JP2000007583A - Lipophilic medicament-containing composition with improved light stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition with improved light stability, in particular as powder, granules, fine granules, etc., by compounding a yellow or red colorant in a light-instable lipophilic medicament. SOLUTION: This composition is obtained by compounding a light-instable lipophilic medicament [e.g. vitamin K (for example, menatetrenone, phytonadione, menadione), coenzyme Q, vitamin A, vitamin D] with at least one substance selected from yellow colorants (e.g. yellow iron sesquioxide, yellow iron oxide, edible Yellow No.4, edible Yellow No.5, edible Yellow No.4 aluminum lake, red iron oxide) and red colorants (e.g. iron sesquioxide, edible Red No.2, edible Red No.3, edible Red No.102) in the weight ratio of the colorant(s) to lipophilic medicament of 0.001 to 100, pref. 0.001 to 50, more pref. 0.01 to 30.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a composition and a preparation containing a fat-soluble drug with improved photostability.

[0002]

BACKGROUND ART Vitamin K, vitamin A, vitamin D,
Many fat-soluble drugs, including fat-soluble vitamins such as coenzyme Q, are unstable to light, heat or oxidation, and various stabilization methods are required for formulating these compounds. Are known. For example, vitamin K such as fat-soluble vitamins such as menatetrenone and phytonadione are:
It has a strong hemostatic effect in the body and is widely used as a therapeutic agent for hypoprothrombinemia, neonatal hypoprothrombinemia, bleeding, etc. It has been done. JP 4
JP-A-2-4062 and JP-A-61-275214 disclose titanium oxide and edible red 4 in a soft capsule base to shield menatetrenone dissolved in fats and oils.
No. 3, Food Red No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102 and the like are disclosed. A gelatin film composition having improved light stability of vitamin K and the like by blending caramel and amino acid in the film is disclosed. All of these techniques contain a colorant and a stabilizer in a capsule film covering a lipophilic drug that is unstable to light, and are difficult to apply to powders, granules, fine granules, etc. is there. On the other hand, examples of directly adding a stabilizer to an unstable fat-soluble drug include JP-A-2-289513 and JP-A-4-26.
No. 670, which is stabilized by blending an oil-soluble vitamin-containing composition stabilized by uniformly mixing the carotenoid with an oil-soluble vitamin and tocopherol and phytonadione described in JP-A-60-1125. Ubidecarenone-containing compositions are disclosed. These technologies are intended to improve the light stability of the target fat-soluble vitamin by adding a substance more unstable to light than the fat-soluble vitamin unstable to light. Effect is not enough.

[0003]

The light stability of the preparation is not sufficient even by the above-mentioned technology, and further improvement is required. That is, it is possible to improve the photostability of capsules and tablets by adding a colorant to the capsule base and tablet film film or by making a sugar-coated tablet by known techniques. It cannot be said that the photostability of fine particles, fine granules and the like is still at a sufficient level. In view of the above current situation, the present invention aims to further stabilize a composition containing a fat-soluble drug, and in particular, powders, granules, light stability of fine granules and the like. It is intended to improve.

[0004]

SUMMARY OF THE INVENTION The present invention provides a composition having improved light stability comprising a light-labile lipophilic drug and one or more substances selected from yellow and red colorants. is there. In addition, the present invention is a light-labile fat-soluble drug to a yellow colorant yellow iron sesquioxide, yellow iron oxide, edible yellow No. 4,
Edible Yellow No. 5, Edible Yellow No. 4 Aluminum Lake and Vengara, Red Colorant Iron Ferric Dioxide, Edible Red 2
No. 1, selected from Food Red No. 3 and Food Red No. 102
A composition comprising at least one kind of substance. Furthermore, the present invention uniformly emulsifies, disperses or suspends a light-labile fat-soluble drug, an oil component, and a yellow and / or red colorant in a water-soluble polymer solution, and adds a formulation aid. It is a formulation with improved light stability, which is mixed, granulated or coated, and dried.

