 20-A was prepared.

By means of the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-A and the powder of the outer layer 20- were compressed TO. By therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-A as the inner core and a coating composition (174.8 milligrams) formed by Compression of the outer layer powder 20-A as the outer layer.

EXAMPLE 11-1 The powder of the inner core 10-A was obtained in the same manner as in Comparative Example 11-1. Apart from the addition of 0.7 parts by weight of anhydrous citric acid together with magnesium stearate, the powder of outer layer 20-B was obtained in the same manner as in Comparative Example 11-1.

Using the OSDrC® rotary compression machine that uses a double-layer punch that has an external punch of 9.5 m F and a punch of 7.5 mm F, the inner core powder 10-A and the powder of the outer layer 20-B were compressed. Therefore, a dry-coated tablet (321.3 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-A as the inner core and a coating composition (176.1 milligrams) formed was produced. by compressing the outer layer powder 20-B as the outer layer.

Evaluation of bitter taste 1 A sensory test was carried out for the tablets dry coated from Comparative Example 11-1 and Example 11-1. As a result, a dry coated tablet of Example 11-1 had a lower degree of bitter taste, as compared to the dry-coated tablet of Comparative Example 11-1. a Table 11-3 shows the compositions of the dry-coated tablets of Comparative Example 11-1 and Example 11-1.

Table II-3 EXAMPLE I I-2 The following were mixed: 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 mixed material was passed through a screen and mixed further for a certain period of time. The mixed material was compacted using a roll compactor. Next, the compacted material was pulverized to the target particle size and then mixed after 1 0.0 parts by weight of crospovidone was added. The mixed material was compacted again by the roll compactor. The compacted material was added to the target particle size and, therefore, the granulated powder was obtained. The compaction and granulation is repeated as necessary, and the obtained granulated powder was mixed to be prepared as the inner core powder 10-B.

Then, the powder of the outer layer 20-B was obtained in the same manner as in Example 11-1.

Using the OSDrC® rotary compression machine employing a double layer punch that has an external punch of 9.5 milliliters F and a punch of 7.5 millimeters F, the inner core powder 10-B and the powder of the outer layer 20- were compressed B. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-B as the inner core and a coating composition (174.8 milligrams) formed was produced. by compressing the outer layer powder 20-B as the outer layer.

EXAMPLE II-3 Apart from the addition of crospovidone in the amount of 9.0 parts by weight and in addition to the addition of 1.0 parts by weight of sodium saccharin, the inner core powder was prepared in the same manner as in Example 11-2 to obtain the internal core powder 10-C. Then, the outer layer powder 20-B was obtained in the same manner as in Example 11-1.

Using the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-C and the powder of the outer layer 20-B were compressed. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-C as the inner core and a coating composition (174.8 milligrams) formed was produced. by compressing the outer layer powder 20-B as the outer layer.

Comparative Example 11-2 Apart from the addition of crospovidone in the amount of 8.0 parts by weight and in addition to the addition of 2.0 parts by weight of sodium saccharin, the inner core powder was prepared in the same manner as in Example II-2 to obtain the internal core powder 10-D. Next, the outer layer powder 20-A was obtained in the same manner as in Example 11-1.

By means of the OSDrC® rotary compression machine that uses a double layer punch that has an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-D and the powder of the outer layer 20- were compressed TO. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-D as the inner core and a coating composition (174.8 milligrams) formed was produced. by compression of outer layer powder 20-A as the outer layer.

Comparative Example 11 - 3 Apart from the addition of crospovidone in the amount of 6.9 parts by weight and in addition to the addition of 3.1 parts by weight of sodium saccharin, the inner core powder was prepared in the same manner as in Example I I-2 to obtain the powder of the internal core 10-E. Thereafter, the outer layer powder 20-A was obtained in the same manner as in Example 11-1.

