JP2948111B2 - Oily composition for oral administration - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oily composition for oral administration of a poorly water-soluble drug for enhancing bioavailability and the like.

[0002]

2. Description of the Related Art When a drug having extremely low solubility in water is orally administered, even if the pharmacological action of the drug is extremely effective, absorption of the drug from the gastrointestinal tract is difficult. Due to the badness, the bioavailability is susceptible to food intake and the like, and there is a problem that it is difficult to obtain a stable effect.

[0003] In order to improve the absorbability of such poorly water-soluble drugs, means for increasing the dissolution property in water have conventionally been adopted. For example, polysorbate 80, sodium lauryl sulfate, sucrose fatty acid esters and the like have been used. Addition of a synthetic surfactant as a solubilizer has been performed.

[0004] However, in order to obtain a sufficient effect by these methods, a large amount of a solubilizing agent is required, which often involves difficulty in application. In addition, synthetic surfactants are known to have toxic and damaging effects on skin, mucous membrane surfaces, cells, and the like. The purpose of use, site of application, combination, toxicity, irritation, interaction with drugs, etc., became problems, and it was complicated to overcome clinical problems.

Further, when a surfactant is added, in addition to the above-mentioned problems, it is often found that the bonding property of the soft capsule is inferior. In order to overcome this, the drug is dissolved in polyethylene glycol 400, propylene glycol, glycerin or the like. A method of directly dissolving the composition into a soft capsule after dissolving it in the preparation has been considered. However, there have been problems in that the dosage form becomes large, and crystals are precipitated by contact with water in the digestive tract.

On the other hand, in order to improve the dissolution property of a drug, drug crystal particles are surface-treated with a surfactant, a hydrophilic polymer, or the like to improve wetting or to make the drug itself finer.
Alternatively, methods such as co-pulverization with a pharmaceutical additive and pulverization or amorphization, or a solid dispersion or solid solution by a coprecipitation method, a melting method, and the like have been considered. Also, there is a problem that the dosage form becomes large and is not always effective for a drug which is easily oxidized.

[0007] Japanese Patent Application Laid-Open No. 49-71127 discloses a technique for orally administering a drug in glycerin by dissolving it in a medium-chain fatty acid ester. JP-A-1-55245
In Japanese Patent Application Laid-Open Publication No. H10-157, a technology is disclosed in which an oily preparation in which nifedipine powder, which is hardly soluble, is suspended in a fatty acid triglyceride having 20 or less carbon atoms makes the onset of drug efficacy manifest quickly and strongly, and further extends the duration. . Further, Japanese Patent Application Laid-Open No. Hei 4-243841 discloses a technique for improving bioavailability and the like by using an oily preparation in which a poorly water-soluble drug is dissolved in a polyoxyethylene sorbitan fatty acid ester as a nonionic surfactant. ing. However, the effects of these techniques have been limited to a certain extent and have not always been clinically satisfactory.

Japanese Patent Application Laid-Open No. 25715/1990 discloses that a drug having an ester or amide bond is suspended or dissolved in a glyceride of a medium-chain fatty acid to suppress the decomposition of an active ingredient by a gastrointestinal enzyme, thereby achieving bioavailability. There is disclosed a technology for improving the performance. However, it is a technology mainly aimed at preventing the degradation of easily water-soluble drugs by digestive tract enzymes, and does not improve the water solubility of the drug itself, and applied a poorly water-soluble substance which does not undergo enzymatic degradation. There is no disclosure of improved bioavailability at times. Therefore, the present invention is directed to drugs having different pharmacokinetics from the present invention.

Further, in this technique, lecithin is used as a viscosity reducing agent, but it is not an essential component for solving the problem, and no mention is made of the improvement of bioavailability by adding lecithin.

Fukui et al. (J. Pharmacobio-Dynamics-
Dynamics), 12, 80-86 (1989).
Year)) shows that d-α supported in a lecithin dispersion
-It has been reported that the bioavailability is improved by simultaneously containing medium-chain fatty acid triglyceride in tocopherol. However, this is an aqueous suspension containing lecithin as a main component, and the amount of medium-chain fatty acid triglyceride used is small, and it is practical to administer it orally by filling it into soft capsules, hard capsules, etc. Was difficult.

