WO2018021416A1

WO2018021416A1 - Methotrexate-containing film coated tablet

Info

Publication number: WO2018021416A1
Application number: PCT/JP2017/027066
Authority: WO
Inventors: 憲志片岡
Original assignee: 日本臓器製薬株式会社
Priority date: 2016-07-27
Filing date: 2017-07-26
Publication date: 2018-02-01
Also published as: JPWO2018021416A1; TWI728156B; CN109475557A; JP7060878B2; CN109475557B; TW201808296A

Abstract

The purpose of the present invention is to provide a tablet whereby misrecognition can be prevented by having a different color for each content specification while preventing light-induced content reduction and generation of analogs of methotrexate as an active ingredient. The present invention provides a methotrexate tablet in which iron oxide is containing in a film coating layer and an uncoated tablet, whereby light-induced content reduction and generation of analogs of methotrexate as the active ingredient are suppressed. The photostability of the methotrexate tablet can be secured even by a light color, and a different color can therefore be imparted for each content specification. The present invention is therefore highly useful for drug management in a medical setting or in drug storage or the like at the home of a patient.

Description

Film-coated tablets containing methotrexate

The present invention relates to a film-coated tablet containing methotrexate and having improved light stability.

Methotrexate, which is an anti-rheumatic drug, has become a first-line drug for the treatment of rheumatism because it has sufficient arthritis and joint destruction suppression effects but rarely causes serious side effects. However, methotrexate is subject to degradation when the amount of exposure is high, increasing the number of harmful related substances and reducing the efficacy as an active substance. Due to the light instability of methotrexate, it has been necessary for oral solid preparations containing methotrexate to have a formulation technique for ensuring stability to light or to be stored in the dark.

Conventionally, various methods for improving the stability of drugs are known for the formulation of drugs that are unstable to light. For example, Patent Document 1 discloses a capsule preparation in which active vitamin D3s are stabilized by a hard capsule containing a tar pigment or Bengala. In addition, methotrexate-containing capsules sold in Japan do not particularly require light-shielding storage. The formulation technique used for that purpose is to contain a colorant in the capsule film covering the drug unstable to light. However, this technology is difficult to apply to tablets. For this reason, all tablets containing methotrexate as an active ingredient sold in Japan are required to be protected from light. For these reasons, there is a demand for the development of tablets that do not require light-shielding storage from the viewpoint of ease of administration and ease of storage at medical sites and patient homes.

As a tablet light stability technique, Patent Document 2 discloses a tablet containing a dihydropyridine derivative coated with a film containing iron oxide, and Patent Document 3 discloses a tablet containing aranidipine to titanium oxide, trioxide. Tablets stabilized against light by coating a film containing iron and yellow ferric oxide are disclosed respectively. However, with regard to methotrexate, there is no prior art document disclosing a tablet that has secured sufficient light stability so that shading storage is not required only by such a film coating technique. Further, when the amount of film coating is increased so as to ensure light stability, workability is deteriorated in actual production. Moreover, since the color of a tablet will become close to black when the compounding quantity of the iron oxide with a high effect as a coating agent is increased too much, the problem that it is not preferable in appearance arises. Therefore, in the development, it is desired that the tablet has good workability in actual production and ensures light stability even in a light color system.

By the way, the method of taking methotrexate preparations for the treatment of rheumatoid arthritis in Japan is to take 6 mg once a week or divided into 2 to 3 times, and the dose has been increased up to 16 mg per week. Yes. On the other hand, in Europe, the United States, and Asian countries, up to 25 mg per week can be used if necessary. In Japan, only 2 mg formulation 1 standard is sold, and the dosage form is capsule and caplet. The capsules do not need to be protected from light, but they have a drawback that they are bulky and difficult to take. Especially when the daily dose is increased, the number of capsules increases, which is a burden on the patient. On the other hand, caplets have the advantage of being easier to take than capsules, but have the disadvantage of having to be stored protected from light. Therefore, it is desired to develop a tablet that is easy to take and does not require light-shielding storage. Furthermore, the development needs for high-content tablets are also considered high from the viewpoint of reducing the burden of dose.

When developing tablets with lower or higher content than the conventional content (hereinafter also referred to as “content” where appropriate, the meaning is the same), prevent mistakes in the medical field and prevent the patient from taking the wrong dose Therefore, one measure is to make tablets of different colors for each content standard. At that time, all methotrexate preparations sold in Japan are yellow 2 mg capsules or caplets. Therefore, about the tablet of 2 mg specification newly marketed, it is preferable from a viewpoint of incorrect prescription prevention that it is yellow or a color close | similar to this. However, as described above, methotrexate preparations are difficult to ensure light stability only by ordinary film coating. However, if you add a lot of highly light-shielding iron oxide to the film layer, not only will it look black and the appearance will deteriorate, but it will also have a clearly different color for each content standard tablet It becomes difficult. Therefore, there is a need for a technique that can ensure light stability even for light-colored tablets.

