TWI728156B - 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

Film-coated tablets containing methotrexate

The present invention relates to a film-coated tablet containing Methotrexate with enhanced light stability.

As an anti-rheumatic agent, methotrexate, although it has the effect of fully inhibiting arthritis and joint destruction, rarely causes major side effects. Because of this nature, it is the first drug of choice for the treatment of rheumatism. However, methotrexate decomposes when exposed to a large amount of exposure, increasing harmful analogues and reducing its effectiveness as an active substance. Due to the light instability of methotrexate, oral solid preparations containing methotrexate must be formulated to ensure light stability or shading storage.

In the past, regarding the formulation of photolabile drugs, various methods for improving the stability of drugs have been known. For example, Patent Document 1 discloses a capsule preparation in which active vitamin D3s are stabilized by hard capsules containing tar-based pigments, iron oxide red, and the like. In addition, the capsules containing methotrexate sold in Japan are also medicines that do not require special shading for preservation. The formulation technology used for this purpose is to include a colorant in the capsule film covering the photolabile drug. However, this technique is difficult to apply to lozenges. Therefore, lozenges with methotrexate as an active ingredient sold in Japan are It is deemed to be obligated to keep all shaded. Therefore, from the viewpoint of the ease of taking and the ease of storage in the medical field or at the patient's home, it is required to develop tablets that do not need to be protected from light.

Regarding the light stability technology of tablets, Patent Document 2 discloses a tablet that is stabilized against light by coating a tablet containing a dihydropyridine derivative with a thin film of iron oxide. The patent Document 3 also discloses a lozenge that is stabilized to light by coating a lozenge containing aranidipine with a thin film of titanium oxide, ferric oxide, and yellow ferric oxide. However, regarding methotrexate, there are no prior technical documents that have disclosed that the film coating technology alone can ensure sufficient light stability without shading and preservation of tablets. In addition, when the amount of film coating is increased in order to ensure light stability, the workability in actual production will deteriorate. In addition, if the blending amount of iron oxide, which has a high effect as a coating agent, is increased too much, the color of the tablet becomes close to black, which causes a problem of poor appearance. Therefore, in terms of development, it is expected that there will be tablets that have good workability in actual production and can ensure light stability even if they are light-colored.

However, the dosage of methotrexate used in the treatment of articular rheumatism in Japan is 6 mg once a week or divided into 2 to 3 times, and the dosage can be increased to 16 mg a week. On the other hand, in European, American and Asian countries, if necessary, it can be used up to 25mg per week. In Japan, only one specification of the 2mg preparation is sold, and the dosage forms are capsules and couplets. Although the capsules are not necessary for shading preservation, they have the disadvantage of being bulky and not easy to take. Especially when the daily dosage increases, the number of capsules will also increase, causing a burden on the patient. On the other hand, the capsule Although lozenges have the advantage of being easier to take than capsules, they have the disadvantage that they must be stored in the dark. Therefore, it is expected to develop a formulation that is easy to take and does not need to be stored in the shade. In addition, from the viewpoint of reducing the burden of taking it, it is believed that the development of high-content lozenges is also necessary.

When developing a lozenge 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 the wrong dose at the medical site and the patient from taking the wrong dose One of the countermeasures is to make tablets of different colors according to the content specifications. At this time, all methotrexate preparations sold in Japan are yellow 2mg capsules or capsule tablets. Therefore, the newly marketed 2 mg tablets are preferably yellow or close to yellow from the viewpoint of preventing prescription errors. However, as mentioned above, it is difficult to ensure light stability for methotrexate preparations using only the usual film coating. On the other hand, if a large amount of iron oxide with high light-shielding properties is blended into the film layer, it will have a black appearance, which is not only poor in appearance, but also difficult to produce clearly different colors according to the various content specifications of the tablets. Therefore, it is necessary to have a technology that can ensure light stability even if it is a light-colored lozenge.

Regarding other methods of photostabilization, Patent Document 4 discloses that a fat-soluble photolabile drug is formulated with one or more substances selected from a yellow colorant and a red colorant to form a composition with improved photostability , But there is no record about Guangdian tablets containing methotrexate.

