JP2013237651A - Orally-disintegrating tablet of pitavastatin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an orally-disintegrating tablet of pitavastatin.SOLUTION: An orally-disintegrating tablet of pitavastatin contains particles containing the pitavastatin, the particle has a coating layer that coats the pitavastatin, and the coating layer contains an ethyl acrylate/methyl methacrylate copolymer.

Description

  The present invention relates to an orally disintegrating tablet of pitavastatin.

  Pitavastatin is known as an agent for hyperlipidemia having an inhibitory action on HMG-CoA reductase (Non-patent Document 1).

  From the viewpoint of improving the patient's quality of life (QOL), there is a need for an orally disintegrating tablet that can be taken without water even in patients with difficulty in swallowing such as the elderly and children. Since it has a strong bitter taste, it has been difficult to provide an orally disintegrating tablet that achieves both a bitter taste masking by tablet coating and the like and a drug dissolution property equivalent to that of a normal tablet.

“Rivalo (registered trademark) lock” package insert

  An object of the present invention is to provide a pitavastatin orally disintegrating tablet excellent in bitterness masking in the oral cavity and excellent in dissolution.

  By disposing a coating layer for coating pitavastatin on particles containing pitavastatin contained in the tablet of pitavastatin, and blending an ethyl acrylate / methyl methacrylate copolymer in the coating layer, Was found to exhibit drug dissolution properties equivalent to that of ordinary tablets marketed together with bitterness masking, and the present invention was completed.

  The present invention provides an orally disintegrating tablet of pitavastatin, wherein the orally disintegrating tablet comprises particles containing the pitavastatin, the particles having a coating layer covering the pitavastatin, the coating layer comprising ethyl acrylate -Contains a methyl methacrylate copolymer.

  In one embodiment, the content of the ethyl acrylate / methyl methacrylate copolymer contained in the particles containing the pitavastatin is 1 to 50% by mass.

  In one embodiment, the content of the pitavastatin contained in the orally disintegrating tablet is 0.1 to 10% by mass.

  ADVANTAGE OF THE INVENTION According to this invention, the orally disintegrating tablet of pitavastatin excellent in the bitter taste masking in the oral cavity and excellent in the dissolution property can be provided.

  The present invention relates to an orally disintegrating tablet of pitavastatin.

  In the present invention, the orally disintegrating tablet refers to a tablet prepared so as to disintegrate in the oral cavity without water or with a small amount of water at the time of taking, and the tablet is a solid molded into a certain shape by a method such as compression formation. Refers to the formulation.

  Pitavastatin also includes pharmaceutically acceptable salts. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include sodium salt, potassium salt, calcium salt, and lower alkylamine salt.

  The content of pitavastatin contained in the orally disintegrating tablet of the present invention is not particularly limited, and is, for example, 0.1 to 10% by mass, preferably 0.5 to 5% by mass.

  The orally disintegrating tablet of the present invention comprises particles containing pitavastatin. The shape of the particles containing pitavastatin is not particularly limited, and examples thereof include fine particles and granules. The size (average particle diameter) of the particles containing pitavastatin is not particularly limited, and is, for example, 10 to 500 μm, preferably 50 to 200 μm.

  The particles containing pitavastatin have a coating layer that coats pitavastatin. The coating agent for forming the coating layer is mainly an ethyl acrylate / methyl methacrylate copolymer. The number average molecular weight of the copolymer is not particularly limited, but is preferably 400,000 to 1,200,000, more preferably 700,000 to 900,000. The mass ratio of the copolymer ethyl acrylate to methyl methacrylate is not particularly limited, but is preferably 1.5: 1 to 2.5: 1, more preferably 1.9: 1 to 2.1: 1. It is. The ethyl acrylate / methyl methacrylate copolymer can be obtained, for example, as an aqueous dispersion. The aqueous dispersion of the ethyl acrylate / methyl methacrylate copolymer is not particularly limited, and examples thereof include Eudragit (registered trademark) NE30D manufactured by Evonik Degussa. The content of the ethyl acrylate / methyl methacrylate copolymer contained in the particles containing pitavastatin is not particularly limited, but is preferably 1 to 50% by mass, more preferably 5 to 20% by mass.

