JPH0335286B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a well-absorbed ubidecarenone-containing solid composition. Ubidecarenone, also known as coenzyme Q ₁₀ , has recently come into widespread clinical use as a drug effective for improving coronary function. This substance is a fat-soluble substance that is solid at room temperature and has a melting point of 48 to 52°C, and is known to be absorbed in living bodies mainly through lymph vessels. However, the amount of absorption of this substance is very small, and according to absorption experiments using rats, when administered dissolved in sesame oil or bile salts, the absorption rate in 48 hours was 1.0%, and HCO- 60
Even when administered after being dissolved, the absorption rate is 1.5
% (Chem, Pharm, Bull (20) 2585
(1972)). In view of these circumstances, the present inventor conducted various studies on a solid composition containing ubidecarenone and its formulation that improves the absorption of ubidecarenone. As a result, the initial objective was to create a composition in which a hydrophilic natural polymer was added to a mixture of ubidecarenone and oleic acid, and the formulation of the composition was in a form that could be granulated by a spray drying method. The present invention was completed based on the knowledge that it satisfies the following. That is, the present inventor previously proposed a solid composition containing ubidecarenone with good dispersibility in Japanese Patent Application No. 110365/1983, which contains 1 part of ubidecarenone and 0.05 part or more of an emulsifier, the composition containing ubidecarenone produced by a spray drying method. The composition was presented. However, in order to further improve the absorption of ubidecarenone in the composition, it has been found that in addition to simply having good dispersibility, it is also necessary for fat or lipolysis products to coexist with ubidecarenone. More specifically, as shown in the effect examples below, oleic acid is good as the above-mentioned fat or fat decomposition product, and as a material for dispersion, hydroxypropyl cellulose or a hydrophilic natural polymer, especially gum arabic. I learned that tragacanth, milk casein, and egg albumin are good. The amount of maoleic acid used in the composition of the present invention is 1 to 5 parts by weight per 1 part by weight of ubidecarenone. Below the lower limit of the range, the effects of the present invention cannot be achieved. Moreover, if it exceeds the upper limit, the amount of dispersing agent will only increase unnecessarily, which is not preferable. The required amount of hydroxypropyl cellulose or hydrophilic natural polymer is determined by the amount of the mixture of ubidecarenone and oleic acid.
In short, it is sufficient that the amount is sufficient to achieve emulsification and to maintain the emulsification stably until the end of spray drying, and the minimum required amount is 0.5 parts by weight per 1 part by weight of ubidecarenone. In addition, dextrin, cornstarch, and lactose may be freely added to the composition of the present invention as fillers, and there are no particular restrictions on the type and amount of fillers. In short, it may be selected as appropriate depending on the conditions of the spray drying to be carried out and the desired content of ubidecarenone in the composition of the present invention. There are no particular restrictions on the spray drying method and conditions used in the present invention, but for example, a nozzle method may be used, with an inlet temperature of 120°C and an outlet temperature of 60-80°C.
The conditions are selected. Next, each particle of the composition of the present invention obtained by the spray drying method appears to be a spherical granule, but when observed under a microscope, it has a fine structure consisting of a large number of small particles of several microns. It can be clearly distinguished from those produced by rolling granulation or extrusion granulation with the same composition. The particle size of each particle is approximately 20 to 200 microns, but this varies depending on the type and amount of filler used and the spray drying conditions. Further, the apparent specific gravity of the composition of the present invention is 0.2 to 0.8.
That's about it. The composition of the present invention may be administered as a powder as is, but suitable excipients may be added to form a dosage form that facilitates administration. That is, it can be made into fine granules or granules by adding a binder, it can be further compressed into tablets, or it can be filled into capsules by filling fine granules or granules into capsules. Next, it will be clarified by the following effect examples that the composition of the present invention has the effect of providing good bioabsorption of ubidecarenone. Preparation of Samples Control Sample (1) Place 1 part of ubidecarenone in a mortar heated over a water solution at 60°C, melt it, and dissolve microcrystalline cellulose.
A mixture of 10 parts of cornstarch, 8 parts of corn starch, and 1 part of hydroxypropylcellulose was added little by little and mixed uniformly. (2) Disperse 1 part of gum arabic in a small amount of water, add 1 part of ubidecarenone and 18 parts of dextrin, mix thoroughly, add water to make an emulsion, and spray dry at an inlet temperature of 100°C. sample. Test sample 1 A sample prepared in the same manner as in test sample (1) except that 1 part of oleic acid was used instead of 1 part of sesame oil. 2 A sample prepared in the same manner as in specimen sample (2) except that 2 parts of milk casein was used instead of 2 parts of gum arabic. 3 A sample prepared in the same manner as in specimen sample (2) except that 2 parts of egg albumin was used instead of 2 parts of gum arabic. 4 A sample prepared in the same manner as in specimen sample (2) except that 4 parts of gum arabic was used instead of 2 parts of gum arabic, and 3 parts of oleic acid was used instead of 1 part of oleic acid. 5 A sample prepared in the same manner as in specimen sample (6) except that 5 parts of oleic acid was used instead of 5 parts of sesame oil. Absorption experiment method 1 Animal experiment Perform thoracic duct lymph cannulation on SD male rats (weight 280-320 g) and leave them in a Bormann cage for 20 hours. Use rats with a lymph outflow volume of 20 ml or more during that time. did. 2 Absorption Experiment After rats were fasted for 15 hours (but allowed access to physiological saline ad libitum), 20 mg of the sample (1 mg as ubidecarenone) was filled into minicapsules for animal experiments and orally administered. Immediately after administration, 1 ml of water was given. The administration was carried out as follows. Prepare 30 rats that underwent thoracic lymph cannulation for the 10 samples described above. Randomize and administer to 3 animals per sample. 2
One day later, each sample is randomized and administered to three animals in the same way. Thus, we conducted six absorption experiments on one sample and confirmed that there was no statistically significant difference at a 5% risk rate between the results of administration on the first day and the results of administration two days later. . 3. Quantification Ubidecarenone was extracted from the collected lymph fluid and measured by high performance liquid chromatography (measured absorption wavelength: 275 mμ). The amount of endogeneous ubidecarenone originally present in the lymph fluid was measured in advance, and the measurements after administration were corrected. Results The composition and lymphatic absorption rate of the control sample and test sample 24 hours after oral administration are shown in the table below.

[Table] A mixture consisting of 1 part of pill cellulose was used From the table above, a composition in which a hydrophilic natural polymer was blended with a mixture of ubidecarenone and sesame oil or oleic acid, which was treated by a spray drying method. was found to improve the absorption of ubidecarenone by about twice or more. There is also a tendency for absorption to increase in proportion to the amount of sesame oil or oleic acid and the amount of hydrophilic natural polymer. Next, the present invention will be explained in more detail with reference to Examples described below. Example 1 600 g of gum arabic is dispersed in 6 parts of water, 100 g of ubidecarenone and 500 g of oleic acid are added thereto, heated to 70°C and thoroughly mixed. Furthermore, 800 g of dextrin is dispersed. Next, spray drying was performed at an inlet temperature of 100°C and an outlet temperature of 65°C to obtain 800 g of a solid composition containing ubidecarenone.
Pass this through a 60 mesh sieve to make a powder.

Claims (1)

[Claims] 1. A solid composition containing one or more of hydroxypropylcellulose, gum arabic, tragacanth, milk casein, or egg albumin in a mixture of 1 part by weight of ubidecarenone and 1 to 5 parts by weight of oleic acid. A solid composition containing ubidecarenone, which is produced by a spray drying method.