An object of the present invention is to further stabilize a composition containing a fat-soluble drug, and by blending a coloring agent directly with the fat-soluble drug, it is possible to obtain a powder, a granule, It is intended to improve the light stability of fine granules and the like. The lipophilic drug unstable to light in the present invention, for example,
Examples of the fat-soluble vitamin include vitamin K, coenzyme Q, vitamin A and vitamin D. Vitamin K
Specific examples of the coenzyme Q include menatetrenone, phytonadione, menadione, ubidecarenone, and the like. Generally, vitamin K is vitamin K1, K
2 and K3 are known, respectively, menatetrenone,
It is also referred to as phytonadione and menadione, and these are all included in the present invention, and if necessary, one or a mixture of two or more of these vitamin K can be used.

[0006] Menatetrenone is a substance listed in the Japanese Pharmacopoeia, and phytonadione is a substance listed in the Japanese Pharmacopoeia, and commercially available ones can be easily obtained. Colorant in the present invention is a yellow and / or red colorant,
Examples of yellow colorants include yellow iron sesquioxide, yellow iron oxide, Food Yellow No. 4, Food Yellow No. 5, Food Yellow No. 4 aluminum lake and red iron oxide. Further, as a red colorant, for example, iron sesquioxide, food red No. 2,
Edible Red No. 3 and Edible Red No. 102 can be mentioned. In the present invention, these can be used alone or in combination of two or more. When the light-labile fat-soluble drug is vitamin K represented by menatetrenone and phytonadione, one kind selected from food yellow 4, food yellow 5, food yellow 4 aluminum lake and yellow iron sesquioxide It is desirable to mix the above colorants. Of the yellow colorants, yellow iron sesquioxide and yellow iron oxide meet the excipient standard,
Food Yellow No. 4, Food Yellow No. 5, Food Yellow No. 4 Aluminum lake and red bengal are substances listed in Food Additive Standards, and commercially available ones can be easily obtained. Further, among the red coloring agents, iron sesquioxide is a pharmaceutical additive standard product, and Food Red No. 2, Food Red No. 3, Food Red No. 102, etc. are substances listed in the Food Additive Standard, In each case, commercially available products can be easily obtained. The mixing ratio of the light-labile fat-soluble drug and the colorant in the present invention is such that the colorant is 0.001 to 1 per 1 part by weight of the fat-soluble drug.
00 parts by weight, preferably 0.001 to 50 parts by weight, more preferably 0.01 to 30 parts by weight.

The composition of the present invention can be produced by mixing a light-labile fat-soluble drug with a yellow and / or red coloring agent, and includes powders, granules, fine granules, tablets, hard capsules and the like. In addition, when excipients such as lactose, sucrose, corn starch, mannitol, and the like are mixed, a binder and the like are added as necessary, and granulation or coating can be performed. . On the other hand, the composition according to the present invention can be made into an excellent preparation having particularly good absorbability and ingestibility by the following method. That is, a light-labile fat-soluble drug, an oily component, and yellow and / or
Or, uniformly emulsify a red colorant in a water-soluble polymer solution,
By dispersing or suspending, adding a formulation aid, mixing, granulating or coating, and drying, a solid formulation excellent in absorbability and ingestibility can be obtained. Here, examples of the oil component include vegetable oil and synthetic oil. Vegetable oils include, for example, soybean oil, corn oil, corn germ oil, cottonseed oil, safflower oil, sesame oil, olive oil, rapeseed oil and the like. Examples of the synthetic oil include glycerin fatty acid ester, propylene glycol fatty acid ester, polyglycerin fatty acid ester, decaglycerin fatty acid ester, and the like. As the water-soluble polymer base, hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,
Hydroxypropyl methylcellulose acetate succinate, sodium carboxymethylcellulose, cellulose acetate phthalate, gum arabic, agar, gelatin,
Examples include sodium alginate, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, macrogol, and the like. In addition, the water-soluble polymer solution may be any of an aqueous solution containing the above-described water-soluble polymer base, various organic solvent solutions, and aqueous organic solvent solutions. Further, when uniformly emulsifying, dispersing or suspending a light-labile fat-soluble drug, an oil component, and a yellow and / or red colorant in a water-soluble polymer solution, adding a surfactant. Can be. Examples of the surfactant include phospholipid, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene Oxyethylene castor oil,
Polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbite fatty acid ester, polyoxyethylene glycerin fatty acid ester and the like can be mentioned. Further, the formulation aid means excipients and additives used when the composition according to the present invention is made into a solid formulation, for example, lactose,
White sugar, corn starch, mannit, starch, partial α
Starch, crystalline cellulose, dextrin, hydroxypropyl starch, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, pullulan, gum arabic, silicic acids, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, Hydroxypropyl methylcellulose acetate succinate, sodium carboxymethylcellulose, cellulose acetate phthalate, gum arabic, agar, gelatin, sodium alginate, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, macrogol, etc. Can be mentioned. When the light-labile lipid-soluble drug is vitamin K represented by menatetrenone, phytonadione, and menadione, the oil component is glycerin fatty acid ester and / or propylene glycol fatty acid ester, and the water-soluble polymer is hydroxy. Preferably, propylmethylcellulose and / or hydroxypropylcellulose are used. In addition, the mixing ratio of the oil-soluble component and the light-labile fat-soluble drug in the present invention is usually 0.1 to 60 parts by weight of the oil component to 1 part by weight of the fat-soluble drug,
Preferably, it is 0.5 to 10 parts by weight. Further, the concentration of the water-soluble polymer solution is usually 0.1 to 40 parts by weight, preferably 1 to 20 parts by weight. Mixing, granulation or coating performed by adding a formulation aid can be performed by a commonly used apparatus, for example, using a fluidized bed granulator, a tumbling granulator, or an extrusion granulator. it can. The resulting powders, granules, fine granules, and the like can be mixed with a disintegrant, a lubricant, or the like, if necessary, to prepare tablets, or filled into hard capsules to form hard capsules. it can.