  The coating layer may contain other coating agents. Other coating agents are not particularly limited, for example, sugar, sugar alcohol, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, triethyl citrate, triacetin, macrogol and other polyethylene glycol (PEG), polysorbates, talc, Examples include titanium oxide. The sugar is not particularly limited, and examples thereof include glucose, fructose, lactose, sucrose, reduced maltose, and trehalose. The sugar alcohol is not particularly limited, and examples thereof include mannitol, erythritol, sorbitol, xylitol, maltitol, and lactitol. These may be single and 2 or more types of mixtures may be sufficient.

  Pitavastatin is coated with the above-mentioned coating layer together with any amount of excipients, disintegrants, stabilizers, fluidizers, binders, colorants and other additives in a range that does not inhibit the efficacy of pitavastatin to form particles. To do.

  Particles containing pitavastatin form an orally disintegrating tablet with any amount of excipients, disintegrants, stabilizers, flavoring agents, lubricants, flavoring agents, etc., within a range that does not inhibit the efficacy of pitavastatin. To do.

  The excipient is not particularly limited, and examples thereof include celluloses (crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose) and the like) and derivatives thereof, starch (corn starch (corn starch), potato). Starch, wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch, etc. and derivatives thereof, sugar (glucose, lactose, sucrose (including refined sucrose), powdered sugar, trehalose, dextran, dextrin, etc.), sugar alcohol (D -Mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (magnesium aluminate metasilicate, synthetic hydrotalcite), light anhydrous silicic acid, anhydrous Calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen hydrate phosphoric acid, inorganic salts such as sodium hydrogen carbonate. Preferred are D-mannitol, lactose, crystalline cellulose, and starch. These may be single and 2 or more types of mixtures may be sufficient.

  The disintegrant is not particularly limited. For example, crospovidone, crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, starch, partially pregelatinized starch, starch glycol Examples include sodium acid, hydroxypropyl starch, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, and synthetic aluminum silicate. Preferred are croscarmellose sodium, sodium starch glycolate, and crospovidone. These may be single and 2 or more types of mixtures may be sufficient.

  The stabilizer is not particularly limited, and examples thereof include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, and dihydrogen phosphate. Examples thereof include sodium, magnesium oxide, magnesium hydroxide, L-arginine, L-lysine, meglumine, and magnesium aluminate metasilicate. Preferably, it is magnesium carbonate. These may be single and 2 or more types of mixtures may be sufficient.

  The fluidizing agent is not particularly limited, and examples thereof include hydrous silicon dioxide, light anhydrous silicic acid, talc, synthetic aluminum silicate, titanium oxide, stearic acid, magnesium stearate, calcium stearate, magnesium aluminate metasilicate. It is done. Talc, hydrous silicon dioxide, and light anhydrous silicic acid are preferred. These may be single and 2 or more types of mixtures may be sufficient.

  The binder is not particularly limited, and examples thereof include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, pullulan. And partially pregelatinized starch. Preferred are hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone. These may be single and 2 or more types of mixtures may be sufficient.

  The colorant is not particularly limited, and examples thereof include titanium oxide, ferric oxide, yellow ferric oxide, edible red No. 2, edible red No. 3, edible yellow No. 4, and edible yellow No. 5. These may be single and 2 or more types of mixtures may be sufficient.

  The taste masking agent is not particularly limited, and examples thereof include alpartame, stevia, sugar alcohol, saccharin sodium, glycyrrhizin dipotassium, thaumatin, acesulfame potassium, and sucralose. Preferred are aspartame, thaumatin and acesulfame potassium. These may be single and 2 or more types of mixtures may be sufficient.

  The lubricant is not particularly limited. For example, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester, talc Is mentioned. Preferred are sodium stearyl fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid ester. These may be single and 2 or more types of mixtures may be sufficient.

  It does not specifically limit as said fragrance | flavor, Mint, a lemon fragrance | flavor, an orange coaton, a pineapple flavor, and 1-menthol are mentioned. These may be single and 2 or more types of mixtures may be sufficient.

  The shape of the orally disintegrating tablet of the present invention is not particularly limited, and examples thereof include a disc shape, a donut shape, a polygonal plate shape, a spherical shape, an oval shape, and a caplet shape. The size is preferably small, preferably about 5 to 12 mm in diameter and about 2 to 5 mm in thickness. The mass is preferably about 50 to 500 mg. Although hardness is not specifically limited, Preferably it is about 40-100N. The disintegration time is not particularly limited, and is, for example, about 10 to 60 seconds in the oral cavity when taken without water.

