HK1082909B - Controlled-release drug composition - Google Patents

Description

Controlled release pharmaceutical composition

Technical Field

The present invention relates to a controlled-release pharmaceutical composition containing an HMG-CoA reductase inhibitor pitavastatin (pitavastatin), a salt thereof or an ester thereof.

Background

Pitavastatin, a salt thereof or an ester thereof is known to have an excellent HMG-CoA reductase inhibitory activity and is useful as a therapeutic agent for hypercholesterolemia (U.S. Pat. No.5,856,336 and European patent No.0,304,063). Therapeutic agents for hypercholesterolemia such as pitavastatin-containing drugs are used as oral preparations such as tablets, granules and capsules (U.S. Pat. nos. 6,465,477 and WO 97/23200). Further, the preparation for oral administration is generally designed such that the concentration of the active ingredient in blood reaches a peak and then rapidly disappears 0.5 to 3 hours after administration. However, since cholesterol is synthesized in the living body in the late night to the early morning, there is a high possibility that the concentration of the active ingredient in the blood does not coincide with the period of time for cholesterol biosynthesis.

Furthermore, it is known that pitavastatin, a salt thereof or an ester thereof is highly effective and safe, but it is desirable not to excessively increase the blood concentration thereof from the viewpoint of preventing side effects.

In addition, pitavastatin, a salt thereof or an ester thereof is also required to maintain its excellent high cholesterol lowering effect for a long period of time.

Accordingly, an object of the present invention is to provide a controlled-release pharmaceutical composition capable of stably maintaining an appropriate blood concentration of pitavastatin, a salt thereof or an ester thereof for a long period of time.

Disclosure of Invention

Accordingly, the present inventors have made various studies to develop a controlled-release pharmaceutical composition of pitavastatin, a salt thereof or an ester thereof. First, as a means for solving the above problems, a sustained-release preparation having 0-time drug-releasing property is proposed. However, the problem cannot be solved because the blood concentration immediately after administration is not easily increased by only the sustained-release preparation having drug release property 0, the maximum blood concentration Cmax is greatly decreased as compared with the ordinary preparation of the same dose, and the area under the blood concentration curve (AUC) corresponding to an index of lowering the high cholesterol level is also greatly decreased.

Accordingly, as a result of studies on the absorption kinetics of pitavastatin, a salt or an ester thereof, it has been found that pitavastatin, a salt or an ester thereof is most easily absorbed in the duodenum and is also well absorbed not only in the small intestine but also in the large intestine, unlike the general tendency that the main absorption site of a drug is the small intestine. As a result of further studies based on this finding, it has been found that a suitable effective blood concentration can be obtained immediately after administration and a suitable blood concentration can be maintained for a long period of time in a preparation in which a composition containing pitavastatin, a salt thereof or an ester thereof, which starts to release these substances at least in the stomach, and an enteric composition containing pitavastatin, a salt thereof or an ester thereof are combined, and the present invention has been completed.

That is, the present invention provides a controlled-release pharmaceutical composition comprising (a) a composition containing pitavastatin, a salt thereof or an ester thereof and starting to release these substances at least in the stomach and (B) an enteric composition containing pitavastatin, a salt thereof or an ester thereof.

Drawings

Fig. 1 shows the results of the dissolution test for the compositions of example 5, comparative example 1 and comparative example 2.

Fig. 2 shows the variation of pitavastatin concentration in plasma when the compositions of example 5, comparative example 1 and comparative example 2 were orally administered to dogs.

Detailed Description

The controlled-release pharmaceutical composition of the present invention comprises (a) a composition containing pitavastatin, a salt thereof or an ester thereof (hereinafter referred to as pitavastatins) and starting to release these substances at least in the stomach and (B) an enteric composition containing pitavastatins. Here, the composition (a) is a composition which starts releasing pitavastatins at least in the stomach, and may be a composition which substantially releases pitavastatins in the composition (a) in the stomach, or may be a composition which releases only a part of pitavastatins in the composition (a) in the stomach. However, from the viewpoint of ensuring the effective blood level of pitavastatins immediately after administration, a composition which releases 30 mass% or more of the pitavastatins in the composition (a) in the stomach is preferred.

Further, the enteric composition (B) is preferably a composition in which pitavastatins or a composition containing pitavastatins are coated with a component that dissolves at a ph of 3.0 or more, or a composition in which pitavastatins are mixed with a component that dissolves at a ph of 3.0 or more. Thus, pitavastatins contained in the enteric composition are not substantially released in the stomach, but are released after passing through the vicinity of the duodenum.

Pitavastatins as the active ingredient of the controlled-release pharmaceutical composition of the present invention are characterized by being well absorbed in the duodenum (see table 1). Thus, the pitavastatins released from the composition (a) in the stomach are considered to be absorbed substantially in the duodenum. While the enteric composition (B) releases pitavastatins after passing through the vicinity of the duodenum, and thus, is absorbed at the earliest in the small intestine. The absorption rate of pitavastatins in the small intestine was about 1/3 (see table 1) of that in the duodenum, if pitavastatins were rapidly released in the small intestine, rapid absorption was not caused. Moreover, since pitavastatins take a certain time to pass through these sites, pitavastatins are slowly absorbed for a certain time from the small intestine to the large intestine. In view of the above, the controlled-release pharmaceutical composition of the present invention can maintain a desired blood level of pitavastatin.

In addition, since the absorption site of a normal drug in the digestive tract is the small intestine, the drug that has passed through the small intestine to reach the large intestine is not substantially absorbed. Thus, there are the following problems: when the sustained release preparation is prepared, the biological utilization rate is reduced compared with the common preparation with the same dosage, and the like. However, since the absorption rate of pitavastatins in the large intestine is very good as in the former duodenum (see table 1), the bioavailability of the controlled-release pharmaceutical composition of the present invention is substantially unchanged compared to the conventional formulation in the same amount.

TABLE 1 absorption sites of pitavastatins in rats (in situ Loop test)

Location of a body part	Absorption rate (%)
			0.5 hour	1 hour
	Stomach (stomach)	8.6±1.1			14.4±1.6
Duodenum			65.9±2.1	60.3±10.2
	Small intestine	23.1±3.8			21.3±3.0
Large intestine			34.4±3.7	51.6±6.7

Pitavastatin used in the controlled-release pharmaceutical composition of the present invention has a chemical name of (+) - (3R, 5S, 6E) -7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -3, 5-dihydroxy-6-heptenoic acid, and as described above, it is known to be an excellent HMG-CoA reductase inhibitor and to be useful as a therapeutic agent for hypercholesterolemia. Examples of the salts of pitavastatin include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salts and magnesium salts, and among them, calcium salts are particularly preferable. Examples of the ester include alkyl esters such as methyl ester, ethyl ester, isopropyl ester, and n-propyl ester.