Using the OSDrC® rotary compression machine employing a double layer punch having an external 9.5 mm F punch and a 7.5 mm F punch, the internal core powder 1 0-E and the powder of the outer layer were compressed 20 A. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 1 0-E as the inner core and a coating composition (1) is produced. 74.8 milligrams) formed by compressing the outer layer powder 20-A as the outer layer.

Evaluation of bitter taste 2 With four participants, a sensory test was performed for the dry-coated tablets of Examples I I-2 and I I-3, and the dry-coated tablets of Comparative Examples I I-2 and I I-3. The bitter taste was classified from low grade and evaluated with the sum of the ranks of the four participants. The result is as shown in Table 11-1.

Table 11-1 Table II-4 shows the compositions of the dry-coated tablets of Examples II-2 and 11-3, and the dry-coated tablets of Comparative Examples II-2 and 11-3.

Table II-4 EXAMPLE 11-4 The following were mixed: 55.2 parts by weight of Valsarian, 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 mixed material was passed through a screen and mixed further for a certain period of time. The mixed material was compacted using a roll compactor. Next, the compacted material was pulverized to the target particle size and then mixed after 6.9 parts by weight of crospovidone and 1.0 parts by weight of sodium saccharin were added. The mixed material was compacted again by the roll compactor. The compacted material was granulated to the target particle size and, therefore, the granulated powder was obtained. The compaction and granulation was repeated as necessary, and the granulated powder obtained was mixed to be prepared as the inner core powder 10-G.

Then, 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 the mixture were mixed. citric acid anhydrous and 0.5 parts by weight fragrance. Then 0.2 parts by weight of magnesium stearate was added, and after further mixing, the powder of outer layer 20-A was prepared.

Through the OSDrC® rotary compression machine that employing a double layer punch having an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-G and the powder of the outer layer 20-C were compressed. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-G as the inner core and a coating composition (174.8 milligrams) formed was produced. by compressing the outer layer powder 20-C as the outer layer.

EXAMPLE II-5 The powder of the inner core 10-G was obtained in the same manner as in Example II-4. Apart from the addition of lactose monohydrate in the amount of 46.3 parts by weight and the aspartame in the amount of 2.0 parts by weight, the powder of the outer layer 20-D was obtained in the same manner as in Example II-4 .

By means of the OSDrC® rotary compression machine that uses a double-layer punch that has an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-G and the powder of the outer layer 20- were compressed D. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-G as the inner core and a coating composition (174.8 milligrams) formed was produced. by compression of outer layer powder 20-D as the outer layer.

EXAMPLE 11-6 The powder of the inner core 10-G was obtained in the same manner as in Example II-4. Apart from the addition of lactose monohydrate in the amount of 44.3 parts by weight and aspartame in the amount of 4.0 parts by weight, the powder of the outer layer 20-E was obtained in the same manner as in Example II-4 .

By means of the OSDrC® rotary compression machine that uses a double-layer punch that has an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-G and the powder of the outer layer 20- were compressed AND. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-G as the inner core and a coating composition (174.8 milligrams) formed was produced. by compressing the outer layer powder 20-E as the outer layer.

EXAMPLE II-7 The powder of the inner core 10-G was obtained in the same manner as in Example II-4. Apart from the addition of lactose monohydrate in the amount of 42.3 parts by weight and the aspartame in the amount of 6.0 parts by weight, the powder of the outer layer 20-F was obtained in the same manner as in Example II-4 .

By means of the OSDrC® rotary compression machine that uses a double-layer punch that has an external punch of 9.5 millimeters F and a punch of 7.5 millimeters F, the internal core powder 10-G and the powder of the outer layer 20- were compressed F. Therefore, a dry-coated tablet (320.0 milligrams) having a pharmaceutical composition (145.2 milligrams) formed by compressing the inner core powder 10-G as the inner core and a coating composition (174.8 milligrams) formed was produced. by compressing the outer layer powder 20-F as the outer layer.