[Prior Technical Literature] [Patent Literature]

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

[Patent Document 2] JP 2003-104888 A

[Patent Document 3] JP 2003-104887 A

[Patent Document 4] JP 2000-7583 A

The problem to be solved by the present invention is to provide a lozenge, which can prevent the reduction of the content of methotrexate as an active ingredient due to light and the generation of the like. In addition, a lozenge is provided, which is changed into different colors according to the content specification to prevent misidentification.

The chemical name of methotrexate is N-{4[(2,4-diaminopteridine-6-ylmethyl)(methyl)amino]benzyl}-L-glutamic acid. Methotrexate is a yellowish-brown crystalline powder that changes slowly due to light, so it is considered that it should be stored in the dark during storage (17th revised edition of the Japanese Pharmacopoeia).

The inventors used film-coated tablets containing 1mg, 2mg, and 4mg of methotrexate in a light stability test. When iron oxide was blended in the film coating layer, the exposure was over 1.2 million lx‧hr. , To confirm that the content reduction in the unpackaged state meets the "no change" criterion in the "tablet and capsule stability test in the unpackaged state" (reply by the Japanese Hospital Pharmacist Association) 3%" (hereinafter referred to as "the benchmark value of the Japanese Hospital Pharmacist Association"). However, if iron oxide is not blended in the film coating layer and only titanium oxide is blended, the result is that the content of methotrexate in 4 mg tablets will decrease beyond the above-mentioned benchmark. Therefore, it will increase the titanium oxide in the coating layer to 4mg Ingots and 4 mg ingots prepared by mixing 1 mg ingots and 2 mg ingots with iron oxides (iron trioxide, yellow iron trioxide) confirmed to have the most light-shielding effects in the coating layer, were again supplied to the light stability test. As a result, with regard to the formulation obtained by increasing the titanium oxide in the coating layer, no improvement in the light-shielding effect was confirmed. On the other hand, with regard to the formulation of iron oxide in the coating layer, it shows a good result that its content is reduced by 0.7%. This suggests that titanium oxide is ineffective in inhibiting the photodecomposition of methotrexate, but iron oxide is effective.

Purity tests were conducted for the above-mentioned 1mg ingots, 2mg ingots and 4mg ingots whose content in the unpackaged (bare ingot) state was reduced after exposure of 1.2 million lx‧hr or more to meet the criterion of "less than 3%". As a result, 4 mg tablets inhibited the production of analogs, but 1 mg tablets and 2 mg tablets were confirmed to have an increase in analogs exceeding 0.3% of the USP original drug standard (hereinafter referred to as "USP standard value"). In addition, for 2mg tablets, it was also confirmed that there was an unknown peak exceeding 0.2% (hereinafter referred to as the "reference value of the impurity guide"), which is the threshold required to determine the structure shown in the impurity guide. Therefore, in order to prevent the increase of analogues in the tablets of the three specifications, research preparations were carried out.

Through the research so far, it is known that if the coating layer contains iron oxide, it has the effect of inhibiting the photodecomposition of methotrexate. However, if the production of methotrexate analogs is to be suppressed, the usual coating amount is not sufficient. It is considered that the iron oxide of the coating layer should be formulated to be more than the usual amount, so that the color of the tablet can be changed to increase the effect. However, if the coating amount is increased, the workability will deteriorate in actual production, and the amount of iron oxide in the coating agent will increase, and the color of the tablet will become close to black, resulting in a problem of poor appearance. In addition, if you want to make all three content specifications different in order to prevent mistakes in the medical field For the color, the light stability must be ensured even if the color of the lozenge does not become close to black. Especially for the 2mg tablet with the same specification as the original drug, it is better not to be too different from the yellow color of the same series.

