JP5181497B2 - Ubidecarenone-containing composition for solid preparations - Google Patents

Description

  The present invention relates to a composition for solid preparations containing a self-emulsion containing ubidecarenone in a high concentration, and belongs to the fields of pharmaceuticals, quasi drugs and foods.

  Ubidecarenone is a coenzyme that is involved in the electron transport system of the mitochondrial inner membrane and plays an important role in the production of ATP, and is used as a therapeutic drug for congestive heart disease in many medical drugs. In recent years, its anti-fatigue action and antioxidant action have attracted attention all over the world, and are widely used as food materials. However, since ubidecarenone is hydrophobic, its solubility in water is low, and its absorbability from the digestive tract is poor (see Non-Patent Document 1).

  Here, as one of the methods for improving the absorption of hydrophobic (lipid-soluble) drugs, a method using a self-emulsified body is known. A method of dissolving ubidecarenone in a fatty acid (see Patent Document 1), fatty acid monoglyceride (See Patent Document 2), a method of dispersing in oil such as soybean oil and filling into small capsules (see Patent Document 3), a method of adding limonene and polyoxyethylene sorbitan ester type emulsifier (Patent Document) 4), a method of dissolving in propylene glycol fatty acid ester (see Non-Patent Document 2), and the like. However, the solubility of ubidecarenone by these methods is small, and it is difficult to dissolve ubidecalenone at a high concentration, for example, 15% by mass or more. Undissolved ubidecarenone not only impairs the appearance of the product, but also has an unfavorable absorbency.

  Further, as a method for improving the absorbability by containing ubidecarenone in a high concentration, a method is known in which an emulsion obtained by emulsifying ubidecalenone with casein, citric acid monoglyceride, and polyglycerol fatty acid ester is spray-dried (see Patent Document 5). ). However, since the manufacturing method is complicated and a special apparatus such as a spray drying apparatus is required, it is not suitable for industrialization.

  Therefore, there has been a demand for the development of a self-emulsified material containing ubidecarenone in a high concentration by a simple method without requiring a special apparatus.

  And since such a self-emulsified substance is liquid even at room temperature, it must be pulverized from the viewpoint of handling in order to be blended into a solid preparation such as a tablet, but in order to prevent ubidecalenone from being deteriorated during pulverization. It needs to be noted.

Japanese Patent Publication No.63-23965 Japanese Patent Publication No. 64-10494 Japanese Examined Patent Publication No. 63-51122 JP 2005-60252 A JP-A-2005-43 Chem. Pharm. Bull., 20, (12) 2585 (1972) T.R.Kommuru, et.al., Int. J. Pharm., 212, 233-246 (2001)

  An object of the present invention is to provide a pulverization technique capable of maintaining the dissolution and stability of ubidecarenone when blending a self-emulsified product containing ubidecarenone in a high concentration into a composition for a solid preparation. .

  Mixing ubidecalenone, menthol and camphor, all of which have a melting point of 37 ° C. or lower, the melting point of the mixture drops, and a liquid containing ubidecalenone at a high concentration is obtained at a temperature near body temperature (37 ° C.). By adding and heating and dissolving a hydrophilic surfactant having an HLB of 10 or more such as polyoxyethylene hydrogenated castor oil 60 and monoglyceryl of a fatty acid having 12 or less carbon atoms such as glyceryl monocaprylate, A self-emulsified product containing ubidecalenone at a high concentration of 15% by mass or more is obtained. The present inventors mixed this self-emulsified product with various solid preparation additives, and conducted a pulverization study.When synthetic aluminum silicate or magnesium aluminate metasilicate was used, the oil absorption was excellent, and It was found that the dissolution property of ubidecarenone can be maintained high.

  One of the embodiments of the present invention obtained by such knowledge is (a) 10% by mass or more of ubidecalenone in the composition, “the menthol is 0.2 parts by mass or more and the melting point is 1 part by mass of the ubidecalenone. Fatty acids having a saturated terpenoid (excluding menthol) at 37 ° C. or higher, 0.1 mass parts or more, a hydrophilic surfactant having an HLB of 10 or more, 0.05 mass parts or more, and a carbon atom number of 12 or less. A self-emulsified product containing 0.05 part by mass or more of a monoglyceride, and (b) at least one of synthetic aluminum silicate and magnesium aluminate metasilicate with respect to 1 part by mass of the self-emulsified product. A solid formulation composition comprising 1.0 part by mass or more of “seed”.