As another light stabilization method, Patent Document 4 discloses a composition having improved light stability, which is obtained by blending one or more substances selected from yellow and red colorants with a light-soluble fat-soluble drug. Although disclosed, there is no mention of light stable tablets containing methotrexate.

JP-A-4-46122 JP 2003-104888 A JP 2003-104887 A Japanese Patent Laid-Open No. 2000-7583

The problem to be solved by the present invention is to provide a tablet that prevents the content of methotrexate, which is an active ingredient, from being reduced by light and the generation of related substances. Moreover, it is providing the tablet which can prevent misidentification by becoming a different color for every content specification.

The chemical name of methotrexate is N- [4 [(2,4-diaminopteridin-6-ylmethyl) (methyl) amino] benzoyl] -L-glutamic acid. Methotrexate is a yellow-brown crystalline powder that changes gradually with light. Therefore, it is stipulated that it should be protected from light when stored (17th revision Japanese Pharmacopoeia).

In the light stability test using film-coated tablets containing 1 mg, 2 mg, and 4 mg of methotrexate, the present inventor has no exposure with an exposure dose of 1.2 million lx · hr or more when iron oxide is added to the film coating layer. Less than 3%, which is the standard for “no change” in the “tablet stability test without tablets / capsules” (reported by the Japan Hospital Pharmacists Association) (hereinafter “Japan Hospital Pharmacists Association standards”) Value)). However, when iron oxide was not blended in the film coating layer but only titanium oxide was blended, the result was that the decrease in methotrexate content in the 4 mg tablet exceeded the above standard. Therefore, the 4mg tablet with increased titanium oxide in the coating layer and the 4mg tablet with the coating layer containing iron oxide (iron sesquioxide, yellow sesquioxide), the most effective light-shielding effect of the 1mg and 2mg tablets, were again used. The sample was subjected to a photostability test. As a result, no improvement in the light-shielding effect was observed in the preparation in which the amount of titanium oxide in the coating layer was increased. On the other hand, in the preparation in which iron oxide was blended in the coating layer, the content reduction was as good as 0.7%. From these results, it was suggested that titanium oxide was ineffective in suppressing photodegradation of methotrexate and iron oxide was effective.

Purity tests were conducted on the above 1 mg tablets, 2 mg tablets and 4 mg tablets satisfying the standard of less than 3% content reduction in an unwrapped (naked tablet) state with an exposure dose of 1.2 million lx · hr or more. As a result, the formation of related substances was suppressed for 4 mg tablets, but for 1 mg tablets and 2 mg tablets, the relatedness exceeded the USP drug substance standard of 0.3% (hereinafter referred to as “USP reference value”). Increased material was observed. In addition, in the 2 mg tablet, an unknown peak exceeding 0.2% (hereinafter referred to as “reference value of impurity guideline”), which is a threshold value required to determine the structure shown in the impurity guideline, was also observed. Therefore, the formulation was examined so that the increase in related substances could be suppressed in all three content-standard tablets.

In previous studies, it was found that the inclusion of iron oxide in the coating layer has the effect of suppressing the photodecomposition of methotrexate. However, in order to suppress the formation of methotrexate-related substances, the usual coating amount is insufficient, and the amount of iron oxide in the coating layer must be added more than usual, and the tablet color must be darkened to enhance the effect. There was thought to be. However, when the coating amount is increased, workability is deteriorated in actual production, and when the amount of iron oxide in the coating agent is increased, the color of the tablet approaches black, resulting in an unfavorable appearance. In addition, it is necessary to ensure light stability even if the color of the tablet does not become close to black in order to make all three content standards different colors in order to prevent confusion in the medical field. there were. In particular, in the 2 mg tablet which is the same standard as the original drug, it was considered preferable that it should not deviate significantly from the yellow color which is similar to it.

Therefore, without increasing the amount of iron oxide in the film coating layer, a film-coated tablet containing iron oxide in the uncoated tablet was prepared and subjected to a photostability test. As a result, surprisingly, it was possible to suppress the generation of related substances by exposure to light below the standard while maintaining a normal coating amount that does not affect the work efficiency in actual production while being light in color. Furthermore, all three content-standard tablets could be of different colors, and the 2 mg tablet could be a pale yellow similar to the previous one. As described above, the present inventor completed the present invention as a result of intensive studies for solving the above problems.

