JPS5877810A - Oral drug composition containing polyglycerol unsaturated fatty acid ester - Google Patents

Abstract

PURPOSE:An oral drug composition having good absorption and high bioavailability, being medicated easily, obtained by adding a polyglycerol unsaturated fatty acid ester, a surface active agent having no toxicity as a drug, to a slightly water-soluble drug. CONSTITUTION:A polyglycerol unsaturated fatty acid ester (PGUFAE) of a surface active agent, especially a polyglycerol ester of oleic acid, linoleic acid, or linolenic acid, is added to a slightly soluble drug, especially a fat-soluble drug easily absorbable from lymph such as ubiquinones, to give an oral drug composition. The composition is obtained by dispersing the slightly soluble agent into PGUFAE or by dispersing the slightly soluble drug and PGUFAE into a liquid oil. The prepared material is made into capsules or powder for use.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an oral pharmaceutical composition containing a Japanese fatty acid ester. However, the above-mentioned drug that is difficult to bathe means a drug that can be bathed in water, and the same applies to the following description. In addition, the above-mentioned polyglycerol unsaturated olofatty acid ester means a polyglycerol ester of oleic acid, linoleic acid or lylunic acid, and when abbreviated for convenience below, P GU F
A. Listed as ester or simply PGUP'AE.

The object of the present invention is to provide an oral drug composition of Kuraki that is well absorbed, has high bioavailability, and is easy to administer. and includes a number of drugs, examples of which include ajmaline, ibuprofeno, erythromycin, erythromycin 7 nostearate, ethylthromycin, chimesamycin, chloramphenicol palmif), Ergocalciferol (v, D2), cholecal/ferol (V, D
s), 7"rogestero-7, testosterone torate in enano, testosterone propionate, methyltestosterone, ethyl estosodiol, d-tonfur (dt
tocopherol, nolotane, phytonadione (V, KI), riboflavin butyrate, tocopherol acetate, methoxyprogesterone acetate, glodyzone, nifedipine, indomethacin, dipyridamole, d-limonene (Liq, ), tricafurilino (L)
iq,), Nicotine Song Tocopherol, Oki/Fuentaso/, Fruzena/Zena/Tate, Ethyl Aminobenzoate, Lidocai 7, Niceritrol, Nitroglycerin, Clofibrate (Liq, ), Phenylpropatol, Linoleic Acid (V, F) Pensinatate, creoso-) (Liq, ), quaiacol (liq, ), vitamin A, ncrocoumarol, menatetrenone (V, Kz
)＞Ribofluentetranicotinate (V, Bl
), COQ7, COQ9, COQ+o (ubidecarenone), which are water-soluble drugs.

Of course, the PGUFAE of the present invention is not limited to the above-mentioned examples. The PGUFAE of the present invention is an ester bond with one or more molecules of oleic acid, linoleic acid, or phosphoric acid per molecule of polyglycerol on a glycerin base. An example of this PGUFA ester, which is a compound that retains one or more water groups of Dalicerino, is diglycerol mo/oleate (diglycerol mo/oleate).
l monooo, 1eat), diglycerolmonol 1nole
nate), triglycerol mo/olex-t (tr
iglycerol monooleate), octaglycerol dioleate (octaglycerol monooleate), octaglycerol dioleate (octaglycerol monooleate)
dio-1eat), decaglycerol decaoleate
e) Pentaglycerol monoline V-) (, pe
ntaglycerol monolinoleate
) etc.

The easily absorbable fat-bath drug described in Claim 2 of this patent is a drug that dissolves in fat-bath water that is easily absorbed by phosphorus and sulfur, and includes vitamins, for example. A. Vitamin D
1 Vitamin E and vitamin K and C0Q7 (ubiquinone-7), CoQs (ubiquinone-9), Co Q+
o (Ubidekare 7)) etc. The oils listed in the scope of claim 5 of this patent include fats and oils, lipids (lipoids), essential oils, and compounds thereof. means. Specifically, vegetable oils such as coma oil, rapeseed oil, soybean oil, lard, het, squalane, squalene, etc. ll2J'+71J oil carauni, cinnamon oil,
Nnonana Nanano, oil, spearmint oil, and other lipids such as essential oils from the 7 temples, phosphorus oil, and quince oil. In addition, Karbok is a pale yellow or colorless oil with a boiling point of 230° C. that is present in spearmint oil and the like.

