TW201808296A - Methotrexate-comprising film-coated tablet - Google Patents

Abstract

The objective of the present invention is to provide a tablet which can prevent reduction in content of methotrexate as an active ingredient due to light and production of analogous substances, and prevent misidentification by changing to different color according to every content standard. The present invention provides a methotrexate tablet comprising iron oxide in a film coating layer and a plain tablet, whereby the reduction in content of methotrexate as the active ingredient due to light and production of analogous substances can be suppressed. The methotrexate tablet can guarantee photostability even if it is in light color, therefore it can be made into different color according to every content standard so that it is highly useful in medicine management at medical site or medicine storage at patient's residence and the like.

Description

Membrane ingot containing methotrexate

The present invention relates to a film-coated tablet containing elevated light stability of Methotrexate.

Methotrexate, which is an anti-rheumatic agent, has little effect of inhibiting arthritis and joint destruction, but rarely causes significant side effects. Because of this property, it is the first drug of choice for the treatment of rheumatism. However, methotrexate decomposes in the case of a large amount of exposure, which increases the harmful analog and lowers the potency as an active substance. Because of the light instability of the methotrexate, the oral solid preparation containing methotrexate must be formulated to ensure photo-safety formulation or shading preservation.

In the past, various methods for improving the stability of drugs have been known for the formulation of drugs for restlessness of light. For example, Patent Document 1 discloses a capsule preparation in which an active vitamin D3 is stabilized by a hard capsule containing a tar pigment or iron oxide red. In addition, the capsule containing methotrexate sold in Japan is also an agent that does not require special light-shielding preservation. The formulation technique used for this purpose contains a coloring agent in a capsule film coated with a light-stable drug. However, this technique is difficult to apply to tablets. Therefore, the tablet used as an active ingredient in the Japanese market is sold as a tablet. It is considered that it is obligatory to keep all the shading. Therefore, from the viewpoint of ease of administration and ease of storage at a medical site or a patient's home, it is required to develop a tablet which does not require light-shielding preservation.

In the light stability technique of a tablet, Patent Document 2 discloses a tablet which is stabilized by light-coating a film prepared by coating iron oxide with a tablet containing a dihydropyridine derivative, and a patent Document 3 also discloses a tablet which is stabilized against light by coating a film containing titanium oxide, ferric oxide and yellow ferric oxide for a tablet containing arrhadipine. However, with regard to methotrexate, no prior art documents have been disclosed which can ensure sufficient light stability with only such a film coating technique without the need to block the stored tablets. Further, when the amount of film coating is increased in order to ensure light stability, the workability in actual production is deteriorated. Further, if the amount of the iron oxide which is a high effect as a coating agent is excessively increased, the color of the tablet becomes nearly black, which causes a problem of poor appearance. Therefore, in terms of development, it is expected that a tablet which is excellent in workability in actual production and which ensures light stability even in a light color system.

However, the administration method of the methotrexate preparation for treating rheumatoid arthritis in Japan is 6 mg once a week or divided into 2 to 3 times, and the dosage can be increased to 16 mg per week. On the other hand, in Europe, America, and Asia, if necessary, it can be used up to 25 mg per week. In Japan, only one specification of a 2 mg preparation is sold, and the dosage form is a capsule and a capsule type. Although the capsule does not have the necessity of shading preservation, it has the disadvantage of being bulky and not easy to take, especially when the dosage is increased on the 1st, the number of capsules will also increase, causing the burden on the patient. On the other hand, capsule Although the tablet has the advantage of being easier to take than the capsule, it has the disadvantage of being shielded from light. Therefore, it is expected to develop a preparation which is both a tablet which is easy to take and which does not need to be stored in a light-shielding manner. In addition, from the viewpoint of reducing the burden of taking, it is considered that it is also necessary to develop a high-content tablet.

When developing a tablet with a low content or a high content compared to the previous content (hereinafter, also referred to as the appropriate "content", but the same meaning), in order to prevent mistakes in the medical field and the wrong dosage of the patient It is one of the countermeasures to make tablets of different colors according to the content specifications. At this time, the methotrexate preparations sold in Japan are all yellow-based 2 mg capsules or capsule-type tablets. Therefore, for the newly-listed 2 mg-sized tablet, it is preferably yellow or nearly yellow in color from the viewpoint of preventing prescription errors. However, as described above, it is difficult to ensure light stability if the methotrexate preparation utilizes only a usual film coating. On the other hand, if a large amount of iron oxide having a high light-shielding property is blended in the film layer, it will have a black appearance, and it is not only inferior in appearance, but also it is difficult to produce different colors depending on the tablet of various content specifications. Therefore, it is necessary to have a technique for ensuring light stability even in a pale color tablet.