That is, the present invention comprises the following aspects.
(1) A film-coated tablet containing methotrexate as an active ingredient and containing iron oxide in an uncoated tablet and a film coating layer.
(2) The film-coated tablet according to the above (1), wherein the iron oxide contained in the uncoated tablet is at least one selected from ferric oxide, yellow ferric oxide and black ferric oxide.
(3) The film-coated tablet according to (2) above, wherein the iron oxide contained in the uncoated tablet is iron sesquioxide.
(4) The film-coated tablet according to any one of (1) to (3) above, wherein the amount of iron oxide contained in the uncoated tablet is 0.05 to 1.5% by weight based on the total amount of the uncoated tablet.
(5) The film-coated tablet according to any one of (1) to (3) above, wherein the amount of iron oxide contained in the uncoated tablet is 0.075 to 1% by weight based on the total amount of the uncoated tablet.
(6) The film-coated tablet according to any one of (1) to (3) above, wherein the amount of iron oxide contained in the uncoated tablet is 0.1 to 0.3% by weight based on the total amount of the uncoated tablet.
(7) The film-coated tablet according to any one of the above (1) to (6), wherein the iron oxide in the film coating layer is at least one selected from iron sesquioxide, yellow sesquioxide and black iron oxide.
(8) The film-coated tablet according to any one of (1) to (7), wherein the content of iron oxide in the film coating layer is 0.1 to 20% by weight based on the total amount of the film coating layer.
(9) The film-coated tablet according to any one of the above (1) to (7), wherein the content of iron oxide in the film coating layer is 0.5 to 15% by weight based on the total amount of the film coating layer.
(10) The film-coated tablet according to any one of (1) to (7), wherein the content of iron oxide in the film coating layer is 1 to 10% by weight based on the total amount of the film coating layer.
(11) The film-coated tablet according to (7), wherein the content of yellow ferric oxide in the film coating layer is 0.005 to 10% by weight with respect to the total amount of the film coating layer.
(12) The film-coated tablet according to (7), wherein the content of yellow ferric oxide in the film coating layer is 0.01 to 5% by weight with respect to the total amount of the film coating layer.
(13) The film-coated tablet according to (7), wherein the content of yellow ferric oxide in the film coating layer is 0.01 to 4% by weight based on the total amount of the film coating layer.
(14) The film-coated tablet according to any one of (11) to (13), wherein the content of iron sesquioxide in the film coating layer is 0.01 to 20% by weight based on the total amount of the film coating layer.
(15) The film-coated tablet according to any one of (11) to (13), wherein the content of iron sesquioxide in the film coating layer is 0.05 to 10% by weight based on the total amount of the film coating layer.
(16) The film-coated tablet according to any one of (11) to (13), wherein the content of iron sesquioxide in the film coating layer is 0.1 to 7% by weight based on the total amount of the film coating layer.
(17) The film-coated tablet according to any one of (11) to (16) above, wherein the content of black iron oxide in the film coating layer is 0.01 to 5% by weight based on the total amount of the film coating layer.
(18) The film-coated tablet according to any one of (11) to (16) above, wherein the content of black iron oxide in the film coating layer is 0.05 to 3% by weight based on the total amount of the film coating layer.
(19) The film-coated tablet according to any one of (11) to (16) above, wherein the content of black iron oxide in the film coating layer is 0.1 to 1% by weight based on the total amount of the film coating layer.
(20) The film-coated tablet according to the above (7), wherein the iron oxide in the film coating layer is yellow ferric oxide and ferric oxide.
(21) The film-coated tablet according to the above (20), wherein the content of yellow ferric oxide in the film coating layer is 0.1 to 10% by weight based on the total amount of the film coating layer.
(22) The film-coated tablet according to the above (20), wherein the content of yellow ferric oxide in the film coating layer is 0.3 to 5% by weight based on the total amount of the film coating layer.
(23) The film-coated tablet according to the above (20), wherein the content of yellow ferric oxide in the film coating layer is 0.5 to 3% by weight based on the total amount of the film coating layer.
(24) The film-coated tablet according to any one of the above (20) to (23), wherein the content of iron sesquioxide in the film coating layer is 0.01 to 10% by weight based on the total amount of the film coating layer.