In addition to the scope of claim 6 of the present application, the powders mentioned in the GPI include, for example, powdered lactose, β-cyclodextrin, microcrystalline cellulose (Asahi Kasei Avicel, etc.), starch, wheat flour, dextrin, cellulose powder, and carbon dioxide. It is a non-toxic powder such as silicon powder.

Examples of the water-bathable polymeric substances described in claim 8 of the present patent include pregelatinized starch, carboxymethyl starch, burlano, gelatin, arahiacom, carboquine methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, As a result of continuing research related to methods for increasing the bioavailability of drugs that are poorly soluble in water, the present inventors have achieved numerous inventions. Special application 1974-442
61 (method for activating drugs soluble in alkalis and acids), Japanese Patent Application No. 1982-75774 (method # for activating drugs), Japanese Patent Application No. 1983
-76203 (Coachnobu method for powdered drugs, patent application 1982)
-70104 (Method for converting drugs to active F+), patent application 1982-11
8135 (absorption-improving ubiquinone preparation), patent application 1982-1
46362 (absorption improving preparation), patent application No. 56-27663
(Absorption-improving preparation) and Japanese Patent Application No. 109777/1987 (Drug containing polynolycerol fatty acid ester).

The present inventors have also conducted various studies on methods of using surfactants as a step to improve the bioavailability of drugs that are poorly soluble in water.

Surfactants include anionic surfactants such as higher fatty acid alkali salts (soaps) and alkyl sulfone salts, cationic surfactants such as reverse soaps, higher amine halogenates, quaternary ammonium salts, and polyethylene glycol. Examples include non-ionoactive agents such as alkyl ether glycol fats, fatty acid esters, and solvitano fatty acid esters. These anionic activators and cationic activators cannot be used not only for food but also for general medicine because they have strong toxic effects, or even if their toxic effects are weak, they have weak emulsifying power. The use of nonionic activators for polyquine ethylene threads has been completely prohibited for food use, but for pharmaceutical use, nonionic activators include polyoquine ethylene hydrogenated human oil and hypolyoxyethylene. Sorbitanmo is 7 years old and the use of drugs such as ethos is permitted.

However, these nonionic activators, which have been used for medical purposes since FX, have problems such as blood-resistance, mucous membrane irritation, and mucosal defects.
. . . Therefore, in many cases, it is difficult to use it as a medicine in practice, and there is a demand for the development of a harmless pharmaceutical surfactant that does not have such side effects.

The present inventors have been actively searching for surfactants that do not have toxic effects among the 5 commercially available surfactants, but they have been relatively recently approved for use as prizes by the US FDA. Noting that polyglycerol fatty R ester (PGFAE) has been approved for use as a prize because it is non-toxic, we conducted an evaluation of its use as a medicine. -PGFAE can be made from high to low HLB, which is the balance between hydrophilicity and lipophilicity, depending on the degree of polymerization of glycerin, the four groups of fatty acids, and the degree of esterification. It has a strong ability to emulsify or make 0T swamp and dissolve the #h sequence, and therefore has the property of promoting the absorption of drugs that are poorly soluble in water. Target 2 is the interface,? Found to be a divination agent 17% above
-109777 (a drug containing PGFAE+).

The non-toxicity of PGFAE is that its constituent polyglycerol is a polymer of natural IJK 5+ glycerin, which is different from polyquineethylene, which has traditionally been used as a pharmaceutical surfactant. The present invention is based on the above-mentioned Japanese Patent Application No. 56-109777 (PGFA).
This drug was developed based on the invention of the drug containing k, which contains poorly soluble i.
agent and PGU? "A" is an oral pharmaceutical composition containing AE.In other words, the non-invention is based on the invention (drug containing PGFAE) in which polyglycerol esters of oleic acid, linoleic acid or linuric acid are used as PGFAE, as described below. As is clear from the Examples and Comparative Examples, it was discovered that the bioavailability of the present invention was particularly remarkable as an oral pharmaceutical composition, and the invention was achieved.