Thus, a film-coated tablet containing iron oxide in the bare ingot without increasing the amount of iron oxide in the film-coated layer was produced and supplied to the light stability test. As a result, it is surprising that although it has a light color, it can maintain the usual coating amount that does not affect the actual production efficiency, and it can also suppress the generation of analogs due to light exposure below the standard. In addition, all 3 types of tablets can be made into different colors, and about 2mg tablets, they can also be made into the same light yellow as the original drug. As described above, the inventors of the present invention conducted intensive studies in order to solve the above-mentioned problems, and as a result, completed the present invention.

That is, the present invention includes the following aspects.

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

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

(3) The film-coated tablet as described in (2) above, wherein the iron oxide contained in the bare ingot is iron trioxide.

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

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

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

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

(8) The film-coated tablet according to any one of (1) to (7) above, wherein the content of iron oxide in the film-coating layer is 0.1 to 20% by weight relative to 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 iron oxide in the film-coating layer is 0.5 to 15% by weight relative to the total amount of the film-coating layer.

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

(11) The film-coated tablet as described in (7) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.005 to 10% by weight relative to the total amount of the film-coating layer.

(12) The film-coated tablet as described in (7) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.01 to 5% by weight relative to the total amount of the film-coating layer.

(13) The film-coated tablet as described in (7) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.01 to 4% by weight relative to the total amount of the film-coating layer.

(14) The film-coated tablet according to any one of (11) to (13) above, wherein The content of iron trioxide in the film coating layer is 0.01 to 20% by weight relative to the total amount of the film coating layer.

(15) The film-coated tablet according to any one of (11) to (13) above, wherein the content of iron trioxide in the film-coating layer is 0.05 to 10% by weight relative to the total amount of the film-coating layer.

(16) The film-coated tablet according to any one of (11) to (13) above, wherein the content of iron trioxide in the film-coating layer is 0.1 to 7% by weight relative to 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 relative to 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 the black iron oxide in the film-coating layer is 0.05 to 3% by weight relative to 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 relative to the total amount of the film-coating layer.

(20) The film-coated tablet as described in (7) above, wherein the iron oxide in the film-coated layer is yellow iron trioxide and iron trioxide.

(21) The film-coated tablet as described in (20) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.1 to 10% by weight relative to the total amount of the film-coating layer.

(22) The film-coated tablet as described in (20) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.3 to 5% by weight relative to the total amount of the film-coating layer.

(23) The film-coated tablet as described in (20) above, wherein the yellow color in the film-coated layer The content of iron trioxide is 0.5 to 3% by weight relative to the total amount of the film coating layer.

(24) The film-coated tablet according to any one of (20) to (23) above, wherein the content of iron trioxide in the film-coating layer is 0.01 to 10% by weight relative to the total amount of the film-coating layer.

(25) The film-coated tablet according to any one of (20) to (23) above, wherein the content of iron trioxide in the film-coating layer is 0.05 to 5% by weight relative to the total amount of the film-coating layer.

(26) The film-coated tablet according to any one of (20) to (23) above, wherein the content of iron trioxide in the film-coating layer is 0.1 to 1% by weight relative to the total amount of the film-coating layer.

(27) The film-coated tablet as described in (7) above, wherein the iron oxide in the film-coated layer is only yellow iron trioxide.

(28) The film-coated tablet as described in (27) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.1 to 10% by weight relative to the total amount of the film-coating layer.

(29) The film-coated tablet as described in (27) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.5 to 5% by weight relative to the total amount of the film-coating layer.

(30) The film-coated tablet as described in (27) above, wherein the content of the yellow iron trioxide in the film-coating layer is 1 to 4% by weight relative to the total amount of the film-coating layer.

(31) The film-coated tablet as described in (7) above, wherein the iron oxide in the film-coated layer is yellow iron trioxide, iron trioxide and black iron oxide.

(32) The film-coated tablet as described in (31) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.005 to 1% by weight relative to the total amount of the film-coating layer.

(33) The film-coated tablet as described in (31) above, wherein the content of the yellow iron trioxide in the film-coating layer is 0.01 to 0.5% by weight relative to the total amount of the film-coating layer.

(34) The film-coated tablet as described in (31) above, wherein the content of the yellow iron trioxide 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 trioxide in the film-coating layer is 0.1 to 20% by weight relative to the total amount of the film-coating layer.

