JPS6230965B2 - - Google Patents

Description

[Detailed description of the invention]

The first invention relates to an oral pharmaceutical composition comprising a poorly soluble drug dispersed in a polyglycerol unsaturated fatty acid ester. The second invention also relates to an oral pharmaceutical composition comprising a poorly soluble drug and a polyglycerol unsaturated fatty acid ester dispersed in a liquid oil. However, the above-mentioned poorly soluble drug means a drug that is poorly soluble in water, and dispersion also includes molecular dispersion, and the same applies in the following description. Moreover, the above-mentioned polyglycerol unsaturated fatty acid ester means a polyglycerol ester of oleic acid, linoleic acid, or linolenic acid, and when abbreviated for convenience below, it is written as PGUFA ester or simply PGUFAE. An object of the present invention is to provide a novel oral pharmaceutical composition that is well absorbed, has high bioavailability, and is easy to administer. The poorly soluble drug of the present invention refers to a drug that is poorly soluble in water, as described above, and includes many drugs, such as ajmaline, ibuprofen, erythromycin, erythromycin stearate, erythromycin ethyl succinate, kitasamycin, Chloramphenicol palmitate, ergocalciferol (VD ₂ ), cholecalciferol (VD ₃ ), progesterone, testosterone enanthate, testosterone propionate, methyltestosterone, ethyl estradiol, d-
Camphor (dl-camphor), tocopherol, halothane, phytonadione (VK ₁ ), riboflavin butyrate, tocopherol acetate, medroxyprogesterone acetate, procazone, nifedipine, indomethacin, dipyridamole, d-limonene (Liq.), tricaprylin (Liq. ), tocopherol nicotinate, oxyphenbutazone, fluphenazine enanthate, ethyl aminobenzoate, lidocaine, niceritrol, nitroglycerin, clofibrate (Liq.), phenylpropanol, linoleic acid (VF) benzonatate,
Creosote (Liq.), Guaiacol (Liq.), Vitamin A, Cyclocoumarol, Menatetrenone (VK ₂ ), Riboflavin Tetranicotinate (V.
B ₁ ), C ₀ Q ₇ , CoQ ₉ , CoQ ₁₀ (ubidecarenone) and other drugs that are difficult to dissolve in water. Of course, the drugs are not limited to the above-mentioned exemplified drugs. The oral pharmaceutical composition of the present invention also contains natural α-tocopherol,
This includes drugs that contain pharmaceutically active substances such as carotene and vitamin A, and are sold as health foods. The PGUFAE of the present invention is one in which one or more molecules of oleic acid, linoleic acid, or linolenic acid are ester bonded to one molecule of polyglycerol obtained by polymerizing glycerin, and one hydroxyl group derived from glycerin is bonded to one molecule of polyglycerol.
It is a compound with more than 100% remaining. Examples of PGUFA esters include diglycerol monooleate, diglycerol monolinoleate, and triglycerol monooleate.
monooleate), octaglyCerol dioleate, decaglycerol decaoleate, pentaglycerol monolinoleate
monolinoleate) etc. The lipophilically absorbable fat-soluble drugs described in claim 2 and other aspects of the present patent are fat-soluble drugs that are easily absorbed into the lymphatic vessels and poorly soluble in water, such as vitamin A, vitamin D, and vitamin E. and vitamin K
It also means ubiquinones such as CoQ ₇ (ubiquinone-7), CoQ ₉ (ubiquinone-9), and CoQ ₁₀ (ubidecarenone). The oils mentioned in Claim 7 and elsewhere refer to oils and fats, lipids (lipoids), essential oils, and mixtures thereof. Specifically, vegetable oils such as sesame oil, rapeseed oil, soybean oil, animal oils such as lard, head, squalane, squalene, etc.
These include essential oils such as l-carvone, phospholipids, and lipids such as glycolipids. However, the oils do not contain poorly soluble drugs such as fat-soluble drugs that are easily absorbed by the lymph. In addition, l-carvone is present in spearmint oil, etc., and has a boiling point of 230℃.