As described above, the composition (a) preferably releases at least 30 mass% of the contained pitavastatin in the stomach, and more preferably, the release amount of the contained pitavastatin in the stomach is controlled to be 30 mass% or more and less than 60 mass%, or 60 mass% or more and less than 85 mass%, or 85 mass% or more. Here, the release rate in the stomach can be determined by the method 2 (slurry method) of the dissolution test method in the general test methods described in "Japanese pharmacopoeia"). Specifically, the test composition (a) was put in 900mL of artificial gastric juice at ph1.2, stirred at 37 ± 1 ℃ and a number of revolutions of 100rpm for 30 minutes, and then the elution amount of pitavastatin was measured, and the gastric release rate was calculated from the content of pitavastatin in the composition (a) contained in the test pharmaceutical composition.

The release rate of pitavastatins in the stomach of the composition (a) can be adjusted by incorporating a sustained-release component into a usual base. Here, as a base usable in the composition (a), for example, an excipient (extender) such as lactose, corn starch, modified corn starch, mannitol, sorbitol, wood cellulose, microcrystalline cellulose, calcium carbonate, or the like; binders such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol (partially saponified product); disintegrants such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylstarch, calcium carboxymethylether cellulose, corn starch, partially gelatinized starch, croscarmellose sodium, and crospovidone; lubricants such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, and the like; saccharides, cellulose derivatives, polyethylene derivatives, oxyalkylene polymers, oils and fats, copolymers of methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, gum arabic, locust bean gum, carrageenan, xanthan gum, alphalated starch, pectin, glucomannan, gluten, casein, gelatin, zein and the like.

Examples of the saccharide include lactose, fructose, glucose, sucrose, maltose, sorbitol, xylitol, maltitol, mannitol, trehalose, cyclodextrin, erythritol, hydrogenated isomaltulose, lactitol and the like.

Examples of the cellulose derivative include methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and low-substituted hydroxypropyl cellulose.

Examples of polyvinyl derivatives include polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol (partially saponified product), and the like.

Examples of the oxyalkylene polymer include polyethylene glycol, polypropylene glycol and the like.

Examples of the oils and fats include sucrose fatty acid esters and polyoxyl 40-stearate esters.

In addition, in order to improve the stability of pitavastatins with time, it is preferable to incorporate into the composition (a) a basic substance capable of adjusting the pH of an aqueous solution or dispersion of the composition (a) to 6.8 or more (preferably 6.8 to 7.8), and for example, antacids such as magnesium metasilicate aluminate, magnesium aluminosilicate, magnesium aluminate, dried aluminum hydroxide, synthetic hydrotalcite, synthetic aluminum silicate, magnesium carbonate, precipitated calcium carbonate, magnesium oxide, aluminum hydroxide, and sodium hydrogen carbonate; pH adjusters such as L-arginine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium citrate, sodium succinate, ammonium chloride and sodium benzoate, and the like. Among them, magnesium metasilicate phosphate, L-arginine, and dipotassium hydrogen phosphate are particularly preferable.

The pH referred to herein is the pH of a 5 w/v% suspension of the pharmaceutical composition of the present invention or each composition [ composition (A) or enteric composition (B) ] per administration amount.

The mode of incorporating the sustained-release component into the composition (a) is preferably such that pitavastatins or a composition containing pitavastatins are coated with the sustained-release component, or pitavastatins are mixed with the sustained-release component. Examples of the sustained-release component for coating include biodegradable polymers, cellulose derivatives, (meth) acrylic (co) polymers, oxyalkylene polymers, fats and oils, silicones, chitin, chitosan, casein, tragacanth gum, guar gum, gellan gum, and gum arabic.

Examples of biodegradable polymers are polylactic acid, polyglycolic acid, poly (hydroxytyrosic acid), poly (alpha-cyanoacrylate), polyorthoesters, polyamino acids, gelatin, and the like.

Examples of the cellulose derivative include methyl cellulose, ethyl cellulose, propyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, carboxypropyl cellulose, methylhydroxypropyl cellulose, cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, polyoxyethyl cellulose phthalate, hydroxyethyl cellulose phthalate, hydroxypropyl cellulose phthalate, cellulose acetate, and salts thereof.

Examples of the (meth) acrylic (co) polymer include ethyl acrylate-methyl methacrylate-ethyl methacrylate trimethylammonium chloride copolymer, butyl methacrylate-dimethylaminoethyl methacrylate copolymer, acrylic acid polymer, methyl acrylate polymer, dimethylaminoethyl methacrylate polymer and the like.

Examples of the oxyalkylene polymer include polyethylene glycol, polypropylene glycol and the like.

Examples of the oils and fats include hydrogenated oils, monoglycerides, triglycerides, waxes, higher fatty acids, sucrose fatty acid esters, higher fatty acid glycerides, and the like.

Examples of the silicone include dimethylpolysiloxane, methylpolysiloxane, silicone oil, a mixture of dimethylpolysiloxane and silica, a silicone defoaming agent, and a mixture of dimethylpolysiloxane such as a silicone resin emulsion.

Examples of the sustained-release component for mixing include biodegradable polymers, starches, dextrans, cellulose derivatives, (meth) acrylic (co) polymers, oxyalkylene polymers, fats and oils, carrageenan, chitin, chitosan, casein, tragacanth, guar gum, gellan gum, paraffin, silicones, gum arabic, polyglutamic acid, polyaspartic acid, polylysine, polyarginine, arginine, pectic acid, and tragacanth.

Examples of biodegradable polymers are polylactic acid, polyglycolic acid, polyhydroxybutyric acid, poly-alpha-cyanoacrylate, polyorthoester, polyamino acid, gelatin, collagen, chondroitin sulfate, hyaluronic acid, albumin, casein, globulin, gluten, and the like.

Examples of starches include starch slurry (. alpha. -amylo-starch), starch paste, carboxymethyl starch, carboxyethyl starch, phosphate starch, acid-treated starch, oxidized starch, dialdehyde starch, low-consistency starch, dextrin and the like.

Examples of dextrans are dextran, dextran sulfate, carboxymethyl dextran, and the like.

Examples of the cellulose derivative include methyl cellulose, ethyl cellulose, propyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxyethyl cellulose, carboxypropyl cellulose, methylhydroxypropyl cellulose, cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, polyoxyethylene cellulose phthalate, hydroxyethyl cellulose phthalate, hydroxypropyl cellulose phthalate, cellulose acetate, and salts thereof.

Examples of the (meth) acrylic (co) polymer include ethyl acrylate-methyl methacrylate-ethyl methacrylate trimethylammonium chloride copolymer, butyl methacrylate-dimethylaminoethyl methacrylate copolymer, acrylic acid polymer, methyl acrylate polymer, dimethylaminoethyl methacrylate polymer and the like.

Examples of the oxyalkylene polymer include polyethylene glycol, polypropylene glycol and the like.

Examples of the oils and fats include hydrogenated oil, hydrogenated castor oil, olive oil, monoglycerides, triglycerides, waxes, higher fatty acids, sucrose fatty acid esters, higher alcohols, higher fatty acid glycerides, and the like.

