JPS5951214A - Preparation of drug having high bioavailability - Google Patents

Abstract

PURPOSE:To obtain a drug having high availability advantageously, by suspending a slightly water-soluble oil-soluble active substance of a drug in water with polyglycerol fatty acid ester, blending it with an aqueous solution containing a specific amount of a water-soluble high polymer, followed by spraying and drying. CONSTITUTION:For example, polyglycerol fatty acid ester as an emulsifying agent is added to a slightly water-soluble oil-soluble active substance of a drug such as vitamin A, D, E, K, ubiquinone 7, 9, 10, etc. having low bioavailability to give an oil-in-water emulsion. This emulsion is blended with three times as much a water-soluble high polymer such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, etc. in an aqueous solution as the active substance of a drug by weight, the blend is sprayed and dried, to raise the bioavailability of the active substance of a drug without causing side effects.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing drugs with high bioavailability, the purpose of which is to significantly increase the bioavailability of water-soluble, oil-soluble pharmaceutical active substances that generally have low bioavailability. 1゜The present invention provides a method for increasing the amount of oil that can be dissolved in water. ()j, for example, vitamin A, vitamin D, vitamin E, vitamins, ubiquinone-7, ubiquinone-9, ubiquinone-1O
Almost insoluble in water, such as ubiquinones, vegetable oils,
-T means a medicinal active substance soluble in a solvent or the like. Hereinafter, this substance will be simply referred to as "oily millet".

Conventionally, polyoxyethylene hydrogenated castor oil,
Note: A method in which all nonionic surfactants such as polyoxyethylene sorbitan monooleate are added is well known, but these surfactants have side effects such as hemolysis and mucosal irritation. Nozomi knew how to do it without jumping.

The present inventor #4 focused on the fact that polyglycerol fatty acid esters, which were widely used for food, do not have the above-mentioned side effects and have surface activity, and developed "oily type" polyglycerol fatty acid esters. A pharmaceutical composition with good bioavailability comprising a diester and optionally a water-soluble polymer j11 has been invented. These inventions are patent applications. (% Gansho 56-109777
゜Special h; [1 1975-175168] The present inventors have continued to make research efforts on improving the bioavailability of such "oil-based systems", but at the time of filing the tenth patent application, one of the "oil-based systems" It was discovered that by adding at least three times the weight of the water-based polymeric substance, which had only been added to 10% of the total weight of the ``oil-based'' product, the bioavailability was unexpectedly significantly improved. However, the present invention was achieved.

Below, aspects of the present invention Example 111 will be described in detail.

The polyglycerol fat hi/ester used in the VC stool of the present invention is a polymer of about 3 to 14 units of glycerin, with at least one fat hi/ester per molecule of the polymer bound by an ester bond, and A compound that retains at least one hydroxyl group derived from
The fatty acid can be appropriately selected from saturated or unsaturated fatty acids having 10 to 20 carbon atoms, such as lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and lyluic acid. The amount of ester used for this ester differs depending on the type of "oily system" to be used, but it is usually at least zO percent, preferably 100% or more and 500% or less, of the oil and herbal medicine. If it is less than 20%, the emulsifying power for "oily systems" is insufficient and it is not suitable for the purpose of the present invention, and if it is more than 500%, there is no problem in terms of performance, but it is economically disadvantageous.

Examples of water-soluble polymer substances used in the present invention include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylethylcellulose, and polyvinyl alcohol.

Synthetic or semi-synthetic polymers such as polyvinylpyrrolidone (-'
49/)'! (Also, gum arabic, gum tragacanth.

Natural polymeric substances such as gelatin can be used alone or in combination as appropriate. The amount to be used will vary depending on the type of "oily type" in question, but at least 3 times the amount of the "oily type".
It is essential to have a maximum of 5. If it is less than 5, the bioavailability, which is the objective of the present invention, is inevitably inferior to some extent.

The reason for this is probably that the "oily type" particles emulsified with polyglycerol fatty acid esters are further protected by a sufficiently thick layer of these water-soluble polymeric substances. Q (cr
The reason for this is that it can prevent particles from becoming coarse due to agglomeration of oil-based substances.