In view of the above, an object of the present invention is to provide an oily composition for oral administration of a poorly water-soluble drug exhibiting high bioavailability, which could not be achieved by conventional formulation techniques. It is.

[0012]

The gist of the present invention is to provide an oily composition for oral administration comprising at least one poorly water-soluble drug selected from the group consisting of dihydrothienopyridine derivatives and probucol, and having 8 to 12 carbon atoms. It is configured to contain a medium-chain fatty acid triglyceride and lecithin.

In the present invention, a poorly water-soluble drug of about 0.05 mg / ml or less is targeted, and a dihydrothienopyridine derivative and probucol are particularly preferred. As the dihydrothienopyridine derivative, (+)-(4S)-
Methyl 4,7-dihydro-6-methyl-4- (3-nitrophenyl) -3-isobutylthieno [2,3-b] pyridine-5-carboxylate (hereinafter, referred to as "compound A")
Is preferred.

Compound A is known as a Ca antagonist having a relaxing effect on vascular smooth muscle and a protective effect on central nervous cell injury, which can be used as an antihypertensive agent, an agent for improving cerebral circulation, an agent for preventing brain cell injury and the like. In addition, it is considered to be a drug that is relatively stable against ester hydrolysis by digestive tract enzymes, and its water solubility is 0.1 μg / ml or less. Probucol has already been clinically used as a therapeutic agent for hyperlipidemia.

The medium-chain triglyceride having 8 to 12 carbon atoms used in the present invention is not particularly limited. For example, ODO (manufactured by Nisshin Oil Co., Ltd.), Miglyol (manufactured by Mitsuba Trading Co., Ltd.), Panassate (Nippon Oil & Fats Co., Ltd.) Manufactured by Kao Corporation) and coco nard (manufactured by Kao Corporation). Those containing a higher fatty acid such as soybean oil or sesame oil as a main component are not preferable for use in the present invention because they hardly dissolve the dihydrothienopyridine derivative according to the present invention and have poor storage stability.

In the present specification, “lecithin” refers to
It contains lysolecithin. Hydrogenated lecithin (saturated type) is excluded as lecithin used in the present invention, and examples of such naturally occurring lecithin include soybean lecithin, egg yolk lecithin, and purified products thereof.
Soy lecithin is preferred.

The composition of the oily composition for oral administration of the present invention is as follows: 0.1 to 200 parts by weight of a poorly water-soluble drug, and 8 to 8 carbon atoms.
It is preferable that 12 medium-chain fatty acid triglycerides be 100 to 300 parts by weight and lecithin be 0.1 to 100 parts by weight. If the composition ratio is outside these ranges, the drug becomes suspended particles, and the effect of adding lecithin is reduced.

In particular, an oily composition for oral administration containing a dihydrothienopyridine derivative may have 8 to 12 carbon atoms.
It is preferred that the dihydrothienopyridine derivative is 0.1 to 10 parts by weight and the lecithin is 0.1 to 10 parts by weight based on 100 parts by weight of the medium-chain fatty acid triglyceride. If the composition ratio is out of these ranges, the dihydrothienopyridine derivative becomes suspended particles, and the effect of adding lecithin is reduced.

The oily composition for oral administration of the present invention may optionally contain an antioxidant. Examples of the antioxidant include α-tocopherol, butylhydroxytoluene, butylhydroxyanisole, and fat-soluble vitamin C.

An oil-soluble solubilizing agent may be added to the oily composition for oral administration of the present invention in order to further increase the solubility of the drug in the medium-chain fatty acid triglyceride. Examples of the oil-soluble solubilizer include triethyl citrate and triacetin.

The method for producing the oily composition for oral administration of the present invention is not particularly limited, and ordinary methods can be used.
However, when the drug in the oily composition for oral administration is in a suspended state, the size of the crystals varies, and it is difficult to obtain a certain bioavailability, which is not preferable.

The oily composition for oral administration of the present invention can be administered orally as it is through an oral tube or as a capsule preparation filled in a soft capsule or a hard capsule.