In other light stabilization methods, Patent Document 4 discloses that a light-stable drug is formulated in a light-stable fat-soluble drug, and one or more selected from the group consisting of a yellow colorant and a red colorant are used to form a composition for enhancing light stability. However, there is no description of the light stabilizer tablet containing methotrexate.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 4-46122

[Patent Document 2] Japanese Patent Laid-Open Publication No. 2003-104888

[Patent Document 3] Japanese Patent Laid-Open Publication No. 2003-104887

[Patent Document 4] Japanese Patent Laid-Open Publication No. 2000-7583

The object of the present invention is to provide a tablet which can prevent a decrease in the content of methotrexate as an active ingredient due to light and the formation of an analog. Further, a tablet is provided which is changed to a different color depending on the content specification to prevent misidentification.

The chemical name of methotrexate is N-{4[(2,4-diaminopteridin-6-ylmethyl)(methyl)amino]benzhydryl}-L-glutamic acid. Methotrexate is a yellow-brown crystalline powder which is believed to be light-shielded when stored due to light changes (the seventeenth revised Japanese Pharmacopoeia).

In the light stability test conducted by the present inventors using a film-coated tablet containing 1 mg, 2 mg, and 4 mg of methotrexate, when the iron oxide is formulated in the film coating layer, the exposure amount is 1.2 million l hr or more. Confirmation that the content reduction in the unpacked state is satisfied with the "No change" benchmark in the "Stability test for tablets and capsules in the unpacked state" (Reply to the Japanese Hospital Pharmacists' Association) 3%" (hereinafter referred to as "the reference value of the Japanese Hospital Pharmacists Association"). However, if only the titanium oxide is blended in the film coat layer, the content of the methotrexate in the 4 mg tablet is lowered to exceed the above criteria. Therefore, the 4 mg of titanium oxide in the coating layer is increased. The ingot and the 4 mg ingot obtained by adjusting the iron oxide (iron trioxide, yellow ferric oxide) having the most light-shielding effect by the 1 mg ingot and the 2 mg ingot in the coating layer were again supplied to the light stability test. As a result, regarding the formulation in which the titanium oxide in the coating layer was increased, the improvement in the light-shielding effect was not confirmed. On the other hand, regarding the formulation in which iron oxide was formulated in the coating layer, a good result of a content reduction of 0.7% was exhibited. Therefore, it is suggested that titanium oxide is ineffective in suppressing photodegradation of methotrexate, but iron oxide is effective.

A purity test was carried out for the above-mentioned 1 mg ingot, 2 mg ingot, and 4 mg ingot which had a reduction in the amount of the unpackaged (bare ingot) in the unpackaged (bare ingot) state, and the above-mentioned 1 mg ingot, 2 mg ingot, and 4 mg ingot. As a result, 4 mg of the ingot inhibited the formation of the analog, but the 1 mg ingot and the 2 mg ingot confirmed an increase in the analog which exceeded 0.3% of the USP original drug standard (hereinafter referred to as "the reference value of the USP"). Further, for the 2 mg ingot, it was confirmed that there was an unknown peak exceeding 0.2% of the threshold value (hereinafter referred to as "the reference value of the impurity guide") required for the structure determined by the impurity guide. Therefore, in order to make the tablet of the three content specifications inhibit the increase of the analog, the research preparation was carried out.

From the studies to date, it has been found that if iron oxide is contained in the coating layer, the effect of inhibiting photodegradation of methotrexate is observed. However, if the formation of the methotrexate analog is to be inhibited, the coating amount is usually insufficient, and it is considered that the iron oxide of the coating layer needs to be formulated to be larger than the usual amount, so that the color of the tablet is changed to increase the effect. However, if the coating amount is increased, the workability is deteriorated in actual production, and the amount of iron oxide in the coating agent is increased, and the color of the tablet becomes black, so that the appearance is not good. In addition, if you want to prevent mistakes at the medical site, you want to make all three specifications different. The color must ensure light stability even if the color of the tablet is not made close to black. In particular, regarding the 2 mg ingot of the same specification as the original drug, it is considered that it is preferably not too different from the yellow of the same color.