[0008] The composition according to the present invention can be produced by a commonly used method. For example, a solution prepared by heating and dissolving 3 g of phytonadione, which is a fat-soluble vitamin, in 17 g of propylene glycol fatty acid ester is mixed with a 10% aqueous solution of hydroxypropyl methylcellulose in 100 g.
g to prepare an emulsion. To this emulsion, 0.19 g of yellow iron sesquioxide is added and uniformly dissolved and dispersed.
Next, 100 g of sucrose was added to this emulsion in a fluidized bed granulator,
Lactose 50g, 10g of corn starch by spraying and granulating, and sieving to adjust the particle size,
Powder preparations such as powders, granules and fine granules can be prepared. To 190 g of this powder preparation, for example, 1 g of magnesium stearate is added and mixed, and the mixture is filled into capsules to produce hard capsules. In addition, a tablet containing 30 mg of phytonadione in one tablet is prepared by mixing 1 g of magnesium stearate or 1 g of magnesium stearate and 10 g of croscarmellose sodium with 190 g of the powder formulation and punching with a 7.5 mm diameter punch. Can be manufactured.

[0009]

According to the present invention, it is possible to stabilize fat-soluble drugs which are very unstable to light, such as menatetrenone and phytonadione, which are represented by vitamin K. The effect example is shown below. Experimental example

Light Stabilizing Effect of Colorant Added in Fine Granules According to the Present Invention Compared with fine granules without added colorant, addition of colorants obtained in Examples 1 to 3 shown below The obtained fine granules were put in a transparent bottle, stored under two light sources of a fluorescent lamp and a xenon lamp having different light wavelength characteristics, and the content was measured by high performance liquid chromatography. Table 1 shows the formulations of the control example and Examples 1 to 3. Table 2 shows the residual ratio under each condition when the content of the product stored in a cool dark place was 100%. Irradiation of fluorescent light 1000Lux light was performed for 2 weeks (33
6000 Lux · hr irradiation) and 30 days irradiation (7200
2000 Lux · hr irradiation), and a xenon lamp 20,000 Lux light irradiation was performed for 2 days (336000 Lux · hr irradiation) and 4 days (720000 Lux · hr irradiation).

[0011]

[Table 1]

[0012]

[Table 2]

From Tables 1 and 2, it can be seen that edible yellow 4 according to the present invention is used.
No. 5, Food Yellow No. 5 and Food Yellow No. 4 aluminum lakes are apparently stabilizing fat-soluble drugs that are very unstable to light, such as vitamin K, such as menatetrenone, phytonadione and menadione.