The embodiments of the present invention are as follows: 1. First of all, the target "oily system" is dissolved or dispersed in the above-mentioned polyglycerol fatty acid ester. J At this time, if the "oil I crude drug" used is solid, there is no problem in heating it to speed up the process. The obtained solution or dispersion is poured into water at room temperature or higher and stirred rapidly using a homomixer, homogenizer, etc. to emulsify and obtain an emulsion. In this case, of course, highly effective stirring is an important factor in injecting an emulsion with sufficiently fine particles. It is also effective to use a commercially available emulsifier that uses ultrasonic waves. The amount of water to be used can be appropriately selected based on the viscosity of the mixed emulsion finally obtained as described below.

Separately, the above-mentioned water-soluble polymer vlJ is dissolved in water and water mW is added.
Then, pour the emulsion obtained as described above into this and stir well to obtain a uniform mixed dispersion. At this time, normal gentle stirring is sufficient. The mixed dispersion thus obtained is finally sprayed and dried. In this final step, in addition to simply spraying and drying the uniform mixed dispersion (so-called spray drying method), it is also possible to dry the dispersion by spraying it onto another carrier. That is, it is also possible to adopt the fluidized rice grain drying method and spray the above-mentioned uniform mixed dispersion onto the surface of fine particles of starch or lactose floating in a fluidized bed and dry them. The above-mentioned method of spraying and drying also generally includes the above-mentioned method. It shows the easiness. In performing the final step of spraying and drying, if the viscosity of the mixed dispersion is too high, it will be difficult to operate, so it is preferable that the viscosity is at least 1000 centipoise or less at 50°C. Therefore, in order to meet this condition, the amount of water used in each process should be adjusted.1. If the viscosity is still too high at the final stage, there is no problem in diluting it with water.

The above-mentioned operation (d) shows one of the embodiments of the present invention and may be changed within the scope of the method of the present invention.For example, to prepare an emulsion (d), add polyglycerol fatty acid ester and ""Oil-basedsystem" may be added dropwise at the same time and stirred in a similar manner.Additionally, water f?4w!L of water-based polymers may be poured into the emulsion and stirred to form a mixed dispersion. In addition, when carrying out the method of the present invention, fatty acid monoglycerides, animal and vegetable oils, organic solvents, etc. may be added to help emulsify the "oil medicine", and color softeners, flavoring agents, and bulking agents may be added. Adding agents etc. also falls within the scope of the present invention (().

As detailed above, the method of the present invention is industrially easy to implement and can significantly increase the bioavailability of "oil 1 herbal medicine", so it can be said to be an extremely useful method industrially. An example of the present invention is shown.

Example Ubiquinone-1012 was combined with decaglycerol decaoleate 0.5r and decaglycerol monooleate 17
was dissolved in the mixture at 60°C, and vigorously stirred (1200 rpm) using a Polytron emulsifier (Model PT 45150, manufactured by Swiss Kinematica) for 50 me
Gradually pour warm water (60°C) into the emulsion and continue stirring for 5 minutes.
PCL) 10 f was dissolved in 200 ml of water, and the emulsion obtained earlier was gradually poured into this and stirred to make a uniform mixed dispersion of about 250 ml! I got it. The viscosity is 3
It was 350 centivoise at 0°C. This was spray-dried using a small spray dryer (model F'5-20 manufactured by Freund Sangyo Co., Ltd.) to obtain about 72 powders with a particle size of 5 μm to 100 μm. This powder 6,252 and lactose (diurnal cycle) 6.2
0f and light silicic anhydride (AERO manufactured by Nippon Aerosil)
8IL 200) 0.05t was mixed to make powder 4
, Example 2 Ubiquinone-1012 was mixed with octadalycerol monooleate 22 and decaglycerol decaoleate 2f under heating (60°C), water was added to this mixture using an ultrasonic homogenizer (manufactured by Nippon Kozueki Manufacturing Co., Ltd.). US-600 model) to obtain an emulsion (400 μAI for 5 minutes).