(36) The film-coated tablet according to any one of (31) to (34) above, wherein the content of iron trioxide in the film-coating layer is 1 to 10% by weight relative to 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 trioxide in the film-coating layer is 2 to 7% by weight relative to 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 relative to 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 bare tablet.

(42) The film-coated tablet as described in any one of (1) to (41) above, which further contains excipients.

(43) The film-coated tablet according to any one of (1) to (42) above, wherein the weight of the film-coated layer is 1 to 20% by weight relative to the total weight of the film-coated tablet.

(44) The film-coated tablet according to any one of (1) to (42) above, wherein the weight of the film-coated layer is 2 to 10% by weight relative to the total weight of the film-coated tablet.

(45) The film-coated tablet according to any one of (1) to (42) above, wherein the weight of the film-coated layer is 4 to 8% by weight relative to the total weight of the film-coated tablet.

(46) The film-coated tablet according to any one of (1) to (45) above, wherein one tablet contains 1 mg of methotrexate.

(47) The film-coated tablet according to any one of (1) to (45) above, wherein one tablet contains 2 mg of methotrexate.

(48) The film-coated tablet according to any one of (1) to (45) above, wherein one tablet contains 4 mg of methotrexate.

(49) The film-coated tablet as described in 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 as described in any one of (1) to (49) above, which has a weight of 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 if exposed to light, and the generation of similar substances is small, so it does not need to be stored under light. In addition, the appearance can be made into better light colors, and tablets of different colors can be made according to the content specifications, which can prevent wrong prescriptions or taking tablets with different methotrexate content.

The film-coated tablet containing methotrexate of the present invention (hereinafter, sometimes referred to as "this tablet") contains methotrexate as an effective ingredient, iron oxide is contained in the bare tablet part, and the other is film-coated The layer contains iron oxide.

The iron oxide contained in the bare ingot of this tablet can use iron trioxide, yellow iron trioxide, black iron oxide, etc. These iron oxides can be used in combination, but are preferably iron trioxide. Iron trioxide refers to a compound represented by the illustrative formula Fe ₂ O ₃ . That is, in this specification, the term "ferric oxide" does not include yellow ferric oxide (Fe ₂ O ₃ ‧H ₂ O).

The content of iron oxide in the bare ingot is not particularly limited, and relative to the total amount of the bare ingot, it can usually be in the range of 0.05 to 1.5% by weight, preferably 0.075 to 1% by weight, and more preferably 0.1 to 0.3% by weight. If the content of iron oxide in the bare ingot does not reach the above range, the light stability of methotrexate may not be sufficiently obtained, which is not good. In addition, if the content of iron oxide exceeds the above range, the user may not like the color of the tablet.

The weight ratio of the film-coated layer to the total amount of the film-coated tablet is not particularly limited, and it can usually be 1 to 20% by weight, preferably 2 to 10% by weight, and more preferably in the range of 4 to 8% by weight. If the weight of the film coating layer does not reach the above-mentioned range, the photostability improvement effect of methotrexate may not be sufficiently obtained. In addition, if the weight of the film coating layer exceeds the above range, the coating time will be longer and the workability in actual production will be poor. In addition, there may be cases where the user does not like the color of the lozenge.

The iron oxide contained in the film coating of this tablet can be used Iron trioxide, yellow iron trioxide, black iron oxide, etc., can also be used alone or in combination corresponding to the color of the purpose. Pre-mixed film coating agents prepared with iron oxide can also be used as commercially available products.