  The method for producing an orally disintegrating tablet of the present invention includes, for example, a granulating step for forming particles containing pitavastatin and a tableting step for forming a tablet from the particles.

  In the granulation step, pitavastatin is mixed with additives such as an excipient, a disintegrant, a stabilizer, a fluidizing agent, a binder, and a colorant, and granulated. A mixing amount and a mixing method are appropriately selected. The mixing method is not particularly limited, and examples thereof include a method of mixing with a powder and a method of mixing after dissolving in a solvent such as water and evaporating the solvent. As the granulation method, either a wet granulation method or a dry granulation method may be used. The wet granulation method is not particularly limited, and examples thereof include a method using a fluidized bed granulation dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulation coating machine, a spray dryer, and the like. . It does not specifically limit as a dry granulation method, For example, the method of using a roller compactor etc. is mentioned. The particles containing pitavastatin may be appropriately sized. The sizing method is not particularly limited, and examples thereof include a method using a sizing machine and a classifier.

  In the course of the granulation process, particles containing pitavastatin being formed are coated with a coating agent. The coating method is not particularly limited, and examples thereof include a spray coating method in which a coating liquid is prepared by dissolving or dispersing a coating agent or the like in a solvent such as water, and the coating liquid is sprayed onto particles containing pitavastatin. The coating liquid may appropriately contain additives such as excipients, disintegrants, stabilizers, fluidizers, binders, and colorants in addition to the coating agent. Further, a plurality of coating liquids may be prepared and used. Other examples include pan coating, fluid coating, and rolling coating. The thickness of the coating layer obtained by coating is not particularly limited.

In the tableting step, the particles containing pitavastatin are further mixed with additives such as an excipient, a disintegrant, a stabilizer, a corrigent, a lubricant, and a fragrance, and tableted. A mixing amount and a mixing method are appropriately selected. The tableting method is not particularly limited. For example, using a tableting die, an upper punch and a lower punch, a hydraulic hand press machine, a single-punch tableting machine, a rotary tableting machine, etc. A method is mentioned. Tableting is performed by adjusting so that the resulting tablet has an appropriate hardness and can be rapidly disintegrated as an orally disintegrating tablet. The tableting pressure is appropriately adjusted according to the tableting method, the device used for tableting, the size of the tablet, and the like. For example, 20~2000kg / cm ^2, preferably 100 to 1000 / cm ^2.

  Since the orally disintegrating tablet of the present invention has a coating layer in which particles containing pitavastatin coat pitavastatin, pitavastatin can be swallowed even if it disintegrates in the oral cavity during use without directly touching the tongue. And since the coating layer which coat | covers pitavastatin melt | dissolves in a digestive tract, pitavastatin is eluted like a normal tablet, and exhibits a medicinal effect. For this reason, almost no bitterness is perceived in the sensory evaluation by humans, and the dissolution property by the dissolution test is good.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

Example 1
Tablets with a total mass of 200 mg containing 2 mg of pitavastatin calcium were produced according to the formulation shown in Table 1 below.

  First, an aqueous solution in which 1,200 g of hydroxypropylcellulose was dissolved in 7,780 g of purified water, and a dispersion in which 6,300 g of titanium oxide, 60 g of yellow iron sesquioxide and 60 g of iron sesquioxide were dispersed in 10,000 g of purified water, Were mixed to obtain a first coating solution.

  Next, an aqueous solution in which 450 g of hypromellose was dissolved in 6,120 g of purified water was mixed with a dispersion in which 960 g of titanium oxide, 60 g of yellow iron sesquioxide and 60 g of iron sesquioxide were dispersed in 5,000 g of purified water. Furthermore, 4,000 g of Eudragit (registered trademark) NE30D (Evonik Degussa) was added to the obtained mixed liquid and mixed. Further, 600 g of talc and 150 g of magnesium carbonate were added to the obtained mixed liquid and mixed to obtain a second coating liquid.