[0023]

The oily composition for oral administration of the present invention is obtained by dissolving a poorly water-soluble drug in a medium-chain fatty acid triglyceride having 8 to 12 carbon atoms and adding a small amount of lecithin to the medium-chain fatty acid triglyceride. High bioavailability that could not be achieved by the conventional technology can be secured. In addition, fluctuations in bioavailability due to the presence or absence of food intake are suppressed, and a stable action can be achieved. In the oily composition for oral administration of the present invention, the addition of a small amount of lecithin makes it possible to double the bioavailability as compared with the case of no addition.

The oily composition for oral administration of the present invention does not use polyethylene glycol and propylene glycol, which are said to have non-negligible mucosal irritation, and further does not use a synthetic or semi-synthetic surfactant, and mainly has a slow effect on the living body. Since it is a very simple preparation composed of natural or biological lipids, it can be used safely for a long period of time.

Heretofore, poorly water-soluble drugs that are easily oxidized in the air cannot be subjected to a high level of pharmaceutical processing, and generally use polyethylene glycol-based or propylene glycol-based solvents. Since the surfactant contained therein promotes oxidation, it was difficult to use them. However, the oily composition for oral administration of the present invention can also prevent the oxidation of these drugs.

[0026]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 In order to compare the bioavailability of Compound A with each of the following formulations, a weight of 9.1 to 11.0 kg (average 1)
0.2 kg) of oil-based Nissan male beagle dogs with a group number of 6 and a dose of 10 mg / d for compound A
It was orally administered with 50 ml of water under fasting conditions so as to be og. After a certain period of time, blood was collected from the forelimb vein, the plasma was separated, and the unchanged compound concentration in the plasma was quantified by the HPLC-ECD method. In addition, compound A was disclosed in Japanese Examined Patent Publication No.
No. 8 and JP-A-4-346927.

The following preparations were administered as they were or filled in hard capsules. Control formulation 1 (solubilized aqueous solution): a formulation in which Compound A was solubilized at 1 mg / ml in an aqueous solution containing polyethylene glycol 400 (20%) and polysorbate 80 (4%). Control formulation 2 (powder with improved wetting): Compound A (1
g), lactose (4.4 g), corn starch (4.4 g)
g), hydroxypropyl methylcellulose E (0.2
g) kneading and pulverizing by a conventional method to improve wettability. Control formulation 3 (amorphous mixed and ground powder): Compound A (1 g),
Lactose (8g), hydroxypropyl methylcellulose E
(1g) is an amorphous mixed and crushed powder produced by a method of crushing with a ball mill. Control formulation 4 (quickly dissolving tablet made of amorphous mixed and crushed powder): Corn mixed starch (38 g) and carmellose calcium (ECG5) were added to the amorphous mixed and crushed powder (100 g) obtained in Control formulation 3.
05) (40 g), silicon dioxide (20 g), and magnesium stearate (2 g) were added, mixed and tableted to form a quick dissolving tablet.

Control Formula a (ODO solution): 10 mg of Compound A bulk powder was dissolved in 990 mg of ODO (manufactured by Nisshin Oil Co., Ltd., medium-chain fatty acid triglyceride) by ultrasonic irradiation and filled into capsules. Formula 2 (Soy lecithin-added ODO solution): soy lecithin (Tsuru-Lecithin Industries, SLP-White S)
P) Dissolve 10 mg in 980 mg ODO. Next, 10 mg of Compound A bulk powder was added, dissolved by ultrasonic irradiation or while heating in a warm bath at about 50 ° C., and filled into capsules.

The test results of Example 1 are shown in Table 1 below.
In Table 1, Cmax represents the maximum plasma concentration of the drug;
UC _0-8hr represents the area under the plasma concentration time curve from 0 to 8 hours after administration, and the bioavailability is the bioavailability. The AUC when a solubilized aqueous solution is separately prepared and injected intravenously Absolute bioavailability (absolute bioavail) calculated by correcting the dose based on
abundance), Mean ± SD means mean ±
Represents the standard deviation.