Examples of the silicone include dimethylpolysiloxane, methylpolysiloxane, silicone oil, a mixture of dimethylpolysiloxane and silica, a silicone defoaming agent, and a mixture of dimethylpolysiloxane such as a silicone resin emulsion.

The enteric composition (B) is preferably obtained by coating pitavastatins or a composition containing pitavastatins with a component that dissolves at ph3.0 or more (preferably at ph4.0 or more, more preferably at ph5.0 or more), or by mixing pitavastatins with a component that dissolves at ph3.0 or more (preferably at ph4.0 or more, more preferably at ph5.0 or more). Examples of the components that dissolve at a ph of 3.0 or more include enteric cellulose derivatives, enteric (meth) acrylic (co) polymers, enteric maleic acid copolymers, and enteric polyvinyl derivatives. These components that dissolve above ph3.0 must not dissolve in artificial gastric juice at ph 1.2.

Examples of the enteric cellulose derivative include cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, cellulose acetate trimellitate, cellulose acetate tetrahydrophthalate, methyl cellulose phthalate, ethyl hydroxyethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, carboxymethyl ethyl cellulose and the like.

Examples of the enteric (meth) acrylic (co) polymer include styrene-acrylic acid copolymers, methyl acrylate-methacrylic acid copolymers, butyl acrylate-styrene-acrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers, methacrylic acid-ethyl acrylate copolymers, methyl acrylate-methacrylic acid-octyl acrylate copolymers and the like.

Examples of the enteric maleic acid copolymer include vinyl acetate-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer, acrylonitrile-methyl acrylate-maleic anhydride copolymer, butyl acrylate-styrene-maleic anhydride copolymer, and the like.

Examples of the enteric polyvinyl derivatives include polyvinyl alcohol phthalate, polyvinyl acetate phthalate, polyvinyl butyrate phthalate, polyvinyl acetoacetate phthalate, and the like.

In the enteric composition (B), a sustained-release component, an excipient, a binder, a disintegrant, a lubricant, and an alkaline substance, which are exemplified as components that can be incorporated in the composition (a), can also be incorporated.

The controlled-release pharmaceutical composition of the present invention comprises the composition (a) and the enteric composition (B), but the mass ratio of pitavastatins in the composition (a) to pitavastatins in the enteric composition (B) can be designed so that the Cmax of pitavastatins can be appropriately controlled when the controlled-release pharmaceutical composition of the present invention is orally administered, the decrease in AUC can be prevented, and a stable blood concentration can be maintained for a long period of time. The appropriate Cmax referred to herein means the maximum blood concentration obtained when the composition (a) containing 1 to 8mg of pitavastatins but no sustained-release component is orally administered to a human.

The mass ratio of pitavastatins in the composition (a) to pitavastatins in the enteric composition (B) varies depending on the release rate of the pitavastatins in the composition (a) in the stomach. When the release rate is 85% by mass or more, the mass is preferably 1: 1 to 1: 40, more preferably 1: 1 to 1: 20, particularly preferably 1: 1 to 1: 7. The mass at the release rate of 60 mass% or more and less than 85 mass% is preferably 15: 1 to 1: 30, more preferably 10: 1 to 1: 20, particularly preferably 5: 1 to 1: 15. When the release rate is 30% by mass or more and less than 60% by mass, the mass is preferably 30: 1 to 1: 20, more preferably 20: 1 to 1: 15, particularly preferably 15: 1 to 1: 10.

The controlled-release pharmaceutical composition of the present invention comprises a composition (a) and an enteric composition (B), and more specifically, a preparation obtained by mixing the composition (a) and the enteric composition (B); preparing the composition (A) or the enteric composition (B) into preparations respectively; a preparation in which the composition (A) covers the outer side of the enteric composition (B).

The form of the controlled-release pharmaceutical composition of the present invention is preferably oral preparations such as tablets, granules and capsules. Here, the tablet includes a bare tablet, a chewable tablet, a film-coated tablet, a sugar-coated tablet, a cored tablet, and a multi-layer tablet. The granule comprises powder and fine granule. The capsule includes hard capsule and soft capsule.

The amount of pitavastatins added to the controlled-release pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.01 to 60% by mass.

The amounts of the usual base, sustained-release component and enteric component to be added in the controlled-release pharmaceutical composition of the present invention vary depending on the kinds of these additives, the design of controlled-release of the drug, etc., but are preferably 0.01 to 80% by mass, more preferably 0.1 to 50% by mass, particularly preferably 1.0 to 30% by mass, respectively.

Further, it is preferable that the amount of the basic substance added is an amount adjusted to the aforementioned pH, for example, 0.01 to 20 mass%, the amount of the extender is 0 to 90 mass%, the amount of the binder is 0 to 20 mass%, the amount of the disintegrant is 0 to 30 mass%, the amount of the lubricant is 0 to 20 mass%, the amount of the sweetener is 0 to 30 mass%, the amount of the taste corrigent is 0 to 30 mass%, and the amount of the colorant is 0 to 5 mass%.

Preferred embodiments of the controlled-release pharmaceutical composition of the present invention include the following examples in order to obtain a good blood concentration of pitavastatins.

(1) The granules of the composition (a) are coated around the enteric composition (B).

(2) Granules obtained by mixing and molding the enteric composition (B) and the composition (A) of the above (1) with pharmaceutical additives such as an extender, a binder and a disintegrant.

(3) A granule comprising at least the composition (A) and the enteric composition (B) and having an elution pattern of 2 or more.

(4) A capsule prepared by filling the granules of (1), (2) and/or (3) above into a capsule.

(5) Capsules obtained by filling the capsules obtained in the above (4) and the composition (A) into capsules.

(6) A tablet formed by incorporating one or more pharmaceutical additives selected from the group consisting of a bulking agent, a binder and a disintegrant into the granule of the above (1), (2) and/or (3).

(7) A multilayer tablet molded by incorporating one or more pharmaceutical additives selected from the group consisting of a bulking agent, a binder and a disintegrant into the granules having 2 or more dissolution modes of the above-mentioned (3).

(8) A multilayer tablet obtained by forming layers of the enteric composition (B) and the composition (A) separately.

(9) A core tablet comprising the enteric composition (B) as a core tablet and the composition (A) as an outer layer.

(10) A core tablet comprising the tablet molded in (8) and/or (9) as a core tablet and the composition (A) as an outer layer.

The controlled-release pharmaceutical composition of the present invention thus obtained is preferably designed to administer pitavastatins in an amount of 0.5 to 64mg, more preferably 1 to 32mg, particularly preferably 4 to 16mg per day.