It is a pale yellow or colorless oil. In addition, the powders described in Claim 5 and others include powdered lactose, β-cyclodextrin, microcrystalline cellulose (Asahi Kasei Avicel, etc.), starch, wheat flour, dextrin, cellulose powder, silicon dioxide powder, etc. It is a non-toxic powder. Examples of the water-soluble polymer substances described in claim 6 of the present invention include pregelatinized starch, carboxymethyl starch, pullulan, gelatin, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl alcohol. , polyvinylpyrrolidone, etc. The present inventors have accomplished numerous inventions as a result of continuing research related to methods for increasing the bioavailability of poorly soluble drugs in water. These inventions are based on Japanese Patent Application No. 54-44261 (method for activating drugs soluble in alkalis and acids), Japanese Patent Application No. 75774-1984 (method for producing activating drugs), and Japanese Patent Application No. 76203-1983 (coating of powdered drugs). (Act), Patent Application 1986-70104 (Method for activating drugs), Patent Application 118135 (Absorption-improving ubiquinone preparation), Patent Application 1987-146362 (Absorption-improving preparation), Patent Application 1987-
27663 (absorption improving preparation) and patent application 1982-109777
(Drugs containing polyglycerol fatty acid esters)
A patent has been applied for. The present inventors have also conducted various studies on methods of using surfactants as a means of improving the bioavailability of drugs that are poorly soluble in water. Surfactants include higher fatty acid alkali salts (soaps), anionic surfactants such as alkyl sulfonates, reverse soaps, higher amine halogenates, cationic surfactants such as quaternary ammonium salts, and polyethylene glycol alkyl ethers. , nonionic surfactants such as polyethylene glycol fatty acid ester and sorbitan fatty acid ester. These anionic activators and cationic activators cannot be used for foods or for general oral medicine because they are highly toxic or have low emulsifying power even if they are less toxic. Polyoxyethylene-based nonionic activators have been completely prohibited for food use, but for pharmaceutical use polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan monostearer are among the nonionic activators. The use of rates is permitted. However, these nonionic activators used medicinally have problems such as hemolysis, mucosal irritation, and mucosal defects, so in many cases, they are hesitant to use them as medicinal products. There is a demand for the development of harmless medical surfactants that do not have such side effects. It is not preferable to use the polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan monostearate in the composition of the present invention. The reason for this is that there is the problem of side effects for medicinal use mentioned above, and when such surfactants are used,
This is because the composition of the present invention causes the following problems. That is, in that case, when the composition of the present invention is mixed with water, depending on the poorly soluble drug, it may be transparently dispersed in the water, which may actually inhibit absorption in the gastrointestinal tract and impair the bioavailability of the present invention. be.
However, if only trace amounts of each of these surfactants are present, the effects of the present invention are not significantly impaired, so this is not a big problem. The present inventors have been earnestly searching for a non-toxic surfactant among hundreds of commercially available surfactants. Noting that ester (PGFAE) was approved for food use as it is non-toxic, we evaluated it 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 type of fatty acid, and its degree of esterification. It has a strong ability to emulsify or solubilize drugs, and has a strong dissolving power, thus promoting the absorption of drugs that are poorly soluble in water, and is non-toxic, making it an innovative surfactant for pharmaceutical use. This discovery led to the invention of the above-mentioned Japanese Patent Application No. 109777/1983 (drugs containing PGFAE). The non-toxicity of PGFAE is also due to the fact that its constituent polyglycerol is a polymer of the natural component glycerin, which is different from the polyoxyethylene derivatives conventionally used as pharmaceutical surfactants. I can fully understand it. The first invention is the above-mentioned patent application No. 56-109777.
