JP5820951B2 - Composition with improved photostability - Google Patents

Description

  The present invention relates to an oral solid composition and formulation containing amlodipine and having improved photostability.

Amlodipine, a dihydropyridine calcium antagonist, plays a central role in antihypertensive therapy because of its sufficient and constant vasodilatory effect and the unlikely nature of tachycardia. However, amlodipine is a compound that is not easily photodegraded among dihydropyridine compounds, but when it is exposed to a large amount of light, it may be decomposed to reduce its effectiveness as an active substance. For this reason, the technique for ensuring the stability with respect to light was required for the amlodipine containing oral solid composition.
Conventionally, regarding the formulation of drugs that are unstable to light, various methods are known in order to stabilize the drugs. For example, Patent Document 1 discloses a soft capsule of nifedipine that prevents degradation and alteration by light, in which nifedipine, which is a drug unstable to light, is sealed in a soft capsule in which a colorant is dispersed in a film. Patent Document 2 discloses a capsule preparation in which active vitamin D3 is stabilized by a hard capsule containing a tar-based pigment, Bengala, or the like. All of these techniques contain a colorant in a capsule film covering a photolabile drug, and are difficult to apply to tablets, granules, fine granules, powders, and the like.

  On the other hand, Patent Document 3 discloses a tablet stabilized with respect to light obtained by coating a tablet of dihydropyridine derivative with a film containing iron oxide. However, with this technique, the number of steps increases due to the coating, and the time and labor required for this increase, and the cost increases. Moreover, in the case of a tablet that requires division, troubles such as filling of the dividing line due to coating are likely to occur, and the divided surface is exposed after division, so that the light stabilization effect cannot be expected. Furthermore, it cannot be applied to a preparation that cannot be coated for some reason. For example, in an orally disintegrating preparation, when a coating is applied to the whole preparation, the rapid disintegration property and fast dissolution property in the oral cavity are impaired, and the function cannot be expressed. In addition, by coating only the drug substance or particles containing the drug substance in the drug product, it is possible to maintain fast disintegration as the drug product. In this case, however, a part of the coated drug product in the oral cavity Is not expected to disintegrate or dissolve, making it extremely difficult to take. Patent Document 4 discloses a light-stable pyridine compound containing titanium oxide as a light-shielding agent and edible yellow No. 5, iron sesquioxide and yellow sesquioxide as a colorant. However, what is actually disclosed in this document is that a coating liquid containing a colorant and a light-shielding agent is sprayed on a preparation in which alanidipine is solid-dispersed with an appropriate excipient. The document substantially discloses a preparation having a coating layer (Patent Document 4, page 2, column 1, line 50 to column 2, line 4 and page 2, column 2, line 32 to 3). Page 4 column 5 line 5 example).

  As a light stabilization method for tablets, granules, fine granules, powders, etc. that are not coated, Patent Document 5 discloses one or more substances selected from fat-soluble drugs that are unstable to light and yellow and red colorants. A composition having improved light stability is disclosed. Patent Document 6 discloses an oral solid composition obtained by adding a colorant to a powder containing a photolabile drug and performing wet granulation. Furthermore, Non-Patent Document 1 describes that when yellow ferric oxide is added to nifedipine, the amount of oxidant produced by light can be suppressed and the decrease in the content of the active ingredient can be suppressed. However, these documents do not describe amlodipine.

Japanese Patent Laid-Open No. 55-22645 JP-A-4-46122 JP 2003-104888 A JP 2003-104887 A JP 2000-7583 A JP 2000-191516 A

International Journal of Pharmaceutics, 103 (1994) 69-76

  The problem to be solved by the present invention is to provide a light-stabilized oral solid composition that easily prevents discoloration and decomposition of amlodipine or a pharmaceutically acceptable salt thereof by light.