(25) The film-coated tablet according to any one of the above (20) to (23), wherein the content of iron sesquioxide in the film coating layer is 0.05 to 5% by weight based on the total amount of the film coating layer.
(26) The film-coated tablet according to any one of the above (20) to (23), wherein the content of iron sesquioxide in the film coating layer is 0.1 to 1% by weight based on the total amount of the film coating layer.
(27) The film-coated tablet according to (7), wherein the iron oxide in the film coating layer is only yellow ferric oxide.
(28) The film-coated tablet according to (27), wherein the content of yellow ferric oxide in the film coating layer is 0.1 to 10% by weight based on the total amount of the film coating layer.
(29) The film-coated tablet according to (27), wherein the content of yellow ferric oxide in the film coating layer is 0.5 to 5% by weight based on the total amount of the film coating layer.
(30) The film-coated tablet according to the above (27), wherein the content of yellow ferric oxide in the film coating layer is 1 to 4% by weight based on the total amount of the film coating layer.
(31) The film-coated tablet according to the above (7), wherein the iron oxide in the film coating layer is yellow ferric oxide, ferric oxide and black iron oxide.
(32) The film-coated tablet according to the above (31), wherein the content of yellow ferric oxide in the film coating layer is 0.005 to 1% by weight based on the total amount of the film coating layer.
(33) The film-coated tablet according to the above (31), wherein the content of yellow ferric oxide in the film coating layer is 0.01 to 0.5% by weight based on the total amount of the film coating layer.
(34) The film-coated tablet according to the above (31), wherein the content of yellow ferric oxide in the film coating layer is 0.01 to 0.1% by weight relative to the total amount of the film coating layer.
(35) The film-coated tablet according to any one of (31) to (34) above, wherein the content of iron sesquioxide in the film coating layer is 0.1 to 20% by weight based on the total amount of the film coating layer.
(36) The film-coated tablet according to any one of the above (31) to (34), wherein the content of iron sesquioxide in the film coating layer is 1 to 10% by weight based on the total amount of the film coating layer.
(37) The film-coated tablet according to any one of (31) to (34) above, wherein the content of iron sesquioxide in the film coating layer is 2 to 7% by weight based on the total amount of the film coating layer.
(38) The film-coated tablet according to any one of (31) to (37) above, wherein the content of black iron oxide in the film coating layer is 0.01 to 5% by weight relative to the total amount of the film coating layer.
(39) The film-coated tablet according to any one of (31) to (37) above, wherein the content of black iron oxide in the film coating layer is 0.05 to 3% by weight based on the total amount of the film coating layer.
(40) The film-coated tablet according to any one of (31) to (37) above, wherein the content of black iron oxide in the film coating layer is 0.1 to 1% by weight relative to the total amount of the film coating layer.
(41) The film-coated tablet according to any one of (1) to (40) above, wherein the content of methotrexate is 0.3 to 5% by weight in 100% by weight of the uncoated tablet.
(42) The film-coated tablet according to any one of (1) to (41), further comprising an excipient.
(43) The film-coated tablet according to any one of (1) to (42), wherein the weight of the film-coated layer is 1 to 20% by weight based on the total weight of the film-coated tablet.
(44) The film-coated tablet according to any one of (1) to (42), wherein the weight of the film-coated layer is 2 to 10% by weight based on the total weight of the film-coated tablet.
(45) The film-coated tablet according to any one of (1) to (42), wherein the weight of the film-coated layer is 4 to 8% by weight based on the total weight of the film-coated tablet.
(46) The film-coated tablet according to any one of (1) to (45) above, wherein 1 mg of methotrexate is contained in one tablet.
(47) The film-coated tablet according to any one of (1) to (45) above, wherein 2 mg of methotrexate is contained in one tablet.
(48) The film-coated tablet according to any one of (1) to (45) above, wherein 4 mg of methotrexate is contained in one tablet.
(49) The film-coated tablet according to any one of (1) to (48) above, which has a diameter of 6.5 mm to 7.5 mm and a thickness of 3.0 mm to 4.0 mm.
(50) The film-coated tablet according to any one of (1) to (49), wherein the weight is 130 to 170 mg.