The composition of the present invention improves the absorption of poorly water-soluble drugs due to the surfactant power of PGUFAE contained therein.
Demonstrates the effect of significantly increasing bioavailability.

In the composition of the present invention, when the poorly soluble drug is dispersed in PGUFAE, the poorly soluble drug is dispersed in PGUFAE.
The degree of dispersion of the poorly soluble drug in the medium is controlled by the degree of affinity between the two, the strength of stirring, etc., but it is preferable to disperse it finely, and the so-called state of molecular dispersion improves absorption and pharmaceutical stability. ) The allocation of PG'UFAE to poorly soluble drugs can be determined either by determining the dispersibility of the poorly soluble drug, or by adding 0.05 part to 30 parts per part of the poorly soluble drug on a weight basis. P G U up to
As an embodiment of the present invention, a dispersion of mra pouring agent and PGUFAE in liquid oil is also used. It is even more effective in increasing your virility.

In order to prepare this embodiment, the purpose can be achieved by adding a sparingly soluble drug and PGUFAE to liquid rto lipid shell, or by stirring the mixture.

The amount of adult fat and oil relative to the poorly soluble drug is determined on a case-by-case basis depending on the dispersibility of the poorly soluble crude drug used in fats and oils. Normally, on a weight basis, poorly soluble chemical cutting lvC lamp [2 PGU for using oils and fats from 095 to 10 O or difficult to bathe cutting
The amount of P'AE is determined while looking at the former dispersibility. As a result of conducting tests on hundreds of poorly soluble drugs, it has often been found that the objective is often achieved by using 1 to 5 parts of PGUF'AEO to 1 part of the soluble drug on a normal weight basis.

Add poorly soluble drugs to liquid PGU TO' AEff for ¥1. In this embodiment, poorly soluble drugs and PG are contained in liquid oils.
In the case of an embodiment in which UF"AE is dispersed, the present applicant has referred to Japanese Patent Application No. 118135/1982 and Japanese Patent Application No. 1983.
When the composition is encapsulated in F6 or 71-crocapsules with a particle size of 3 mm or more as disclosed in Japanese Patent No. 146362, absorption is promoted and difficult compared to when it is filled in conventional ordinary phase capsules. The reason for the ability to further increase the pio-apabiliday γ of soluble drugs is as follows:
l/ko is estimated.

In general, oils have a large surface tension, and in order to emulsify them during digestion and treatment, it is necessary to mechanically subdivide them in advance. Orally administered oil enters the stomach and intestines (8) and is subdivided by the IIL stirring action by these.However, this stirring action is weaker than mechanical stirring. Even when edible oil is administered in a rather large amount, it is often not digested and the amount of 7L is excreted.Therefore, oils prepared by dispersing a common solid cross-linking agent in water are often used. Alternatively, if a preparation filled with PGUP'AE in microcapsules is administered orally, the oils will be preliminarily subdivided, and the secretion of bile and lipase will be reduced, as in sick or elderly patients, and the secretion of bile and lipase will be reduced. Even if the stirring function is weak, oils or PG [J
It is thought that the emulsification of F'All; takes place smoothly, and that the drug is absorbed from the gastrointestinal tract into the blood and I/J lymphocytes. The above inference can be easily understood from the fact that by reducing the particle diameter of the same oil, the number of surface species increases at an accelerated rate, making it easier to digest. Particularly limiting the diameter to 3 m or less is advantageous from the viewpoint of the absorption rate and absorption rate due to the increase in surface species as described above, and from the viewpoint of a convenient dosage form for administration. For example, by adjusting the number of pills with a particle size of 3 u + m, the dosage can be adjusted for adults, children, severe and mild illnesses, and the particle size is 0.1 = l.
In the case of m, it can be administered as granules, or in the case of 1+ mm or more, it can be filled into sheath capsules or administered as fine granules or agglomerates.