  Since amlodipine has high photostability as a dihydropyridine compound, a decrease in the content within the range where it is usually used as a pharmaceutical is hardly a problem. The present inventors paid attention to the fact that, unlike nifedipine, in amlodipine, discoloration is observed in a range where no decrease in content is detected by light, and it has been an object to prevent this coloring. Since Non-Patent Document 1 does not describe any discoloration, there is no description or suggestion of such a problem. The issue of this document is to improve the generation of degradation products by 45% when a nifedipine tablet is irradiated with 400 foot candela for 14 days. On the other hand, as shown in the test examples described later, since the oxidant production in the amlodipine tablet is about 1%, the degree of decomposition is completely different. Therefore, it was clarified that the main problem in amlodipine is the prevention of coloration, which is a phenomenon completely different from the content reduction, which is the main problem in nifedipine.

  Furthermore, the present inventors have found that the coloring behavior itself is completely different between nifedipine and amlodipine. That is, when tablets were actually prepared and confirmed, completely different coloring behavior was exhibited when similarly prepared nifedipine and amlodipine tablets were placed under a fluorescent lamp. In the case of nifedipine, the nifedipine tablet, which is yellow from the beginning due to the color of nifedipine itself, begins to fade in a few hours, and then becomes brown in spots. On the other hand, in the case of amlodipine, it is white at first, and it becomes slightly yellow colored much more slowly than nifedipine. This also shows that the coloring reaction of nifedipine and the coloring reaction of amlodipine show completely different behaviors, and it is notable at all that it is impossible to predict whether a measure for improving the photostability against nifedipine can be applied to amlodipine. On the other hand, it is menatetrenone and sofalcone that have actually confirmed the effects in Patent Documents 5 and 6 above, and are not even adihydropyridine drugs having the same skeleton rather than amlodipine, so the effects of amlodipine are predicted from these documents It is more difficult to do.

  Furthermore, the present inventors have found that when titanium oxide is added to amlodipine as shown in the test examples described later, the decomposition by light is accelerated and the stability is not improved. Antioxidants such as dibutylhydroxytoluene and butylhydroxyanisole are well known as stabilizers that suppress oxidative degradation, but these antioxidants suppress the amount of degradation products produced by oxidation of amlodipine. However, it has been found that the discoloration is not suppressed at all. In other words, at least in amlodipine, it was found that the decomposition and discoloration by light do not always exhibit the same behavior. For this reason, the discoloration inhibitory effect at the time of mix | blending iron oxide with amlodipine could not be anticipated at all.

  In recent years, an aging society has progressed, and the number of elderly people with reduced or impaired food intake functions (such as mastication and swallowing) due to decreased physiological functions or senile dementia is increasing. When such an elderly patient is orally administered as a tablet, problems such as difficulty in taking it have arisen. On the other hand, because of the advantage that it can be taken at any time and place in a busy modern society, there is a demand for the development of an oral preparation that is stable, low in volume and convenient to carry without requiring water at the time of taking. As a result of various studies, the present inventors have been able to obtain an orally disintegrating preparation of amlodipine with improved dosing properties. However, as described above, there has been no effective means that can achieve light stabilization of amlodipine for a preparation that cannot be coated to express its function, such as an orally disintegrating tablet. For this reason, the present inventors considered that if an amlodipine tablet that is stable against light can be provided without coating, it can be applied to orally disintegrating tablets and the like.

  As a result of intensive studies, the present inventors incorporated iron oxide into amlodipine or a pharmaceutically acceptable salt thereof, so that it is very easy and stable without requiring a coating layer for light stabilization. It was found that an amlodipine-containing oral solid composition was obtained. In addition, by applying this technology, it has been found that by incorporating iron oxide into amlodipine or a pharmaceutically acceptable salt thereof, it is possible to very easily and photostabilize an orally disintegrating preparation excellent in dosage. Completed the invention.