According to the present invention, methotrexate-containing film-coated tablets that do not require light-shielding storage can be provided because the methotrexate content hardly decreases even when exposed to light, and the production of related substances is small. Moreover, it can also be made into a light-colored color that is preferable in appearance, and can be made into tablets having different colors for each content standard so that it is possible to prevent erroneous formulation or taking of tablets having different methotrexate contents.

The methotrexate-containing film-coated tablet of the present invention (hereinafter, sometimes referred to simply as “the tablet”) includes an active ingredient methotrexate and iron oxide in an uncoated tablet portion, and iron oxide is further contained in the film coating layer. It is characterized by including.

As iron oxide contained in the uncoated tablet part of this tablet, iron sesquioxide, yellow iron sesquioxide, black iron oxide, etc. can be used. These iron oxides can be combined, but iron trioxide is particularly preferred. Iron sesquioxide is a compound represented by the characteristic formula Fe ₂ O ₃ . That is, in this specification, the term “iron sesquioxide” does not include yellow iron sesquioxide (Fe ₂ O ₃ .H ₂ O).

The content of iron oxide in the uncoated tablet is not particularly limited, but is usually 0.05 to 1.5% by weight, preferably 0.075 to 1% by weight, particularly preferably 0.1 to 0.1% by weight based on the total amount of the uncoated tablet. The range can be 0.3% by weight %%. If the content of iron oxide in the uncoated tablet is less than the above range, the photostability of methotrexate may not be sufficiently obtained, which is not preferable. Moreover, when content of iron oxide exceeds the said range, the color of a tablet may become unpreferable for a user.

The weight ratio of the film coating layer to the total amount of the film-coated tablet is not particularly limited, but can be usually in the range of 1 to 20% by weight, preferably 2 to 10% by weight, particularly preferably 4 to 8% by weight. When the weight of the film coating layer is less than the above range, the light stability improving effect of methotrexate may not be sufficiently obtained. On the other hand, when the weight of the film coating layer exceeds the above range, the coating time becomes long and workability is poor in actual production. Moreover, the color of a tablet may become unpreferable for a user.

As iron oxide contained in the film coating layer of this tablet, iron sesquioxide, yellow iron sesquioxide, black iron oxide, etc. can be used, and can be used alone or in combination depending on the target color. It is. A premix film coating agent containing iron oxide can also be used as a commercial product.

The content of iron oxide in the film coating layer is not particularly limited, but is usually 0.1 to 20% by weight, preferably 0.5 to 15% by weight, particularly preferably 1 to 10% by weight based on the total amount of the film coating layer. % Range. The content of yellow iron sesquioxide used alone or in combination with other iron oxides is not particularly limited, but is usually 0.005 to 10% by weight, preferably 0.01 to 5% by weight, particularly preferably. It can be in the range of 0.01 to 4% by weight. The content when iron sesquioxide is used alone or in combination with other iron oxides is not particularly limited, but is usually 0.01 to 20% by weight, preferably 0.05 to 10% by weight, particularly preferably 0. It can be in the range of 1-7% by weight. The content when black iron oxide is used alone or in combination with other iron oxides is not particularly limited, but is usually 0.01 to 5% by weight, preferably 0.05 to 3% by weight, particularly preferably 0. The range may be from 1 to 1% by weight.

The content when yellow ferric oxide and ferric oxide are used in combination in the film coating layer is not particularly limited, but yellow ferric oxide is usually 0.1 to 10% by weight, preferably based on the total amount of the film coating layer. Is in the range of 0.3 to 5% by weight, particularly preferably 0.5 to 3% by weight, and iron sesquioxide is usually 0.01 to 10% by weight, preferably 0.05 to 5% by weight, particularly preferably. Each can be in the range of 0.1 to 1% by weight.

The content in the case where only yellow iron sesquioxide is used for the film coating layer is not particularly limited, but is usually 0.1 to 10% by weight, preferably 0.5 to 5% by weight, particularly with respect to the total amount of the film coating layer. Preferably, it can be in the range of 1 to 4% by weight.

The content when yellow iron sesquioxide, iron sesquioxide and black iron oxide are used in combination in the film coating layer is not particularly limited, but yellow iron sesquioxide is usually 0.005-1 to the total amount of the film coating layer. In the range of wt%, preferably 0.01 to 0.5 wt%, particularly preferably 0.01 to 0.1 wt%, iron sesquioxide is usually 0.1 to 20 wt%, preferably 1 to 10 wt%. The iron oxide is usually in the range of 0.01 to 5% by weight, preferably 0.05 to 3% by weight, particularly preferably 0.1 to 1% by weight. You can do each.

Methotrexate decomposes due to light exposure and produces related substances. As a result, the methotrexate content in the drug composition is reduced. However, the presence of iron oxide in both the uncoated tablet and the film coating layer of the film-coated tablet containing methotrexate significantly suppresses the production of related substances due to light exposure. In particular, iron sesquioxide has the highest effect among iron oxides. By containing iron sesquioxide in both the film coating layer and the uncoated tablet, a sufficient light stability improving effect of methotrexate is exhibited.

The film-coated tablet of the present invention may contain a conventional carrier component or additive in the uncoated tablet unless the effects of the present invention are impaired. Carrier components or additives include excipients, disintegrants, binders, lubricants, antioxidants, preservatives, solubilizers, surfactants, fluidizers, plasticizers, pH adjusters, colorants Examples include flavoring agents, sweetening agents, flavoring agents, adsorbents, preservatives, wetting agents and the like. These carrier components or additives can be used alone or in combination of two or more.