Examples

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

(1) Example 1

TABLE 2

Composition (I)			Addition amount (mg)
				Enteric granule A	Particle A	Refined sugar ball-shaped granule	114.00
Pitavastatin calcium salt	12.00
		Sucrose	30.75
Hydroxypropyl methylcellulose (trade name: TC-5R)	18.00
		Magnesium metasilicate aluminate	2.40
Talcum powder	0.60
		Citric acid triethyl ester	2.25
Small counter	180.00
			Methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit L)			41.58
Talcum powder					8.28
			Citric acid triethyl ester			4.14
Small counter					234.00
			Pitavastatin calcium salt			4.00
Sucrose							10.25
			Hydroxypropyl radicalMethylcellulose (trade name: TC-5R)			6.00
Magnesium metasilicate aluminate							0.80
			Talcum powder			0.20
Citric acid triethyl ester							0.75
			Total up to			256.00

To 3000.0g of purified water were added 240.0g of pitavastatin calcium salt, 615.0g of sucrose, 360.0g of hydroxypropylmethylcellulose (trade name: TC-5R), 48.0g of magnesium aluminate metasilicate, 12.0g of talc and 45.0g of triethyl citrate, and the mixture was dissolved and dispersed in a disperser to prepare a drug-containing coating solution.

2280.0g of refined white sugar spherical particles were transferred to a rotary flow type granulation drying coater and heated to about 36 ℃. Coating refined white sugar spherical granule with coating solution containing medicine to form medicine layer, and making into granule A3600.0 g.

To 6912.0g of ethanol were added 831.6g of methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit L), 82.8g of triethyl citrate, and 165.6g of talc, and the mixture was dissolved and dispersed with a disperser to prepare an enteric coating solution.

The granules A3600.0g were transferred to a rotating flow granulation drying coater and warmed to about 36 ℃. The granule a was coated with an enteric coating solution to form an enteric film, thereby producing 4680.0g of enteric granule a.

80.0g of pitavastatin calcium salt, 205.0g of sucrose, 120.0g of hydroxypropyl methylcellulose (trade name: TC-5R), 16.0g of magnesium aluminate metasilicate, 4.0g of talcum powder and 15.0g of triethyl citrate are added into 1000.0g of purified water, and the mixture is dissolved and dispersed by a disperser to prepare a coating solution containing the medicament.

The enteric granules A4680.0 g were transferred to a rotary flow granulation drying coater and warmed to about 36 ℃. Enteric particles A were coated with a coating solution containing the drug to form a drug layer, and 5120.0g of the thus-obtained granules were divided into small packets of 256.0mg each to obtain 20000 packets of granules.

(2) Example 2

TABLE 3

Composition (I)			Addition amount (mg)
				Enteric granule	Granules	Particle A	30.00
Ethyl acrylate-methyl methacrylate-ethyl methacrylate-trimethyl ammonium chloride copolymer (trade name: Eudragit RS)	12.40
		Hydroxypropyl cellulose	3.10
Talcum powder	0.95
		Citric acid triethyl ester	1.55
Small counter	48.00
		Pitavastatin calcium salt				4.00
Sucrose					10.25
		Hydroxypropyl methylcellulose (trade name: TC-5R)				6.00
Magnesium metasilicate aluminate					0.80
		Talcum powder				0.20
Citric acid triethyl ester					0.75
		Hydroxymethyl propyl cellulose phthalate				16.17
Talcum powder					3.22
		Citric acid triethyl ester				1.61
Small counter					91.00
		Pitavastatin calcium salt				4.00
Sucrose					10.25
			Hydroxypropyl methylcellulose (trade name: TC-5R)			6.00

Magnesium metasilicate aluminate	0.80
		Talcum powder	0.20
Citric acid triethyl ester	0.75
		Total up to	113.00

Pellets A (300.0 g) were prepared in the same manner as in example 1.

To 1200.0g of ethanol were added 124.0g of a copolymer of ethyl acrylate, methyl methacrylate, ethyl methacrylate and trimethylammonium chloride (trade name: Eudragit RS), 31.0g of hydroxypropylcellulose, 15.5g of triethyl citrate and 9.5g of talc, and the mixture was dissolved and dispersed in a disperser to prepare a coating solution.

300.0g of the granules A were transferred to a rotary flow granulation drying coater and warmed to about 36 ℃. The granules A were coated with the above coating solution to give 480.0g granules.

40.0g of pitavastatin calcium salt, 102.5g of sucrose, 60.0g of hydroxypropyl methylcellulose (trade name: TC-5R), 8.0g of magnesium aluminate metasilicate, 2.0g of talcum powder and 7.5g of triethyl citrate are added into 500.0g of purified water, and the mixture is dissolved and dispersed by a disperser to prepare a coating solution containing the medicament.

161.7g of hydroxymethyl propyl cellulose phthalate, 16.1g of triethyl citrate and 32.2g of talcum powder are added into 1312.5g of ethanol, and are dissolved and dispersed by a disperser to prepare an enteric coating solution.

480.0g of the granules were transferred to a rotary flow granulation drying coater and warmed to about 36 ℃. First, the granules were coated with a coating solution containing a drug, and then, coating with an enteric coating solution was continued to form an enteric film, thereby producing 910.0g of enteric granules.

40.0g of pitavastatin calcium salt, 102.5g of sucrose, 60.0g of hydroxypropyl methylcellulose (trade name: TC-5R), 8.0g of magnesium aluminate metasilicate, 2.0g of talcum powder and 7.5g of triethyl citrate are added into 500.0g of purified water, and the mixture is dissolved and dispersed by a disperser to prepare a coating solution containing the medicament.

910.0g of enteric granules were transferred to a rotary flow granulation drying coater and warmed to about 36 ℃. Enteric granules were coated with a coating solution containing the drug to form a drug layer, and 1130.0g of the granules thus obtained were divided into small packets of 113.0mg each to obtain 10000 packets of granules.

(3) Example 3

TABLE 4

Composition (I)		Addition amount (mg)
			Granules	Particle A	180.00
Ethyl fibreVegetable extract	10.00
		Hydroxypropyl methylcellulose (trade name: TC-5R)		32.50
Talcum powder	8.25
		Citric acid triethyl ester		3.25
Small counter	234.00
		Enteric granule		Particle A	60.00
Methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit S)	13.86
			Talcum powder	2.76
Citric acid triethyl ester	1.38
			Small counter	78.00
Total up to					312.00

Pellets A2400.0 g were produced in the same manner as in example 1.

An aqueous solution obtained by adding 325.0g of hydroxypropylmethylcellulose (trade name: TC-5R) to 1500g of purified water and dissolving the mixture in a dispenser was mixed with an ethanol solution obtained by adding 100.0g of ethylcellulose, 7.5g of triethyl citrate and 82.5g of talc to 4000.0g of ethanol and dissolving and dispersing the mixture in a dispenser to prepare a coating solution.

A portion (1800.0g) of granule a was transferred to a rotating flow granulation drying coater and warmed to about 36 ℃. Granule A was coated with the coating solution to give 2340.0g of granule.

138.6g of methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit S), 13.8g of triethyl citrate and 27.6g of talc were added to 1152.0g of ethanol, and dissolved and dispersed in a disperser to prepare an enteric coating solution.

A portion (600.0g) of the granules a was transferred to a rotating flow granulation drying coater and warmed to about 36 ℃. The granule a was coated with an enteric coating solution to form an enteric film, thereby producing 780.0g of enteric granules.