That is, the present invention relates to the following.
[1] An oral solid composition containing (a) amlodipine besylate, (b) iron oxide, and (c) mannitol and croscarmellose sodium and having no coating layer.
[2] The oral solid composition according to [1], which is an oral solid composition containing no titanium oxide.
[3] The oral solid composition according to [1] or [2], which is an orally disintegrating preparation.
[4] Furthermore, (d) selected from the group consisting of starch, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, low-substituted carboxymethyl starch sodium, and crospovidone Oral solid composition in any one of [1]-[3] containing 1 or more types.
[5] The oral solid composition according to any one of [1] to [4], further comprising (e) sodium stearyl fumarate.
[6] The oral solid composition according to any one of [1] to [5], wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide.
[7] The oral solid composition according to any one of [1] to [5], wherein the iron oxide is yellow ferric oxide.
[8] The oral solid composition according to any one of [1] to [5], wherein the iron oxide is yellow iron oxide.
[9] The oral solid composition according to any one of [1] to [5], wherein the iron oxide is iron sesquioxide.
[10] The oral solid composition according to any one of [1] to [9], comprising a mixture of (a) amlodipine besylate and (b) iron oxide.
[11] The oral solid composition according to any one of [1] to [10], comprising a composition obtained by granulating a mixture of (a) amlodipine besylate and (b) iron oxide.
[12] The oral solid composition according to any one of [1] to [11], wherein iron oxide is added in preparation of an oral solid composition containing amlodipine besylate, mannitol, and croscarmellose sodium Manufacturing method.
[13] The production method of [12], wherein the oral solid composition is an orally disintegrating preparation.
[14] The production method of [12] or [13], wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide.
[15] The production method of [12] or [13], wherein the iron oxide is yellow ferric oxide.
[16] The production method according to [12] or [13], wherein the iron oxide is yellow iron oxide.
[17] The production method of [12] or [13], wherein the iron oxide is iron sesquioxide.
[18] Use of iron oxide for preparing a composition in which discoloration by light is suppressed in the preparation of the oral solid composition according to any one of [1] to [11].
[19] The use according to [18], wherein the oral solid composition is an orally disintegrating preparation.
[20] Use of [18] or [19], wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide.
[21] The use according to [18] or [19], wherein the iron oxide is yellow ferric oxide.
[22] The use according to [18] or [19], wherein the iron oxide is yellow iron oxide.
[23] Use according to [18] or [19], wherein the iron oxide is iron sesquioxide.
[24] A method for suppressing discoloration due to light in an obtained oral solid composition, wherein iron oxide is further added to a component containing amlodipine besylate, mannitol and croscarmellose sodium.
[25] The method according to [24], wherein the oral solid composition is an orally disintegrating preparation.
[26] The method according to [24] or [25], wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide.
[27] The method according to [24] or [25], wherein the iron oxide is yellow ferric oxide.
[28] The method according to [24] or [25], wherein the iron oxide is yellow iron oxide.
[29] The method according to [24] or [25], wherein the iron oxide is iron sesquioxide.
[30] In the oral solid composition according to any one of [1] to [11], a photodiscoloration inhibitor comprising iron oxide for inhibiting discoloration by light.

  According to the present invention, it is possible to provide an amlodipine-containing oral oral solid composition that is very light-stable very easily. In addition, this makes it possible to maintain the quality of light-stabilized preparations such as amlodipine orally disintegrating tablets of amlodipine that cannot be coated, and patients who have difficulty in swallowing such as elderly people and people who have a busy social life However, it is possible to provide a light-stable amlodipine oral solid composition that can be easily taken in any situation.

Amlodipine [2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl] has an optically active center. Therefore, (S)-(−) isomer and (R)-(+) isomer exist, but any one or a mixture thereof can be used in the present invention. Preferably, the (S)-(−) isomer and the racemate are used.
Examples of pharmaceutically acceptable salts of amlodipine include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, succinic acid, salicylic acid, methanesulfonic acid, Examples thereof include salts with benzenesulfonic acid and toluenesulfonic acid. Preferred is a salt with benzenesulfonic acid, that is, amlodipine besylate.

