JP2016098187A - Orally disintegrating tablets - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an orally disintegrating tablet containing statin particles in which the light stability of an orally disintegrating tablet is improved while achieving both excellent bitterness masking and drug release properties. The present invention relates to an orally disintegrating tablet containing statin particles, wherein the statin particles are composed of a statin and a coating layer coated with the statin, and the coating layer is ethyl acrylate / methacrylic acid. An orally disintegrating tablet comprising an acid methyl copolymer and the statin is at least one drug selected from the group consisting of rosuvastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin and mevastatin is there. [Selection figure] None

Description

  The present invention relates to an orally disintegrating tablet, and more particularly to an orally disintegrating tablet with improved light stability.

  Statins are drugs that lower cholesterol levels in the blood by inhibiting the action of HMG-CoA reductase. For example, pitavastatin is known as an agent for hyperlipidemia having HMG-CoA reductase inhibitory action. (Non-Patent Document 1). In addition, many commercial products are currently provided for other drugs belonging to the statin (for example, rosuvastatin and atorvastatin).

  In recent years, from the viewpoint of improving a patient's quality of life (QOL), there has been a demand for an orally disintegrating tablet that can be taken without water even in patients with difficulty in swallowing such as elderly people and children. Here, since the statin has a very strong bitter taste, it has been desired to reduce the bitter taste by masking by tablet coating while retaining the drug eluting property of the statin itself.

  For example, an orally disintegrating tablet containing pitavastatin has been proposed as an orally disintegrating tablet that can achieve both such bitterness masking and drug dissolution (Patent Document 1).

  However, since the above-mentioned statin also lacks light stability, it is desired to reduce the generation of related substances during the storage period for orally disintegrating tablets containing the statin.

JP2013-237651A

“Rivalo (registered trademark) lock” package insert

  An object of the present invention is to solve the above-mentioned problems, and the object of the present invention is to provide a statin particle having improved light stability of an orally disintegrating tablet while achieving both excellent bitterness masking and drug release properties. It is in providing an orally disintegrating tablet containing.

The present invention relates to an orally disintegrating tablet containing statin particles, wherein the statin particles are composed of a statin and a coating layer coated with the statin, and the coating layer is composed of an ethyl acrylate / methyl methacrylate copolymer. An orally disintegrating tablet comprising a combination and wherein the statin is at least one drug selected from the group consisting of rosuvastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin and mevastatin.

  In one embodiment, the content of the ethyl acrylate / methyl methacrylate copolymer in the statin particles is 1% to 50% by weight based on the weight of the statin particles.

  In one embodiment, the content of the statin is 0.1% to 10% by weight with respect to the weight of the orally disintegrating tablet.

  In one embodiment, the statin is rosuvastatin.

The present invention is a method for improving the photostability of an orally disintegrating tablet containing statin particles,
Covering the statin with a coating layer containing ethyl acrylate / methyl methacrylate copolymer to obtain the orally disintegrating tablet containing the statin particles;
Wherein the statin is at least one drug selected from the group consisting of pitavastatin, rosuvastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin and mevastatin.

  In one embodiment, the content of the ethyl acrylate / methyl methacrylate copolymer in the statin particles is 1% to 50% by weight based on the weight of the statin particles.

  In one embodiment, the content of the statin is 0.1% to 10% by weight with respect to the weight of the orally disintegrating tablet.

  In one embodiment, the statin is rosuvastatin.

  According to the present invention, bitterness can be effectively masked in the oral cavity without reducing the elution of statin. Furthermore, the orally disintegrating tablet of the present invention is excellent in light stability and can suppress the generation of related substances even for long-term storage.

  Hereinafter, the present invention will be described in detail.

  The orally disintegrating tablet of the present invention contains statin particles.

  As used herein, the term “orally disintegrating tablet” refers to a tablet prepared so as to disintegrate in the oral cavity with no water or with a small amount of water when taken, and the tablet refers to a method such as compression molding. A solid preparation molded into a fixed shape.

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

  The statin particles are particles containing a statin as a main component, and are composed of the statin and a coating layer coated with the statin.

  Examples of statins contained in the statin particles include pitavastatin, rosuvastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin, mevastatin, and salts thereof, and combinations thereof. A salt of a statin is a pharmaceutically acceptable salt. The pharmaceutically acceptable salt of statin is not particularly limited, and examples thereof include sodium salt, potassium salt, calcium salt, and lower alkylamine salt. In the present invention, rosuvastatin is preferably used. In the orally disintegrating tablet of the present invention, the content of the statin is not necessarily limited, but is preferably 0.1% by weight to 10% by weight, more preferably 0.5% by weight, based on the weight of the orally disintegrating tablet. ~ 5% by weight.