This invention is a further development of the invention of (drug containing PGFAE), and is an oral drug composition with high bioavailability in which a poorly soluble drug is dispersed in PGFAE. That is, the present invention provides that when polyglycerol esters of oleic acid, linoleic acid, or linolenic acid are used as PGFAE in the earlier invention (drugs containing PGFAE), oral It was discovered that the bioavailability of the pharmaceutical composition is particularly remarkable, and the present invention was achieved. The composition of the invention comprises
The surfactant power of PGUFAE improves the absorption of poorly water-soluble drugs and significantly increases bioavailability. The first invention is advantageous because the poorly soluble drug is easily emulsified in the gastrointestinal tract while being dispersed in PGUFAE. The degree of dispersion of the poorly soluble drug in PGUFAE 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 dissolved state, that is, the molecular dispersion, will improve absorption and formulation. It is also advantageous in terms of physical stability. The ratio of PGUFAE to the poorly soluble drug is determined by looking at the dispersibility of the poorly soluble drug, and usually 0.05 parts to 30 parts of PGUFAE are used per 1 part of the poorly soluble drug on a weight basis. Dispersing a poorly soluble drug and PGUFAE in a liquid oil according to the second invention is also more effective in promoting absorption of the poorly soluble drug and increasing bioavailability. To prepare this product, the purpose can be achieved, for example, by adding the poorly soluble drug and PGUFAE as they are or in finely divided form into a liquid oil and stirring the mixture. The amount of liquid fat and oil relative to the poorly soluble drug is determined on a case-by-case basis depending on the dispersibility of the sparingly soluble drug used in the fat and oil. Usually, 0.5 to 10 parts of oil and fat are used per 1 part of the poorly soluble drug on a weight basis. Furthermore, the amount of PGUFAE for poorly soluble drugs is determined by considering the dispersibility of the former. As a result of conducting tests on several hundred types of poorly soluble drugs, the objective is often achieved with 0.1 to 5 parts of PGUFAE per 1 part of the poorly soluble drug on a normal weight basis. The first invention in which a poorly soluble drug is dispersed in liquid PGUFAE, and the poorly soluble drug in liquid oil.
Japanese Patent Application No. 55-118135 and Japanese Patent Application No. 118-118 filed by the present applicant regarding the second invention dispersing PGUFAE
As disclosed in Japanese Patent No. 55-146362, when the composition is encapsulated or microencapsulated to a particle size of 3 mm or less, absorption is more accelerated than when the composition is filled in a conventional ordinary sheath capsule, and the poorly soluble drug is bioavailability can be further increased. The reason is presumed as follows. In general, oils have a high surface tension, and in order to emulsify them in the gastrointestinal tract, it is necessary to mechanically fragment them in advance. Orally administered oil is fragmented in the stomach and intestines due to their stirring action. However, this stirring action is weaker than mechanical stirring. As a result, even if edible oil is administered orally in large quantities, it is often excreted in feces without being digested. Therefore, oils containing solid drugs that are poorly soluble in water or
Oral administration of a preparation filled with PGUFAE in microcapsules means that the oils have been preliminarily subdivided, and this can be used in patients who are sick or elderly, who secrete little bile or lipase, and have weak stomach and intestine stirring functions. It is thought that emulsification of oils or PGUFAE is carried out smoothly, and that the drug is accordingly well absorbed from the gastrointestinal tract into the blood and/or lymph vessels. The above reasoning can be easily understood from the fact that for the same amount of oil, by reducing the diameter of the particles, the surface area increases at an accelerated rate, making it easier to digest. Furthermore, the particle size is particularly limited to 3 mm or less, which is advantageous from the viewpoint of the absorption rate and absorption rate due to the increase in surface area as described above, as well as from the viewpoint of a convenient dosage form for administration. For example, by adjusting the number of capsules with a particle size of 3 mm as a pill, the dosage can be adjusted for adults, children, severe and mild diseases, and the particle size is 0.1 ~
If it is 1 mm, it can be administered as a granule, and if it is less than 1 mm, it can be filled into a sheath capsule or administered as a fine granule or powder. Now, in order to encapsulate particles with a particle size of 3 mm or less, it is practically difficult to manufacture them with ordinary sheath capsules or soft capsules, not only in terms of prototyping but also in terms of production, the ratio of coating agent to content drug, etc. be. Therefore, it is practical to use so-called seamless minicapsules. To fill seamless mini capsules, for example, the Dutch-made Globex Mark capsule coating machine (7-1 Tenjinbashi, Oyodo-ku, Osaka City) shown in Figure 1 is used.
―10 Tenrokuzakakyu Building Co., Ltd. Handled by Miniature Trading Co., Ltd. GLOBEX INTERNATIONAL LIMITED
gelatin aqueous solution is used as a coating solution. To explain this seamless mini capsule filling operation with reference to Fig. 1, first, liquid oil or liquid is added to the above-mentioned Globex capsule coating machine.
A system in which poorly soluble drugs are dispersed using PGUFAE as a dispersion medium and a heated gelatin aqueous solution are prepared.
By synchronizing the pulsating pump 4 and the shutoff valve 6, the spherical gelatin capsule containing the dispersion liquid is dropped into the cooling oil 5, and the gelatin forming the shell of the capsule is cooled and solidified.