The content of iron oxide in the film coating layer is not particularly limited. Relative to the total amount of the film coating layer, it can usually be 0.1 to 20% by weight, preferably 0.5 to 15% by weight, and more preferably in the range of 1 to 10% by weight. . As far as iron oxide is concerned, the content of yellow iron trioxide when used alone or in combination with other iron oxides is not particularly limited. Usually it can be 0.005 to 10% by weight, preferably 0.01 to 5% by weight, more preferably In the range of 0.01 to 4% by weight. As far as iron oxide is concerned, the content of iron trioxide when used alone or in combination with other iron oxides is not particularly limited. It can usually be 0.01 to 20% by weight, preferably 0.05 to 10% by weight, more preferably in the range of 0.01 to 20% by weight. The range of 0.1 to 7% by weight. As far as iron oxide is concerned, the content of black iron oxide when used alone or in combination with other iron oxides is not particularly limited, and is usually 0.01 to 5 wt%, preferably 0.05 to 3 wt%, and more preferably 0.1 To the range of 1% by weight.

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

In the film coating layer, the content when only using yellow iron trioxide is not particularly limited. Relative to the total amount of the film coating layer, it can usually be between 0.1 and 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 yellow iron trioxide, iron trioxide and black iron oxide in combination is not particularly limited. Relative to the total amount of the film coating layer, the amount of yellow iron trioxide is usually 0.005 to 1 weight %, preferably 0.01 to 0.5% by weight. It is more preferably in the range of 0.01 to 0.1% by weight. Iron trioxide can usually be in the range of 0.1 to 20% by weight, preferably 1 to 10% by weight, more preferably in the range of 2 to 7% by weight, and black iron oxide can usually be in the range of 0.01 to 5% by weight, preferably in the range of 0.05 to 3% by weight, more preferably in the range of 0.1 to 1% by weight.

Methotrexate will decompose due to light exposure and produce analogs. As a result, the content of methotrexate in the pharmaceutical composition will decrease. However, if the film-coated tablet containing methotrexate contains iron oxide in both the bare tablet and the film-coated layer, it can significantly inhibit the generation of analogs caused by light exposure. In particular, iron trioxide has the highest effect among iron oxides. If iron trioxide is contained in both the film coating layer and the bare tablet, the effect of fully enhancing the photostability of methotrexate can be exerted.

The film-coated tablet of the present invention can also contain conventional carrier components or additives in the bare tablet without damaging the effect of the present invention. Carrier components or additives can be exemplified as excipients, disintegrants, binders, lubricants, antioxidants, preservatives, dissolution aids, surfactants, fluidizers, plasticizers, pH adjusters, colorants, and flavors. Agents, sweeteners, fragrances, adsorbents, preservatives, wetting agents, etc. These carrier components or additives can be used alone, or two or more of them can be used in combination.

Excipients can be exemplified such as sugar alcohols (D-sorbitol, erythritol, xylitol, powdered reduced maltose syrup, etc.), sugars (lactose, glucose, fructose, white sugar, etc.) and their hydrates, crystalline cellulose, Powdered cellulose, starches (potato starch, corn starch, wheat starch, etc.), dextrin, β-cyclodextrin, sodium carboxymethyl cellulose, light anhydrous silicic acid, hydrous silica, silica, sedimentation Calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, titanium oxide, calcium lactate, magnesium aluminum metasilicate, synthetic hydrotalcite, talc, kaolin, etc.

The disintegrant can be exemplified by carboxymethyl cellulose (e.g. carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crystalline cellulose‧carboxymethyl Sodium cellulose, etc.), carboxymethyl starches (such as sodium carboxymethyl starch, etc.), crospovidone, low-substituted hydroxypropyl cellulose, low-substituted sodium hydroxymethyl starch, starches (Corn starch, etc.), alginic acid, bentonite, etc. Preferably, exemplified are croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose Methylcellulose, crystalline cellulose‧Sodium carboxymethylcellulose, sodium hydroxymethyl starch with low degree of substitution. More preferably, examples thereof include low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch. These disintegrants can be used alone or in combination of two or more.

Lubricants can be exemplified by stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hardened oil, polyethylene glycol, dimethyl polysiloxane, palm wax, Sodium lauryl sulfate, beeswax, white beeswax, etc. These lubricants can be used alone or in combination of two or more kinds. Among these lubricants, stearates such as magnesium stearate are widely used.

The fluidizing agent can be exemplified by light anhydrous silicic acid, talc, and hydrous silica.