2340.0g of granules and 780.0g of enteric-coated granules are mixed and divided into small bags of 312.0mg respectively to obtain 10000 bags of granules.

(4) Example 4

TABLE 5

Composition (I)		Addition amount (mg)
			Particle A		60.00
Granules	Pitavastatin calcium salt	4.00
			Ethyl acrylate-methyl methacrylate-ethyl methacrylate-trimethyl ammonium chloride copolymer (trade name: Eudragit RS)	65.52
	Lactose	43.68
			Low-substituted hydroxypropyl cellulose	6.00
	Magnesium metasilicate aluminate	0.80
			Small counter	120.00
	Enteric granule	Particle A			90.00
Hydroxypropyl methylcellulose acetate succinate			20.79
		Talcum powder		4.14
Citric acid triethyl ester			2.07
		Small counter		117.00
Total up to			297.00

Pellets A2250.0 g were produced in the same manner as in example 1.

60.0g of pitavastatin calcium salt, 982.8g of ethyl acrylate-methyl methacrylate-ethyl methacrylate-trimethyl ammonium chloride copolymer (trade name: Eudragit RS), 655.2g of lactose, 90.0g of low-substituted hydroxypropyl cellulose and 12.0g of magnesium metasilicate silicate were mixed to prepare a uniform powder mixture, and an appropriate amount of ethanol was added to prepare granules by a stirring granulation method, thereby obtaining 1800.0g of granules.

311.85g of hydroxypropyl methyl cellulose acetate succinate, 31.05g of triethyl citrate and 62.1g of talcum powder are added into 5225.5g of ethanol, and are dissolved and dispersed by a disperser to prepare an enteric coating solution.

A portion (1350.0g) of granule a was transferred to a rotating flow granulation drying coater and warmed to about 36 ℃. The granule a was coated with an enteric coating solution to form an enteric film, thereby producing 1755.0g of enteric granules.

900.0g of the granule A, 1800.0g of the granule A and 1755.0g of the enteric granule were mixed and divided into 297.0mg packets each to obtain 15000 packets of granules.

(5) Example 5

TABLE 6

Composition (I)	Addition amount (mg)
		Particle A	60.00
Enteric granule A	234.00
		No. 1 gelatin capsule	-
Total up to	294.00

Pellets A1200.0 g were prepared in the same manner as in example 1.

Enteric pellets A4680.0 g were prepared in the same manner as in example 1.

1200.0g of the granule A and 4680.0g of the enteric-coated granule A are mixed, 294.0mg of the granule A is filled in each capsule, and 20000 capsules (No. 1 gelatin capsules) are prepared.

(6) Example 6

TABLE 7

Composition (I)		Addition amount (mg)
			Particle A		90.00
Enteric granule	Particle A	90.00
			Methacrylic acid ethyl acrylate copolymer (trade name: Eudragit L-30D55)	20.79
	Talcum powder	4.14
			Citric acid triethyl ester	2.07
	Small counter	117.00
			Crystalline cellulose		214.62
Hydroxypropyl methylcellulose (trade name: TC-5R)		14.70
			Low-substituted hydroxypropyl cellulose		58.80
Magnesium stearate		5.88
			Total up to		501.00

Pellets A1800.0 g were prepared in the same manner as in example 1.

207.9g of an ethyl methacrylate/ethyl acrylate copolymer (trade name: Eudragit L-30D55), 20.7g of triethyl citrate, and 41.4g of talc were added to 2304.0g of purified water, and dissolved and dispersed in a disperser to prepare an enteric coating solution.

A portion (900.0g) of the granules a was transferred to a rotating flow granulation drying coater and warmed to about 36 ℃. The particles A were coated with an enteric coating solution to form an enteric film, whereby 1170.0g of enteric particles were prepared.

900.0g of granule A, 1170.0g of enteric granule, 2146.2g of crystalline cellulose, 147.0g of hydroxypropylmethylcellulose (trade name: TC-5R), 588.0g of low-substituted hydroxypropylcellulose and 58.8g of magnesium stearate were mixed, and the mixture was tabletted so that 501.0mg of granules per tablet was made into 10000 tablets.

(7) Example 7

TABLE 8

Composition (I)		Addition amount (mg)
			Enteric granule A		195.00
Mixed particles	Pitavastatin calcium salt	4.00
			Lactose	345.00
	Low-substituted hydroxypropyl cellulose	77.00
			Hydroxypropyl methylcellulose (trade name: TC-5R)	8.80
	Magnesium metasilicate aluminate	0.80
			Magnesium stearate	4.40
	Small counter	440.00
			Total up to		635.00

Enteric pellets A1950.0 g were prepared in the same manner as in example 1.

40.0g of pitavastatin calcium salt, 3450.0g of lactose, 770.0g of low-substituted hydroxypropyl cellulose, 88.0g of hydroxypropyl methylcellulose (trade name: TC-5R) and 8.0g of magnesium metasilicate are mixed to prepare a uniform powder mixture, and a proper amount of purified water is added to prepare granules by a stirring granulation method. 44.0g of magnesium stearate was mixed with the granules to prepare 4400.0g of mixed granules.

Mixing enteric-coated granule A1950.0 g and mixed granule 4400.0g, and tabletting to obtain tablet of 635.0mg each to obtain 10000 tablets.

(8) Example 8

TABLE 9

Composition (I)		Addition amount (mg)
			Layer A	Particle A	60.00
Crystalline cellulose	43.80
		Hydroxypropyl methylcellulose (trade name: TC-5R)		3.00
Low-substituted hydroxypropyl cellulose	12.00
		Magnesium stearate		1.20
Small counter	120.00
		Layer B		Enteric granule A	78.00
Crystalline cellulose	56.94
			Hydroxypropyl methylcellulose (trade name: TC-5)R)	3.90
Low-substituted hydroxypropyl cellulose	15.60
			Magnesium stearate	1.56
Small counter	156.00
			Total up to		276.00

Pellets A600.0 g were prepared in the same manner as in example 1.

Enteric pellets A780.0 g were prepared in the same manner as in example 1.

A mixture of 600.0g of granule A, 438.0g of crystalline cellulose, 30.0g of hydroxypropylmethylcellulose (trade name: TC-5R), 120.0g of low-substituted hydroxypropylcellulose and 12.0g of magnesium stearate and a mixture of 780.0g of enteric granule A, 569.4g of crystalline cellulose, 39.0g of hydroxypropylmethylcellulose (trade name: TC-5R), 156.0g of low-substituted hydroxypropylcellulose and 15.6g of magnesium stearate were compressed into a bilayer tablet, and 276.0mg (120.0 g for the A layer and 156.0mg for the B layer) was weighed per tablet to obtain a 10000 bilayer tablet.