Examples of excipients include sugar alcohols (D-sorbitol, erythritol, xylitol, powdered reduced maltose starch syrup, etc.), sugars (lactose, glucose, fructose, sucrose, etc.) and hydrates thereof, crystalline cellulose, powdered cellulose, starch (Potato starch, corn starch, wheat starch, etc.), dextrin, β-cyclodextrin, carmellose sodium, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, Examples thereof include titanium oxide, calcium lactate, magnesium aluminate metasilicate, synthetic hydrotalcite, talc, and kaolin.

Examples of the disintegrant include carboxymethyl celluloses (for example, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crystalline cellulose / carmellose sodium, etc.), carboxymethyl starches (for example, carboxymethyl starch sodium, etc.) Crospovidone, low substituted hydroxypropylcellulose, low substituted hydroxymethyl starch sodium, starches (such as corn starch), alginic acid, bentonite and the like. Preferably, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, carmellose sodium, carmellose calcium, carmellose, crystalline cellulose / carmellose sodium, low-substituted hydroxymethyl starch sodium . More preferable examples include low-substituted hydroxypropylcellulose, carmellose calcium, croscarmellose sodium, and sodium carboxymethyl starch. These disintegrants may be used alone or in any combination of two or more.

Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, polyethylene glycol, dimethylpolysiloxane, carnauba wax, sodium lauryl sulfate, beeswax and beeswax wax it can. These lubricants can be used alone or in combination of two or more. Of these lubricants, stearates such as magnesium stearate are widely used.

Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like.

Hereinafter, the present invention will be specifically described, but the present invention is not limited thereto.

The relationship between the type and content of iron oxide in the film coating layer and the formation of related substances when the obtained tablets were exposed to light was examined. The results are shown in Tables 2-9. This will be described below.
Formula No. shown in Table 2 1-No. According to No. 3, weigh out 0.2 kg of methotrexate, 3.58 kg of crystalline cellulose, 2.00 kg of corn starch, 7.47 kg of lactose hydrate, 0.87 kg of croscarmellose sodium and 0.03 kg of iron sesquioxide for 2 mg tablets. It was. The weighed powder was put into a high-speed agitation granulator (FG-GS-50, Fukae Pautech) and premixed. To the mixed powder, 2.00 kg of purified water was added, granulated with stirring, and dried using a fluidized bed dryer (2011-141, Jeil Machine). The size was adjusted using an oscillator sizer to obtain 14.15 kg of granules. The obtained granules were put into a double cone mixer (SY-M, BOSEONG machine), 0.10 kg of light anhydrous silicic acid and 0.25 kg of magnesium stearate were added and mixed to obtain granules. For the 1 mg tablet, among the methods for producing the 2 mg tablet, granules were obtained in the same manner with a methotrexate content of 0.1 kg and a lactose hydrate content of 7.57 kg. For the 4 mg tablet, among the methods for producing the 2 mg tablet, granules were obtained in the same manner with methotrexate content of 0.4 kg and lactose hydrate content of 7.27 kg.

The 1 mg tablet, 2 mg tablet and 4 mg tablet uncoated tablet were used with a rotary tableting machine (HT-P22-A-3, Hata Iron Works) using a 7.0 mm diameter mortar and kin. A 50 kg uncoated tablet was produced.

Table 2 Example Nos. 1-No. As shown in 3, as a film coating solution, 1 mg tablet was formulated with yellow ferric oxide and ferric oxide, 2 mg tablet was blended with only yellow ferric oxide, and 4 mg tablet was treated with yellow sesquioxide. The ones containing iron, iron sesquioxide and black iron oxide were used. 14.50 kg of uncoated tablets were put into a coating apparatus and coated to a prescribed amount. After drying, film-coated tablets (weight 155 mg, diameter 7.0 mm, thickness 3.5 mm) containing 1 mg, 2 mg, and 4 mg of methotrexate in one tablet were obtained.

(Comparative Examples 1 to 3)
As shown in Comparative Examples 1 to 3 (Formulation No. 4 to No. 18) in Tables 4, 6 and 8, no iron sesquioxide was added to the uncoated tablet part, and the type and amount of iron oxide in the film coating layer were determined. A film-coated tablet containing methotrexate was obtained in the same manner as in the Examples except that the amount of other additives was finely adjusted.

