JPH0335287B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a well-dispersed CoQ _10- containing composition. CoQ ₁₀ has recently come to be widely used clinically as a drug effective for improving coronary peripheral function. This substance is a fat-soluble substance that is solid at room temperature and has a melting point of 48-52°C, and is known to be absorbed mainly through lymph vessels in living bodies. However, this substance has poor dispersibility in water and only a small amount of absorption, and has many problems that need to be solved in terms of formulation technology. The present inventor has conducted various studies to improve the dispersibility and absorbability of CoQ ₁₀ . First, one of the inventors of the present invention proposed CoQ ₁₀ as shown in Japanese Patent Application No. 54-110365.
By using a composition containing 1 part of the above and 0.05 part or more of an emulsifier and produced by a spray drying method, we succeeded in achieving good dispersion. On the other hand, the dispersibility of CoQ ₁₀ is an important factor in the absorption of CoQ ₁₀ , and when it is spray-dried with sesame oil or oleic acid and hydrophilic natural polymers in its composition, absorption is significantly reduced. I also knew it would get better. Based on this knowledge, the present inventors investigated how to make the mixture of CoQ ₁₀ and oleic acid even more dispersible, and as a result, they decided to use the fluidized bed granulation method instead of the spray drying method. The present invention was completed based on the knowledge that the dispersibility was improved when the product was produced in a similar manner. That is, the gist of the present invention is to produce well-dispersed CoQ by producing a solid composition in which a hydrophilic natural polymer or a cellulose derivative is blended with a mixture of CoQ ₁₀ and oleic acid by a fluidized bed granulation method. _10- containing composition. The hydrophilic natural polymer in the present invention is a polymer of animal or plant origin, and due to its hydrophilicity, the molecule as a whole has a dispersing power, such as gum arabic, tragacanth, milk casein, etc. egg albumin and gelatin. Furthermore, the cellulose derivatives in the present invention include methylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose,
After all, it has the power of decentralization. The amount of these hydrophilic natural polymers or cellulose derivatives may be such that the mixture of CoQ ₁₀ and oleic acid is dispersed and the dispersion remains stable until the end of fluidized bed granulation, and the minimum required amount is The amount is 0.1 part by weight per part by weight of the mixture of CoQ ₁₀ and oleic acid. One of the inventors of the present invention previously found that for the absorption of CoQ ₁₀ , it is preferable for fat or lipolysis products to coexist with CoQ ₁₀ . Later, I learned that sesame oil is a good fat and oleic acid is a good fat decomposition product. From this point of view, in the present invention,
This includes the case of a mixture of CoQ ₁₀ and oleic acid. That is, although the purpose of this composition is to promote absorption, it is included in the present invention because it is also subject to treatment for improving dispersion, which is the subject of the present invention, as in the case of CoQ ₁₀ alone. Further, the amount of oleic acid is 5 parts by weight or less per 1 part by weight of CoQ ₁₀ . If the amount is more than this, the amount of dispersing agent will increase unnecessarily, which is not preferable. Furthermore, the composition of the present invention may optionally contain dextrin, cornstarch, lactose, crystalline cellulose, and mannitol as fillers.
There are no particular restrictions on the type and amount of the filler. In short, it may be appropriately selected depending on the conditions of the fluidized bed granulation to be carried out and the desired content of CoQ ₁₀ in the composition of the present invention. The fluidized bed granulation carried out in the present invention may be carried out by a conventional method, and there are no particular restrictions on the method and conditions, but for example, the inlet temperature of the dry air used to form the fluidized bed is set at 70-80°C. Further, as an apparatus for performing fluidized bed granulation, for example, WSG15 (Glatz) and FL10 (Freund) can be used. Next, each particle of the composition of the present invention obtained by the fluidized bed granulation method appears to be a spherical granule, but
According to observation using an electron microscope, it appears to be in the form of a large number of small pieces of several microns, and it is clearly distinguishable from those produced by rolling granulation or extrusion granulation with the same composition. can. The particle size of each particle is approximately 20-200 microns, but this varies depending on the type and amount of filler used and the conditions of fluidized bed granulation. Further, the apparent specific gravity of the composition of the present invention is about 0.2 to 0.8. 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 fine granules or granule capsules to make capsules. Next, it will be clarified by the following effect examples that the composition of the present invention has the effect of providing good dispersion of CoQ ₁₀ . Example of effect Sample (1) Sample composition CoQ ₁₀ 5 parts Oleic acid 5 parts Casein 10 parts Dextrin 5 parts Cornstarch 60 parts Lactose 15 parts Total 100 parts (2) Prepared fluidized bed granulated product Add a small amount of dispersing agent in advance dispersed in water,
CoQ ₁₀ and oleic acid were added to this to form an emulsified dispersion. This dispersion was sprayed into a fluidized bed containing a mixture of crystalline cellulose, cornstarch, lactose, dextrin, etc. (inlet temperature 80°C).
°C) to obtain fluidized bed granulated products of each composition. Extrusion granulation product Dispersing agent is dispersed in a small amount of water in advance,
CoQ ₁₀ and oleic acid were added to this to form an emulsified dispersion. This dispersion is mixed into crystalline cellulose,
The mixture was added to a mixture of cornstarch, lactose, dextrin, etc., kneaded, passed through a 20-mesh screen, and granulated, and dried at 50°C for 3 hours to obtain extrusion granules of each composition. It should be noted that it was impossible to prepare an extrusion granulated product having the composition of G. Dispersity Measurement Method The dispersibility of each sample was determined by the following method. Add 100 mg of the sample to 100 ml of purified water, put it in a sedimentation measurement cylinder, let it stand in a dark place at 25°C for 24 hours, and then place it at the specified position at the bottom of the cylinder (8 cm from the bottom).
Sample from. This sampling solution is diluted with ethanol, and the absorbance at 275 nm is measured to determine the weight (Umg) of ubidecarenone present in 1 ml of the sampling solution. Dispersity (%)
is derived from the following equation. Dispersity (%) = U x 100 Since sedimentation separation is clearly seen when the dispersibility is 50% or less, samples with a dispersity of 50% or more are considered to have good dispersibility. Experimental Results Table 1 shows the degree of dispersion of fluidized bed granules and extrusion granules with the compositions shown in (1).