The capsules are conveyed together with the circulating oil onto a sieve 8, where the oil is separated and collected in a capsule receiver 9. There are also inventions that improve the productivity of seamless capsules, such as those disclosed in Japanese Patent Publication No. 53-1067. When the poorly soluble drug of the present invention is a lipid-soluble drug that is easily absorbed by lymph, it is well absorbed directly into the lymph vessels in the small intestine after being emulsified with Swiss fluid, 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 a lipid-soluble drug that is easily absorbed into the lymph, it is also absorbed into the blood, and together with lymph absorption, bioavailability is increased. Lipid-soluble drugs that are easily absorbed by the lymph include vitamins A, D, E, K, and CoQ ₇ , CoQ ₉ , CoQ ₁₀
As mentioned above, these are included. Next, in the embodiment of the present invention in which a system in which a poorly soluble drug is dispersed in PGUFAE is adsorbed to a powder, since the dispersion system is finely dispersed on the powder, the dispersion system is easily absorbed after oral administration. Easily emulsified. Therefore, absorption of poorly soluble drugs is particularly promoted, which is advantageous. In this embodiment, if the poorly soluble drug is a lipid-soluble drug that is easily absorbed into the lymph, it goes without saying that lymph absorption will be further promoted. In the first invention, the poorly soluble drug is PGUFAE
In order for a dispersed system to be adsorbed onto a powder, the dispersion system must be in a liquid state. Although there is no particular method for adsorption, it is preferable to spray the dispersion system and make it adsorb onto the powder. Since it is preferable for the product to be finished in powder form, good results can generally be obtained by setting the ratio of the dispersed system in the poorly soluble drug PGUFAE to 1 part of the powder on a weight basis to be 1.0 or less. Although not mentioned in the embodiments of the claims, the embodiment in which a system in which a poorly soluble drug and PGUFAE are dispersed in liquid oil is adsorbed to powder in the second invention also has almost the same reason as the above embodiment. It is effective in promoting the absorption of poorly soluble drugs and increasing their bioavailability. This embodiment can also be prepared by a method similar to the above method. As an embodiment of the first invention, the embodiment listed in claim 6 above, that is, the poorly soluble drug is
There is a system obtained by emulsifying a system dispersed in water in the presence of a water-soluble polymeric substance if necessary, and then removing water from the emulsion by evaporation. This embodiment is also a particularly effective composition. To prepare the composition of this embodiment, a poorly soluble drug is added as it is or finely pulverized to PGUFAE, stirred and dispersed, and the resulting system is emulsified in an aqueous solution of a water-soluble polymeric substance or in water together with a water-soluble polymeric substance. Then, let the water in the emulsion evaporate. It is preferable to evaporate water by spraying. In order to improve the absorption of drugs that are poorly soluble in water, it is necessary to form them into fine particles in some way in the gastrointestinal tract. In the case of lipid-soluble drugs that are easily absorbed by lymph, it is known that they are finely emulsified with bile, lipase, etc., become micelles, and are absorbed into the lymph vessels. In vivo, the rate of absorption from the lymphatic vessels when a drug is administered is measured by cannulating the animal's thoracic lymphatic vessels and collecting lymph fluid using Bollman's method. However, to easily predict this in vitro, the ability of a drug or a preparation containing it to form micelles in a bile salt solution can be determined by the rate of passage through a fine filter. That is, the emulsifying power of PGUFAE for lipid-soluble drugs that are easily absorbed by the lymph can be determined in vitro by measuring the particle size of the emulsified liquid and its passage rate using a fine filter such as a Millipore filter, and determining the bioavailability of PGUFAE for the drug. It is possible to estimate the effectiveness of improving performance. The present invention will be explained in more detail below by describing the implementation of the present invention and testing of its effects. Example 1 20g of dl-α-tocopherol acetate
Decaglycerol decaoleate (Product name: Santone10)
10-0 (manufactured by Durkee, USA) and dissolved by heating. The obtained liquid was charged into the Growth Vex Mark capsule coating machine shown in Fig. 1, and spherical seamless minicapsules with a particle size of 1 mm were obtained using the same machine. The content of tocopherol in the capsule of this example was 15% by weight. As mentioned above, Santone 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 Purification of 80 g of erythromycin stearate
It was dissolved in 120 g of carvone by heating (approximately 50°C). Add pentaglycerol monooleate (product name SY-) to this solution.