  Another aspect of the present invention is: (a) 10% by mass or more of ubidecalenone in the composition, “hydrophilic surfactant having an essential oil of 0.3 parts by mass or more and an HLB of 10 or more per 1 part by mass of the ubidecalenone. 0.12 parts by mass or more of the agent and 0.13 parts by mass or more of monoglycerides of fatty acids having 12 or less carbon atoms, and (b) 1 of the self-emulsified product The composition for solid preparations contains 1.0 part by mass or more of “at least one of synthetic aluminum silicate and magnesium aluminate metasilicate” with respect to parts by mass.

  According to the present invention, it has become possible to provide a composition for solid preparations that contains a self-emulsified substance containing ubidecarenone at a high concentration and that retains high ubidecarenone elution.

  “Ubidecarenone” is a kind of coenzyme synthesized in vivo and is also called coenzyme Q, vitamin Q and ubiquinone. It is hardly soluble in water and has a melting point of about 48 ° C.

  The content (formulation) of ubidecarenone is 10% by mass or more in the ubidecarenone-containing self-emulsified product. From the significance of the present invention that a high-concentration self-emulsified product of ubidecarenone is contained, the content (formulation) of ubidecarenone is preferably 15% by mass or more in the ubidecalenone-containing self-emulsified product. Further, from the viewpoint of stably emulsifying the self-emulsified product, the upper limit of the content (formulation) of ubidecarenone is 65% by mass in the ubidecalenone-containing self-emulsified product. It is difficult to self-emulsify ubidecarenone exceeding 65 mass% in the self-emulsified material due to the limited amount of menthol, saturated terpenoids and essential oils having a melting point of 37 ° C. or higher, and hydrophilic surfactants. It is.

  “Menthol” includes all of L-form, D-form and DL-form, all of which are extremely insoluble in water. The melting point of the DL form is about 27 to 28 ° C., and the melting point of the L form is about 42 to 43 ° C.

  The content (formulation) of menthol is 0.2 parts by mass or more with respect to 1 part by mass of ubidecarenone, and if considering the content of ubidecarenone in the self-emulsified product, 0.5 to 1.0 parts by mass is obtained. preferable. Moreover, since the digestive tract movement will be inhibited and irritation | stimulation will become strong if there are too many compounding quantities of menthol, the upper limit of the compounding quantity is 1.5 mass parts.

  The “terpenoid” is also called a terpene, and in the present invention, a saturated terpenoid having a melting point of 37 ° C. or higher is applicable. However, menthol is not included. Specifically, camphor (including all of D-form, L-form and DL-form, melting point of about 175 to 180 ° C.), borneol (including all of D-form, L-form and DL-form, melting point of about 205 to 210 ° C.) Etc. These may be used alone or in combination of two or more.

  The content (mixture) of saturated terpenoids (excluding menthol) having a melting point of 37 ° C. or higher is 0.1 parts by mass or more with respect to 1 part by mass of ubidecarenone, and the balance between the content of ubidecalenone and solubility. Is considered to be 0.5 to 1.0 part by mass, and the upper limit is 1.5 parts by mass.

  “Essential oil” is preferably orange oil or grapefruit oil from the viewpoint of the stability and odor of ubilecarenone, and these oils may be used alone or in combination.

  The content (formulation) of “essential oil” is 0.3 parts by mass or more with respect to 1 part by mass of ubidecarenone, and considering the balance between the content of ubidecalenone and solubility, 1.0 to 2.0 parts by mass is Preferably, the upper limit is 3.0 parts by mass.

  The “hydrophilic surfactant having an HLB of 10 or more” is preferably one having a low melting point and good compatibility with ubidecalenone and terpenoid from the viewpoint of emulsification. For example, it has a branched molecular structure or has a hydrophobic part. Those having an unsaturated bond are preferred. Specific examples of the hydrophilic surfactant having an HLB of 10 or more include polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and decaglycerin monooleate. These may be used alone or in combination of two or more.

  The content (formulation) of the hydrophilic surfactant having an HLB of 10 or more is 0.05 parts by weight or more with respect to 1 part by weight of ubidecarenone, and considering the balance between the content of ubidecarenone and the emulsifiability, 3.0 parts by mass is preferred.

  “Monoglycerides of fatty acids having 12 or less carbon atoms” are preferably those having a low melting point and good compatibility with ubidecarenone and terpenoids from the viewpoint of emulsification. Specific examples include caprylic acid monoglyceride, capric acid monoglyceride and lauric acid monoglyceride. These may be used alone or in combination of two or more.

  The content (formulation) amount is 0.05 parts by weight or more with respect to 1 part by weight of ubidecarenone, and considering the balance between the content of ubidecarenone and emulsification, 0.1 to 3.0 parts by weight is preferable.

