JP7598213B2 - Ramelteon-containing coated tablets - Google Patents

Description

The present invention relates to a technology for a coated tablet containing ramelteon that has excellent storage stability and appearance.

In Japan, due to factors such as the aging of the population, diversifying lifestyles, disrupted daily rhythms in a 24-hour society, and stress, approximately 21% of the general adult population suffers from insomnia, and approximately 15% are aware of daytime sleepiness. Sleep disorders cause daytime sleepiness, lethargy, and reduced concentration, which interfere with daily life and, in extreme cases, can lead to accidents. In addition, if lack of sleep or sleep disorders persist for a long time, it is easier to develop lifestyle-related diseases and depression. For these reasons, it is considered important to deal with sleep disorders appropriately (Ministry of Health, Labor and Welfare, Everyone's Mental Health General Site).

Benzodiazepine and non-benzodiazepine hypnotics are used to treat insomnia, and their mechanism of action is to bind to GABA _A receptors in the central nervous system and enhance the central nervous system depressant effect to exert a sleep-inducing effect. However, these therapeutic drugs have side effects such as dependence, amnesia, residual effects, muscle relaxant effects, rebound insomnia, and withdrawal symptoms, and are therefore designated as psychotropic and habit-forming drugs.

Ramelteon acts on melatonin receptor type 1 and melatonin receptor type 2, which are involved in the sleep-wake rhythm, inducing sleep by giving dominance to the sleep center and suppressing the autonomic nervous system by keeping the parasympathetic nervous system dominant. In other words, it is a drug that regulates the action of melatonin, which is related to the sleep-wake cycle of the biological rhythm, and induces natural sleepiness. Since it is almost non-addictive, it was developed as a medicine that is not designated as a psychotropic drug or a habit-forming drug.

As for pharmaceuticals containing ramelteon, a technology for improving the variability in dissolution behavior (Patent Document 1) and a technology for improving the stability (Patent Document 2) have been disclosed. Patent Document 1 is a technology for improving the variability in dissolution behavior by compounding ramelteon in a tablet in combination with magnesium stearate and hydroxypropyl cellulose having a specific viscosity.

Non-Patent Document 1 discloses that crushing a commercially available tablet containing ramelteon increases impurities due to its photoinstability. The commercially available tablet contains titanium oxide and yellow ferric oxide, which are ingredients used as light-blocking agents, and therefore it is presumed that tablets containing ramelteon are preparations that require coating.

Patent Document 2 is a technology that identifies the cause of decomposition of ramelteon-containing tablets during storage as polyethylene glycol, a plasticizer contained in the coating components, and finds that copolydone, a water-soluble vinyl polymer, is useful as an alternative plasticizer.

On the other hand, in Patent Document 2, Comparative Examples 2 and 4, which do not contain any copolydone or other plasticizers, show the same level of stability as the Examples containing copolydone. Patent Document 2 states that the addition of a plasticizer is essential in tablet coating to increase film strength, improve spreadability during processing, and improve appearance. Therefore, it is presumed that the ramelteon-containing tablets of Comparative Examples 2 and 4, which do not contain any plasticizer, have problems with film strength, spreadability, appearance, etc., and are coated tablets that are substantially unsuitable for commercialization. Therefore, Patent Document 2 merely discloses that copolydone is a component suitable for blending with ramelteon and has a function as a plasticizer during tablet coating, but does not indicate that the decomposition of ramelteon is suppressed by blending copolydone. Therefore, a technology for ramelteon-containing coated tablets that has no problems with appearance during tablet coating and has good stability even without using copolydone or other plasticizers, or a technology for ramelteon-containing coated tablets that has good stability even if a general plasticizer is included, is desired.