VC, which has a grain size of 3 capsules or less, cannot be treated with normal sheath capsules or soft capsules, apart from prototyping. It is difficult to do so.

Therefore, it is practical to use so-called seamless minicapsules.

The first step in applying light to a seamless mini capsule is fat.
Oranoda's GLO-PEX mark shown in the figure ■ Capsule Love Corps (7-1-1 Tenjinbashi, Oyodo-ku, Osaka City, Tenroku Hankyu Building Co., Ltd. Handled by Miniature Trading Co., Ltd. GLOBEX)
gelatin water bath dffi was used as a coating solution.

The operation of filling the slimless minicapsules will be explained with reference to Fig. 1. First, a poorly soluble drug, etc., using liquid oil or liquid PGUF'AE as a dividing medium, is dispersed in the ground into which the Glowpex capsule is broken. System and heated Seratino water bath solution, pulsating hop IJi and the cutoff valve (6) are syncronized for 5 minutes.
A spherical gelatino capsule encapsulating gelatin a is poured into cooling oil (5) and the gelatin ki constituting the cuff cell is cooled and solidified. The capsule sieves (8) with the circulating oil.
After the oil is separated by this sieve, it is collected in a capsule receiver (9).

There is also an invention based on the production of this seamless capsule, for example, as disclosed in Japanese Patent Publication No. 53-1067.

When the poorly soluble drug of the present invention is an easily absorbable fat bath drug, it is well absorbed directly into the lymphatic system in the small intestine in an emulsified state with watermelon, bile, etc. Direct absorption into the lymph is very advantageous because it is not transported to the liver via the portal vein and undergoes metabolism, unlike when absorbed into the blood. Of course, in the case of an easy-to-inject, lymph-absorbing drug, it is also absorbed into the blood, and combined with lymph absorption, increases bioavailability. Vitamin A for easily absorbed drugs
%4 D1 same E, 1 river and C0Q7, C0Q9 +
As mentioned above, COQ+o, etc. are included.

Next, the Kanpo of the present invention, in which threads in which a poorly soluble drug is dispersed in PGU P''AI-; After administration, the dispersion system can be easily emulsified. Therefore, absorption of poorly soluble drugs is particularly promoted, which is advantageous. Of course, if this type of bath is used as a fat bath with easy absorbency, lymph absorption will be further promoted.

In order to adsorb a system in which a poorly soluble drug is dispersed in P G Ll )i''p, E into a powder, the dispersion system must be of good quality.There is no particular method to choose for rC in order to adsorb it. However, it is preferable to spray the dispersion system and adsorb it onto the powder.Since it is preferable to apply the dispersion system in the form of a powder, it is generally recommended that -i1 [[agent] p G T
J F A E K: Good results can be obtained when the minute i & Li yarn is 1.0 or less.

Although not mentioned in the embodiments of the claims, an embodiment in which a system in which refractory oxidation agent 1j and PGUFAE are dispersed in liquid oil and fat is adsorbed into powder is also available for almost the same reason as the above embodiment. It is effective in promoting the absorption of poorly soluble drugs and improving their bioavailability. This embodiment can also be prepared by a method similar to the above method.

As an embodiment of the present invention, the embodiment υ1 listed in Claim 8 is a system in which the poorly soluble injection agent i11 is dispersed in l'GUFAE. ! There is a product obtained by emulsifying the emulsion in water in the presence of liquid and removing the water from the emulsion by evaporation. This embodiment is also a particularly effective sieve composition. To prepare the composition of this embodiment, the poorly soluble drug can be used as is or by finely pulverizing PGU.
The system added to FAE and stirred and dispersed is emulsified in a water bath liquid of a water bathable polymer substance or in water together with a water bath polymer substance, and then the water in the emulsion liquid is evaporated. It is preferable to ejaculate in order to evaporate the water.