Good absorption characteristics of the preparation according to the present invention Menatetrenone 30 mg obtained in Example 4 shown below
Or 2 capsules of soft capsule containing 15 mg as a control were administered together with 30 ml of water to 5 male beagle dogs fasted for 24 hours before administration, and 0.5, 0.75, 1, 1 before and after administration. 1.5,2,3,4,6,8,10,12,14,16,24
After time, 1.5 ml of blood was collected. In addition, a 5-week crossover test (1 in total) after a 1-week drug holiday
0 animals). The plasma obtained by centrifuging the collected blood was subjected to a liquid-liquid extraction operation, and the change in plasma menatetrenone concentration was evaluated by high performance liquid chromatography using fluorescence and UV detection methods. Table 3 shows the formulations of the control example and Example 4. FIG. 1 shows changes in plasma menatetrenone concentration after administration of the preparation to a beagle dog, and Table 4 shows biopharmaceutical parameters.

[0015]

[Table 3]

[0016]

[Table 4]

As shown in FIG. 1 and Table 4, no significant difference was observed between the fine granules and the soft capsules with respect to the changes in plasma menatetrenone concentration and biopharmaceutical parameters such as AUC. there were. The soft capsule used as a control was a preparation with improved absorbability as shown in JP-A-62-294612, and the fine granule according to the present invention was equivalent to this. The good absorption of the formulation according to the invention is evident.

[0018]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Examples 1 to 3 In a solution prepared by heating and dissolving 15 g of menatetrenone in a mixed oil component of 35 g of propylene glycol fatty acid ester and 50 g of glycerin fatty acid ester, 50 g of hydroxypropyl methylcellulose was previously dissolved in 450 g of purified water. 500 g of a 10% aqueous solution of hydroxypropyl methylcellulose was added. In this emulsion,
Further, 0.95 g of each of Food Yellow No. 4, Food Yellow No. 5 or Food Yellow No. 4 aluminum lake was added, and the resulting emulsion was uniformly dissolved and dispersed.
The mixture was coated on a mixed powder of 00 g, lactose 250 g and corn starch 50 g, and sieved to prepare a fine granule.
The formulation is shown in Table 1.

Example 4 To 380 g of the powder obtained in Example 1, 2 g of calcium stearate and 18 g of low-substituted hydroxypropylcellulose were added.
Was added and mixed, and the mixture was tableted to give a tablet of 300 mg containing 6 mg of menatetrenone.

Example 5 In a solution prepared by heating and dissolving 15 g of menatetrenone in a mixed oil component of 35 g of propylene glycol fatty acid ester and 50 g of glycerin fatty acid ester, 50 g of hydroxypropyl methylcellulose was previously dissolved in 450 g of purified water. An emulsion was prepared by adding 500 g of a 10% aqueous solution of propylmethylcellulose. Separately, after mixing 500 g of mannitol, 250 g of lactose and 50 g of corn starch, granulation is performed by a tumbling granulator while gradually adding a 10% aqueous solution of hydroxypropyl cellulose in which 35 g of hydroxypropyl cellulose is dissolved. I got The above-mentioned emulsion was sprayed on the granules in a fluidized-bed granulator to prepare granules having a small volume, which were then sieved to obtain fine granules.

[0022]

[Brief description of the drawings]

[0023]

FIG. 1 is a graph showing changes in plasma menatetrenone concentration after administration of a preparation to a beagle dog.

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Claims (8)

[Claims] 1. A composition having improved light stability, comprising a light-labile fat-soluble drug and one or more substances selected from yellow and red colorants. 2. The yellow colorant is yellow iron sesquioxide, yellow iron oxide, edible yellow No. 4, edible yellow No. 5, edible yellow No. 4 aluminum lake and red iron, red colorant is iron sesquioxide, edible red 2. The composition according to claim 1, which is No. 3, Food Red No. 3 and Food Red No. 102. 3. The composition according to claim 1, wherein the fat-soluble drug unstable to light is vitamin K. 4. The composition according to claim 3, wherein the vitamin K is menatetrenone, phytonadione or menadione. 5. A light-labile fat-soluble drug, an oil component, and a yellow and / or red colorant are uniformly emulsified, dispersed or suspended in a water-soluble polymer solution, and a formulation aid is added. A formulation with improved photostability which is mixed, granulated or coated, and dried. 6. The preparation according to claim 5, wherein the oil component is a glycerin fatty acid ester and / or a propylene glycol fatty acid ester. 7. The preparation according to claim 5, wherein the mixing, granulation or coating is carried out by a fluidized bed granulator, a tumbling granulator or an extrusion granulator. 8. The preparation according to claim 5, wherein the preparation is a powder, granule, fine granule, tablet or hard capsule.