Patent No. 5220408 Patent No. 3633895

Pharmaceutical Interview Form Rozerem Tablets 8mg Revised July 2020 (9th edition)

An object of the present invention is to provide a tablet having excellent storage stability that does not contain a plasticizer and has no problems with film strength, spreadability, appearance, etc., and does not cause plasticizer-derived decomposition of ramelteon.Another object of the present invention is to provide a tablet having excellent storage stability in which decomposition products derived from ramelteon are suppressed by adding a specific substance, even if a plasticizer is used to maintain film strength, spreadability, appearance, etc.

As a result of intensive research, the inventors have found that by preparing hypromellose having a specific weight-average molecular weight to a concentration of 9% w/w% or less in water, and coating a core tablet containing ramelteon with this coating liquid in which the colorants titanium oxide and yellow ferric oxide are suspended in a specific ratio relative to the hypromellose, it is possible to obtain tablets with excellent storage stability that do not cause problems with film strength, spreadability, appearance, etc. during coating, and that do not cause decomposition of ramelteon due to plasticizers.

In addition, it was found that the decomposition of ramelteon-containing tablets during storage is mainly caused by the plasticizer in the film component, but the addition of a colorant to this plasticizer further accelerates the decomposition.As a result of trying to add a radical scavenger, it was surprisingly found that the decomposition of ramelteon-containing coated tablets was dramatically suppressed even when a plasticizer was included, and this led to the completion of the present invention.

The present invention includes the following inventions.
(1) A method for producing a coated tablet containing ramelteon, characterized in that a core tablet containing ramelteon is coated with a coating component containing hypromellose and a colorant selected from the group consisting of titanium oxide and yellow ferric oxide, the method comprising a step of coating a core tablet containing ramelteon with a coating liquid containing hypromellose having a weight-average molecular weight of 30,000 to 40,000 at a concentration of 9 w/w% or less relative to water, wherein the masses of titanium oxide and yellow ferric oxide relative to the mass of hypromellose are 11 to 16 w/w% and 0.2 to 0.4 w/w%, respectively, and the coating component does not contain a plasticizer.
(2) The method for producing coated tablets according to (1), wherein the total amount of decomposition products increased when the coated tablets are stored at 70° C. for 130 hours is 0.1% or less.
(3) A ramelteon-containing coated tablet comprising a core tablet containing ramelteon and a coating layer containing hypromellose, a colorant, a plasticizer and a radical scavenger.
(4) The coated tablet according to (3), wherein the plasticizer is triethyl citrate.
(5) The coated tablet according to (3) or (4), wherein the radical scavenger is benzhydroxytoluene.
(6) The coated tablet according to (5), wherein the amount of benzhydroxytoluene added relative to the amount of triethyl citrate added is 0.6 to 0.7.
(7) The coated tablet according to any one of (3) to (6), wherein the weight-average molecular weight of hypromellose is 30,000 to 40,000.
(8) The coated tablet according to any one of (3) to (7), wherein the colorant is titanium oxide and/or yellow ferric oxide.
(9) The coated tablet according to (8), wherein the masses of titanium oxide and yellow ferric oxide relative to the mass of hypromellose are 11 to 16 w/w% and 0.2 to 0.4 w/w%, respectively.
(10) The coated tablet according to any one of (3) to (9), wherein when the coated tablet is stored at 70° C. for 130 hours, the total amount of decomposition products increased is 0.1% or less.

According to the present invention, it is possible to provide a high-quality ramelteon-containing tablet having excellent storage stability.

Coating state of ramelteon-containing coated tablets obtained in Example 1 and Comparative Examples 1 to 5 HPLC chart of decomposition products of coated tablets containing ramelteon during storage

In the present invention, the core tablet containing ramelteon is a tablet obtained by compressing ramelteon together with medicamentously acceptable additive components as necessary. The shape and size of the core tablet are not particularly limited, but it is preferable that the tablet surface has a curved surface suitable for film coating, and further, it is preferable that the tablet is a circular tablet with a diameter of 7 to 9 mm, which is easy to handle and take as a tablet.