In order to improve the absorption of drugs that are poorly soluble in water, it is necessary to make them into granules in the gastrointestinal tract. It is known that imitation i+- is emulsified into micelles and absorbed into the lymphatic system in vivo. The absorption rate from the lymphatic vessels is 8011ma
Kidraku AU, 'K ld, which uses KinvHro to easily predict the azalea's rL by cannulating the animal's chest lymph fluid and collecting and measuring lymph fluid using n's h-type VC.
This can be seen in the pass rate of micelles in a bile salt solution of the formulation. In other words, the PGUF that is easily absorbed into the liquid
'It is possible to estimate the efficacy of PGUFAE in improving the bioavailability of the drug by imitating the emulsifying power of AE with innohydro and measuring the passage rate using a fine filter such as a millipore filter. I can do it.

EXAMPLES The present invention will be explained in more detail below by describing examples of the present invention and tests of its effects. ) Example 1 dt-α-toco7erol acetate 202 was deca
glycerol decaoleate (147 product name 5 antone (g) 10-10-0 US Lm
(manufactured by Durkee) 80 rl/[710]. The obtained liquid is reduced to No. 11A, filled with Growpex Mark Capsules M & M, and reduced to particle size 1 by the same machine.
Spherical seamless minicapsules of III11 were obtained. The content of tocopherol in capsule All of this example was 15% by weight.

As mentioned above, 5antone is manufactured by Durkee in the United States, so only the product name will be described below and the company name will be omitted.

Example 2 Erythromycin stearate 80 tk, purified was dissolved in monocarvone 1201 by heating (approximately 50°C). Pentaglycerol monooleat was added to this solution.
e (trade name: SY-Glister MO-500 manufactured by Itamoto Yakuhin Kogyo Co., Ltd.) 501 was added to obtain a liquid composition.

Separately, 45 parts of gelatin, 5 parts of glycerin, and 50 parts of purified water were dissolved while heating [7] (prescription t).

Furthermore, methyl acrylate/methacrylic acid copolymer CM
PM-05) 8 parts and 3 parts of sodium carbonate water bath solution 9
Prepared by dissolving 2 parts (Formulation 2) 0 A mixture of the above prescription 1 and Formulation 2 at a liquid ratio of 95:5 (volume ratio) was prepared as a base material for capsules according to the plate method to approximately 0.6 A gelatin sheet for the throat was produced. 250 ml of the erythromycin stearate bath solution previously prepared in the recesses of this sheet.
~ was poured into the mixture, another seratin sheet was placed on top, and the mixture was pressed using a compressor to produce soft capsules with a diameter of about 8 vans. This l-capsule contains approximately 80 kg of erythromycin stearate.

Example 3 The erythromycin stearate yukata prepared in Example 2 was charged into the GLO-PEX/MARCRO capsule coating machine shown in Fig. g1, and spherical minicapsules with a particle size of 2.8 mm were obtained using the same machine. The content of erythromycin stearate in this capsule was 25% by weight.

Example 4 Octag phytonadione (V, ni+)”150 f
lycerol monooleate (p, 5 product name 5 antone 8-1-0) 50 f, t
riglycerol trioleate (product name S
Y-Glister TO-310 (manufactured by Itamoto Yakuhin Kogyo Co., Ltd.) 50t
A liquid composition was obtained by dissolving the mixture in a bath. The solution of this example can be applied to soft capsules and liquid preparations.

Example 5 The liquid composition 2502 obtained in Example 4 was heated and added to Ad Solider 101 (manufactured by Freund Sangyo Co., Ltd.) 750f.
15% phytonadione powder obtained by adsorption on.

Example 6 CoQ+o (ubidecarenone) powder 20ftlflH1
-Carboy 50't, octaglyCero
l monooleate (product name 5 antone 8
-1-0) 50 f and decaglycerol
decaoleate (product name 5antone10-
10-0) It was added to the mixed solution of 20f and dissolved under heating to obtain a liquid composition.

Example 7 In addition to the liquid composition obtained in Example 6, 100 f of gelatin,
A gelatin yukata was prepared by gradually dissolving 35 f of gum arabic powder in purified water while heating it. The above two types of shin are the first
The mixture was charged into the Growpex Mark ■ capsule crusher shown in the figure, and seamless minicapsules with a particle size of 1+mn were obtained using the same machine. The content of C8Q+o in this capsule was 5 tons.