  Next, 600 g of pitavastatin calcium, 300 g of crospovidone, 600 g of magnesium carbonate, and 5,400 g of D-mannitol are mixed and put into a fluidized bed granulator (manufactured by POWREC, Inc .: FD-GPCG-15-SPC type). Granulation started. Immediately after the start of granulation, intermediate fine particles were obtained by spraying the first coating liquid into the granulator. Further, the second coating liquid was sprayed into the granulator, and the obtained fine particles were dried in the granulator, thereby obtaining 1,800 g of pitavastatin coated fine particles.

  To 1,800 g of coated fine particles of pitavastatin, 2,280 g of D-mannitol, 120 g of acesulfame potassium, 1,500 g of crystalline cellulose, 180 g of crospovidone, 60 g of magnesium carbonate, 60 g of sodium stearyl fumarate and 6 g of l-menthol were added, (Tokuju Kogyo Co., Ltd .: TCV-30) was added and mixed to obtain granules for tableting. The obtained granules were put into a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VGRGO) and tableted to obtain tablets having a tablet diameter of about 8.5 mm, a mass of about 200 mg, and a hardness of 40 N or more.

(Comparative Example 1)
A tablet was produced in the same manner as in Example 1 except that Eudragit (registered trademark) RL30D (Evonik Degussa) was used instead of Eudragit (registered trademark) NE30D. That is, tablets having the formulations described in Table 2 below were produced.

(Comparative Example 2)
A tablet was produced in the same manner as in Example 1 except that hypromellose was used instead of Eudragit (registered trademark) NE30D. That is, tablets having the formulations shown in Table 3 below were produced.

(Test Example 1: Dissolution test)
The tablets obtained in Example 1 and Comparative Examples 1 and 2 and “RIVALO (registered trademark) 2 mg” (manufactured by Kowa Co., Ltd.) (Reference Example 1) were subjected to a dissolution test for pitavastatin calcium. The test solution was 900 mL of water, and the change over time in the dissolution rate (%) for 30 minutes was measured at a paddle rotation number of 50 rpm. “Rivalo (registered trademark) 2 mg” is an ordinary pitavastatin tablet. Each test was performed three times. The results are shown in Table 4.

  As is clear from Table 4, the tablet of Example 1 showed the same dissolution properties as the tablet of Reference Example 1, and the tablets of Comparative Examples 1 and 2 were more soluble than the tablet of Example 1 and the tablet of Reference Example 1. Was bad. Therefore, it was effective to add Eudragit (registered trademark) NE30D to the coating layer covering pitavastatin because of the dissolution property equivalent to that of ordinary tablets.

(Test Example 2: Bitter taste test)
The tablets obtained in Example 1 and Comparative Examples 1 and 2 were subjected to a bitterness test. In the bitterness test, five subjects took the tablets of Example 1 and Comparative Examples 1 and 2 so as to disintegrate in the oral cavity, and evaluated the bitterness. The results are shown in Table 5.

  As is clear from Table 5, all the subjects did not feel bitterness in the tablet of Example 1, but 3 tablets felt bitterness in the tablet of Comparative Example 1, and all the subjects felt bitterness in the tablet of Comparative Example 2. . Therefore, it was effective to add Eudragit (registered trademark) NE30D to the coating layer covering pitavastatin for masking the bitter taste during taking.

  As described above, by blending Eudragit (registered trademark) NE30D in the coating layer covering pitavastatin, it was possible to achieve the dissolution property equivalent to that of ordinary tablets as well as bitterness masking at the time of taking. That is, it was possible to provide a pitavastatin orally disintegrating tablet excellent in bitterness masking in the oral cavity and having excellent dissolution properties.

  ADVANTAGE OF THE INVENTION According to this invention, the orally disintegrating tablet of pitavastatin excellent in the bitter taste masking in the oral cavity and excellent in the dissolution property can be provided.

Claims (3)

  An orally disintegrating tablet of pitavastatin, comprising particles containing the pitavastatin, the particles having a coating layer covering the pitavastatin, the coating layer containing an ethyl acrylate / methyl methacrylate copolymer Orally disintegrating tablets.   The orally disintegrating tablet according to claim 1, wherein the content of the ethyl acrylate / methyl methacrylate copolymer contained in the particles containing pitavastatin is 1 to 50% by mass.   The orally disintegrating tablet according to claim 1 or 2, wherein a content of the pitavastatin contained in the orally disintegrating tablet is 0.1 to 10% by mass.