[0031]

[Table 1]

Example 2 In order to compare the bioavailability of Compound A with each of the following formulations, a weight of 9.1 to 11.0 kg (average 1)
0.2 kg) of oil-based Nissan male beagle dogs with a group number of 6 and a dose of 10 mg / d for compound A
It was orally administered with 50 ml of water under fasting conditions so as to be og. After a certain period of time, blood was collected from the forelimb vein, the plasma was separated, and the unchanged compound concentration in the plasma was quantified by the HPLC-ECD method.

The following formulation was filled in a hard capsule and administered. Control formulation a (ODO solution): same as described in Example 1. Control formulation b (ODO solution with hydrogenated soybean lecithin): The soybean lecithin of Formulation 2 described in Example 1 was replaced with hydrogenated soybean lecithin (SLP-White manufactured by Tsuru-Lecithin Industry Co., Ltd.).
H). Formulation 2 (Soy lecithin added ODO solution): Example 1
Same as described in.

Formulation 21 (ODO solution with yolk lecithin): The soybean lecithin in Formula 2 above was replaced with yolk lecithin (Basis LP-20E, manufactured by Asahi Kasei Corporation). Formulation 22 (Soy lysolecithin added ODO solution): The soybean lecithin of Formula 2 above was replaced with soybean lysolecithin. Formulation 23 (soy lecithin-added miglyol solution):
A composition in which the ODO of the above Formulation 2 has been replaced with another medium-chain fatty acid triglyceride, Miglyol. Formulation 24 (soybean lecithin-added panassate solution): A product obtained by replacing the ODO of Formulation 2 with panassate, which is another medium-chain fatty acid triglyceride.

The test results of Example 2 are shown in Table 2 below.
In Table 2, Cmax represents the maximum concentration of the drug in plasma;
UC _0-8hr represents the area under the plasma concentration time curve from 0 to 8 hours after administration, and the bioavailability is the bioavailability. The AUC when a solubilized aqueous solution is separately prepared and injected intravenously Absolute bioavailability (absolute bioavail) calculated by correcting the dose based on
abundance), Mean ± SD means mean ±
Represents the standard deviation.

[0036]

[Table 2]

Example 3 In order to compare the bioavailability of Compound A with each of the following formulations, a weight of 9.1 to 11.0 kg (average 1
0.2 kg) of oil-based Nissan male beagle dogs with a group number of 6 and a dose of 10 mg / d for compound A
It was orally administered with 50 ml of water under fasting conditions so as to be og. After a certain period of time, blood was collected from the forelimb vein, the plasma was separated, and the unchanged compound concentration in the plasma was quantified by the HPLC-ECD method.

The following formulation was filled in a hard capsule and administered. Control formulation a (ODO solution): same as described in Example 1. Formulation 1 (ODO solution with 0.5% soy lecithin):
The soybean lecithin concentration of the formulation 2 described in Example 1 was changed from 1.0% to 0.5%. Formula 2 (1.0% soy lecithin added ODO solution):
Same as described in Example 1. Formula 3 (Soy lecithin 2.0% added ODO solution):
The soybean lecithin concentration of Formula 2 described in Example 1 was changed from 1.0% to 2.0%. Formulation 4 (SOD lecithin 5.0% added ODO solution):
A composition in which the concentration of soybean lecithin in Formula 2 described in Example 1 was changed from 1.0% to 5.0%.

The test results of Example 3 are shown in Table 3 below.
In Table 3, Cmax represents the maximum plasma concentration of the drug,
UC _0-8hr represents the area under the plasma concentration time curve from 0 to 8 hours after administration, and the bioavailability is the bioavailability. The AUC when a solubilized aqueous solution is separately prepared and injected intravenously Absolute bioavailability (absolute bioavail) calculated by correcting the dose based on
abundance), Mean ± SD means mean ±
Represents the standard deviation.

[0040]

[Table 3]

Example 4 In order to compare the bioavailability of probucol according to each of the following formulations, a body weight of 220 to 250 g (9 to 10 g) was used.
Weeks) SLC-Wistar male rats using a group of 3-7 populations and fasting for 18 hr so that the dose is 20 mg / kg for probucol,
The following formulation was administered in a syringe with an oral probe, and
ml was loaded. After a certain period of time, blood was collected from the tail vein under ether anesthesia, plasma was separated, and the unchanged compound concentration in the plasma was quantified by HPLC.