Example 8 - CoQ+o powder 102 with triglycerol mo
nooleate (product name SY-blister MO-50
Example 9 The liquid composition 502 obtained in Example 8 was heated to 50°C to obtain a liquid composition. Microcrystalline cellulose (
Avicel (manufactured by Asahi Kasei Corporation) 1509 was added to the mixture, and the mixture was stirred, dispersed, and adsorbed to obtain a 5% CoQ+O powder.

Example 1 CoQ+O powder ior, octaglycerol
monooleate (product name! 9antone 8-
1-0) 10 f- and deca-glycerol
decaoleate (Product name 5antone l
It was added to a mixed solution of O-1O-0)2Or and dissolved by heating to obtain a liquid composition.

Actual tJ@Example 11 To 40 ml of the liquid composition obtained in Example 1O, 5 oz of water,
Milk; 11M30 and 0'f# x to') 7309
In addition, Swiss-made Polytron emulsification & (POL, YTRON
■Tybe PT 45/50 KINEMAT
ICAGmbH) at 12,000 rpm for 5 minutes
K Te'A conversion 1. ft.

This emulsion was sprayed to evaporate water to obtain a powder.

Example 12 Griseofulvin 502 and polyethylene glycol 400 (PEG-400) 15F7I.

decaglycerql decaoleate (
Product name 5antone10-10-0) 20 f
Xdecaglycerol'monooleate
(trade name: 5antone 10-1) 302 was dissolved in a mixed solution of ethanol and chloroform (volume ratio 1:1). This bath liquid contains 202% lactose and 102% light silicic anhydride.
Add purified water 2009 in which
J') Emulsification was performed at 12.00 OrpmK for 5 minutes using Ron. This emulsion was sprayed to remove water and obtain a powder.

Strict example 13 Kitasamaishi: 150 tons of pentaglycero
lmonoo, 1eat (trade name: sy-Glister MO-500 manufactured by Itamoto Pharmaceutical Co., Ltd.) was added to 30 tons, heated and dispersed, and the dispersion system was dissolved in oil. This bath solution, which was dissolved in 200 grams of ethanol at 710 °C, was sprayed and the ethanol was evaporated to obtain a powder composition.

Example 14 Zenacetin 80t, decaglycerol
decaoleate (Product name 5antone l
O-10-0)202 was dissolved in chloroform at 500 rVC. To this bath solution, 100 tons of 5-hydroxyglopylcellulose (Type L manufactured by Minato Soda Co., Ltd.) prepared separately was added and emulsified for 15 minutes using an Ultrasonic homogenizer (manufactured by Ultrasonic Corporation in the United States).This emulsion was then sprayed. , moisture and chloroform were removed to obtain a powder.

Next, the effects of the present invention will be specifically demonstrated by describing the tests and results of each pharmaceutical composition in Examples.

(1) Test of the drug of Example 1 When this drug was administered to kerats, the absorption rate from the lymphatic vessels was determined by the Bol 1man method. The sample was dt-α-tocopherol acetate, and 5μ was orally administered to 5 rats (average weight 300 tons), and the lymph fluid flowing out from the cannula placed in the thoracic lymphatic vessel over 24 hours after administration was collected. The amount of tocopherol transferred to was quantified. As a control, a suspension of dt-α-toco7erol acetate in water was forcibly stirred and then orally administered without encapsulation. The results are shown in Figure 2.0 (2) Testing of the drugs of Examples 5 and 8.9 Dispersion permeation of these drug compositions in water (Group A) and mixed bile acid solution (Group B) The above mixed bile acid bath solution is a mixed bile acid bath solution with a molar ratio of 1:1 of sodium taurocholate and sodium taurothioxycholate, and its concentration is as follows: Measurement of dispersion permeability and micelle forming ability was carried out by injecting each of the above drug compositions into 100 ml of water, 30% of water or 30% of the above bile acid bath solution.
In addition, the mixture is filtered through a 5p Millipore filter shaken at 37°C, and then further filtered through a 0.45μ Millipore filter. The drug that passed through the 0.45μ filter was quantified to determine the dispersion transmittance and micelle formation rate. As a control, instead of the drug composition of the example, each of the active substances, ie, phytonadione and C8Q+o itself, was treated in the same manner to determine the dispersion transmittance and micelle formation rate. The results are shown in Table 1.