  In the present invention, examples of the iron oxide include yellow iron sesquioxide, yellow iron oxide, iron sesquioxide, red iron oxide, and black iron oxide, preferably yellow iron sesquioxide, yellow iron oxide, and iron sesquioxide. More preferably, yellow ferric oxide is used.

  The appropriate blending amount of these iron oxides varies depending on the type of iron oxide and dosage form to be blended.For example, in the case of tablets containing yellow iron sesquioxide, if a large amount is blended, black spots will be formed at the time of tableting and the quality will be improved. If the blending amount is too small, a sufficient effect cannot be obtained. Therefore, a preferable addition amount is 0.01 to 10% by weight. More preferable addition amount is 0.01 to 5% by weight, further preferable addition amount is 0.03 to 2% by weight, and further preferable addition amount is 0.03 to 1% by weight. Particularly preferred addition amount is 0.05 to 0.5% by weight.

  The particle size of the iron oxide in the present invention is not particularly limited as long as it is a size that can be uniformly dispersed and blended in an oral solid composition in terms of quality as a pharmaceutical, but for example, using a laser diffraction scattering type particle size distribution measuring device The volume average particle diameter when measured is 0.01 to 1.0 μm, more preferably 0.01 to 0.5 μm, and still more preferably 0.1 to 0.5 μm.

  Examples of the oral solid composition in the present invention include granular preparations such as jelly preparations, gummi preparations, dry syrups, powders, fine granules and granules, and preparations such as tablets, chewable preparations and orally disintegrating preparations. . More preferred are jelly preparations, gummi preparations, chewable preparations, and orally disintegrating preparations that can be taken at any time and place because water is not required at the time of taking. More preferred is an orally disintegrating preparation, and particularly preferred is an orally disintegrating tablet.

The coating layer in this invention is a layer which covers the outermost part of the unit orally administered directly, and does not include packaging, such as a PTP sheet.
Specifically, for example, a film forming property to an oral solid composition obtained by dry granulation or wet granulation of an active ingredient, an excipient, a disintegrant, a binder, etc., and if necessary, molding such as tableting. An outer layer formed with a composition different from the oral solid composition applied to the outside of the oral solid composition by spraying, drying, or the like is used. Various additives are usually added to the film-forming polymer solution as long as film formation is not inhibited. Coating refers to the formation of such a coating layer.
Other coating layers include capsules such as soft capsules and hard capsules.

  Although there is no particular limitation on the content of amlodipine or a pharmaceutically acceptable salt thereof in the present invention, since amlodipine is usually administered at 2.5 to 5 mg per day, amlodipine or a pharmaceutically acceptable salt thereof is taken into consideration in terms of the size of the preparation. It is desirable to add an acceptable salt in an amount of 0.1 to 10% by weight as amlodipine. More preferably, amlodipine or a pharmaceutically acceptable salt thereof is formulated so as to contain 0.25 to 6.25% by weight as amlodipine, more preferably 1 to 6.25% by weight, particularly preferably 2 Formulated to contain ~ 5% by weight.

The orally disintegrating preparation in the present invention is a preparation that can be dissolved or disintegrated rapidly in the oral cavity without water and can be taken with water in the same manner as a normal preparation. Examples of the dosage form include granular preparations such as powders, fine granules, granules, and tablets.
The dissolution or disintegration time in the oral cavity of the orally disintegrating granular preparation and orally disintegrating tablet in the present invention is usually within 1 minute, preferably within 45 seconds, more preferably within 30 seconds.
In the orally disintegrating preparation of the present invention, it is preferable to add a water-soluble excipient as an excipient from the viewpoint of ingestion. Examples of water-soluble excipients include water-soluble sugar alcohols, saccharides, sweet amino acids having a good sweetness when taken, and mixtures thereof, preferably water-soluble sugar alcohols, sugars, glycine and mixtures thereof. Particularly preferred are water-soluble sugar alcohols.