  The ubidecalenone-containing self-emulsified product of the present invention includes, for example, a predetermined amount of ubidecalenone, menthol, camphor as a saturated terpenoid having a melting point of 37 ° C. or higher, polyoxyethylene hydrogenated castor oil 60, carbon as a hydrophilic surfactant having an HLB of 10 or higher. Capillic acid monoglyceride is mixed as a monoglyceride of fatty acid having 12 or less atoms, heated to 50 to 60 ° C. and melted, and then cooled to room temperature (about 25 ° C.).

  “Synthetic aluminum silicate” is used as a gastric mucosal protective agent and antacid, as well as having a very large specific surface area, high oil-absorbing ability, and excellent properties in compression molding. It also has applications as an additive for promoting properties.

  “Magnesium aluminate metasilicate” has a use as an antacid and is used as a raw material for gastrointestinal preparations. In addition, the specific surface area is very large, it has high oil absorption and adsorption capacity, and is excellent in compression moldability, and is used as tablets, powders, granules, excipients, binders, disintegrants and adsorbent powdering agents. Blended into capsules and the like.

  The content (formulation) of the synthetic aluminum silicate or magnesium aluminate metasilicate in the composition for solid preparation is 1.0 part by mass or more with respect to 1 part by mass of the self-emulsified product containing ubidecarenone, preferably Is 1.0 to 5.0 parts by mass. If the amount is less than 1.0 part by mass, the amount of the synthetic aluminum silicate or magnesium aluminate metasilicate is small compared to the amount of the self-emulsified material. Since a composition cannot be obtained, it is not preferable. On the other hand, if it exceeds 5.0 parts by mass, it is difficult to prepare a solid preparation containing ubidecarenone at a high concentration of 5.0% by mass or more. However, even if blended in an amount exceeding 5.0 parts by mass, the effects of the present invention are not immediately lost, and a slight deterioration in compression moldability and a deterioration in handling due to the powder becoming bulky are caused. Only.

  Synthetic aluminum silicate and magnesium aluminate metasilicate may be used alone or in combination of two.

  Other well-known additives can be mix | blended with the composition for solid preparations of this invention in the range which does not impair the effect of this invention. Examples of such additives include stabilizers such as preservatives and antioxidants, and flavoring agents such as sugars and fragrances.

  The composition for solid preparation of the present invention is obtained, for example, by mixing a ubidecalenone-containing self-emulsifier with a predetermined amount of magnesium aluminate metasilicate, sieving, mixing with other additives, granulating, and drying. A lubricant can be added to the resulting powder, and further mixed, compression molded, and provided as a tablet.

  Reference examples, examples, comparative examples and test examples are given below to describe the present invention in more detail.

Reference example 1
Ubidecarenone 16.7 g, DL-menthol 16.7 g, DL-camphor 16.7 g, polysorbate 80 (Nikkor TO10; Nikko Chemicals) 30.0 g, caprylic acid monoglyceride 20.0 g were mixed and heated to 50-60 ° C. And dissolved to obtain 100.1 g of a self-emulsified product.

Reference example 2
Ubidecalenone 16.7 g, orange oil 33.3 g, polysorbate 80 (Nikkor TO10; Nikko Chemicals) 30.0 g, caprylic acid monoglyceride 20.0 g are mixed and heated to 50-60 ° C. to dissolve and self-emulsified 100 0.0 g was obtained.

Example 1
10 g of the self-emulsified body prepared in Reference Example 1 and 10 g of magnesium aluminate metasilicate were mixed to obtain a powdery composition.

Example 2
10 g of the self-emulsified body prepared in Reference Example 1 and 10 g of synthetic aluminum silicate were mixed to obtain a powdery composition.

Example 3
10 g of the self-emulsified body prepared in Reference Example 2 and 10 g of synthetic aluminum silicate were mixed to obtain a powdery composition.

Comparative Example 1
10 g of the self-emulsified body prepared in Reference Example 1 and 20 g of magnesium silicate were mixed to obtain a powdery composition.

Comparative Example 2
10 g of the self-emulsified body prepared in Reference Example 1 and 20 g of magnesium carbonate were mixed to obtain a powdery composition.

Comparative Example 3
10 g of the self-emulsified body prepared in Reference Example 1 and 30 g of aluminum hydroxide gel were mixed to obtain a powdery composition.

Comparative Example 4
10 g of the self-emulsified body prepared in Reference Example 1 and 20 g of magnesium oxide were mixed to obtain a powdery composition.