[Table] From the above experimental results, a solid composition in which a hydrophilic natural polymer or a cellulose derivative is blended with a mixture of CoQ ₁₀ and oleic acid, which is produced by the fluidized bed granulation method, is confirmed. , is found to give good dispersibility. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 200g of gum arabic was added to 2 parts of water and dispersed,
The mixture was heated to 70° C., 400 g of CoQ ₁₀ was added, and mixed to obtain an emulsified dispersion. 2 kg of lactose, 2 kg of cornstarch
The emulsified dispersion was sprayed into a fluidized bed (dry air inlet temperature: 80° C.) in which a mixture of 3.4 kg of crystalline cellulose and 3.4 kg of crystalline cellulose was fluidized. After spraying the entire liquid amount, fluidized drying was further performed for 10 minutes. The resulting CoQ ₁₀ -containing composition is 7.5
It was Kg. Fill 100 mg of this powder into a No. 4 capsule, and
Capsules were prepared containing ₁₀ 5 mg of CoQ per capsule. Example 2 Hydroxypropyl cellulose 30g, lactose 70g
Add 400ml of water to disperse, heat to 70℃,
100 g of CoQ ₁₀ and 600 ml of water were added and mixed to form an emulsified dispersion. The emulsified dispersion was sprayed into a fluidized bed containing a mixture of 400 g of crystalline cellulose, 200 g of corn starch, and 200 g of lactose (dry air inlet temperature: 70° C.). After the entire liquid was sprayed, it was allowed to flow for an additional 10 minutes and dried. 950 g of the resulting CoQ ₁₀ -containing composition
A small amount of magnesium stearate was added to the solution to form tablets with a diameter of 6 mm and a weight of 100 mg. Example 3 40 g of hydroxypropyl cellulose and 1 g of sucrose ester were dispersed in 500 ml of water, heated to 70° C., and 100 g of CoQ ₁₀ was added and mixed to obtain an emulsified dispersion. Fluidized bed containing a mixture of 1000 g of lactose and 859 g of mannitrate (dry air inlet temperature 70°C)
The emulsified dispersion was sprayed into the container. After the entire liquid was sprayed, it was allowed to flow for an additional 5 minutes and dried. Obtained CoQ ₁₀
The composition contained was 1965g. This powder was passed through a 32-mesh sieve to produce fine granules.

Claims (1)

[Claims] 1. A solid composition containing a hydrophilic natural polymer or a cellulose derivative in a mixture of CoQ ₁₀ and oleic acid, characterized in that it is produced by a fluidized bed granulation method. CoQ ₁₀ -containing composition. 2. The method according to claim 1, wherein 1 part by weight of the mixture of CoQ ₁₀ and oleic acid contains 0.1 part by weight or more of a hydrophilic natural polymer or a cellulose derivative.
CoQ ₁₀ -containing composition. 3. The CoQ _10- containing composition according to claims 1 and 2, wherein the mixture is a mixture of 1 part by weight of CoQ ₁₀ and 5 parts by weight or less of oleic acid.