  The water-soluble sugar alcohol in the present invention means, for example, that when 1 g of sugar alcohol is added to water and shaken strongly every 5 minutes at 20 ° C. for 30 seconds to dissolve within about 30 minutes, the amount of water required is less than 30 ml. A certain sugar alcohol etc. are mentioned. Examples of water-soluble sugar alcohols include sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol and the like, and two or more of these may be used in an appropriate ratio. Preferred water-soluble sugar alcohols include mannitol, xylitol, and erythritol, more preferably mannitol and erythritol, and particularly preferably mannitol. Although it does not specifically limit as content of the water-soluble sugar alcohol in this invention, For example, 50-99.9 weight% is mentioned, Preferably, 70-97 weight% is mentioned, More preferably, 70-90 weight% is mentioned, Especially preferably, 75-85 weight% is mentioned.

  The orally disintegrating preparation in the present invention preferably contains a disintegrating agent from the viewpoint of disintegrating property. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, low substituted hydroxypropyl cellulose, carboxymethyl starch sodium, low substituted carboxymethyl starch sodium, croscarmellose sodium, crospovidone, Two or more of these may be mixed at an appropriate ratio. Preferably, starch, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, croscarmellose sodium, and crospovidone are used. More preferred are starch, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, croscarmellose sodium, and crospovidone, and still more preferred are starch and low-substituted hydroxypropylcellulose. Particularly preferred is starch.

  The starch in the present invention includes all starches derived from any natural starch that can be used in pharmaceuticals. Examples thereof include potato starch, corn starch, wheat starch, rice starch and soluble starch, partially pregelatinized starch, pregelatinized starch, hydroxypropylated starch, and the like, and preferably corn starch. The starch content is, for example, 1 to 50% by weight, preferably 2 to 30% by weight, more preferably 3 to 20% by weight, and still more preferably 5 to 15% by weight.

  In the orally disintegrating preparation of the present invention, the binder is not particularly limited, but starch (including partially pregelatinized starch), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, methylcellulose, gum arabic powder, polyvinyl alcohol And alkyl hydroxyethyl cellulose. From the viewpoint of disintegration, it is desirable to use substantially no starch other than starch. The term "substantially" means that the oral disintegrating preparation, particularly the dissolution or disintegration rate in the oral cavity, and other binders are allowed in an amount that does not affect the light stabilization effect of the present invention. means.

  In the oral solid composition of the present invention, in addition to the above-mentioned components, nontoxic and inert additives usually used in the pharmaceutical field can also be added. These additives include those that are substantially added as pharmaceutical additives without substantially affecting the effects of the present invention. For example, excipients such as lactose, corn starch, mannitol, xylitol, sorbitol, erythritol, glycine, talc, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, crystalline cellulose, stearic acid, magnesium stearate, calcium stearate, Lubricants such as sodium stearyl fumarate, disintegrants such as carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, methylcellulose, Binders such as gum arabic powder, polyvinyl alcohol, alkyl hydroxyethyl cellulose, etc. Agents, flavoring agents, perfumes, adsorbents, preservatives, stabilizers, wetting agents, antistatic agents, pH adjusting agents and the like.

  In particular, a lubricant is used in producing the tablet of the present invention, and among them, magnesium stearate and sodium stearyl fumarate are preferable.

  In addition, blended with high-sweetness artificial sweeteners such as aspartame, acesulfame K, saccharin, sodium saccharin, stevia, sucralose, and flavoring agents such as peppermint, spearmint, menthol, lemon, orange, grapefruit, pine, fruit, yogurt In particular, when aspartame and a mint-based fragrance are blended, a more preferable dosing feeling can be obtained.

  Examples of the method for producing the oral solid composition of the present invention include known methods. For example, as a granulation method, an extrusion granulation method, a crushing granulation method, a dry compaction granulation method, a fluidized bed granulation method, Examples thereof include a rolling granulation method, a rolling fluidized bed granulation method, and a high-speed stirring granulation method. Examples of the tableting method include a wet tableting method and a direct tableting method.

  Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not necessarily limited thereto.

Tablet formulation (mg)

１．商品名Ｄ−マンニトール（協和発酵工業株式会社）
２．商品名コーンスターチ(XX16)W（日本食品化工株式会社）
３．商品名プルーブ（Penwest Pharmaceuticals社（米国））
４．商品名黄色三二酸化鉄（癸巳化成化成株式会社）
５．商品名三二酸化鉄（キシ化成株式会社）
６．商品名精製脱砒酸化チタン（ザクトレーベンケミエ社（ドイツ））
７．商品名3-t-ブチル-4-ヒドロキシアニソール（ナカライテスク株式会社）
８．商品名2,6-ジ-t-ブチル-p-クレゾール（ナカライテスク株式会社）
９．商品名食用黄色５号（三栄源エフ・エフ・アイ株式会社）
１０．商品名食用黄色５号アルミニウムレーキ（三栄源エフ・エフ・アイ株式会社）
１１．商品名食用赤色５号（三栄源エフ・エフ・アイ株式会社）
１２．商品名食用赤色１０２号（三栄源エフ・エフ・アイ株式会社）

実施例１〜３および比較例１〜８に関しては表１の処方に従い、処方の１２倍量の各成分を乳鉢にてよく混合した後、１錠処方量を秤取して油圧式プレス機（理研製）を用いて５０ｋｇｆの圧力で圧縮し、直径７ｍｍの錠剤を得た。

1. Product name D-mannitol (Kyowa Hakko Kogyo Co., Ltd.)
2. Product Name Corn Starch (XX16) W (Nippon Food Chemical Co., Ltd.)
3. Product name Prove (Penwest Pharmaceuticals (USA))
4). Product name Yellow iron sesquioxide (Hana Kasei Chemical Co., Ltd.)
5. Product name Ferric oxide (Kishi Kasei Corporation)
6). Product name Refined dearsenic oxide (Zactreben Chemie (Germany))
7). Product name 3-t-butyl-4-hydroxyanisole (Nacalai Tesque)
8). Product name 2,6-di-t-butyl-p-cresol (Nacalai Tesque)
9. Product name Edible Yellow No. 5 (Saneigen FFI Co., Ltd.)
10. Product name Food Yellow 5 Aluminum Lake (San-Eigen FFI Co., Ltd.)
11. Product name Food Red 5 (Saneigen FFI Co., Ltd.)
12 Product name red food No. 102 (San-Eigen FFI Co., Ltd.)

For Examples 1 to 3 and Comparative Examples 1 to 8, according to the prescription in Table 1, each component of 12 times the amount of the prescription was mixed well in a mortar, and then 1 tablet prescription was weighed and a hydraulic press machine ( The tablet was compressed at a pressure of 50 kgf using a product of RIKEN, and a tablet having a diameter of 7 mm was obtained.

Test Example A photostability test was performed on the preparations of Examples 1 to 3 and Comparative Examples 1 to 8. Table 2 shows the results of the appearance and the amount of oxidant generated in the fluorescent lamp 4000 lux × 2 weeks. The oxidant (2-[(2-aminoethoxy) methyl] -4- (o-chlorophenyl) -6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl ester 5-methyl ester) was quantified by liquid chromatography. Analyzed by the graph method.
HPLC analysis column: octadecyl group-bonded silica gel (average particle size 5 μm, inner diameter 4.6 × length 150 mm) (Nacalai Tesque, Inc., trade name COSMOSIL 5C18)
Solution A: 30mmol / L phosphate buffer (pH6.0) / methanol mixture (1: 1)
Liquid B: Methanol / 30mmol phosphate buffer (pH 6.0) mixed solution (19: 1)
B liquid: 80% → 0% gradient detector: UV
Detection wavelength: 237nm