Comparative Example 5
10 g of the self-emulsified body prepared in Reference Example 1 and 40 g of dextrin were mixed to obtain a powdery composition.

Comparative Example 6
10 g of the self-emulsified body prepared in Reference Example 1 and 40 g of anhydrous calcium hydrogen phosphate were mixed to obtain a powdery composition.

Comparative Example 7
10 g of the self-emulsified body prepared in Reference Example 1 and 40 g of synthetic hydrotalcite were mixed to obtain a powdery composition.

Comparative Example 8
10 g of the self-emulsified body prepared in Reference Example 1 and 40 g of starch were mixed to obtain a powdery composition.

Comparative Example 9
10 g of the self-emulsified body prepared in Reference Example 1 and 30 g of crystalline cellulose were mixed to obtain a powdery composition.

Comparative Example 10
10 g of the self-emulsified body prepared in Reference Example 1 and 10 g of Adsolider 101 (trade name) which is light anhydrous silicic acid were mixed to obtain a powdery composition.

Comparative Example 11
10 g of the self-emulsified body prepared in Reference Example 1 and 10 g of Erogil 200 (trade name) which is light anhydrous silicic acid were mixed to obtain a powdery composition.

Comparative Example 12
10 g of the self-emulsified body prepared in Reference Example 1 and 10 g of fluorite (trade name) which is calcium silicate were mixed to obtain a powdery composition.

Comparative Example 13
10 g of the self-emulsified body prepared in Reference Example 1 and 4.9 g of magnesium aluminate metasilicate were mixed to obtain a slurry-like semisolid composition.

Test example 1
About 50 mg of each of the powdered compositions prepared in Examples 1 and 2 and Comparative Examples 1 to 12 was collected, put into a 50 mL centrifuge tube, added with 25 mL of purified water heated to 37 ° C. After shaking for 18 hours on a shaker heated to ℃, after centrifugation (3000 rpm, 10 minutes), 2 mL of the supernatant was collected, 2 mL of tetrahydrofuran was added, and the concentration of ubidecalenone in the sample was adjusted to high speed liquid. The elution rate was calculated by measurement with a chromatograph or an ultraviolet absorption measurement device. The results are shown in Table 1.
The measurement conditions of the high performance liquid chromatograph are as follows.

High-speed liquid chromatographic conditions Detection wavelength: 275 nm
Column: ODS (4.6 mmφ × 150 mm)
Column temperature: constant temperature around 35 ° C. Mobile phase: methanol / ethanol (99.5) mixture (1: 1)
Flow rate: 1.0 mL / min Injection volume: 10 μL
The ultraviolet absorption measurement was performed at a wavelength of 275 nm using a quartz cell having an optical path length of 1 cm.

For each powder carrier component in Table 1, FIG. 1 shows the amount (g) of carrier required to absorb 10 g of the self-emulsified body.
Further, for each powder carrier in Table 1, the elution rate (%) of ubidecarenone from the composition is shown in FIG.
1 and 2, it was found that the carrier having excellent self-emulsifying oil absorption ability and good elution of ubidecarenone is magnesium aluminate metasilicate and synthetic aluminum silicate.

  The solid preparation composition of the present invention is expected to provide a small-sized tablet with good dosage that contains a self-emulsion containing a high concentration of ubidecarenone.

It is a graph which shows the quantity (g) of a support | carrier required to oil-absorb the ubidecarenone containing self-emulsion (10g). It is a graph which shows the elution rate (%) of ubidecarenone from the composition.

Claims (2)

(A) the composition 10 wt% or more of ubidecarenone, "0.5 to 1.0 parts by weight with respect to 1 part by weight, the menthol of the ubidecarenone, 0.5 to 1.0 parts by weight of camphor, Polysorbate 80 0.1 to 3.0 parts by weight, and, self-emulsifying material characterized by containing 0.1 to 3.0 parts by weight "caprylic acid monoglyceride, and (b) 1 part by mass of the self-emulsifying body The composition for solid preparations containing 1.0 to 5.0 parts by mass of “at least one of synthetic aluminum silicate and magnesium aluminate metasilicate”. (A) 10% by mass or more of ubidecalenone in the composition, “ 1.0 to 2.0 parts by mass of orange oil and 0.1 to 3.0 parts by mass of polysorbate 80 with respect to 1 part by mass of ubidecalenone , And 0.1 to 3.0 parts by mass of caprylic acid monoglyceride , and (b) “synthetic aluminum silicate and metasilicate with respect to 1 part by mass of the self-emulsified product” A solid preparation composition comprising 1.0 to 5.0 parts by mass of “at least one kind of magnesium aluminate”.

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