Then, a film ingot which did not increase the amount of iron oxide in the film coating layer but also contained iron oxide in the bare ingot was prepared and supplied to the light stability test. The result is surprisingly that although it is light in color, it can maintain a usual coating amount which does not affect the efficiency of actual production work, and can also suppress analogs generated by light exposure below the reference. In addition, the three kinds of tablets can be made into different colors, and the 2 mg ingot can be made into the same pale yellow color as the original drug. As described above, the inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, have completed the present invention.

That is, the present invention encompasses the following aspects.

(1) A film-coated tablet containing methotrexate as an active ingredient and containing iron oxide in a bare ingot and a film coating layer.

(2) The film-coated ingot according to the above (1), wherein the iron oxide contained in the bare ingot is one or more selected from the group consisting of ferric oxide, yellow ferric oxide, and black iron oxide.

(3) The film-coated ingot according to the above (2), wherein the iron oxide contained in the bare ingot is ferric oxide.

(4) The film-coated ingot according to any one of (1) to (3) above, wherein the amount of the iron oxide contained in the bare ingot is 0.05 to 1.5% by weight based on the total amount of the bare ingot.

(5) The film-coated ingot according to any one of (1) to (3), wherein the amount of iron oxide contained in the bare ingot is 0.075 to 1 by weight relative to the total amount of the bare ingot. %.

(6) The film-coated ingot according to any one of (1) to (3), wherein the amount of iron oxide contained in the bare ingot is 0.1 to 0.3% by weight based on the total amount of the bare ingot.

(7) The film-coated ingot according to any one of (1) to (6), wherein the iron oxide in the film coating layer is selected from the group consisting of ferric oxide, yellow ferric oxide, and black iron oxide. One or more of them.

The film-coated tablet of any one of the above-mentioned (1) to (7), wherein the content of the 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 (1) to (7) above, wherein the content of the iron oxide in the film coating layer is from 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 the above (1) to (7) wherein the content of the iron oxide in the film coating layer is from 1 to 10% by weight based on the total amount of the film coating layer.

(11) The film-coated tablet according to the above (7), wherein the content of the 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.

(12) The film-coated tablet according to the above (7), wherein the content of the yellow ferric oxide in the film coating layer is 0.01 to 5% by weight based on the total amount of the film coating layer.

(13) The film-coated tablet according to the above (7), wherein the content of the 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 coating ingot according to any one of the above (11) to (13), wherein The content of ferric oxide in the film coating layer is from 0.01 to 20% by weight based on the total amount of the film coating layer.

The film-coated ingot according to any one of the above (11) to (13) wherein the content of the ferric oxide 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 the above (11), wherein the content of the ferric oxide in the film coating layer is 0.1 to 7% by weight based on the total amount of the film coating layer.

The film-coated ingot according to any one of the above-mentioned (11), wherein the content of the black iron oxide in the film coating layer is from 0.01 to 5% by weight based on the total amount of the film coating layer.

The film-coated ingot according to any one of the above-mentioned (11), 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.

The film-coated ingot according to any one of the above-mentioned (11), wherein the content of the 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 the 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 ingot according to the above (20), wherein the content of the yellow ferric oxide in the film coating layer is from 0.3 to 5% by weight based on the total amount of the film coating layer.

(23) The film ingot according to (20) above, wherein the yellow layer in the film layer The content of ferric oxide is from 0.5 to 3% by weight based on the total amount of the coating layer.

(24) The film-coated tablet according to any one of the above-mentioned (20), wherein the content of the ferric oxide 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), wherein the content of the ferric oxide in the film coating layer is 0.05 to 5% by weight based on the total amount of the film coating layer.

The film-coated tablet according to any one of the above-mentioned (20), wherein the content of the ferric oxide 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 ingot according to (7) above, wherein the iron oxide in the film coating layer is only yellow ferric oxide.

(28) The film-coated tablet according to the above (27), wherein the content of the 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 the above (27), wherein the content of the yellow ferric oxide in the film coating layer is from 0.5 to 5% by weight based on the total amount of the film coating layer.

(30) The film-coated ingot according to the above (27), wherein the content of the yellow ferric oxide in the film coating layer is from 1 to 4% by weight based on the total amount of the film coating layer.