(Light stability test)
The light stability test of the film-coated tablets obtained in Examples and Comparative Examples was performed under the following conditions. Each film-coated tablet is uniformly placed on a petri dish, and the integrated illuminance is 1.25 million lx · hr or more in a constant temperature and humidity chamber maintained at 25 ° C. and 60% RH for 15 days at 3500 lx or 13 days at 4000 lx Irradiated so that

(Quantitative test)
After the light exposure, a sample solution was prepared according to the method of JP, and the content of the solution was measured by measuring the peak area of methotrexate by liquid chromatography. The results are shown in Tables 3, 5, 7, and 9. In Comparative Example 1, a film coating layer containing no titanium oxide but containing only titanium oxide. In 6 and 7, the decrease in methotrexate content exceeded 3%, the standard value of the Japan Hospital Pharmacists Association. On the other hand, for the other formulations (No. 4, 5, 8-9 and 11-18) in which iron oxide was blended in the film coating, the decrease in content was below the same reference value. The test conditions are as follows.
〔Test conditions〕
Detector: UV absorptiometer (measurement wavelength: 302 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography (for example, Wakopak (registered trademark) Wakosil-II5C18HG manufactured by Wako Pure Chemical Industries, Ltd.).
Column temperature: Constant temperature around 25 ° C. Mobile phase: Anhydrous sodium dihydrogen phosphate (6.00 g) is dissolved in water, and adjusted to pH 6.0 by adding sodium hydroxide reagent to 1000 mL. 110 mL of acetonitrile is added to 890 mL of this solution.
Flow rate: 1.0 mL per minute

(Purity test)
After exposure to light, the sample stock solution for the quantitative test was filtered through a membrane filter with a pore size of 0.45 μm or less according to the Japanese Pharmacopoeia. Excluding the first filtrate of 1 mL or more, The mobile phase of the quantitative method was added so that a solution containing about 0.2 mg of methotrexate in 1 mL was used as a sample solution. The production amounts of related substances B, C and E were measured by liquid chromatography.
Related substance B is chemical name (S) -2- [4-[(2,4-diaminopteridin-6-yl) methylamino] benzamide] pentandionic acid, which is reproductive toxic and suspected to be carcinogenic. It is a substance.
The related substance C has the chemical name (S) -2- (4-[[(2-amino-4-oxo-1,4-dihydropteridin-6-yl) methyl] (methyl) amino] benzamide) pentandionic acid It is.
The related substance E is the chemical name 4-[[((2,4-diaminopteridin-6-yl) methyl] (methyl) amino] benzoic acid, which is a substance that may cause an allergic skin reaction.
The measurement results are shown in Tables 3, 5, 7, and 9. The test conditions are as described below.
Formulation No. 1 of Comparative Example 1 In 4 to 6 and 8, one or more unknown peaks with any related substance having a USP reference value of 0.3% or more or a impurity guideline reference value of 0.2% or more were observed.
Formulation No. 2 of Comparative Example 2 Similarly, in 9 and 10, one or more unknown peaks with any related substance having a USP reference value of 0.3% or more or an impurity guideline reference value of 0.2% or more were observed. In addition, prescription No. No. 11 was able to ensure light stability without containing iron oxide in the uncoated tablet, but it was evaluated that the coating layer was thick and the workability in actual production was poor. In Comparative Example 2, the light stability could be ensured with two standards (prescription Nos. 12 to 15) of 2 mg tablets and 4 mg tablets, and different colors could be obtained, but the 1 mg tablets did not meet the standards.
The prescription No. of Comparative Example 3 In the case of 16-18, light stability was ensured without containing iron oxide in the uncoated tablets, but all of them had an orange-like appearance and could not have different colors for each standard.
〔Test conditions〕
Detector: UV absorptiometer (measurement wavelength 280 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography (for example, Wakopak (registered trademark) Wakosil-II5C18HG manufactured by Wako Pure Chemical Industries, Ltd.).
Column temperature: Phosphate buffer solution at a constant temperature of around 6.0 ° C. pH 6.0: Anhydrous sodium dihydrogen phosphate (3.40 g) was dissolved in water, and 1000 mL was added to the solution to a pH of 6.0 by adding a sodium hydroxide test solution. adjust.
Mobile phase A: acetonitrile / pH 6.0 phosphate buffer mixture (1:19)
Mobile phase B: acetonitrile / pH 6.0 phosphate buffer mixture (1: 1)
Transfer of mobile phase: Concentration control is performed by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1.

Table 10 shows the relationship between the type and amount of iron oxide in the uncoated tablet and the related substances when the obtained uncoated tablet was exposed to light.
Compared with [1] which does not use iron oxide at all, [2] to [4] using any iron oxide could suppress the increase of related substances.
Compared with iron oxide [2] using iron sesquioxide alone [3], using iron sesquioxide alone [3], and combining iron sesquioxide and yellow sesquioxide [4]. A low percentage increase in related substances was obtained. Also, regarding the number of unknown peaks of 0.2% or more and 0.5% or more, [2] using iron sesquioxide alone was the least. From this, it was found that the photostability of methotrexate can be improved by using iron sesquioxide alone in the uncoated tablet. Further, it was shown that the amount of iron sesquioxide to be added should be about 0.2 to 0.4 mg (0.1 to 0.3% by weight with respect to the whole uncoated tablet).