（酸化体量は、HPLCの面積百分率値に補正係数の２をかけた数値（酸化体のＵＶ吸収強度がアムロジピンの１／２であるため））

(The amount of oxidant is a numerical value obtained by multiplying the HPLC area percentage value by a correction factor of 2 (because the UV absorption intensity of the oxidant is 1/2 that of amlodipine))

  From Table 2, it can be seen that the formulation of Comparative Example 1 which has not been light-stabilized has a large change in appearance and the amount of oxidant produced exceeds 1%. In contrast, the preparation containing titanium oxide of Comparative Example 2 not only prevented discoloration but also increased the amount of oxidant produced. For light stabilization by applying a coating layer, coating with titanium oxide, which has a strong light-shielding effect, is usually performed, but instead of coating, titanium oxide was mixed with the main agent and excipients. The formulation was found to be poorly photostable with respect to amlodipine. Therefore, it was found that the general idea that a light-stabilizing method can be applied to amlodipine by mixing a substance with a strong covering power with an active ingredient or excipient.

  Comparative Examples 3 and 4 are preparations to which antioxidants butylhydroxyanisole and dibutylhydroxytoluene are added, and Comparative Example 6 is a preparation to which edible yellow No. 5 aluminum lake is added. Although the amount produced was suppressed, the change in appearance could not be suppressed. Therefore, it was found that neither the addition of antioxidants nor the addition of pigments had any effect.

  In Comparative Examples 5, 7, and 8, which are preparations to which food yellow No. 5, food yellow No. 3, and food red No. 102, which are other yellow and red pigments, are added, respectively, both appearance change and oxidant production can be suppressed. There wasn't. Therefore, it was found that the addition of a dye generally has no light stabilization effect.

  As described above, it has been found that any of the light-shielding agent, the antioxidant, and the dye generally cannot suppress the formation of the oxidant and / or the appearance change, whereas the yellow three of Examples 1 to 3 It was found that in the preparation containing iron dioxide or iron sesquioxide, both appearance change and oxidant production were suppressed. Therefore, the general method cannot suppress both the appearance change and the oxidant generation amount, and the appearance change and the oxidant generation amount can be suppressed only by a specific combination of amlodipine and iron oxide.

In addition, the following are mentioned as an aspect of this invention.
[1] An oral solid composition containing (a) amlodipine or a pharmaceutically acceptable salt thereof and (b) iron oxide and having no coating layer.
[2] The oral solid composition according to [1], which is an oral solid composition substantially free of titanium oxide.
[3] The oral solid composition according to [1] or [2], which is an orally disintegrating preparation.
[4] The oral solid composition according to any one of [1] to [3], comprising the following components (a) to (d):
(a) Amlodipine or a pharmaceutically acceptable salt thereof
(b) Iron oxide
(c) Mannitol
(d) Corn starch
[5] The oral solid composition according to any one of [1] to [4], further containing sodium stearyl fumarate, wherein the oral solid composition is an orally disintegrating tablet.
[6] (a) The content of amlodipine or a salt thereof in an oral solid composition is 2 to 5% by weight as amlodipine,
(b) the content of iron oxide in the oral solid composition is 0.03 to 2% by weight;
(c) the content of mannitol in the oral solid composition is 70 to 90% by weight,
(d) the content of corn starch in the oral solid composition is 5 to 15% by weight, and
(e) The content of sodium stearyl fumarate in the oral solid composition is 1 to 3% by weight,
[5] The oral solid composition according to [5].
[7] The oral solid composition according to any one of [1] to [6], wherein the iron oxide is yellow ferric oxide.
[8] The oral solid composition according to any one of [1] to [7], comprising (a) amlodipine or a pharmaceutically acceptable salt thereof, and (b) a mixture of iron oxide.
[9] The composition according to any one of [1] to [8], comprising a composition obtained by granulating a mixture of (a) amlodipine or a pharmaceutically acceptable salt thereof, and (b) iron oxide. Oral solid composition.