In the present invention, the method for producing the core tablets containing ramelteon is not particularly limited and any method commonly used for producing tablets, such as direct compression, dry granulation, wet granulation, or fluidized bed granulation, is possible.

In the present invention, the content of ramelteon contained in the ramelteon-containing coated tablet is not particularly limited as long as it is an amount suitable for treatment, but 8 mg, which is generally used in medical treatment, is preferable.

There are no particular limitations on the pharma- ceutically acceptable additive components as long as they are components that can be used for tableting. However, excipients, binders, disintegrants, lubricants, stabilizers, colorants, and the like can be used as desired as components that do not cause the problem of impurity generation when mixed with ramelteon and are necessary for maintaining manufacturability in the tableting process, as well as appropriate tablet functions such as strength, disintegrability, and dissolution properties.

(Excipients)
As the excipient in the ramelteon-containing tablet according to the present invention, any component can be used, for example, sugars such as lactose hydrate, anhydrous lactose, sucrose, mannitol, erythritol, sorbitol, xylitol, trehalose, and sucrose, celluloses such as crystalline cellulose and low-substituted hydroxypropylcellulose, starches such as corn starch, potato starch, rice starch, and partially pregelatinized starch, and inorganic salts such as calcium hydrogen phosphate and calcium carbonate can be used alone or in appropriate combination. In the present invention, lactose hydrate and corn starch are particularly preferred.

(Disintegrant)
In the ramelteon-containing tablet according to the present invention, the disintegrant is not particularly limited, and corn starch, sodium starch glycolate, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, etc. can be used alone or in appropriate combination. In the present invention, croscarmellose sodium is particularly preferred.

(Binder)
In the ramelteon-containing tablet according to the present invention, the binder can be selected from, for example, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, macrogol, and the compounds listed above as excipients. These binders can be used alone or in appropriate combination. In the present invention, hydroxypropyl cellulose is particularly preferred.

(lubricant)
In the ramelteon-containing tablet according to the present invention, the lubricant can be selected from, for example, magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol, etc. These lubricants can be used alone or in appropriate combination. In the present invention, calcium stearate is preferred.

(Coating Agent)
The coating component composition of the ramelteon-containing tablet according to the present invention contains hypromellose. It may further contain a coating agent that can be used for medical purposes. For example, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, PVA copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, Opadry, carnauba wax, hypromellose acetate succinate, hypromellose phthalate, methacrylic acid copolymer, etc. It is preferable to use hypromellose whose viscosity is 3 to 7 mPa·s when measured according to the official method. The weight average molecular weight of hypromellose is preferably 30,000 to 40,000, more preferably 30,000 to 35,000, and particularly preferably 32,800.

(Plasticizer)
In the coating component composition of the ramelteon-containing tablet according to the present invention, examples of the plasticizer include triethyl citrate, propylene glycol, polyalkylene glycol, glycerin, fatty acid triglyceride, etc. In the present invention, triethyl citrate is particularly preferred.

(Coloring Agent)
In the coating component composition of the ramelteon-containing tablet according to the present invention, examples of the colorant include titanium oxide, yellow ferric oxide, ferric oxide, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food No. 5, Food Green No. 3, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, and the like. In the present invention, titanium oxide and yellow ferric oxide are particularly preferred. The amount of titanium oxide added is preferably 11 to 16 w/w% relative to hypromellose, more preferably 11 to 12 w/w%, and particularly preferably 11.1 w/w%. The amount of yellow ferric oxide added is preferably 0.2 to 0.4 w/w% relative to hypromellose, more preferably 0.2 to 0.3 w/w%, and particularly preferably 0.22 w/w%.