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

(Example)

Investigate the relationship between "the type and content of iron oxide in the film coating layer" and "the generation of analogs when the tablets obtained are exposed to light". The results are shown in Tables 2-9. This is explained below.

According to the prescription No.1 to No.3 shown in Table 2, for 2mg tablets, weigh 0.2kg methotrexate, 3.58kg crystalline cellulose, 2.00kg corn starch, 7.47kg lactose hydrate, and cross-linked carboxymethyl 0.87kg of sodium cellulose and 0.03kg of ferric oxide. Put the weighed powder into a high-speed mixing granulator (FG-GS-50, manufactured by Shenjiang Powtec Co., Ltd.), and prepare for mixing. Add 2.00 kg of purified water to the mixed powder, stir and granulate, and dry it with a fluidized bed dryer (2011-141, Jeil Machine). A vibrator granulator was used for granulation to obtain 14.15 kg of granules. Put the obtained granules into a double cone mixer (SY-M, BOSEONG machine), add 0.10 kg of light anhydrous silicic acid and 0.25 kg of magnesium stearate to mix to obtain granules. Regarding the 1 mg tablet, the compounding amount of methotrexate in the above-mentioned 2 mg tablet manufacturing method was changed to 0.1 kg, and the compounding amount of lactose hydrate was changed to 7.57 kg, and the granules were obtained in the same way. Regarding the 4mg tablet, the compounding amount of methotrexate in the above 2mg tablet manufacturing method was changed to 0.4kg, and the compounding amount of lactose hydrate was changed to 7.27kg, and the granules were obtained in the same way.

1mg tablets, 2mg tablets and 4mg tablets of bare tablets are used in diameter A 7.0mm mortar/pusher was used to produce a bare ingot of 14.50kg using a rotary tableting machine (HT-P22-A-3, manufactured by Hatako Co., Ltd.).

As shown in the embodiment No.1 to No.3 in Table 2, regarding the film coating liquid, for 1mg tablet, it is used to mix yellow iron trioxide and iron trioxide, and for 2mg tablet it is only used to mix yellow For those with iron trioxide, the 4mg tablet is prepared with yellow iron trioxide, iron trioxide and black iron oxide. Put 14.50 kg of the bare ingot into the coating device, and coat until the 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 methotrexate in one tablet were obtained.

(Comparative Examples 1 to 3)

As shown in Tables 4, 6 and 8 of Comparative Examples 1 to 3 (prescription No. 4 to No. 18), except for the bare ingot portion where no iron trioxide is blended, the type and amount of iron oxide in the film coating layer are Except for various changes and fine adjustment of the formulation amounts of other additives, the same operation as in the example was performed to obtain a film-coated tablet containing methotrexate.

(Light stability test)

The film-coated tablets obtained in the Examples and Comparative Examples were subjected to a light stability test under the following conditions. Place each film-coated tablet uniformly on a glass plate, and irradiate it with 3500lx for 15 days or 4000lx for 13 days in a constant temperature and humidity tank maintained at 25℃ and 60% RH, so that the cumulative illuminance becomes more than 1.25 million lx‧hr .

(Quantitative test)

After the above-mentioned light exposure, a sample solution was prepared based on the method of the Japanese Pharmacopoeia, and the peak area of methotrexate was measured by liquid chromatography to determine its content. The results are shown in Tables 3, 5, 7 and 9. In Comparative Example 1, where the film coating layer did not contain iron oxide but only contained titanium oxide, the content of methotrexate decreased by more than 3% of the standard value of the Japanese Hospital Pharmacist Association. On the other hand, for other prescriptions (No. 4, 5, 8 to 9 and 11 to 18) of iron oxide blending in the film coat, the content reduction is below the same reference value. The test conditions are as follows.

[Test conditions]

Detector: ultraviolet absorbance photometer (measurement wavelength: 302nm)

Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is filled with 5μm octadecyl silyl silica gel for liquid chromatography (for example, Wakopak (registered trademark) Wakosil-II5C18HG manufactured by Wako Pure Chemical Industries, Ltd.) ).