(31) The film ingot 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 the 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) A film-coated tablet according to the above (31), wherein the content of the 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 the yellow ferric oxide in the film coating layer is 0.01 to 0.1% by weight based on the total amount of the film coating layer.

The film-coated tablet according to any one of the above-mentioned (31), wherein the content of the ferric 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 any one of the above-mentioned (31), wherein the content of the ferric oxide in the film coating layer is from 1 to 10% by weight based on the total amount of the film coating layer.

The film-coated tablet according to any one of the above-mentioned (31), wherein the content of the ferric oxide in the film coating layer is 2 to 7% by weight based on the total amount of the film coating layer.

The film-coated tablet of any one of the above-mentioned (31) to (37), wherein the content of the black iron oxide in the film coating layer is from 0.01 to 5% by weight based on the total amount of the film coating layer.

The film-coated tablet of any one of the above-mentioned (31) to (37), 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.

The film-coated ingot according to any one of the above-mentioned (31) to (37), wherein the content of the 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.

(41) The film-coated tablet according to any one of (1) to (40) above, wherein the content of methotrexate is from 0.3 to 5% by weight based on 100% by weight of the bare ingot.

(42) The film-coated tablet according to any one of the above (1) to (41) which further contains an excipient.

The film-coated tablet of any one of the above-mentioned (1) to (42), wherein the film coating layer has a weight of from 1 to 20% by weight based on the total weight of the film ingot.

The film-coated tablet of any one of the above-mentioned (1) to (42) wherein the weight of the film coating layer is from 2 to 10% by weight based on the total weight of the film ingot.

(45) The film-coated tablet of any one of the above-mentioned (1) to (42), wherein the film coating layer has a weight of 4 to 8% by weight based on the total weight of the film ingot.

(46) The film-coated tablet according to any one of the above (1), wherein the one tablet contains 1 mg of methotrexate.

The film-coated tablet according to any one of the above-mentioned (1), wherein the one tablet contains 2 mg of methotrexate.

The film-coated tablet according to any one of the above-mentioned (1), wherein the one tablet contains 4 mg of methotrexate.

The film ingot according to any one of the above (1) to (48), which has a diameter of from 6.5 mm to 7.5 mm and a thickness of from 3.0 mm to 4.0 mm.

(50) The film-coated tablet according to any one of the above (1) to (49), which has a weight of from 130 to 170 mg.

According to the present invention, it is possible to provide a film-coated tablet containing methotrexate which hardly reduces the content of methotrexate even when exposed to light, and the formation of the analog is small, so that it is not required to be shielded from light. In addition, the appearance can be made into a better light color, and can be made into tablets of different colors according to the content specification, and can prevent the wrong prescription or the dosage of the tablet having different content of methotrexate.

The film-coated tablet containing the methotrexate of the present invention (hereinafter also referred to as "the present tablet") contains methotrexate as an active ingredient, and contains iron oxide in the bare ingot portion, and is also in the film coat. The layer contains iron oxide.

As the iron oxide contained in the bare ingot portion of the tablet, iron oxide, yellow ferric oxide, black iron oxide, or the like can be used. These iron oxides may be used in combination, but are preferably ferric oxide. Ferric oxide refers to a compound represented by the formula Fe ₂ O ₃ . That is, in the present specification, the term "ferric oxide" does not include yellow ferric oxide (Fe ₂ O ₃ ‧ H ₂ O).

The content of the iron oxide in the bare ingot is not particularly limited, and may be usually from 0.05 to 1.5% by weight, preferably from 0.075 to 1% by weight, more preferably from 0.1 to 0.3% by weight, based on the total amount of the bare ingot. If the content of the iron oxide in the bare ingot is less than the above range, the light stability of the methotrexate may not be sufficiently obtained, which is not preferable. Further, if the content of the iron oxide exceeds the above range, the user does not like the color of the tablet.

The weight ratio of the film coat layer to the total amount of the film coat is not particularly limited and may be usually from 1 to 20% by weight, preferably from 2 to 10% by weight, more preferably from 4 to 8% by weight. If the weight of the film coating layer is less than the above range, the effect of improving the light stability of the methotrexate may not be sufficiently obtained. Further, if the weight of the film coating layer exceeds the above range, the coating time becomes long, and the workability in actual production is inferior. In addition, there will be cases where the user does not like the color of the tablet.

Iron oxide contained in the film coating layer of the tablet can be used Iron oxide, yellow ferric oxide, black iron oxide, etc. may also be used alone or in combination depending on the color of the purpose. A premixed film coating agent prepared with iron oxide or the like can also be used as a commercial product.