Glister MO-500 (manufactured by Sakamoto Pharmaceutical Co., Ltd.) 50g
was added to obtain a liquid composition. Separately, Seratin 45
1 part, 5 parts of glycerin, and 50 parts of purified water were dissolved while heating (Formulation 1). Furthermore, methyl acrylate
3 parts of 8 parts of methacrylic acid copolymer (MPM-05)
A solution was prepared by dissolving it in 92 parts of a wt% aqueous sodium carbonate solution (Formulation 2). A gelatin sheet of approximately 0.6 mm was prepared using a mixture of the liquids of Prescription 1 and Prescription 2 at a ratio of 65:5 (volume ratio) as a base material for capsules according to the flat plate method. 250 mg of the erythromycin stearate solution previously prepared was poured into the recesses of this sheet, another gelatin sheet was placed on top of the gelatin sheet, and the gelatin sheet was compressed to produce soft capsules with a diameter of about 8 mm. Each capsule contained approximately 80 mg of erythromycin stearate. Example 3 The solution of erythromycin stearate prepared in Example 2 was charged into the Globex Mark capsule coating machine shown in FIG. 1, 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 is 25
It was in weight%. Example 4 Phytonadione (VK ₁ ) 150g was added to octaglycerol
monooleate (product name Santone 8-1-0) 50g,
triglycerol trioleate (product name SY-Glister TO)
-310 manufactured by Sakamoto Pharmaceutical Co., Ltd.) to obtain a liquid composition. The solution in this example is a soft capsule,
It can be applied to liquids. Example 5 A 15% phytonadione powder was obtained by heating 250 g of the liquid composition obtained in Example 4 and adsorbing it on 750 g of Ad Solider 101 (manufactured by Front Sangyo Co., Ltd.). Example 6 Purify 20g of CoQ ₁₀ (ubidecarenone) powder.
50g of carvone, 50g of octaglycerol monooleate (product name Santone 8-1-0) and
Decaglyceroldecaoleate (Product name: Santone10-10
-0) It was added to 20 g of the mixed solution and dissolved under heating to obtain a liquid composition. Example 7 Separately from the liquid composition obtained in Example 6, gelatin 100
A gelatin solution was prepared by gradually dissolving 35 g of gum arabic powder in purified water while heating. Above 2
The different types of liquid are charged into the Globex Mark capsule coating machine shown in Figure 1, and the machine coats the particles with a particle size of 1.
mm seamless minicapsules were obtained. The content of CoQ ₁₀ in this capsule was 5% by weight. Example 8 10 g of CoQ ₁₀ powder was added to 40 g of triglycerol monooleate (trade name: SY-Blister MO-500, manufactured by Sakamoto Pharmaceutical Co., Ltd.) and dissolved by heating to obtain a liquid composition. Example 9 50g of the liquid composition obtained in Example 8 was heated to 50°C to make it into a liquid, then added to 150g of microcrystalline cellulose (Avicel manufactured by Asahi Kasei Corporation) heated to 50°C, and dispersed by stirring. CoQ ₁₀ 5% powder was obtained by adsorption. Example 10 10g of CoQ ₁₀ powder was added to octaglycerol monooleate.
(Product name Santone8-1-0) 10g and decaglycerol
decaoleate) (trade name: Santone 10-10-0) and was added to 20 g of the mixture and heated to dissolve it to obtain a liquid composition. Example 11 Add 800 g of water to 40 g of the liquid composition obtained in Example 10.
g, 30 g of lactose and 30 g of dextrin, Swiss-made Polytron emulsifier (POLYTRON)
5 using TypePT45/50KINEMATICAGmbH)
Emulsification was performed at 12,000 rpm for minutes. This emulsion was sprayed to evaporate water to obtain a powder. Example 12 50g griseofulvin, 15g polyethylene glycol 400 (PEG-400), decaglycerol
decaoleate (product name Santone 10-10-0) 20g,
Decaglycerol monooleate (product name Santone10-1
-0) 30g was dissolved in a mixture of ethanol and chloroform (volume ratio 1:1). 20g of lactose in this solution
Add 200 g of purified water in which 10 g of light anhydrous silicic acid has been dispersed, and mix for 5 minutes using the Swiss Polytron mentioned above.