Column temperature: a certain temperature near 25℃

Mobile phase: Add sodium hydroxide test solution to 1000 mL of anhydrous sodium dihydrogen phosphate 6.00 g dissolved 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 light exposure, according to the Japanese Pharmacopoeia method, filter the sample solution of the quantitative test with a membrane filter with a pore size of 0.45μm or less, remove more than 1mL of the first filtrate, and add the quantitative method to the following filtrate according to the indicated amount Of the mobile phase, making it into about 1 mL containing methotrexate A 0.2mg solution was used as the sample solution. The amount of analogs B, C and E produced was determined by liquid chromatography.

The chemical name of analogue B is (S)-2-{4-[(2,4-diaminopteridine-6-yl)methylamino]benzamide}glutaric acid, which has Reproductive toxicity and also suspected of carcinogenic substances.

The chemical name of analog C is (S)-2-(4-{[(2-amino-4-side oxy-1,4-dihydropteridine-6-yl)methyl](methyl) Amino} benzamide) glutaric acid.

The chemical name of analogue E is 4-{[(2,4-diaminopteridine-6-yl)methyl](methyl)amino}benzoic acid, which is a substance that may cause allergic skin reactions .

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 analogue is above 0.3% of the USP reference value, or there is more than one unknown peak above 0.2% of the reference value of the impurity guide.

The same applies to Nos. 9 and 10 in Comparative Example 2. Any analogue is above 0.3% of the USP reference value, or more than one unknown peak above 0.2% of the reference value of the impurity guide can be seen. In addition, in prescription No. 11, iron oxide is not contained in the bare ingot and the light stability can be ensured, but the coating layer is thick, which is evaluated for poor workability in actual production. In Comparative Example 2, 2 specifications (prescription Nos. 12 to 15) of 2 mg tablets and 4 mg tablets can ensure light stability and can be made into different colors, but 1 mg tablets are not up to the standard.

In Comparative Example 3, Nos. 16 to 18 do not contain iron oxide in the bare ingot and can ensure light stability, but all of them have an appearance similar to orange, and cannot be made into different colors according to specifications.

[Test conditions]

Detector: ultraviolet absorbance photometer (measurement wavelength 280nm)

Column: A stainless steel tube with an inner diameter of 4.6mm and a length of 25cm is filled with 5μm octadecylsilyl silica gel for liquid chromatography (for example, Wakopak (registered trademark) Wakosil-II5C18HG manufactured by Wako Pure Chemical Industries, Ltd.) .

Column temperature: a certain temperature near 25℃

Phosphate buffer of pH 6.0: Dissolve 3.40 g of anhydrous sodium dihydrogen phosphate in water to make a 1000 mL solution, add sodium hydroxide test solution to it, and adjust the pH to 6.0.

Mobile phase A: Acetonitrile/pH6.0 phosphate buffer mixture (1:19)

Mobile phase B: acetonitrile/pH6.0 phosphate buffer mixture (1:1)

Liquid feeding of mobile phase: Change the mixing ratio of mobile phase A and mobile phase B as shown in Table 1, and control the concentration gradient.

Flow rate: 1.0mL per minute

Area measurement range: 40 minutes after sample solution injection

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

Compared with [1] which does not use iron oxide at all, the use of any iron oxide [2] to [4] can suppress the increase of analogs.

In terms of iron oxide, the use of iron trioxide alone [2], when compared with the use of yellow iron trioxide alone [3], and the combination of two iron trioxide and yellow iron trioxide [4] , The result of a low increase rate of analogues was obtained. In addition, with regard to the number of unknown peaks above 0.2% and 0.5%, the use of iron trioxide alone [2] is the least. It can be seen that the use of iron trioxide alone in the bare ingot can improve the light stability of methotrexate. Furthermore, it is shown that the blending amount of the iron trioxide needs to be about 0.2 to 0.4 mg (0.1 to 0.3% by weight relative to the whole bare ingot).