(Radical scavenger)
The radical scavenger according to the present invention is not particularly limited as long as it has an antioxidant effect, and examples thereof include ascorbic acid, sodium azide, benzhydroxytoluene, dibutylhydroxytoluene, sodium hydrogensulfite, sodium sulfite, alpha-thioglycerin, sodium edetate, cysteine hydrochloride, citric acid, sodium thioglycolate, sodium thiomalate, sodium pyrosulfite, butylhydroxyanisole, tyrosine, tryptophan, cysteine, L-amino acids such as histidine, D-mannitol, etc. In the present invention, benzhydroxytoluene is particularly preferred.
The radical scavenger is preferably present in an amount of 0.1 to 1.0 w/w % relative to the plasticizer, more preferably 0.6 to 0.7 w/w %, and particularly preferably 0.67 w/w %.

The ramelteon-containing coated tablet according to the present invention can obtain a tablet having excellent storage stability without problems such as film strength, spreadability, and appearance in the coating, and without decomposition of ramelteon caused by plasticizers, by using a coating component containing hypromellose and a colorant, even if the tablet coating component does not contain a plasticizer. Even if a plasticizer is contained in the coating component, by adding a radical scavenger in addition, a tablet having excellent storage stability without problems such as film strength, spreadability, and appearance in the coating, and without decomposition of ramelteon being suppressed can be obtained.

The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

(Reference Example 1)
Preparation of ramelteon-containing core tablets 800 g of ramelteon, 9687 g of lactose hydrate, and 1552 g of corn starch were charged into a fluidized bed granulator (FLO-15, Freund Corporation), and a liquid in which 473 g of hydroxypropyl cellulose was dissolved in water to a total weight of 7883 g was sprayed and granulated. The resulting granules were dried and sized using a granulator (QC-197S, manufactured by QUADORO). The sized product was charged into a mixer (TVC-60, manufactured by Tokuju Seisakusho), and corn starch and calcium stearate were further added and mixed. The resulting mixture was compression-molded using a rotary tablet press (HT-AP18SSII, manufactured by Hata Iron Works) to obtain tablets (ramelteon-containing core tablets) with a diameter of 7 mm and a mass of 130 mg.

The ramelteon-containing core tablets were placed in a film coating device (HiCoater HCT-60, manufactured by Freund Corporation), and 450 g of hypromellose with a weight-average molecular weight of 32,800 was dissolved in 6,000 g of water. A suspension of 50 g of titanium oxide and 1 g of yellow ferric oxide in 1,200 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 1)
The ramelteon-containing core tablets were placed in a film coating device (Hicoater HC-LABO, manufactured by Freund Corporation), and 22.5 g of hypromellose with a weight-average molecular weight of 32,800 was dissolved in 150 g of water. A suspension of 2.5 g of titanium oxide and 0.05 g of yellow ferric oxide in 50 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 2)
The ramelteon-containing core tablets were placed in a film coating device (HiCoater HC-LABO, manufactured by Freund Corporation), and 18.8 g of hypromellose having a weight-average molecular weight of 32,800 and 3.8 g of triethyl citrate were dissolved in 200 g of water, and a suspension of 2.5 g of titanium oxide and 0.05 g of yellow ferric oxide was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 3)
The ramelteon-containing core tablets were placed in a film coating device (HiCoater HC-LABO, manufactured by Freund Corporation), and 22.5 g of hypromellose with a weight-average molecular weight of 20,000 was dissolved in 250 g of water. A suspension of 2.5 g of titanium oxide and 0.05 g of yellow ferric oxide in 50 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 4)
The ramelteon-containing core tablets were placed in a film coating device (HiCoater HC-LABO, manufactured by Freund Corporation), and 22.5 g of hypromellose with a weight-average molecular weight of 56,400 was dissolved in 250 g of water. A suspension of 2.5 g of titanium oxide and 0.05 g of yellow ferric oxide in 50 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 5)
The ramelteon-containing core tablets were placed in a film coating device (HiCoater HC-LABO, manufactured by Freund Corporation), and 20.0 g of hypromellose with a weight-average molecular weight of 32,800 was dissolved in 215 g of water. A suspension of 5 g of titanium oxide and 0.05 g of yellow ferric oxide in 50 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Test Example 1)
The workability during coating and the coating state of the tablets after coating were observed for the ramelteon-containing coated tablets obtained in Example 1 and Comparative Examples 1 to 5. The results are shown in Table 1 and Figure 1.