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

In the present invention, the coating layer constituting the statin particles is formed by a coating agent. The coating agent is mainly an ethyl acrylate / methyl methacrylate copolymer. The number average molecular weight of the ethyl acrylate / methyl methacrylate copolymer contained in the coating layer is not particularly limited, but is preferably 400,000 to 1,200,000, more preferably 700,000 to 900,000.
The mass ratio of ethyl acrylate and methyl methacrylate constituting the copolymer is not particularly limited, but is preferably 1.5: 1 to 2.5: 1, more preferably 1.9: 1 to 2. 1: 1.

  In the present invention, 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 constituting the statin particles is not particularly limited, but is preferably 1% by weight to 50% by weight, more preferably 5% by weight to 20% by weight with respect to the weight of the statin particles. %. If the content of the ethyl acrylate / methyl methacrylate copolymer is less than 1% by weight, it becomes difficult to sufficiently mask the bitter taste of the statin itself, and the obtained tablet does not have sufficient light stability. There is a case. When the content of ethyl acrylate / methyl methacrylate copolymer exceeds 50% by weight, as an orally disintegrating tablet, for example, when taken without water, it is difficult to disintegrate in the oral cavity with the disintegration time as described above. There is a case.

  The coating layer constituting the statin particles may also contain other coating agent in addition to the above coating agent. 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, And titanium oxide, and combinations thereof. The sugar is not particularly limited, and examples thereof include glucose, fructose, lactose, sucrose, reduced maltose, and trehalose and combinations thereof. The sugar alcohol is not particularly limited, and examples thereof include mannitol, erythritol, sorbitol, xylitol, maltitol, and lactitol, and combinations thereof. The content of the other coating agent in the statin particles is not particularly limited and can be appropriately selected by those skilled in the art.

  In the statin particles, the coating layer preferably covers the entire surface of the particles. Moreover, it is preferable that the thickness of a coating layer is substantially equal over the front surface of a statin particle. The thickness of the coating layer in the statin particles constituting the present invention is not particularly limited, and an appropriate thickness can be set by those skilled in the art.

  In the present invention, the statin particles contain additives such as an optional excipient, disintegrant, stabilizer, corrigent, lubricant, and fragrance in an amount that does not inhibit the medicinal effects of the statin contained. Also good.

  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 purified 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 phosphorus Calcium, precipitated calcium carbonate, calcium silicate, calcium hydrogen hydrate phosphoric acid, inorganic salts such as sodium hydrogen carbonate, and combinations thereof. Examples of preferred excipients include D-mannitol, lactose, crystalline cellulose, and starch, and combinations thereof.

  The disintegrant is not particularly limited, and for example, crospovidone, crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, starch, partially pregelatinized starch, sodium starch glycolate , Hydroxypropyl starch, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, and combinations thereof. Examples of preferred disintegrants include croscarmellose sodium, sodium starch glycolate, and crospovidone, and combinations thereof.

  The stabilizer is not particularly limited. For example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium dihydrogen phosphate , Magnesium oxide, magnesium hydroxide, L-arginine, L-lysine, meglumine, magnesium aluminate metasilicate, and combinations thereof. An example of a preferred stabilizer is magnesium carbonate.

  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, and the like. The combination of these is mentioned. Examples of preferred fluidizing agents include talc, hydrous silicon dioxide, and light silicic anhydride, and combinations thereof.

  The binder is not particularly limited, and for example, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, gelatin, agar, alginic acid, sodium alginate, dextrin, chitansan gum, gum arabic powder, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, pullulan, Partially pregelatinized starch, as well as combinations thereof. Examples of preferred binders include hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone, and combinations thereof.

  The colorant is not particularly limited, and examples thereof include titanium oxide, iron sesquioxide, yellow iron sesquioxide, food red No. 2, food red No. 3, food yellow No. 4, and food yellow No. 5, and combinations thereof. Can be mentioned.

  The corrigent is not particularly limited, and examples thereof include aspartame, stevia, sugar alcohol, saccharin sodium, dipotassium glycyrrhizin, thaumatin, acesulfame potassium, and sucralose, and combinations thereof. Preferred flavoring agents are aspartame, thaumatin, and acesulfame potassium, and combinations thereof.

  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, and talc. And combinations thereof. Preferred lubricants are sodium stearyl fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid esters, and combinations thereof.