The content of the iron oxide in the film coating layer is not particularly limited, and may be usually from 0.1 to 20% by weight, preferably from 0.5 to 15% by weight, more preferably from 1 to 10% by weight, based on the total amount of the film coating layer. . In the case of iron oxide, the content of yellow ferric oxide alone or in combination with other iron oxide is not particularly limited, and it is usually from 0.005 to 10% by weight, preferably from 0.01 to 5% by weight, more preferably. It is in the range of 0.01 to 4% by weight. In the case of iron oxide, the content of the iron oxide alone or in combination with other iron oxide is not particularly limited, and it is usually from 0.01 to 20% by weight, preferably from 0.05 to 10% by weight, more preferably It is in the range of 0.1 to 7% by weight. In the case of iron oxide, the content of black iron oxide alone or in combination with other iron oxide is not particularly limited, and it is usually from 0.01 to 5% by weight, preferably from 0.05 to 3% by weight, more preferably 0.1. To the range of 1% by weight.

In the film coating layer, the content of the yellow ferric oxide and the ferric oxide in combination is not particularly limited, and the yellow ferric oxide is usually 0.1 to 10% by weight, preferably in the total amount of the film coating layer. From 0.3 to 5% by weight, more preferably from 0.5 to 3% by weight, the ferric oxide is usually in the range of 0.01 to 10% by weight, preferably 0.05 to 5% by weight, more preferably 0.1 to 1% by weight.

In the film coating layer, the content of only the yellow ferric oxide is not particularly limited, and is usually 0.1 to 0.1 with respect to the total amount of the film coating layer. 10% by weight, preferably 0.5 to 5% by weight, more preferably 1 to 4% by weight.

In the film coating layer, the content of the yellow ferric oxide, the ferric oxide and the black iron oxide is not particularly limited, and the yellow ferric oxide can be usually used in an amount of 0.005 to 1 by weight relative to the total amount of the film coating layer. %, preferably from 0.01 to 0.5% by weight. More preferably in the range of 0.01 to 0.1% by weight. The ferric oxide may generally be in the range of 0.1 to 20% by weight, preferably 1 to 10% by weight, more preferably 2 to 7% by weight, and the black iron oxide may usually be in the range of 0.01 to 5% by weight, preferably 0.05 to 3 wt%, more preferably in the range of 0.1 to 1 wt%.

Methotrexate causes decomposition and produces analogs due to light exposure. As a result, the content of methotrexate in the drug composition is lowered. However, if the film-coated tablet containing the methotrexate has iron oxide in both the bare ingot and the film coat layer, the formation of the analog due to light exposure can be remarkably suppressed. In particular, ferric oxide has the highest effect in iron oxide. If both of the film coating layer and the bare ingot contain iron oxide, the effect of sufficiently improving the light stability of the methotrexate can be exhibited.

The film-coated tablet of the present invention may contain a conventional carrier component or additive in a bare ingot without damaging the effects of the present invention. The carrier component or the additive may, for example, be an excipient, a disintegrator, a binder, a lubricant, an antioxidant, a preservative, a dissolution aid, a surfactant, a fluidizer, a plasticizer, a pH adjuster, a colorant, and a flavor. Agents, sweeteners, fragrances, adsorbents, preservatives, wetting agents, and the like. These carrier components or additives may be used singly or in combination of two or more.

Examples of the excipients include sugar alcohols (D-sorbitol, erythritol, xylitol, powder-reduced maltose, etc.), sugars (lactose, glucose, fructose, white sugar, etc.) and hydrates thereof, crystalline cellulose, Powdered cellulose, starch (potato starch, corn starch, wheat starch, etc.), dextrin, β-cyclodextrin, sodium carboxymethylcellulose, light anhydrous citric acid, aqueous cerium oxide, cerium oxide, sedimentation Calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, aluminum magnesium metasilicate, synthetic hydrotalcite, talc, kaolin and the like.

The disintegrant can be exemplified by carboxymethylcellulose (e.g., carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crystalline cellulose ‧ carboxymethyl Cellulose sodium, etc.), carboxymethyl starch (such as sodium carboxymethyl starch), crospovidone, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl starch, starch (corn starch, etc.), alginic acid, bentonite, and the like. Preferably, for example, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, or a carboxy group are exemplified. Methyl cellulose, crystalline cellulose ‧ sodium carboxymethyl cellulose, low-substituted sodium carboxymethyl starch. More preferably, for example, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, or sodium carboxymethyl starch. These disintegrating agents may be used alone or in combination of two or more.