As shown in Table 1 and FIG. 1, in Example 1, even though no plasticizer was used, the tablet surface was extremely smooth and high quality tablets were obtained. On the other hand, in Comparative Example 1, the roughness of the tablet surface after coating was noticeable, and there was a problem in terms of quality. It was presumed that this roughness of the tablet surface was due to the large spray mist of the coating liquid sprayed from the spray gun with high viscosity. Although improvement can be expected by diluting the coating liquid concentration to reduce the viscosity, there is a problem in terms of cost because the coating time increases. In Comparative Example 2, the condition of the tablet surface after coating was good. In Comparative Example 3, the tablet surface after coating, traces of partial peeling of the film layer on the side, and tablets in a state where pieces of the peeled film were attached to the tablet surface were observed, and there was a problem in terms of quality. In Comparative Example 4, the tablet surface after coating was slightly rough and the quality was poor. In Comparative Example 5, tablets with rough tablet surfaces and blackening were observed, and the quality was significantly poor. This is believed to be a phenomenon caused by the high ratio of titanium oxide in the film components, and in particular the blackening was believed to be a phenomenon caused by the increased frequency of friction between the increased amount of titanium oxide and the coating pan.

Adding a plasticizer to hypromellose used for tablet coating makes the tablet surface smooth, resulting in high-quality tablets. On the other hand, in the case of coating without using a plasticizer, it was found that the weight-average molecular weight of hypromellose, the concentration of the aqueous solution, and the mass of the colorants titanium oxide and yellow ferric oxide in the coating components relative to the mass of hypromellose are very important in order to obtain high-quality coated tablets without problems in appearance.

The ramelteon-containing core tablets were placed in a film coating device (Hicoater HC-LABO, manufactured by Freund Corporation), and 8.1 g of hypromellose having a weight-average molecular weight of 32,800 and 1.9 g of triethyl citrate were dissolved in 82.5 g of water. A suspension of 1.3 g of BHT , 1.3 g of titanium oxide and 0.025 g of yellow ferric oxide in 25 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 6)
The ramelteon-containing core tablets were placed in a film coating device (HiCoater HC-LABO, manufactured by Freund Corporation), and 18.8 g of hypromellose having a weight-average molecular weight of 32,800 and 3.8 g of triethyl citrate were dissolved in 200 g of water, and a solution of 2.5 g of titanium oxide suspended in 50 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 7)
The ramelteon-containing core tablets were placed in a film coating device (HiCoater HC-LABO, manufactured by Freund Corporation), and 21.3 g of hypromellose having a weight-average molecular weight of 32,800 and 3.8 g of triethyl citrate were dissolved in 232.5 g of water, and a solution prepared by suspending 0.05 g of yellow ferric oxide in 50 g of water was sprayed onto the solution and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Comparative Example 8)
The ramelteon-containing core tablets were placed in a film coating device (HiCoater HC-LABO, manufactured by Freund Corporation), and a solution of 21.3 g of hypromellose having a weight-average molecular weight of 32,800 and 3.8 g of triethyl citrate dissolved in 282.5 g of water was sprayed onto and dried to obtain coated tablets containing ramelteon with a mass of 135 mg.

(Test Example 2)
The ramelteon-containing coated tablets obtained in Example 1, Example 2, Comparative Example 2, and Comparative Examples 6 to 8 were each placed in a glass bottle, sealed and stored at 70°C, and the total amount of decomposition products generated at the start of storage, after 60 hours of storage, and after 130 hours of storage was determined by high performance liquid chromatography. The results are shown in Table 2.