  According to the present invention, it is possible to easily prevent discoloration and decomposition of amlodipine or a pharmaceutically acceptable salt thereof by light and provide a light-stabilized oral solid composition. As a result, the quality of an orally disintegrating preparation of amlodipine or a pharmaceutically acceptable salt thereof can be improved, and at the same time, a simpler and more portable packaging form can be achieved, which enables elderly people and busy modern working adults. It can be easily carried anywhere and can easily take amlodipine or a pharmaceutically acceptable salt thereof in any scene without ingesting water.

Claims (32)

  An oral solid composition containing (a) amlodipine besylate, (b) iron oxide, and (c) mannitol and croscarmellose sodium, and having no coating layer.   The oral solid composition according to claim 1, which is an oral solid composition containing no titanium oxide.   The oral solid composition according to claim 1 or 2, which is an orally disintegrating preparation.   And (d) one selected from the group consisting of starch, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethylstarch, low-substituted sodium carboxymethylstarch, and crospovidone The oral solid composition in any one of Claims 1-3 containing the above. Further, (e) also magnesium stearate containing sodium stearyl fumarate, Claims 1 to 4 oral solid composition according to any one. The oral solid composition according to claim 5, wherein component (e) is magnesium stearate . The oral solid composition according to claim 5, wherein component (e) is sodium stearyl fumarate . The oral solid composition according to any one of claims 1 to 7 , wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide. The oral solid composition according to any one of claims 1 to 7 , wherein the iron oxide is yellow ferric oxide. The oral solid composition according to any one of claims 1 to 7 , wherein the iron oxide is yellow iron oxide. The oral solid composition according to any one of claims 1 to 7 , wherein the iron oxide is iron sesquioxide. The oral solid composition according to any one of claims 1 to 11 , comprising a mixture of (a) amlodipine besylate and (b) iron oxide. (a) amlodipine besylate, and (b) containing granulated product of a mixture of iron oxide, claim 1-12 oral solid composition according to any one. The method for producing an oral solid composition according to any one of claims 1 to 13 , wherein iron oxide is blended in preparing an oral solid composition containing amlodipine besylate, mannitol, and croscarmellose sodium. The method according to claim 14 , wherein the oral solid composition is an orally disintegrating preparation. The production method according to claim 14 or 15 , wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide. The manufacturing method of Claim 14 or 15 whose iron oxide is yellow ferric oxide. The manufacturing method of Claim 14 or 15 whose iron oxide is yellow iron oxide. The manufacturing method of Claim 14 or 15 whose iron oxide is ferric oxide. In the preparation of claims 1 to 13 oral solid composition according to any use of the iron oxide to a composition discoloration due to light is suppressed. 21. Use according to claim 20 , wherein the oral solid composition is an orally disintegrating formulation. The use according to claim 20 or 21 , wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide. The use according to claim 20 or 21 , wherein the iron oxide is yellow ferric oxide. Use according to claim 20 or 21 , wherein the iron oxide is yellow iron oxide. Use according to claim 20 or 21 , wherein the iron oxide is iron sesquioxide.   A method for suppressing discoloration due to light in an obtained oral solid composition, wherein iron oxide is further added to a component containing amlodipine besylate, mannitol, and croscarmellose sodium. 27. The method of claim 26 , wherein the oral solid composition is an orally disintegrating formulation. 28. A method according to claim 26 or 27 , wherein the iron oxide is yellow ferric oxide, yellow ferric oxide, or ferric oxide. 28. A method according to claim 26 or 27 , wherein the iron oxide is yellow ferric oxide. 28. A method according to claim 26 or 27 , wherein the iron oxide is yellow iron oxide. 28. The method of claim 26 or 27 , wherein the iron oxide is iron sesquioxide. The oral solid composition according to any one of claims 1 to 13 , wherein the photodiscoloration inhibitor comprises iron oxide for suppressing discoloration by light.