The lubricant may, for example, be stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hardened oil, polyethylene glycol, dimethyl polyoxyalkylene, palm wax, Sodium lauryl sulfate, beeswax, white beeswax, and the like. These lubricants may be used singly or in combination of two or more. Among these lubricants, stearates such as magnesium stearate are widely used.

The fluidizing agent can be exemplified by light anhydrous citric acid, talc, aqueous cerium oxide or the like.

The invention is specifically described below, but the invention is not limited thereby.

(Example)

The relationship between "the type and content of iron oxide in the film coating layer" and "the formation of an analog when the obtained tablet is exposed to light" is investigated. The results are shown in Tables 2 to 9. This will be explained below.

According to Table No. 1 to No. 3 shown in Table 2, for the 2 mg ingot, 0.2 kg of methotrexate, 3.58 kg of crystalline cellulose, 2.00 kg of corn starch, 7.47 kg of lactose hydrate, and croscarmyl group were weighed. The cellulose sodium was 0.87 kg and the ferric oxide was 0.03 kg. The powder obtained was put into a high-speed stirring granulator (FG-GS-50, manufactured by Shenjiang Powtec Co., Ltd.) and prepared for mixing. 2.00 kg of purified water was added to the mixed powder, stirred and granulated, and dried using a fluidized bed dryer (2011-141, Jeil Machine). The granules were granulated using an oscillator granulator to obtain 14.15 kg of granules. The obtained pellets were placed in a double cone mixer (SY-M, BOSEONG machine), and 0.10 kg of light anhydrous citric acid and 0.25 kg of magnesium stearate were added and mixed to obtain granules. Regarding the 1 mg ingot, the amount of the methotrexate in the above-mentioned 2 mg ingot production method was changed to 0.1 kg, and the blending amount of the lactose hydrate was changed to 7.57 kg, and the pellet was obtained in the same manner. Regarding the 4 mg ingot, the amount of the methotrexate in the above 2 mg ingot production method was changed to 0.4 kg, and the blending amount of the lactose hydrate was changed to 7.27 kg, and the pellet was obtained in the same manner.

1mg ingot, 2mg ingot and 4mg ingot After 7.0 mm/臼, a rotary ingot machine (HT-P22-A-3, manufactured by KK) was used to manufacture 14.50 kg of bare ingot.

As shown in the examples in Table 2, No. 1 to No. 3, regarding the film coating liquid, yellow iron oxide and ferric oxide are used in the 1 mg ingot, and only yellow is used in the 2 mg ingot. In the case of ferric oxide, the 4 mg ingot is prepared using yellow ferric oxide, ferric oxide and black iron oxide. 14.50 kg of the bare ingot was put into the coating device and applied to the prescription amount. After drying, a film-coated tablet (weight: 155 mg, diameter: 7.0 mm, thickness: 3.5 mm) containing 1 mg, 2 mg, and 4 mg of methotrexate in one tablet was obtained.

(Comparative Examples 1 to 3)

As shown in Comparative Examples 1 to 3 (Prescription No. 4 to No. 18) of Tables 4, 6 and 8, in addition to the type and amount of iron oxide in the uncoated iron oxide portion and the coating layer in the bare ingot portion, In the same manner as in the examples, a film-coated ingot containing methotrexate was obtained, except for various changes and fine adjustment of the amount of other additives.

(light stability test)

The film-coated tablets obtained in the examples and the comparative examples were subjected to a light stability test under the following conditions. Each film ingot was uniformly placed on a glass plate, and irradiated at 3500 lx for 15 days or at 4000 lx for 13 days in a constant temperature and humidity chamber maintained at 25 ° C and 60% RH, so that the cumulative illuminance became 1.25 million l ‧ hr or more .

(quantitative test)

After the above-mentioned light exposure, the sample solution was prepared based on the method of the Japanese Pharmacopoeia, and the peak area of methotrexate was measured by liquid chromatography, and the content thereof was measured. The results are shown in Tables 3, 5, 7 and 9. In Comparative Example 1, No. 6 and 7 in which the iron oxide layer was not contained in the film coating layer and only the titanium oxide was contained, the content of the methotrexate was decreased by more than 3% of the reference value of the Japanese Hospital Pharmacists Association. On the other hand, other formulations of iron oxide (No. 4, 5, 8 to 9 and 11 to 18) were formulated in the film coat, and the content was reduced to be equal to or lower than the reference value. The test conditions are as follows.