In Table 1, the column for group A shows the dispersed transmittance, and the column for group B shows the micelle formation rate. The numbers at the top of Table 1 indicate the shaking time in minutes (MIN) for the above test ants.

Table 1: Dispersion transmittance and micelle formation rate Note: The values in this table are percentages (3) Test of the drug of Example 2 and Example 3 Erythromycin stearate was orally administered at 500 μl at 12 o'clock time. The concentration of erythromycin in the serum of patients was measured. As a control, two commercially available Erythromy/Instearate 250 tablets were administered, and the results are shown in Figure 3.

(4) Test of the drug of Practical IM Example 9 Regarding the powder of Example 9, the dispersibility of fine particles of ubidecarenone in water was measured by the method described above.

First, add 900f of water to the bath tester (for paddle method manufactured by Toyama Sangyo).
f17! The paddle rotation speed was 10,100 rpm, the bathing time was 15 minutes, and the sample contained 500 WM of ubidecarenone.
The above powder containing i was weighed and elution was performed. Next, the obtained eluate was filtered using a Millipore filter (manufactured by Hhon Millipore Co., Ltd.) with pore sizes of 1Op, 3μ, and 0.45μ, and ubidecarenone in the p solution was quantitatively analyzed.
The migration rate to M was measured. The following were used as controls. According to the method described in Example 5 of JP-A-52-136911, ubidecarenone 3F and hydroxypropyl cellulose (HPC) were dissolved in ethanol 30- and this was adsorbed onto lactose 952. The mixture was then granulated using a 20-mesh screen and dried at 50°C for 3 hours. The amount of RPC added was adjusted so that the RPC content in the granules was 3% and 7%. The results are shown in Table 2. RPC content 3%
The sample with HPC content of 7% was shown as Control 1, and the sample with 7% HPC content was shown as Control 2. The concentration of ubidecarenone in the serum was measured 2 hours after continuous oral administration once a day for 5 days. The results are shown in Table 3. As controls, the granules of Control 1 and Control 2 used in the drug test of Example 9 in (4) above were used as Control 1 and Control 2, respectively. The results are shown in Table 3.

Table 3 11) Further, the drug of Example 11 is a drug that is easily absorbed by the IJ lymphocytes, and the lymphatic transfer rate was determined for the purpose of determining the degree of activation.

The absorption experiment was performed using five male Wistar rats (body weight 250 to 30
After giving 01 only physiological saline for 24 hours, C□Q+o
A sample containing the equivalent of 1q is directly administered as powder, and 2
The saliva fluid flowing out over a period of 4 hours was collected. CoQ+ migrated into lymph fluid.

was determined by high performance liquid chromatography.

Note that the control 1 used in the drug test of Example 9 was used as the control 1, and the control 2 used was the same as that used in the drug test of Example 9.
According to the method described in Example 1, ubidecarenone 41 and monoolein 281 were placed in a mortar and heated to about 60°C.
Melt the crystalline cellulose on a hot water bath and mix.
8f was added to feed it, and it was used as a sucking end of ubidecarenone. The results are shown in Table 4.

Table 4 (6) Testing of the comfort medicine of Example 12 The griseofulvin powder of Example 12 and the griseofulvin crystal powder as a control were administered to three adult males as griseofulvin at a dose of 250 to 0 4 times a day. The blood concentration of O was measured over time and the results are shown in Figure 4.

(7) Test of the powder preparation of Example 13 The powder preparation of Example 13 and the crystalline powder of kitasamycin used as a control were administered to 6 adult males as kitasamycin at 600 μl.
Changes in blood concentration over time after oral administration were measured. The results are shown in FIG.