Evaluation of bitter taste 2 With four participants, a sensory test was performed for the dry-coated tablets of Examples 11 -4-7. The bitter taste was classified from a low grade and evaluated with the sum of the ranges of the four participants. The result is as shown in Table II-2.

Table II-2 Table 11-5 shows compositions of the dry-coated tablets of Examples 11-4 to 11-7.

Table 11-5 EXAMPLE III The dry-coated tablets PT1 and PT2 having the composition as shown in Table III were produced.

Table III Explanation of reference numbers 100, 110: compressed; 10, 11: internal core; 20, 21: outer layer; 30: slot.

All patents, patent applications, publications and the like cited in this application are incorporated herein by reference in their entirety.

This invention includes the following modalities: [1] A tablet consisting of a pharmaceutical composition comprising a Valsarian or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant and a lubricant, wherein the tablet is administered orally through disintegration in the mouth by saliva or water in an amount similar to saliva. [2] An orally disintegrating tablet comprising an internal core consisting of a pharmaceutical composition comprising a Valsarian or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant, and a lubricant, and an outer layer that coats the core internal. [3] The tablet according to [2], wherein the outer layer comprises a crystalline cellulose, a disinfectant and a lubricant. [4] The tablet according to any of [1] to [3], wherein the de-inking agent comprises at least one component selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, carboxymethyl-starch sodium, carmellose, calcium carmellose, partially pregelatinized starch, starch, sodium carmellose, alginic acid, sodium alginate and guar gum. [5] The tablet according to any one of [1] to [4], wherein the disintegrating agent comprises at least low substituted hydroxypropylcellulose. [6] The tablet according to any one of [1] to [5], wherein the disintegrating agent also comprises at least one component selected from the group consisting of crospovidone, croscarmellose sodium and sodium carboxymethyl starch, and hydroxypropyl cellulose of low substitution. [7] The tablet according to any one of [1] to [6], wherein the slip agent preferably comprises at least one component selected from the group consisting of silicic acid, anhydrous silicic acid, aluminum silicate, sodium silicate, Calcium, magnesium aluminometasilicate, aluminum oxide, aluminum hydroxide, magnesium oxide and magnesium hydroxide. [8] The tablet according to any one of [1] to [7], wherein the slip agent comprises light anhydrous silicic acid and / or synthetic aluminum silicate. [9] The tablet according to any one of [1] to [8], wherein the lubricant preferably comprises at least one component selected from the group consisting of magnesium stearate, aluminum stearate, calcium stearate, acid ester sucrose, hydrogenated oil, poly (ethylene glycol) and talc. [10] The tablet according to any one of [1] to [9], wherein the lubricant comprises at least magnesium stearate. [11] The tablet according to any one of [1] to [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] to [11], wherein the pharmaceutical composition further comprises an aliskiren or a pharmaceutically acceptable salt thereof. [12-1] The tablet according to any one of [1] to [12], wherein the outer layer is formed by a coating composition containing a pH adjuster that makes the interior of the mouth slightly 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, sodium saccharin, dipotassium glycyrrhizate, aspartame, sucralose, acesulfame potassium, stevia and thaumatin. [12-5] The tablet according to [12-5], wherein the sweetening agent is a fast-acting sweetening agent, and the pharmaceutical composition also contains a slow-acting sweetening agent. [12-6] The tablet according to [12-5], wherein the rapid-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 sodium saccharin. [13] A dry-coated agent comprising an inner core consisting of a pharmaceutical composition containing Valsartan or its pharmaceutically acceptable salt, and an outer layer that coats the inner core and consists of a coating composition containing a pH adjuster that makes the inside of the mouth slightly 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 tablet according to [13] or [14], wherein the coating composition further contains a sweetening agent. [16] The dry-coated agent according to [15], wherein the The sweetening agent contains at least one component selected from the group consisting of saccharin, sodium saccharin, 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 also contains a slow-acting sweetening agent. [18] The dry-coated agent according to [17], wherein the rapid-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 sodium saccharin. [19-1] The dry-coated agent according to any of [13 to 19], wherein the inner core consisting of a pharmaceutical composition comprising a Valsarian or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant and a lubricant, wherein the dry-coated agent is administered orally through disintegration in the mouth by saliva or water in an amount similar to saliva. [19-2] The dry-coated agent according to any of [13 to 19], wherein the inner core consisting of a pharmaceutical composition comprises a Valsartan or a salt pharmaceutically acceptable thereof, a disintegrating agent, 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 of [19-1] to [19-3], wherein the disintegrating agent comprises at least one component selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, carboxymethyl-sodium starch, carmellose, calcium carmellose, partially pregelatinized starch, starch, sodium carmellose, alginic acid, sodium alginate and guar gum. [19-5] The dry-coated agent according to any one of [19-1] to [19-4], wherein the disintegrating agent comprises at least low substituted hydroxypropylcellulose. [19-6] The dry-coated agent according to any one of [19-1] to [19-5], wherein the disintegrating agent also comprises at least one component selected from the group consisting of crospovidone, croscarmellose sodium and sodium carboxymethyl starch, and low substituted hydroxypropyl cellulose. [19-7] The dry-coated agent according to any one of [19-1] to [19-6], wherein the slip agent preferably comprises at least one component selected from the group consisting of silicic acid, Silicic anhydrous, aluminum silicate, calcium silicate, aluminometasilicate magnesium, aluminum oxide, aluminum hydroxide, magnesium oxide and magnesium hydroxide. [19-8] The dry-coated agent according to any one of [19-1] - [19-7], wherein the slip agent comprises light anhydrous silicic acid and / or synthetic aluminum silicate. [19-9] The dry-coated agent according to any one of [19-1] to [19-7], wherein the lubricant preferably comprises at least one component selected from the group consisting of magnesium stearate, stearate aluminum, calcium stearate, sucrose fatty acid ester, hydrogenated oil, poly (ethylene glycol) and talc. [19-10] The dry-coated agent according to any one of [19-1] - [19-9], wherein the lubricant comprises at least magnesium stearate. [19-11] The dry-coated agent according to any one of [19-1] to [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] to [19-11], wherein the pharmaceutical composition further comprises an aliskiren or a pharmaceutically acceptable salt thereof.