Separately, hydroxypropyl methyl cellulose (Shin-Etsu Chemical TC-5R) 15F was mixed with water at 300 mQ4,
The emulsion obtained earlier was added to this and mixed to obtain about 400 ml of a uniform dispersion.

This was spray-dried using a small spray dryer (Mobil Minor Spray Dryer manufactured by Ashizawa Niro Atomizer Co., Ltd.), and the particle size was 1 to 40 μm. A microencapsulated powder of about 152 n was obtained.

10 F of this powder was mixed with 10 F of crystalline cellulose (Avicel PH-301 manufactured by Seikasei Co., Ltd.) to prepare a powder.

Comparative Example 1-a Actual Bin Example I A song in which monodarycerol trioleate 1.52 was used instead of decaglycerol decaoleate and decaglycerol monooleate-1 in VC was treated in the same manner to obtain a powder. Ta.

Comparative Example 1-b The components were the same as in Example I, and to obtain a mixed dispersion, ubiquinone-IO decaglycerol decaoleate and hydecaglycerol monooleate were added while stirring the hydroxyglobil cellulose aqueous solution with a Polytron emulsifier. Add l' blue lysate to. Thereafter, the same treatment as in Example 1 was carried out to obtain a powder. Comparative Example 2-a In Example 2, 0.52 hydroxyglobyl methylcellulose and sucrose were added in place of 15 q of hydroxyglobil methyl (15 q of Ruth). Approximately J.22 of the powder was chewed using the same procedure except for using 14.sy.

This powder 102 was mixed with 102 crystalline cellulose to make a hashish drug. Comparative Example 2-b In Example 2Vc, the components were the same, but to obtain a mixed dispersion, ubiquinone-10. A warm mixture of octaglycerol monooleate and hytecaglycerol decaoleate is added and subjected to ultra-i1 wave treatment.

Thereafter, the powder was treated in the same manner as in Example 2, and the plasma concentration was measured.Example 1. In Comparative Example 1-a and Comparative Example 1-b, 1 group of 5
The head was peagle-sized (approximately 10 liters in each body) and was administered orally. The dosage is ubiquinone-10 per 1!11
25 mg. After administration, the plasma concentration of ubiquinone-10 was measured and the results are shown in FIG. Also, Example 2
．． One group of the ubiquinone-10K compositions obtained in Comparative Example 2-a and Comparative Example 2-b was prepared in the same manner as described above.
Ubiquinone was orally administered to a peagle-sized area of the head, and the plasma concentration of ubiquinone was then measured, and the results are shown in Figure 2.

[Brief explanation of the drawing]

Figure 1-d implementation? lJl, Comparative Example 1-a and Comparative Counterexample 1
- Administering Suno's ubiquinone-IO-containing composition to pegle dogs [
It is a figure showing the course of concentration of ubiquinone-1O in plasma after one injection. FIG. 2 shows Example 2. 11 is a diagram showing the course of the concentration of ubiquinone-IO in plasma after oral administration of the -1 biquinone-containing compositions of Comparative Example 2-a and Comparative Example 2-b to a Pegle-sized dog. IE
Continuing from page 1 0 Inventor Futsuko Hesumi Freund Sangyo Co., Ltd. 2-14-2 Takadanobaba, Shinjuku-ku, Tokyo 0 Inventor Emiko Sudo Freund Sangyo Co., Ltd. 2-14-2 Takadanobaba, Shinjuku-ku, Tokyo 0 within the company Inventor Taku Tsujino - 2-14- Takadanobaba, Shinjuku-ku, Tokyo 2 Freund Sangyo Co., Ltd. @ Applicant Freund Sangyo Co., Ltd. 2-14 Takadanobaba, Shinjuku-ku, Tokyo

Claims (1)

[Claims] I: Insoluble in water;
An oil-in-water emulsion is prepared using polyglycerol fat J.P ester as an emulsifier, and then mixed with an aqueous solution containing a water-soluble polymer having an amount of at least three times the type of the pharmaceutically active substance, and then sprayed into A method for producing a drug with high bioavailability, the method comprising drying the drug by drying.