  The fragrance is not particularly limited, and examples thereof include mint, lemon fragrance, orange corton, pineapple flavor, and l-menthol.

  In addition to the statin particles, the orally disintegrating tablet of the present invention may also contain any excipient, disintegrant, stabilizer, fluidizing agent, binder in an amount that does not inhibit the medicinal effects of the statin contained in the particles. And may contain additives such as colorants. Specific examples of these additives are the same as those of the additives that can be contained in the statin particles.

  The orally disintegrating tablet of the present invention can be produced, for example, as follows.

  First, core particles containing statin are coated with a coating agent to produce statin particles.

  In the production of statin particles, the above-mentioned additives such as excipients, disintegrants, stabilizers, fluidizing agents, binders, and coloring agents are mixed with the statin as necessary, and granulated by a predetermined method. As a result, core particles are formed. For this mixing, for example, a method of mixing with powder, a method of mixing after dissolving in a solvent such as water, and evaporating the solvent can be employed. The granulation method used for the production of the core particles may be either a wet granulation method or a dry granulation method. Examples of the wet granulation method include a method using a fluidized bed granulator / dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulation coating machine, a spray dryer, and the like. Examples of the dry granulation method include a method using a roller compactor. At this stage, the core particles may be appropriately sized. The sizing method is not particularly limited, and examples thereof include a method using a sizing machine and a classifier.

  Thereafter, the core particles are coated with a coating agent (which may contain the other coating agent as necessary). 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 core liquid is sprayed with the coating liquid. Alternatively, a pan coating method, a fluid coating method, a rolling coating method, or the like may be employed. In addition to the coating agent, the above-mentioned additives such as excipients, disintegrants, stabilizers, fluidizing agents, binders, and colorants may be appropriately added to the coating liquid. Further, a plurality of coating liquids having different components may be prepared and used.

  In this way, statin particles in which the outer periphery of the core particle is covered with the coating layer are formed.

  The statin particles are then tableted.

In tableting of statin particles, the above-mentioned additives such as excipients, disintegrants, stabilizers, corrigents, lubricants, fragrances and the like are further added to the statin particles obtained above as necessary. Mixed. The mixing method is not particularly limited. The method that can be employed for tableting is not particularly limited. For example, a hydraulic hand press machine, a single tablet machine, a rotary tablet machine using a tableting die, a tableting upper punch and a lower punch. The method performed by a machine etc. is mentioned. Tableting is preferably 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 can be appropriately adjusted according to the tableting method, the equipment used for tableting, the size of the tablet, and the like. Tableting pressure is preferably ^{20kg / cm 2 ~2000kg / cm 2} , preferably ^{100kg / cm 2 ~1000kg / cm 2} .

  Thus, the orally disintegrating tablet of the present invention is produced.

  The obtained orally disintegrating tablet is enclosed in a container using means known in the art. After enclosing in a container, the orally disintegrating tablet of the present invention is stored under appropriate storage conditions until use.

  The orally disintegrating tablet of the present invention can be swallowed easily without touching the tongue directly even if it disintegrates in the oral cavity at the time of use by the coating layer constituting the statin particles. In the gastrointestinal tract, the coating layer that coats the statin dissolves with an appropriate disintegration time, and the statin dissolves in the same manner as a conventional ordinary tablet and can exhibit excellent medicinal effects.

  In addition, by obtaining the orally disintegrating tablet as described above, in the present invention, in addition to coexistence of the dissolution property of the statin and the masking of bitterness, it is possible to improve the light stability of the orally disintegrating tablet itself. it can. As a result, the generation of related substances due to the degradation of statins through light exposure during the storage period can be suppressed, so that the storage period is substantially extended.

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

(Example 1: Production of pitavastatin tablets)
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. Further, 4,000 g of Eudragit (registered trademark) NE30D (Evonik Degussa; ethyl acrylate / methyl methacrylate copolymer dispersion) was added to and mixed with the obtained mixture. 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 Co., Ltd .: 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 pitavastatin tablets having a tablet diameter of about 8.5 mm, a mass of about 200 mg, and a hardness of 40 N or more.

(Example 2: Production of rosuvastatin tablet)
Tablets with a total mass of 200 mg containing 2 mg of rosuvastatin calcium were produced as follows.

  A rosuvastatin tablet having a tablet diameter of about 8.5 mm, a mass of about 200 mg, and a hardness of 40 N or more was obtained in the same manner as in Example 1 except that 600 g of rosuvastatin calcium was used instead of pitavastatin calcium. That is, in this example, Eudragit (registered trademark) NE30D (Evonik Degussa; ethyl acrylate / methyl methacrylate copolymer dispersion) and hypromellose were used in the same manner as in Example 1 for the second coating agent. used.