(9) Example 9

Watch 10

Composition (I)		Addition amount (mg)
			Layer A	Mixed particles	440.00
Layer B	Pitavastatin calcium salt	8.00
			Carboxymethyl ethyl cellulose	101.04
	Lactose	67.36
			Low-substituted hydroxypropyl cellulose	20.00
	Magnesium metasilicate aluminate	1.60
			Magnesium stearate	2.00
	Small counter	200.00
			Total up to		640.00

4400.0g of a mixed pellet was prepared in the same manner as in example 7.

80.0g of pitavastatin calcium salt, 1010.4g of carboxymethyl ethyl cellulose, 673.6g of lactose, 200.0g of low-substituted hydroxypropyl cellulose and 16.0g of magnesium metasilicate are mixed to prepare a uniform powder mixture, and a proper amount of ethanol is added to prepare granules by a stirring granulation method. This granulation was mixed with 20.0g of magnesium stearate to prepare 2000.0g of enteric granules.

4400.0g of the mixed granules and 2000.0g of the enteric-coated mixed granules were compressed into a double-layer tablet weighing 640.0mg (440.0 g for the A layer and 200.0mg for the B layer) to obtain 10000 double-layer tablets.

(10) Example 10

TABLE 11

Composition (I)		Addition amount (mg)
			Layer A	Pitavastatin calcium salt	8.00
Ethyl acrylate-methyl methacrylate-ethyl methacrylate-trimethyl ammonium chloride copolymer (trade name: Eudragit RS)	56.88
		Lactose		160.32
Low-substituted hydroxypropyl cellulose	12.00
		Magnesium metasilicate aluminate		1.60
Magnesium stearate	1.20
		Small counter		240.00

Layer B	Pitavastatin calcium salt	4.00
			Carboxymethyl ethyl cellulose	50.52
	Lactose	33.68
			Low-substituted hydroxypropyl cellulose	10.00
	Magnesium metasilicate aluminate	0.80
			Magnesium stearate	1.00
	Small counter	100.00
			Total up to		340.00

80.0g of pitavastatin calcium salt, 568.8g of ethyl acrylate-methyl methacrylate-trimethyl ammonium methacrylate chloride copolymer (trade name: Eudragit RS), 1603.2g of lactose, 120.0g of low-substituted hydroxypropyl cellulose and 16.0g of magnesium metasilicate were mixed to prepare a uniform powder mixture, and a suitable amount of ethanol was added to prepare granules by stirring granulation. 12.0g of magnesium stearate was mixed with the granules to prepare 2400.0g of mixed granules.

40.0g of pitavastatin calcium salt, 505.2g of carboxymethyl ethyl cellulose, 336.8g of lactose, 100.0g of low-substituted hydroxypropyl cellulose and 8.0g of magnesium metasilicate are mixed to prepare a uniform powder mixture, and a proper amount of ethanol is added to prepare granules by a stirring granulation method. This granule was mixed with 10.0g of magnesium stearate to prepare 1000.0g of enteric mixed granules.

2400.0g of the mixed granules and 1000.0g of the enteric-coated mixed granules were pressed into a double-layer tablet weighing 340.0mg (240.0 g for the layer A and 100.0mg for the layer B) to obtain 10000 double-layer tablets.

(11) Example 11

TABLE 12

Composition (I)		Addition amount (mg)
			Chip	Pitavastatin calcium salt	6.00
Lactose	32.40
		Low-substituted hydroxypropyl cellulose		4.50
Hydroxypropyl methylcellulose (trade name: TC-5R)	0.75
		Magnesium metasilicate aluminate		0.90
Magnesium stearate	0.45
		Methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit S)		15.40
Talcum powder	1.54
		Citric acid triethyl ester		3.06
Small counter	65.00
		Outer layer		Mixed particles	220.00
Total up to			285.00

80.0g of pitavastatin calcium salt, 324.0g of lactose, 45.0g of low-substituted hydroxypropyl cellulose, 7.5g of hydroxypropyl methyl cellulose (trade name: TC-5R) and 9.0g of magnesium metasilicate are mixed to prepare a uniform powder mixture, and a proper amount of purified water is added to prepare granules by a stirring granulation method. This granule was mixed with 4.5g of magnesium stearate, and the mixture was compressed into tablets, each tablet weighing 45.0mg, to prepare 450.0g of bare chips (10000 tablets).

To 2560.0g of ethanol were added 154.0g of methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit S), 30.6g of triethyl citrate and 5.4g of talc, and the mixture was dissolved and dispersed by a disperser to prepare an enteric coating solution.

450.0g of die was transferred to a coating pan and warmed to 40-45 ℃. An enteric film was formed by coating a bare chip with an enteric coating solution, thereby making 650.0g (10000 tablets) of enteric tablets.

2200.0g of a mixed pellet was prepared in the same manner as in example 7.

650.0g of the enteric-coated tablet was used as a core tablet, and 2200.0g of the mixed granules was used as an outer layer, and the core tablet was compressed so that 285.0mg of each tablet weighed to obtain 10000 tablets having a core.

(12) Example 12

Watch 13

Composition (I)		Addition amount (mg)
			Chip	Pitavastatin calcium salt	9.00
Methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit S)	38.07
		Lactose		25.38
Low-substituted hydroxypropyl cellulose	4.85
		Magnesium metasilicate aluminate		1.80
Magnesium stearate	0.90
		Small counter		80.00
Outer layer	Mixed particles				330.00
		Total up to		410.00

3300.0g of a mixed pellet was prepared in the same manner as in example 7.

90.0g of pitavastatin calcium salt, 380.7g of methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit S), 253.8g of lactose, 48.5g of low-substituted hydroxypropylcellulose and 18.0g of magnesium metasilicate were mixed to prepare a uniform powder mixture, and an appropriate amount of ethanol was added to the powder mixture to prepare granules by a stirring granulation method. This granule was mixed with 9.0g of magnesium stearate, and the mixture was compressed into tablets, each weighing 80.0mg, to prepare 800.0g (10000 tablets) of enteric-coated tablets.

800.0g of enteric-coated tablets were used as core tablets, and 3300.0g of mixed granules were used as outer layers, which were pressed into cored tablets, each weighing 410.0mg, to obtain 10000 cored tablets.

(13) Example 13

TABLE 14

Composition (I)			Addition amount (mg)
				Enteric granule A	Particle A	Refined sugar ball-shaped granule	40.00
Pitavastatin calcium salt	12.00
		Sucrose	14.35
Hydroxypropyl methylcellulose (trade name: TC-5R)	8.40
		Magnesium metasilicate aluminate	2.40
Talcum powder	0.60
		Citric acid triethyl ester	2.25
Cellulose acetate phthalate	18.48
		Talcum powder	3.68
Citric acid triethyl ester	1.84
		Small counter	104.00
Crystalline cellulose						75.92
		Hydroxypropyl methylcellulose (trade name: TC-5R)			5.20
Low substitutionHydroxypropyl cellulose of (5)						20.80
		Magnesium stearate			2.08
Small counter						208.00
		Outer layer	Mixed particles		440.00
Total up to						648.00

120.0g of pitavastatin calcium salt, 143.5g of sucrose, 84.0g of hydroxypropyl methylcellulose (trade name: TC-5R), 24.0g of magnesium metasilicate aluminate, 6.0g of talc and 22.5g of triethyl citrate are added into 4000.0g of purified water, and the mixture is dissolved and dispersed by a disperser to prepare a coating solution containing the drug.