[Test conditions]

Detector: UV spectrophotometer (measuring wavelength: 302 nm)

Pipe column: a octadecyl oxime alkyl phthalate for liquid chromatography using a liquid crystal of 5 μm in an inner diameter of 4.6 mm and a length of 25 cm (for example, Wakopak (registered trademark) Wakosil-II5C18HG manufactured by Wako Pure Chemical Industries, Ltd.) ).

Column temperature: a certain temperature around 25 ° C

Mobile phase: A sodium hydroxide test solution was added to a 1000 mL solution prepared by dissolving 6.00 g of anhydrous sodium dihydrogen phosphate in water to adjust the pH to 6.0. 110 mL of acetonitrile was added to 890 mL of this solution.

Flow rate: 1.0mL per minute

(purity test)

After exposure to light, the sample solution of the quantitative test is filtered with a membrane filter having a pore diameter of 0.45 μm or less, based on the method of the Japanese Pharmacopoeia, and the first filtrate is removed by 1 mL or more, and the quantitative method is added to the filtrate in the following. Move the phase to make it contain a meglumine in 1 mL. A 0.2 mg solution was used as a sample solution. The amount of formation of the analogs B, C and E was determined by liquid chromatography.

The chemical name of the analog B is (S)-2-{4-[(2,4-diaminopteridin-6-yl)methylamino]benzamide>glutaric acid, which is A substance that is reproductively toxic and is also suspected of being carcinogenic.

The chemical name of the analog C is (S)-2-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl](methyl) Amino}benzamide)pentanedione acid.

The chemical name of the analog E is 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, and the test conditions are as described later.

In Comparative Example 1 No. 4 to 6 and 8, any of the analogs was 0.3% or more of the USP reference value, or one or more unknown peaks of 0.2% or more of the impurity guide reference value were observed.

In the case of Comparative Example 2, Nos. 9 and 10 are the same, and any of the analogs has a reference value of 0.3% or more of the USP, or an unknown peak of more than 0.2% of the reference value of the impurity guide is visible. Further, in the prescription No. 11, the iron oxide was not contained in the bare ingot to ensure light stability, but the coating layer was thick, and the workability in actual production was poorly evaluated. In Comparative Example 2, 2 mg of ingot and 4 mg of ingot (prescription No. 12 to 15) ensured light stability and could be made in different colors, but the 1 mg ingot did not reach the standard.

In No. 16 to 18 of Comparative Example 3, iron oxide was not contained in the bare ingot to ensure light stability, but any of them was similar to an orange-like appearance, and it was not possible to make different colors depending on the specifications.

[Test conditions]

Detector: UV spectrophotometer (measurement wavelength 280nm)

Pipe column: a octadecyl oxime alkyl phthalate for liquid chromatography using a liquid crystal of 5 μm in an inner diameter of 4.6 mm and a length of 25 cm (for example, Wakopak (registered trademark) Wakosil-II5C18HG manufactured by Wako Pure Chemical Industries, Ltd.) .

Column temperature: a certain temperature around 25 ° C

Phosphate buffer solution at pH 6.0: 3.40 g of anhydrous sodium dihydrogen phosphate was dissolved in water to prepare a 1000 mL solution, and a sodium hydroxide test solution was added thereto to adjust the pH to 6.0.

Mobile phase A: acetonitrile / pH 6.0 phosphate buffer mixture (1:19)

Mobile phase B: acetonitrile / pH 6.0 phosphate buffer mixture (1:1)

Liquid feeding of the mobile phase: The mixing ratio of the mobile phase A and the mobile phase B was changed as shown in Table 1, and the concentration gradient was controlled.

Flow rate: 1.0mL per minute

Area measurement range: 40 minutes after the injection of the sample solution

The relationship between "the type and amount of iron oxide in the bare ingot" and "the analog when the bare ingot is exposed to light" is shown in Table 10.

When compared with [1] which does not use iron oxide at all, the use of any of the iron oxides [2] to [4] can suppress an increase in the analog.