(8) Test of the powder formulation of Example 14 The powder formulation of Example 14 and the commercially available zenacetin crystal powder used as a control were orally administered as zenacetin in an amount of 1.5 g to six adult males, and the subsequent blood concentration was determined. was measured over time. The results are shown in Figure 6.

[Brief explanation of the drawing]

FIG. 1 is an explanatory diagram of manufacturing seamless minicapsules using the GLO-PEX Mark 1 capsule coating machine. 1. Filling (liquid), 2. Gelatin bath liquid. 2'... Automatic control valve, 3... Gelatin bath liquid, 4...
・Pulsating pump, 5. Cooling oil, 6. Cutoff box, 7. Cooling device, filter and pump, 8. Face, 9. Turnip 7 receiver. = I'lll's dt-
α-Tocopherol acetate seamless minicapsules and their controls were administered to rats I/(Fig. 3), which shows the lymphatic absorption over time after oral administration. Approximately 8 throat soft capsules (Example 2
) or seamless minicapsules with a particle size of 28 (Example 3)
FIG. 3 is a diagram showing the results of measuring blood concentration over time when a capsule filled with 100 mg/kg of chloride was orally administered to an adult male. FIG. 4 is a diagram showing the test results of the drug of Example 12. FIG. 5 and FIG. 6 are diagrams showing the test results of the powder formulations of Example 13 and Example 14, respectively. Agent: Patent Attorney Tadashi Hori Figure 1: 9 - Cloud 1-14 - ← (Kyo) Procedural amendment (self-motivated) Showa year 2016//month 1999 Dear Commissioner of the Japan Patent Office, Showa 6 Order of patents filed on January 1, 2017: J Title of the invention: Oral pharmaceutical composition containing polyglycero-diyl-unsaturated orolytic acid ester French style, implantation 1611 Telephone 03-31i-o≠ri6 Amended from The subject matter of 1 Specification 6 Contents of the amendment is not limited to 1. on lines 72-73 of Specification No. ≠ Sada. '' followed by the following phrase: [Also, the oral pharmaceutical composition of the present invention contains drugs that have pharmaceutically active substances such as natural α-tocopherol, carotene, and vitamin A, and are marketed as health foods. ''Continued from page 1 0 Inventor Emiko Sudo 2-14- Takadanobaba, Shinjuku-ku, Tokyo ' 2 Freund Sangyo Co., Ltd. 0 Inventor Taku Tsujino 2-14 Takadanobaba, Shinjuku-ku, Tokyo 2 Freund Sangyo Co., Ltd. 0 applicants Freund Sangyo Co., Ltd. 2-14- Takadanobaba, Shinjuku-ku, Tokyo

Claims (1)

[Claims] 1. A poorly soluble drug and a polyglycerol-free Japanese fatty acid varnish,
Oral pharmaceutical composition comprising chill. 2. The oral pharmaceutical composition according to claim 1, wherein the soluble drug is an easily absorbable fat bathing mulberry. 3. Oral pharmaceutical composition according to claim 2, wherein the easily absorbable fat bathing drug is a ubiquinone, and the 4#I bathing drug is dispersed in a polyglycerol unsaturated fatty acid ester. Oral pharmaceutical composition according to claim 1, claim 2, or claim 3. Claim comprising an @-soluble drug and a polyglycerol unsaturated fatty acid ester dispersed in liquid oil. The oral pharmaceutical composition according to item 1, item 2, or item 3. 6. An oral pharmaceutical composition according to claim 4 or paragraph 5J, which is filled into capsules having a particle size of 3 mm or less. 7. An oral pharmaceutical composition according to claim 1, claim 2, or claim 3, which is obtained by sucking blood into a powder using threads in which a bath-resistant drug shavings are dispersed in polyglycerol unsaturated fatty acid ester. 8. A system in which a bath-resistant drug is dispersed in a polyglycerol unsaturated fatty acid ester is emulsified in water in the presence of a water-bathable polymeric substance if necessary, and the water in the emulsion is removed by evaporation. Oral pharmaceutical composition 0 of Section 1, Section 1, -'' Section 2 or Section 3 of the same