JP7209555B2 - Film-coated tablets containing ramelteon - Google Patents

Description

The present invention relates to a film-coated tablet stably containing ramelteon.

Ramelteon is a melatonin receptor agonist that exhibits sleep-inducing effects, but because it is photolabile, commercial formulations are coated for the purpose of stabilization. On the other hand, polyethylene glycol is commonly used as a plasticizer for water-soluble films such as hypromellose to improve film strength and spreadability. A replacement plasticizer was needed.

Therefore, Patent Document 1 describes a ramelteon-containing film-coated tablet with good stability using copolyvidone as a plasticizer in place of polyethylene glycol.

However, there is no disclosure or suggestion regarding the stabilizing effect of the coating agent contained in the coating layer on ramelteon, and the search for a coating agent that stabilizes ramelteon has remained one of the issues.

Japanese Patent No. 3633895

An object of the present invention is to provide a new means of improving the stability of ramelteon using a coating agent.

The present inventors have made intensive studies to solve the above problems, and surprisingly, by using a combination of hypromellose and hydroxypropyl cellulose or propylene glycol as a coating agent, or polyvinyl alcohol-polyethylene glycol graft The inventors have found that the use of a copolymer as a coating agent remarkably suppresses ramelteone-related substances, and completed the present invention.

That is, the present invention <1> provides a film-coated tablet obtained by coating a ramelteon-containing uncoated tablet with hypromellose and hydroxypropylcellulose or propylene glycol, or provides a film-coated tablet coated with a polyvinyl alcohol/polyethylene glycol/graft copolymer. do.

<2> Provide the film-coated tablet according to <1>, which is coated with hypromellose and propylene glycol.
<3> The film-coated tablet according to <1>, which is coated with a polyvinyl alcohol/polyethylene glycol/graft copolymer.
<4> Provide the film-coated tablet according to <1> to <3>, further comprising a light shielding agent in the coating.

<5> The fill-coated tablet according to <4> above, wherein the light shielding agent is titanium oxide and yellow ferric oxide.

INDUSTRIAL APPLICABILITY The ramelteon-containing film-coated tablet of the present invention suppresses the production of analogues of ramelteon, which is an active ingredient, and is therefore useful as a medicament with good stability of ramelteon.

In the present invention, ramelteon (N-{2-[(8S)-1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide) is It is a compound represented by a chemical formula. Ramelteon can be produced, for example, by the method described in Japanese Patent No. 2884153. Also, the content of ramelteon is preferably 1 to 20% by weight, more preferably 5 to 10% by weight per film-coated tablet.

In the present invention, coating agents include, for example, hypromellose, hydroxypropyl cellulose, propylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol methyl acrylate methacrylate copolymer and polyethylene glycol. However, from the viewpoint of stability of ramelteon, hypromellose, hydroxypropyl cellulose, propylene glycol and polyvinyl alcohol polyethylene glycol graft copolymer are preferred, and hypromellose and propylene glycol are more preferred. The content of hypromellose is preferably 50 to 90% by weight, more preferably 60 to 80% by weight per coating part of one film-coated tablet, and hydroxypropylcellulose is 5 to 30% by weight per coating part of one film-coated tablet. %, more preferably 10 to 20% by weight, propylene glycol, preferably 5 to 30% by weight, more preferably 10 to 20% by weight per coating part of one film-coated tablet.

In the present invention, the light-shielding agent includes, for example, titanium oxide, yellow iron sesquioxide, iron sesquioxide, black iron oxide, food yellow No. 5, and food red No. 102, with titanium oxide and yellow iron sesquioxide being more preferred. .

In the present invention, additives refer to excipients, binders, disintegrants and lubricants, but are not particularly limited to these. In addition to the additives, colorants, antioxidants, thickeners, buffering agents, sweetening agents, flavoring agents, perfume agents, etc. used in the art may be added to the film-coated tablet of the present invention. good too. Sweetening agents include aspartame, acesulfame potassium, sucralose, stevia, maltitol, glycerin, lactitol, galactitol and the like.

In the present invention, excipients such as D-mannitol, lactose (lactose hydrate, spray-dried lactose, fluid bed granulated lactose, isomerized lactose, reduced lactose, etc.), corn starch, sucrose, erythritol, sorbitol, xylitol and the like. In the present invention, lactose and corn starch are preferred.

In the present invention, binders include, for example, hydroxypropylcellulose, hypromellose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose and the like. Hydroxypropyl cellulose and hypromellose can also be used as coating agents in the present invention.

In the present invention, disintegrants include, for example, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, alginic acid, partially pregelatinized starch, bentonite and the like.

In the present invention, examples of lubricants include magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, and talc.

In the present invention, the film-coated tablet may be an orally disintegrating tablet coated with a coating agent.

The film-coated tablet of the present invention can be produced by a conventional tablet production method.
Specifically, the ramelteon-containing film-coated tablet of the present invention is produced, for example, by mixing ramelteon and excipients, granulating with a fluidized bed granulator while spraying a liquid in which a binder is dissolved, and then with a stainless sieve. After sizing, mixing the sizing product with a lubricant, tableting to obtain uncoated tablets, the uncoated tablets are obtained by spraying a coating agent.

EXAMPLES The present invention will be described in more detail with reference to Examples and the like below, but the present invention is not limited to the following Examples and the like.