Based on the above results, the film-coated tablets containing methotrexate produced in the examples can suppress the decrease in methotrexate content due to light exposure by mixing iron oxide in the film coating layer. Below the value. In addition, when the appearance is made light-colored due to the selection of iron oxide or content in the film coating layer, if iron oxide is blended in the bare ingot, the decrease in methotrexate content can be suppressed and the similarity can be improved. The generation situation becomes below the reference value, and the number of unknown peaks can also be suppressed. In addition, 1 mg tablets, 2 mg tablets, and 4 mg tablets can be made into different colors.

(Possibility of industrial use)

The film-coated tablet containing methotrexate of the present invention can reduce the content of active ingredients or suppress the increase of the like below the reference value even after light exposure, so it does not need to be stored under light shielding. In addition, since it can also be made into different colors according to the content specification, it can ensure the identification of the patient or the medical person, and the convenience is high.

Claims (20)

A film-coated tablet, which contains methotrexate as an active ingredient, and contains iron trioxide in the bare ingot and iron oxide in the film coating layer. The amount of iron trioxide contained in the bare ingot is relative to the total amount of the bare ingot. 0.1 to 0.3% by weight. The film-coated tablet described in item 1 of the scope of patent application, wherein the iron oxide in the film-coated layer is one or more selected from the group consisting of ferric oxide, yellow ferric oxide, and black iron oxide. The film-coated tablet described in item 1 of the scope of patent application, wherein the content of iron oxide in the film-coating layer is 0.1 to 20% by weight relative to the total amount of the film-coating layer. The film-coated tablet described in item 2 or item 3 of the scope of patent application, wherein the content of yellow iron trioxide in the film-coating layer is 0.005 to 10% by weight relative to the total amount of the film-coating layer. The film-coated tablet described in item 2 or item 3 of the scope of patent application, wherein the content of iron trioxide in the film-coating layer is 0.01 to 20% by weight relative to the total amount of the film-coating layer. The film-coated tablet described in item 2 or item 3 of the scope of patent application, 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. Such as the film-coated tablet described in item 2 or item 3 of the scope of patent application, wherein the iron oxide in the film coating layer is yellow iron trioxide and iron trioxide. The film-coated tablet described in item 7 of the scope of patent application, wherein the yellow iron trioxide in the film-coating layer is 0.1 to 10% by weight relative to the total amount of the film-coating layer. The film-coated tablet described in item 7 of the scope of patent application, wherein, in the film-coated layer The content of iron trioxide is 0.01 to 10% by weight relative to the total amount of the film coating layer. For the film-coated tablet described in item 2 or item 3 of the scope of patent application, the iron oxide in the film-coating layer is only yellow iron trioxide. The film-coated tablet described in item 10 of the scope of patent application, wherein the content of the yellow iron trioxide in the film-coating layer is 0.1 to 10% by weight relative to the total amount of the film-coating layer. Such as the film-coated tablet described in item 2 or item 3 of the scope of patent application, wherein the iron oxide in the film coating layer is yellow iron trioxide, iron trioxide and black iron oxide. The film-coated tablet described in item 12 of the scope of patent application, wherein the content of the yellow iron trioxide in the film-coating layer is 0.005 to 1% by weight relative to the total amount of the film-coating layer. The film-coated tablet described in item 12 of the scope of patent application, wherein the content of iron trioxide in the film-coating layer is 0.1 to 20% by weight relative to the total amount of the film-coating layer. The film-coated tablet described in item 12 of the scope of patent application, 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. According to the film-coated tablet described in item 1 of the scope of the patent application, the content of methotrexate is 0.3 to 5% by weight in 100% by weight of the bare tablet. The film-coated tablet described in item 1 of the scope of patent application, wherein the weight of the film-coated layer relative to the total weight of the film-coated tablet is 1 to 20% by weight. The film-coated tablet described in item 7 of the scope of patent application, one tablet contains amine Methotrexate 1mg. The film-coated tablet described in item 10 of the scope of patent application contains 2 mg methotrexate in one tablet. The film-coated tablet described in item 12 of the scope of patent application contains 4 mg methotrexate in one tablet.