400.0g of the refined white sugar spherical particles are transferred to a rotary flow type granulation drying coating machine and heated to about 36 ℃. Coating refined white sugar spherical granule with coating solution containing medicine to form medicine layer, and making into granule 800.0 g.

184.8g of cellulose acetate phthalate, 18.4g of triethyl citrate and 36.8g of talcum powder are added into 2304.0g of acetone, and the mixture is dissolved and dispersed by a disperser to prepare an enteric coating solution.

800.0g of the granules were transferred to a rotary flow granulation drying coater and warmed to about 36 ℃. The granules were coated with an enteric coating solution to form an enteric film, thereby producing 1040.0g of enteric granules.

1040.0g of enteric-coated granules, 759.2g of crystalline cellulose, 52.0g of hydroxypropylmethylcellulose (trade name: TC-5R), 208.0g of low-substituted hydroxypropylcellulose and 20.8g of magnesium stearate were mixed, and the mixture was tabletted so that each tablet weighed 208.0mg to prepare 2080.0g of core tablets (10000 tablets).

4400.0g of a mixed pellet was prepared in the same manner as in example 7.

The core tablet 2080.0g and mixed granules 4400.0g as the outer layer were tabletted to make 10000 tablets of the nucleated tablet weighing 648.0mg each.

Production examples 1 and 2

The pitavastatin controlled-release tablets were obtained according to the formulation described in table 15. After the core tablet is prepared, a drug controlled-release film layer is formed on the core tablet. A methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit L; trade name: Gutter Kogyo) is an enteric polymer which dissolves at pH6-14, and ethylcellulose (trade name: Ethocel; product of Dow Chemical) is a pH-independent sustained-release polymer. The obtained tablet is a controlled release tablet of pitavastatin.

Watch 15

	Composition (I)	Production example (mg/T)
				1	2
		Chip	Pitavastatin calcium salt lactose low-substituted hydroxypropyl cellulose hydroxypropyl methyl cellulose magnesium metasilicate magnesium stearate			8.094.412.02.02.41.2	8.094.412.02.02.41.2
Small counter	120.0			120.0
			Controlled release drug film		Methacrylic acid methyl methacrylate copolymer ethyl cellulose triethyl citrate talcum powder titanium oxide	8.01.22.51.3	8.01.22.51.3
Small counter	13.0	13.0
				Total up to		133.0	133.0

Example 14

The tablets of production example 1 were further coated with the pitavastatin-containing composition of table 16. The tablet of example 14 obtained a stable and long-lasting release of pitavastatin immediately after administration by combining the immediate-release portion of the outermost layer with the controlled-release portion of the inner layer.

TABLE 16

Composition (I)		Example 14(mg/T)
			Inner layer	Tablet of production example 1	133.0
Outermost layer	Pitavastatin calcium salt lactose low-substituted hydroxypropyl cellulose hydroxypropyl methyl cellulose magnesium metasilicate magnesium stearate	8.0304.036.06.02.43.6
			Small counter	360.0
	Total up to				493.0

Example 15

Pitavastatin controlled-release granules were obtained according to the formulation described in table 17. After the core particle is prepared, a drug controlled release film layer is formed. The controlled-release granules can be prepared by mixing the core granules with granules obtained by forming a drug controlled-release film layer on the core granules.

TABLE 17

	Composition (I)	Example 15 (mg/day)
			Core particle	Pitavastatin calcium salt D-mannitol carboxymethyl cellulose calcium hydroxypropyl cellulose magnesium metasilicate silicate	8.0334.021.021.016.0
Small counter	400.0

Controlled release drug film	Methacrylic acid methyl methacrylate copolymer triethyl citrate talcum powder titanium oxide	54.012.050.04.0
			Small counter	120.0

Example 16

Granules having slower release than the drug of example 15 were prepared according to the formulation shown in Table 18 in the same manner as in example 15.

Watch 18

	Composition (I)	Example 16 (mg/day)
			Core particle	Pitavastatin calcium salt D-mannitol carboxymethyl cellulose calcium hydroxypropyl cellulose magnesium metasilicate silicate	8.0334.021.021.016.0
Small counter	400.0
		Controlled release drug film		Methacrylic acid methyl methacrylate copolymer ethyl cellulose triethyl citrate talcum powder titanium oxide	54.027.018.075.06.0
Small counter	180.0

The core granules of table 17, the controlled-release drug film-forming granules of table 17, and the controlled-release drug film-forming granules of table 18 were mixed and filled into capsules to obtain capsules with controlled release of pitavastatin.

The core granules of table 17, the film-forming granules of controlled release drug of table 17 and the film-forming granules of controlled release drug of table 18 were mixed, molded and tableted to obtain tablets with controlled release of pitavastatin.

The core granules of table 17 and the drug controlled-release film-forming granules of table 17 were formed into a laminate, respectively, and pressed into a tablet to obtain a multilayer tablet in which the pitavastatin release property was controlled.

Production example 3

According to the formulation of Table 19, pitavastatin controlled-release tablets were obtained. That is, the core sheets shown in Table 19 were prepared, and then compression-molded with the components corresponding to the outer layers shown in Table 19 in the outer layers thereof to obtain core sheets.

Watch 19

Composition (I)		Production example 3(mg/T)
			Chip	Pitavastatin calcium salt lactose crosslinked polyvinylpyrrolidone hydroxypropyl methylcellulose magnesium metasilicate magnesium acrylate ethyl acrylate methyl methacrylate ethyl methacrylate trimethyl ammonium chloride copolymer*1 monoglyceride magnesium stearate	8.046.420.02.02.420.020.01.2
Total up to		120.0
			Outer layer	Pitavastatin calcium salt lactose low-substituted hydroxypropyl cellulose hydroxypropyl methyl cellulose magnesium metasilicate magnesium stearate	8.0304.036.06.02.43.6
Small counter	360.0

^*1：Eudragit RS; gutter mouth business party sales

Comparative example 1

Watch 20

Composition (I)	Addition amount (mg)
		Pitavastatin calcium salt	16.00
Lactose	86.40
		Low-substituted hydroxypropyl cellulose	12.00
Hydroxypropyl methylcellulose (trade name: TC-5R)	2.00

Magnesium metasilicate aluminate	2.40
		Magnesium stearate	1.20
Small counter	120.00

Was made according to example 5 of WO 97/23200.

400.0g of pitavastatin calcium salt, 2160.0g of lactose, 300.0g of low-substituted hydroxypropyl cellulose, 50.0g of hydroxypropyl methylcellulose (trade name: TC-5R) and 60.0g of magnesium metasilicate were mixed to prepare a uniform powder mixture, 594.0g of purified water was added to the powder mixture, and the powder mixture was granulated by a stirring granulation method. This granule was mixed with 30.0g of magnesium stearate and compressed into tablets to a weight of 120.0mg per tablet, to obtain 25000 tablets.