Emulsification was performed at 12,000 rpm. This emulsion was sprayed to remove water and obtain a powder. Example 13 Kitasamycin 50g with pentaglycerol
monooleate (Product name SY-Glister MO-500
(manufactured by Sakamoto Pharmaceutical Co., Ltd.) and dispersed under heating. This dispersion system was dissolved in ethanol containing 5 g of hydroxypropyl cellulose (Nippon Soda Type L).
It was added to 200g and dissolved. This solution was sprayed and the ethanol was evaporated to obtain a powder composition. Example 14 Phenacetin 80g, decaglycerol decaolete
(Product name: Santone 10-10-0) 20g was dissolved in 500g of chloroform. In this solution, separately prepared 5
% hydroxypropyl cellulose (manufactured by Nippon Soda)
Add 100g of TypeL) aqueous solution and use an Ultrasonic homogenizer (manufactured by Ultrasonic, USA).
and emulsified for 15 minutes. This emulsion was sprayed to remove water and chloroform 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) Testing of the drug of Example 1 When this drug was administered to rats, the absorption rate from lymph vessels was determined by Bollman's method.
The sample was dl-α-tocopherol acetate, and 5 mg was orally administered to each of 5 rats (average weight 300 g), and the lymph fluid flowing out from the cannula placed in the thoracic lymphatic duct was collected for 24 hours after administration. , tocopherols transferred into lymph fluid were quantified. As a control, a suspension of dl-α-tocopherol acetate in water was forcibly stirred and then orally administered without encapsulation. The results are shown in FIG. (2) Testing of drugs of Examples 5, 8, and 9 These drug compositions were measured for their dispersion permeability in water (group A) and micelle formation ability in a mixed bile acid solution (group B). The mixed bile acid solution mentioned above is a mixed bile acid solution with a molar ratio of sodium taurocholate and sodium taurodeoxycholate of 1:1, and its concentration is as follows.
The concentration is 15 mmolar. Both the dispersion transmittance and micelle formation ability were measured using 1 g of each of the above drug compositions and 30 ml of water.
Alternatively, add to 30 ml of the above bile acid solution, shake at 37°C, filter through a 5μ Millipore filter, and then further filter through a 0.45μ Millipore filter. Quantitate the drug that passed through the 0.45μ filter,
Dispersed transmittance and micelle formation rate were determined. As a control, 1 g each of each active drug, ie, phytonadione and CoQ ₁₀ itself, was treated in the same manner instead of the drug composition of the example, and the dispersion transmittance and micelle formation rate were determined. The results are shown in Table 1. In addition, A in Table 1
The group column shows the dispersed transmittance, and the group B column shows the micelle formation rate. The numbers at the top of Table 1 indicate the shaking time in minutes (MIN) in the above test.

[Table] (3) Test of the drug of Example 2 and Example 3 For the purpose of determining the degree of activation of the drug of Example 2 and the same drug, the same drug was administered to 5 male adults after 4 hours of fasting and erythromycin stearate. as 500mg
The concentration of erythromycin in the serum was measured 12 hours after administration. As a control, two commercially available 250 mg tablets of erythromycin stearate were administered. The results are shown in Figure 3. (4) Testing of the drug of Example 9 Regarding the powder of Example 9, the dispersibility of fine particles of ubidecarenone in water was measured by the following method. First, add water to the dissolution tester (for paddle method manufactured by Toyama Sangyo).
Add 900ml, paddle rotation speed 100rpm, elution time 15
A sample of the above powder containing 500 mg of ubidecarenone was weighed out and elution was performed. Next, the obtained eluate was filtered using Millipore filters (manufactured by Nippon Millipore Co., Ltd.) with pore sizes of 10μ, 3μ, and 0.45μ, and ubidecarenone in the filtrate was quantitatively analyzed to measure the transfer rate to the filtrate. The following were used as controls. According to the method described in Example 5 of JP-A-52-136911, ubidecarenone 3
g and hydroxypropyl cellulose (HPC) were dissolved in 30 ml of ethanol, and this was adsorbed onto 95 g of lactose. The mixture was then granulated using a 20-mesh screen and dried at 50°C for 3 hours. The amount of HPC added is
The content of HPC in the granules was adjusted to 3% and 7%. The results are shown in Table 2. HPC content 3%
The sample with HPC content of 7% was shown as Control 1 and Control 2.

[Table] Note: Transfer rate indicates fine particle dispersibility.