Commercial formulation (fine granules): Synlestal (trade name, manufactured by Daiichi Pharmaceutical Co., Ltd.) (5 g of probucol and 5 g of excipient)
(Containing polyoxyethylene sorbitan fatty acid ester)
Consisting of). Control formulation a '(ODO solution): a preparation prepared by dissolving 1.2 g of probucol (manufactured by Sigma) in 30 g of ODO. Control formulation b'1 (ODO with 1.0% hydrogenated soy lecithin)
Solution): a preparation obtained by further adding 1.0% of hydrogenated soybean lecithin to the above-mentioned control formulation a '. Control formulation b'2 (ODO with 5.0% hydrogenated soy lecithin)
Solution): a preparation obtained by further adding 5.0% of hydrogenated soybean lecithin to the above-mentioned control formulation a '.

Formula 1 '(ODO solution containing 0.5% soy lecithin): 0.5 g of soy lecithin in 30 g of ODO
A formulation in which probucol was dissolved and 1.2 g of probucol was further dissolved. Formula 2 '(1.0% soy lecithin added ODO solution): The soy lecithin in Formula 1' was changed from 0.5% to 1.0%. Formula 3 ′ (ODO solution with 2.0% soy lecithin): The soy lecithin in Formula 1 ′ was changed from 0.5% to 2.0%. Formula 4 ′ (SOD lecithin 5.0% added ODO solution): A solution obtained by changing the concentration of soy lecithin in Formula 1 ′ from 0.5% to 5.0%. Formulation 5 '(SOD lecithin 10.0% added ODO solution): The soybean lecithin concentration of Formula 1' was changed from 0.5% to 10.0%.

The test results of Example 4 are shown in Table 4 below.
In Table 4, Tmax represents the time to the maximum plasma concentration of the drug, Cmax represents the maximum plasma concentration of the drug,
AUC _0-24hr represents the area under the plasma concentration time curve from 0 to 24 hours after administration, and Mean ± SD represents the mean ± standard deviation.

[0045]

[Table 4]

Example 5 In order to examine the change in the bioavailability of Compound A due to diet, the body weight was 9.1 to 11.0 kg (average of 10.1 kg).
2 kg) of oil-based Nissan male beagle dogs with a group number of 6 and a dose of 10 mg / dog for compound A
Under fasting or under non-fasting (about 1 hour after feeding)
r) orally with 50 ml of water. After a certain period of time, blood was collected from the forelimb vein, the plasma was separated, and the unchanged compound concentration in the plasma was quantified by the HPLC-ECD method. The following formulation was filled in a hard capsule and administered. Control formulation 2 (powder with improved wetting): same as described in Example 1. Formula 2 (1.0% soy lecithin added ODO solution):
Same as described in Example 1.

The test results of Example 5 are shown in Table 5 below.
In Table 5, the bioavailability is the bioavailability, and the absolute bioavailability (Absolute) calculated by correcting the dose based on the AUC when a solubilized aqueous solution was separately prepared and injected intravenously was used as a reference. bioavailabili
ty), and Mean ± SD represents the mean ± standard deviation.

[0048]

[Table 5]

Example 6 In order to examine the change in bioavailability of probucol due to diet, a body weight of 220 to 250 g (9 to 10 w
eks) SLC-Wistar male rats with a group number of 4 to 7 and injection of the following formulation with an oral sonde under fasting or non-fasting for 18 hr so that the dose is 20 mg / kg for probucol. Dosing was vial and at the same time 1 ml of water was loaded. After a certain period of time, blood was collected from the tail vein under ether anesthesia, plasma was separated, and the unchanged compound concentration in the plasma was quantified by HPLC. Commercial formulation (fines): same as described in Example 4. Formula 2 ′ (1.0% soy lecithin added ODO solution): Same as described in Example 4.