(Comparative Example 1: Production of pitavastatin tablet (Prescription B))
A pitavastatin tablet was produced in the same manner as in Example 1 except that the content of titanium oxide per tablet was 1.35 times. That is, in this comparative example, Eudragit (registered trademark) RL30D, Example 1 and hypromellose were used as the coating agent. That is, in this comparative example, Eudragit (registered trademark) RL30D (Evonik Degussa; aminoalkyl methacrylate copolymer dispersion) and hypromellose were used in the same manner as in Example 1 for the second coating solution.

(Comparative Example 2: Production of pitavastatin tablet (prescription C))
Example except that Eudragit (registered trademark) NE30D as a coating agent was not added, hypromellose was increased by an appropriate amount, and the content per tablet of iron sesquioxide and yellow iron sesquioxide was increased 1.5 times. As in 1, pitavastatin tablets were produced.

(Comparative Example 3: Production of pitavastatin tablet (prescription D))
A pitavastatin tablet was produced in the same manner as in Example 1 except that the content per tablet of iron sesquioxide and yellow iron sesquioxide was halved. That is, in this comparative example, Eudragit (registered trademark) RL30D, Example 1 and hypromellose were used as the coating agent. That is, in this comparative example, Eudragit (registered trademark) RL30D (Evonik Degussa; aminoalkyl methacrylate copolymer dispersion) and hypromellose were used in the same manner as in Example 1 for the second coating solution.

(Test Example 1: Light stability test)
The tablets obtained in Example 1 and Comparative Examples 1 to 3 were subjected to pitavastatin photostability test as follows.

  Each tablet was irradiated with light at an intensity of 1440,000 lx · hour for 3 days. The related substances (peak total area other than pitavastatin) in each tablet by this light irradiation were measured by liquid chromatography, and the increase rate was calculated as a percentage. The obtained results are shown in Table 2.

  As shown in Table 2, the tablet of Example 1 uses such a large amount of titanium oxide as compared with the tablet of Comparative Examples 1 and 2 in which the amount of titanium oxide added is increased to improve the light shielding property. Without the same or better light stability. In addition, it can be seen that the tablet obtained in Example 1 was able to sufficiently suppress the increase in the related substances as compared with that obtained in Comparative Example 3.

(Test Example 2: Temperature / humidity severe test)
About the tablet obtained in Example 1 and Comparative Examples 1-3, the temperature / humidity severe test of pitavastatin was performed as follows.

  Each tablet was stored in a dark place under high temperature and high humidity conditions of 60 ° C. and 75% RH for 3 days. The related substances (peak total area other than pitavastatin) in each tablet under high temperature and high humidity were measured by liquid chromatography, and the increase rate was calculated as a percentage. The obtained results are shown in Table 3.

  As shown in Table 3, it can be seen that the tablet of Example 1 effectively suppressed the generation of related substances during storage under high temperature and high humidity as compared with the tablets of Comparative Examples 1 to 3.

  As described above, by blending Eudragit (registered trademark) NE30D with a coating layer that coats a statin such as pitavastatin or rosuvastatin, the obtained tablets have the same dissolution properties as ordinary tablets with bitterness masking when taken. It can be seen that it is possible to effectively suppress the generation of related substances under light stability and high temperature and high humidity.

  According to the present invention, bitterness can be effectively masked in the oral cavity without reducing the elution of statin. Furthermore, the orally disintegrating tablet of the present invention is excellent in light stability and can suppress the generation of related substances even for long-term storage. For this reason, it is useful as a preparation that can be more easily administered to a desired patient while sufficiently retaining the medicinal effects of statins contained as medicinal ingredients.

Claims (4)

A method for improving the photostability of orally disintegrating tablets containing statin particles,
Covering the statin with a coating layer containing ethyl acrylate / methyl methacrylate copolymer to obtain the orally disintegrating tablet containing the statin particles;
Wherein the statin is at least one drug selected from the group consisting of pitavastatin, rosuvastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin and mevastatin.   2. The method according to claim 1, wherein the content of the ethyl acrylate / methyl methacrylate copolymer in the statin particles is 1 wt% to 50 wt% with respect to the weight of the statin particles.   The method according to claim 1 or 2, wherein the content of the statin is 0.1 to 10% by weight based on the weight of the orally disintegrating tablet.   The method according to any one of claims 1 to 3, wherein the statin is rosuvastatin.