(5) Testing of the drug of Example 11 In order to find out the degree of activation of the drug of Example 11, the drug was tested in rats as ubidecarenone.
The concentration of ubidecarenone in the serum was measured 2 hours after continuous oral administration of 100 mg/Kg/day 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 result is the third
As shown in the table.

[Table] Furthermore, the drug of Example 11 is a lipid-soluble drug that is easily absorbed into the lymph, and the lymph transfer rate was determined in order to find out the degree of its activation. In the absorption experiment, five male Wistar rats (weighing 250-300 g) whose thoracic lymphatic vessels were cannulated were given only physiological saline for 24 hours, and then each was given a sample containing the equivalent of 1 mg of CoQ ₁₀ . The powder was administered directly, and the lymph fluid flowing out over 24 hours after administration was collected. CoQ ₁₀ transferred into lymph fluid was quantified by high performance liquid chromatography. The control 1 used in the drug test of Example 9 was used as the control 1, and the control 2 was prepared using 4 g of ubidecarenone and 28 g of monoolein according to the method described in Example 1 of JP-A-56-18914.
Put g in a mortar, melt and mix on a water bath at about 60℃. Add 68 g of crystalline cellulose to this and grind to obtain an adsorbed powder of ubidecarenone. The results are shown in Table 4.

[Table] (6) Test of the drug of Example 12 The griseofulvin powder of Example 12 and the griseofulvin crystal powder as a control were orally administered to each of three adult males at 250 mg as griseofulvin four times a day. Blood concentrations were measured over time. The results are shown in FIG. (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 orally to each of six adult males at 600 mg as kitasamycin, and the changes in blood concentration over time were measured. . The results are shown in FIG. (8) Test of the powder preparation of Example 14 The powder preparation of Example 14 and the commercially available phenacetin crystal powder used as a control were orally administered as phenacetin in an amount of 1.5 g to each of six adult males, and the subsequent blood concentration was measured. Measured over time. The results are shown in FIG.

[Brief explanation of the drawing]

FIG. 1 is an explanatory diagram of manufacturing seamless minicapsules using the Globex Mark capsule coating machine. 1... Filling (liquid), 2... Gelatin solution,
2'... automatic control valve, 3... gelatin solution, 4...
...Pulsating pump, 5...Cooling oil, 6...Shutoff valve, 7...Cooling device, filter and pump, 8...
Sieve, 9...Capsule receiver. Figure 2 shows dl-α of Example 1, which is a drug of the present invention.
- This is a diagram showing the lymphatic absorption over time after oral administration of tocopherol acetate seam Remini capsules and its control to rats. Figure 3 shows capsules filled with the erythromycin stearate solutions of Examples 2 and 3 in soft capsules with a diameter of approximately 8 mm (Example 2) or seamless minicapsules with a particle diameter of 2.8 mm (Example 3). FIG. 2 is a diagram showing the results of measuring blood concentration over time when the drug was orally administered to a male. FIG. 4 is a diagram showing the test results of the drug of Example 12. Figures 5 and 6 are examples of implementation, respectively.
13 is a diagram showing the test results of powder formulations of Example 13 and Example 14. FIG.

Claims (1)

[Scope of Claims] 1. An oral pharmaceutical composition with high bioavailability, comprising a poorly soluble drug dispersed in a polyglycerol unsaturated fatty acid ester. 2. The oral pharmaceutical composition according to claim 1, wherein the poorly soluble drug is a lipid-soluble drug that is easily absorbed by lymph. 3. The oral pharmaceutical composition according to claim 2, wherein the lipophilically absorbable lipophilic drug is a ubiquinone. 4. The oral pharmaceutical composition according to claim 1, wherein the dispersion system is filled into capsules having a particle size of 3 mm or less. 5. The oral pharmaceutical composition according to claim 1, which is obtained by adsorbing a dispersion system to a powder. 6. The oral pharmaceutical composition according to claim 1, which is obtained by emulsifying the dispersion in water in the presence of a water-soluble polymeric substance if necessary, and removing water from the emulsion by evaporation. 7. An oral pharmaceutical composition with high bioavailability comprising a poorly soluble drug and a polyglycerol unsaturated fatty acid ester dispersed in a liquid oil. 8. The oral pharmaceutical composition according to claim 7, wherein the dispersion is filled into capsules with a particle size of 3 mm or less.