32 g of ramelteon, 376 g of lactose hydrate, and 80 g of corn starch were mixed, and the liquid obtained by dissolving 16 g of hydroxypropylcellulose (viscosity: 2 to 2.9 mPa s) in 250.7 g of purified water was sprayed in a fluid bed granulator. After granulation, the granules were sieved with a stainless steel sieve with an opening of 850 µm. After mixing 8 g of sodium stearyl fumarate with 252 g of this sieved product, the mixture was tableted to obtain uncoated tablets containing ramelteon. Furthermore, 104.7 g of hypromellose and 21 g of hydroxypropyl cellulose (viscosity 2 to 2.9 mPa s) were dissolved in 1350 g of purified water, and 15 g of titanium oxide, 9 g of crown talc, and 0.3 g of yellow ferric oxide were dispersed. While spraying, 5 mg per tablet was coated with a film coating machine to obtain film-coated tablets (weight per tablet: 135 mg).

32 g of ramelteon, 376 g of lactose hydrate, and 80 g of corn starch were mixed, and the liquid obtained by dissolving 16 g of hydroxypropylcellulose (viscosity: 2 to 2.9 mPa s) in 250.7 g of purified water was sprayed in a fluid bed granulator. After granulation, the granules were sieved with a stainless steel sieve with an opening of 850 µm. After mixing 8 g of sodium stearyl fumarate with 252 g of this sieved product, the mixture was tableted to obtain uncoated tablets containing ramelteon. Furthermore, 104.7 g of hypromellose, 21 g of propylene glycol dissolved in 1350 g of purified water, 15 g of titanium oxide, 9 g of crown talc, and 0.3 g of yellow ferric oxide were dispersed while spraying 5 mg per tablet with a film coating machine. to obtain film-coated tablets (weight per tablet: 135 mg).

32 g of ramelteon, 376 g of lactose hydrate, and 80 g of corn starch were mixed, and the liquid obtained by dissolving 16 g of hydroxypropylcellulose (viscosity: 2 to 2.9 mPa s) in 250.7 g of purified water was sprayed in a fluid bed granulator. After granulation, the granules were sieved with a stainless steel sieve with an opening of 850 µm. After mixing 8 g of sodium stearyl fumarate with 252 g of this sieved product, the mixture was tableted to obtain uncoated tablets containing ramelteon. Furthermore, while spraying a liquid dispersed with 15 g of titanium oxide, 9 g of crown talc, and 0.3 g of yellow ferric oxide in which 125.7 g of polyvinyl alcohol/polyethylene glycol/graft copolymer was dissolved in 1350 g of purified water, it was coated with a film coating machine. Film-coated tablets were obtained by coating 5 mg per tablet (weight per tablet: 135 mg).

(Comparative example 1)
32 g of ramelteon, 376 g of lactose hydrate, and 80 g of corn starch were mixed, and the liquid obtained by dissolving 16 g of hydroxypropylcellulose (viscosity: 2 to 2.9 mPa s) in 250.7 g of purified water was sprayed in a fluid bed granulator. After granulation, the granules were sieved with a stainless steel sieve with an opening of 850 µm. After mixing 8 g of sodium stearyl fumarate with 252 g of this sieved product, the mixture was tableted to obtain uncoated tablets containing ramelteon. Furthermore, 104.7 g of hypromellose and 21 g of macrogol 6000 were dissolved in 1350 g of purified water, and 15 g of titanium oxide, 9 g of crown talc, and 0.3 g of yellow ferric oxide were dispersed. 5 mg of coating was applied to obtain film-coated tablets (weight per tablet: 135 mg).

The compositions of Examples 1 to 3 and Comparative Example are shown in Table 1.

(Test example 1)
The tablets of Examples 1 to 3 and Comparative Example 1 were stored under sealed conditions at 60° C. for 1 month, and the storage stability was evaluated by measuring the total amount of unknown related substances derived from ramelteon.

<Evaluation method>
Ramelteon was dissolved in a water/acetonitrile mixture (1:1) to a concentration of about 1 mg/mL, and filtered through a membrane filter (0.45 μm) to obtain a sample solution. Exactly 1 mL of this liquid was taken, and a mixture of water/acetonitrile (1:1) was added to make exactly 100 mL, which was used as a standard solution. Exactly 10 μL each of the sample solution and the standard solution were taken and measured by high performance liquid column chromatography (HPLC) under the following conditions. The % content of related substances was determined by the following formula.
Amount (%) of total related substances derived from ramelteon = A _T / A _S
A _S : Peak area of ramelteon in the standard solution _AT : Total area of ramelteon in the sample solution and peaks other than formulation excipients with a relative retention time of about 3.96 to ramelteon

<Measurement conditions>
HPLC conditions Detector: UV-visible spectrophotometer, measurement wavelength 230 nm
Column: XBridge Phenyl, 5 μm, inner diameter: 4.6 mm, length: 250 mm
Column temperature: 30°C
Mobile phase (A):
0.05 mol/L dipotassium hydrogen phosphate solution (pH 6.8) containing 0.1% triethylamine
Mobile phase (B): acetonitrile flow rate: 1 mL / min
Gradient program

As a result, as shown in Table 1, Examples 1 to 3 were tablets with excellent storage stability compared to Comparative Example 1.

Claims (5)

A film-coated tablet obtained by coating a ramelteon-containing uncoated tablet with hypromellose and hydroxypropylcellulose, or coating with polyvinyl alcohol/polyethylene glycol/graft copolymer. The film-coated tablet according to claim 1, coated with hypromellose and hydroxypropylcellulose, wherein the content of hydroxypropylcellulose is 10% by weight or more per coating part of the film-coated tablet. The film-coated tablet according to claim 1, which is coated with a polyvinyl alcohol/polyethylene glycol/graft copolymer. The film-coated tablet according to any one of claims 1 to 3, further comprising a light shielding agent in the coating. 5. The film-coated tablet according to claim 4, wherein the light-shielding agents are titanium oxide and yellow ferric oxide.