In the case of iron oxide, [2] using ferric oxide alone, when compared with [3] using yellow ferric oxide alone [3], combining ferric oxide with yellow ferric oxide [4] The result is that the analog increase rate is low. In addition, regarding the number of unknown peaks of 0.2% or more and 0.5% or more, the use of iron oxide [2] alone is the least. It can be seen that the use of ferric oxide alone in the bare ingot can enhance the light stability of the methotrexate. Further, regarding the blending amount of ferric oxide, it is shown to be about 0.2 to 0.4 mg (0.1 to 0.3% by weight based on the entire bare ingot).

According to the above results, the film-coated ingot containing the amine methotrexate produced in the examples can suppress the decrease in the methotrexate content due to light exposure by the iron oxide in the film coating layer. Below the value. In addition, when the appearance is made into a light color system by selecting the iron oxide or the content in the film coating layer, if the iron oxide is formulated in the bare ingot, the reduction of the methotrexate content can be suppressed, and the analog can be made. The generation situation is below the reference value, and the number of unknown peaks can also be suppressed. In addition, 1 mg ingot, 2 mg ingot, and 4 mg ingot can be made into different colors.

(industrial use possibility)

In the film-coated tablet containing the methotrexate of the present invention, the content of the active ingredient can be reduced or the increase of the analog can be suppressed to be lower than the reference value even after exposure to light, so that it is not necessary to shield the light. In addition, since different colors can be produced according to the content specifications, the identification of the patient or the medical relationship can be ensured, and the convenience is high.

Claims (23)

A film-coated ingot containing methotrexate as an active ingredient and containing iron oxide in a bare ingot and in a film coating layer. The film-coated ingot according to the first aspect of the invention, wherein the iron oxide contained in the bare ingot is one or more kinds of iron oxide selected from the group consisting of ferric oxide, yellow ferric oxide and black iron oxide. The film coating ingot according to claim 2, wherein the iron oxide contained in the bare ingot is ferric oxide. The film-coated ingot according to any one of claims 1 to 3, wherein the iron oxide contained in the bare ingot is 0.05 to 1.5% by weight based on the total amount of the bare ingot. The film-coated ingot according to any one of claims 1 to 4, wherein the iron oxide in the film coating layer is selected from the group consisting of ferric oxide, yellow ferric oxide and black iron oxide. More than one type. The film-coated tablet according to any one of claims 1 to 5, wherein the content of the iron oxide in the film coating layer is from 0.1 to 20% by weight based on the total amount of the film coating layer. The film-coated tablet of claim 5, wherein the content of yellow ferric oxide in the film coating layer is from 0.001 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 the ferric oxide in the film coating layer is from 0.01 to 20% by weight based on the total amount of the film coating layer. A film coating as claimed in any one of claims 5 to 8 The ingot, wherein the content of black iron oxide in the film coating layer is from 0.01 to 5% by weight based on the total amount of the film coating layer. The film coating ingot according to claim 5, wherein the iron oxide in the film coating layer is yellow ferric oxide and ferric oxide. The film coating ingot according to claim 10, wherein the yellow ferric oxide in the film coating layer is from 0.1 to 10% by weight based on the total amount of the film coating layer. The film-coated ingot according to claim 10, wherein the content of the ferric oxide in the film coating layer is from 0.01 to 10% by weight based on the total amount of the film coating layer. The film coating ingot according to claim 5, wherein the iron oxide in the film coating layer is only yellow ferric oxide. The film-coated ingot according to claim 13, wherein the content of the 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 coating ingot according to claim 5, wherein the iron oxide in the film coating layer is yellow ferric oxide, ferric oxide and black iron oxide. The film coating ingot according to claim 15, wherein the content of the 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 of claim 15 or 16, wherein the content of the ferric oxide in the film coating layer is from 0.1 to 20% by weight based on the total amount of the film coating layer. The film-coated ingot according to any one of claims 15 to 17, wherein the content of black iron oxide in the film coating layer is from 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 from 0.3 to 5% by weight based on 100% by weight of the bare ingot. The film-coated ingot according to any one of claims 1 to 19, wherein the film coating layer has a weight of from 1 to 20% by weight based on the total weight of the film ingot. A film-coated tablet according to any one of claims 1 to 20, which contains 1 mg of methotrexate in one tablet. A film-coated tablet according to any one of claims 1 to 20, which contains 2 mg of methotrexate in one tablet. A film-coated tablet according to any one of claims 1 to 20, which contains 4 mg of methotrexate in one tablet.