From the above results, the methotrexate-containing film-coated tablets produced in the examples were able to suppress the decrease in methotrexate content due to light exposure to a reference value or less by blending iron oxide in the film coating layer. In addition, even when a light-colored appearance is selected depending on the selection and content of iron oxide in the film coating layer, the reduction of methotrexate content can be suppressed and the production of related substances can be controlled by blending iron oxide into the uncoated tablet. The number of unknown peaks could be reduced. Furthermore, 1 mg tablets, 2 mg tablets, and 4 mg tablets could have different colored appearances.

The methotrexate-containing film-coated tablet according to the present invention does not require light-shielding storage because the decrease in the content of active ingredients and the increase in related substances can be suppressed below the reference value even after exposure to light. Moreover, since a different color can be given for each content standard, it is possible to ensure the identifiability for patients and medical personnel, and the convenience is high.

Claims

A film-coated tablet containing methotrexate as an active ingredient and containing iron oxide in an uncoated tablet and a film coating layer.
The film-coated tablet according to claim 1, wherein the iron oxide contained in the uncoated tablet is at least one iron oxide selected from iron sesquioxide, yellow iron sesquioxide and black iron oxide.
The film-coated tablet according to claim 2, wherein the iron oxide contained in the uncoated tablet is iron sesquioxide.
The film-coated tablet according to any one of claims 1 to 3, wherein the iron oxide contained in the uncoated tablet is 0.05 to 1.5% by weight based on the total amount of the uncoated tablet.
The film-coated tablet according to any one of claims 1 to 4, wherein the iron oxide in the film coating layer is at least one selected from iron sesquioxide, yellow iron sesquioxide and black iron oxide.
The film-coated tablet according to any one of claims 1 to 5, wherein the content of iron oxide in the film coating layer is 0.1 to 20% by weight based on the total amount of the film coating layer.
The film-coated tablet according to claim 5 or 6, wherein the content of yellow ferric oxide in the film coating layer is 0.005 to 10% by weight based on the total amount of the film coating layer.
The film-coated tablet according to any one of claims 5 to 7, wherein the content of iron sesquioxide in the film coating layer is 0.01 to 20% by weight based on the total amount of the film coating layer.
The film-coated tablet according to any one of claims 5 to 8, wherein the content of black iron oxide in the film coating layer is 0.01 to 5% by weight based on the total amount of the film coating layer.
The film-coated tablet according to claim 5 or 6, wherein the iron oxide in the film coating layer is yellow ferric oxide and ferric oxide.
The film-coated tablet according to claim 10, wherein the yellow iron sesquioxide in the film coating layer is 0.1 to 10% by weight based on the total amount of the film coating layer.
The film-coated tablet according to claim 10 or 11, wherein the content of iron sesquioxide in the film coating layer is 0.01 to 10% by weight based on the total amount of the film coating layer.
The film-coated tablet according to claim 5 or 6, wherein the iron oxide in the film-coating layer is only yellow ferric oxide.
The film-coated tablet according to claim 13, wherein the content of yellow ferric oxide in the film coating layer is 0.1 to 10% by weight based on the total amount of the film coating layer.
The film-coated tablet according to claim 5 or 6, wherein the iron oxide in the film coating layer is yellow ferric oxide, ferric oxide, and black ferric oxide.
The film-coated tablet according to claim 15, wherein the content of yellow ferric oxide in the film coating layer is 0.005 to 1% by weight based on the total amount of the film coating layer.
The film-coated tablet according to claim 15 or 16, wherein the content of iron sesquioxide in the film coating layer is 0.1 to 20% by weight based on the total amount of the film coating layer.
The film-coated tablet according to any one of claims 15 to 17, wherein the content of black iron oxide in the film coating layer is 0.01 to 5% by weight based on the total amount of the film coating layer.
The film-coated tablet according to any one of claims 1 to 18, wherein the content of methotrexate is 0.3 to 5% by weight in 100% by weight of the uncoated tablet.
The film-coated tablet according to any one of claims 1 to 19, wherein the weight of the film-coated layer is 1 to 20% by weight based on the total weight of the film-coated tablet.
The film-coated tablet according to any one of claims 1 to 20, wherein 1 mg of methotrexate is contained in one tablet.
The film-coated tablet according to any one of claims 1 to 20, wherein 2 mg of methotrexate is contained in one tablet.
The film-coated tablet according to any one of claims 1 to 20, wherein 4 mg of methotrexate is contained in one tablet.