Comparative example 2

TABLE 21

Composition (I)	Addition amount (mg)
		Pitavastatin calcium salt	16.00
Lactose	48.00
		Hydroxypropyl methylcellulose (trade name: Methocel K100 LV)	80.00
Magnesium metasilicate aluminate	6.40
		Low-substituted hydroxypropyl cellulose	8.00
Magnesium stearate	1.60
		Total up to	160.00

320.0g of pitavastatin calcium salt, 960.0g of lactose, 1600.0g of hydroxypropyl methylcellulose (trade name: Methocel K100 LV), 128.0g of magnesium aluminate metasilicate and 160.0g of low-substituted hydroxypropyl cellulose are mixed to prepare a uniform powder mixture, 1108.0g of purified water is added, and granules are prepared by a stirring granulation method. To the granules, 32.0g of magnesium stearate was mixed and the mixture was compressed into tablets, each weighing 160.0mg, to obtain 20000 tablets.

Test example 1 dissolution test

The dissolution properties of pitavastatin were measured for each of the formulations of example 5 [ a formulation comprising the combination of the composition (a) and the enteric composition (B) ], comparative example 1 (ordinary formulation) and comparative example 2 (sustained-release formulation) by the following method.

Dissolution test [ (dissolution test method 2 (slurry method)) in general test methods of Japanese pharmacopoeia ]

7.0mL of hydrochloric acid containing 36% hydrogen chloride and water were added to 2.0g of sodium chloride, and the mixture was adjusted to 1000mL to prepare an artificial gastric juice having a pH of 1.2.

118mL of 0.2mol/L sodium hydroxide solution and water were added to 250mL of 0.2mol/L potassium dihydrogen phosphate solution, and the mixture was adjusted to 1000mL to prepare an artificial intestinal juice having a pH of 6.8.

1 part of each of the preparations of example 5, comparative example 1 and comparative example 2 was put into 900mL of artificial gastric juice having a pH of 1.2, and stirred at 37. + -. 1 ℃ at a speed of 100rpm for 3 hours from the start of the test. Then, the dissolution test solution was quickly changed to 900mL of an artificial intestinal solution having a pH of 6.8, and the dissolution test was carried out at a temperature of 37. + -. 1 ℃ and a paddle rotation speed of 100rpm for 21 hours to measure the amount of dissolution. The sample solutions collected at each time were filtered through a cellulose acetate membrane filter (DISMIC-25 cs manufactured by Toyo Filter paper Co., Ltd.) having a pore diameter of 0.45 μm, and the dissolution rate of pitavastatin was measured by high-speed liquid chromatography using a reverse-phase analytical column (Dvelosil ODS-HG-5 manufactured by Nomura chemical Co., Ltd.). The results are shown in FIG. 1.

Test example 2 absorbency test

Each of the preparations of example 5, comparative example 1 and comparative example 2 was orally administered to prairie beagle dogs (body weight: about 10kg) of HRA system under fasting condition, followed by periodic blood collection and centrifugation at 24 hours after the administration, and then the pitavastatin concentration in the blood was measured by high performance liquid chromatography. The results are shown in Table 22 and FIG. 2. In addition, pharmacokinetic values are shown in table 23. These results show that the controlled release formulation of the present invention has a Cmax decreased by about 1/2 compared to the conventional formulation, and that an AUC equivalent to that of the conventional formulation can be obtained. Compared with the common preparation, the Cmax and the AUC of the sustained-release preparation with 0 times of drug release are also greatly reduced. Therefore, the controlled-release preparation of the present invention is a safe and highly effective preparation.

TABLE 22 pitavastatin blood concentrations at respective time points after administration of the formulations of example 5 and comparative examples 1 and 2 to beagle dogs

Time (h)	0	0.5	1	1.5	2	3	4	6	8	10	24
												Example 5(ng/mL)	0	229.7	505.7	533.3	536.8	386.0	373.0	229.3	112.5	59.8	8.2
Comparative example 1(ng/mL)	0	1246.3	1179.7	690.8	475.2	323.7	226.5	155.8	49.3	29.0	8.3
												Comparative example 2(ng/mL)	0	10.2	52.2	73.7	76.5	131.3	161.8	171.7	49.0	25.3	3.2

TABLE 23 pharmacokinetics of pitavastatin after administration of the formulations of example 5, comparative examples 1 and 2 to beagle dogs

	Tmax(h)	Cmax(ng/mL)	AUC(ng·hr/mL)
				Example 5	1.8	748.0	3202
Comparative example 1	0.7	1434.8	3279
				Comparative example 2	4.7	210.5	1166

Possibility of industrial application

By using the controlled-release pharmaceutical composition of the present invention, a suitable blood level of pitavastatin can be obtained immediately after administration and maintained for a long period of time, and thus, safe and highly effective hypercholesterolemia treatment can be performed.

Claims (5)

1. A controlled-release pharmaceutical composition characterized by comprising (A) a composition containing pitavastatin, a salt or an ester thereof and releasing 30% by mass or more of the contained pitavastatin, a salt or an ester thereof at least in the stomach and (B) an enteric composition containing pitavastatin, a salt or an ester thereof,

the mass ratio of the pitavastatin, the salt or the ester thereof in the composition (A) to the pitavastatin, the salt or the ester thereof in the enteric composition (B) is 30: 1 to 1: 40.

2. The controlled-release pharmaceutical composition according to claim 1, wherein the composition (A) releases at least 85 mass% of pitavastatin, a salt or an ester thereof contained therein in the stomach, and the mass ratio of the pitavastatin, the salt or the ester thereof in the composition (A) to the pitavastatin, the salt or the ester thereof in the enteric composition (B) is 1: 1 to 1: 40.

3. The controlled-release pharmaceutical composition according to claim 1, wherein the composition (A) releases 60% by mass or more and less than 85% by mass of pitavastatin, a salt or an ester thereof contained therein in the stomach, and the mass ratio of the pitavastatin, the salt or the ester thereof in the composition (A) to the pitavastatin, the salt or the ester thereof in the enteric composition (B) is 15: 1 to 1: 30.

4. The controlled-release pharmaceutical composition according to claim 1, wherein the composition (A) releases more than 30% by mass and less than 60% by mass of pitavastatin, a salt or an ester thereof contained therein in the stomach, and the mass ratio of the pitavastatin, the salt or the ester thereof in the composition (A) to the pitavastatin, the salt or the ester thereof in the enteric composition (B) is 30: 1 to 1: 20.

5. The controlled-release pharmaceutical composition according to any one of claims 1 to 4, wherein the enteric composition (B) is a composition obtained by coating pitavastatin, a salt or an ester thereof with a component that dissolves at a pH of 3.0 or more, or a composition obtained by mixing pitavastatin, a salt or an ester thereof with a component that dissolves at a pH of 3.0 or more.