The total amount of decomposition products after storage was small for the ramelteon-containing coated tablet of Example 1, in which hypromellose was coated with titanium oxide and yellow ferric oxide. On the other hand, the total amount of decomposition products after storage was large for the ramelteon-containing coated tablet of Comparative Example 2, in which hypromellose and triethyl citrate were coated with titanium oxide and yellow ferric oxide, compared with Example 1. The total amount of decomposition products after storage was small for the ramelteon-containing coated tablet of Comparative Example 8, in which only hypromellose and triethyl citrate were coated, compared with Comparative Example 2. In addition, the total amounts of decomposition products for the ramelteon-containing coated tablets of Comparative Example 6, in which hypromellose and triethyl citrate were coated with titanium oxide, and Comparative Example 7, in which hypromellose and triethyl citrate were coated with yellow ferric oxide, were larger than those of Comparative Example 8 and smaller than those of Comparative Example 2, respectively.

From the above results, it was suggested that the generation of decomposition products in the ramelteon-containing coated tablets is largely influenced by the plasticizer triethyl citrate, but that triethyl citrate is not the only cause, and that the colorants titanium oxide and yellow ferric oxide are also synergistically involved. In addition, the types and characteristics of the decomposition products of the ramelteon-containing coated tablets in these comparative examples during storage were almost identical to the decomposition products obtained when azobisisobutyronitrile (AIBN), which is used as a radical initiator in forced decomposition tests for pharmaceuticals, was added to ramelteon, as shown in Figure 2. Therefore, it was inferred that the main decomposition mechanism of the above ramelteon-containing coated tablets is due to radical reactions.

Therefore, in Example 2, BHT was further added as a radical scavenger to the coating components containing hypromellose, triethyl citrate, titanium oxide, and yellow ferric oxide, and coating was performed. As a result, it was found that the decomposition products of the ramelteon-containing coated tablet were greatly reduced by the addition of BHT, which led to the completion of the present invention.

The present invention provides a coated tablet containing ramelteon which is of good quality, having excellent uniformity of the active ingredient, storage stability and appearance.

Claims (7)

A core tablet containing ramelteon,
1) Hypromellose , and
2) A method for producing a coated tablet containing ramelteon, comprising coating the tablet with a coating component containing a colorant selected from the group consisting of titanium oxide and yellow ferric oxide,
The method includes a step of coating a core tablet containing ramelteon with a coating liquid containing hypromellose having a weight average molecular weight of 30,000 to 40,000 at a concentration of 9 w/w% or less based on water,
The mass of titanium oxide relative to the mass of hypromellose is 11 to 16 w/w%, and the mass of yellow ferric oxide relative to the mass of hypromellose is 0.2 to 0.4 w/w%, and
A manufacturing method in which the coating components do not contain plasticizers. The method for producing coated tablets according to claim 1, in which the total amount of decomposition products increased by 0.1% or less when the coated tablets are stored at 70°C for 130 hours. A core tablet containing ramelteon;
1) Hypromellose,
2) one or more colorants selected from the group consisting of titanium oxide and yellow ferric oxide ;
3) Triethyl citrate, and
4) Dibutylhydroxytoluene
and a coating layer comprising the compound. The coated tablet according to claim 3 , wherein the amount of dibutylhydroxytoluene added is 0.6 to 0.7 w/w % relative to the amount of triethyl citrate added. The coated tablet according to claim 3 or 4 , wherein the weight average molecular weight of hypromellose is 30,000 to 40,000. The coated tablet according to claim 5 , wherein the mass of titanium oxide relative to the mass of hypromellose is 11 to 16 w/w%, and the mass of yellow ferric oxide relative to the mass of hypromellose is 0.2 to 0.4 w/w%. 7. The coated tablet according to claim 3, wherein when the coated tablet is stored at 70°C for 130 hours, the total amount of decomposition products increased is 0.1% or less.