Claims (19)

CLAIMING IS

1 . A tablet consisting of a pharmaceutical composition comprising a Valsartan or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant and a lubricant, wherein the tablet is administered orally through disintegration in the mouth by saliva or by water in a quantity similar to saliva.

2. An orally disintegrating tablet comprising an internal core consisting of a pharmaceutical composition comprising a Valsartan or a pharmaceutically acceptable salt thereof, a disintegrating agent, a glidant, and a lubricant, and an outer layer that coats 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 to 3, wherein the disintegrating agent comprises at least one component selected from the group consisting of low substitution hydroxypropylcellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, carmellose, carmellose of calcium, partially pregelatinized starch, starch, sodium carmellose, algic acid, sodium alginate and guar gum.

5. The tablet according to any of Claims 1 to 4, wherein the disintegrating agent comprises at least Low substitution hydroxypropylcellulose.

6. The tablet according to any of Claims 1 to 5, wherein the disintegrating agent also comprises at least one component selected from the group consisting of crospovidone, croscarmellose sodium and sodium carboxymethyl starch, and low substituted hydroxypropyl cellulose.

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

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

9. The tablet according to any one of Claims 1 to 8, wherein 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.

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

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

13. A dry-coated agent comprising an internal core consisting of a pharmaceutical composition containing Valsarian or its pharmaceutically acceptable salt, and an outer layer that coats the inner core and consisting of a coating composition containing a pH adjuster that makes the inside of the mouth slightly 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 tablet according to Claims 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, sodium saccharin, 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 rapid-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 Claims 17 or 18, wherein the slow-acting sweetening agent contains saccharin and / or sodium saccharin.