The test results of Example 6 are shown in Table 6 below.
In Table 4, Tmax represents the time to the maximum plasma concentration of the drug, Cmax represents the maximum plasma concentration of the drug,
AUC _0-24hr represents the area under the plasma concentration time curve from 0 to 24 hours after administration, and Mean ± SD represents the mean ± standard deviation.

[0051]

[Table 6]

Example 7 Regarding the formation of oxidized form and the storage stability of the compound A during preparation of the preparation, the following preparations (1) were prepared and (2) 40
℃, sealed, 1 month after the storage of Compound A after storage
And the amounts of oxidized products were compared. Control formulation 3 (mixed and ground powder): the same as described in Example 1. Control formulation a (ODO solution): same as described in Example 1. Control formulation c (ODO solution with 1% polysorbate 80): The soybean lecithin of formulation 2 described in Example 1 was replaced with polysorbate 80, a nonionic surfactant. Control formulation d (HCO-60 1% added ODO solution): The soy lecithin of the formulation 2 described in Example 1 was used as a nonionic surfactant polyoxyethylene hydrogenated castor oil (HCO
-60, Nikko Chemicals). Control formulation e (SO-10 1% added ODO solution): Soy lecithin of formulation 2 described in Example 1 was replaced with sorbitan monooleate (SO-10, manufactured by Nikko Chemicals) as a nonionic surfactant. thing.

Control formulation f (Polysorbate 60 16%
(Added ODO solution): the soybean lecithin of the formulation 2 described in Example 1 was used as a nonionic surfactant polysorbate 60.
And a concentration of 16% to obtain a self-emulsifying type. Control formulation g (soybean oil solution): a formulation in which 10 mg of compound A was dissolved in 990 mg of soybean oil. Formulation 2 (Soy lecithin 1% added ODO solution): Same as described in Example 1. Formulation 22 (Soy lysolecithin added ODO solution): Same as described in Example 2. The test results of Example 7 are shown in Table 7 below. In Table 7, the amount of the oxidant was shown by the ratio to the remaining compound A.

[0054]

[Table 7]

Example 8 The storage stability of probucol was determined for each of the following formulations.
℃, sealed and stored for 2 months after storage for 2 months
It was quantified by LC and the degree of coloring was compared. Control formulation a '(ODO solution): a formulation in which 300 mg of probucol was dissolved in 3 g of ODO. Control formulation e '(ODO solution with 1% SO-10): a formulation in which 1% SO-10 was added to the above formulation a'. Formulation 1 '(ODO solution containing 0.5% soy lecithin): a preparation obtained by adding 0.5% soybean lecithin to the above formula a'. Formulation 2 '(ODO solution containing 1% soy lecithin): A preparation obtained by adding 1% soybean lecithin to the above-mentioned formula a'. The test results of Example 8 are shown in Table 8 below. In Table 8, the greater the number of +, the greater the degree of coloring.

[0056]

[Table 8]

Evaluation (1) Gastrointestinal Absorption In Example 1, the oily composition for oral administration of the present invention was obtained by comparing the compound A with a conventional solid preparation technique widely used for poorly water-soluble drugs. Bioavailability was significantly improved and blood levels increased. In particular, as is clear from the comparison with the control formulation 1, the oily composition has a relative bioavailability (relative bioavailability).
(biliability) reached almost 100%. Example 2
When the effect of adding various lecithins on Compound A was compared, unsaturated lecithin (including lysolecithin) was effective. Further, various medium-chain fatty acid triglycerides were used, but all were good. In Example 3, the relationship between the concentration of lecithin added and the effect of Compound A showed that a trace amount of 0.5% or more was sufficient. In Example 4, in the oily composition for oral administration of the present invention, the bioavailability of probucol was significantly improved and the blood concentration of probucol was increased as compared with the commercial preparation. When comparing the effects of lecithin and hydrogenated lecithin, lecithin is more effective, and when examining the relationship between lecithin addition concentration and effect,
A trace amount of 0.5% or more was sufficient.

(2) Fluctuation of Bioavailability Due to Meal In Example 5, the oily composition for oral administration of the present invention showed that compound A had a stable biodegradability without being affected by food compared to a solid general-purpose preparation. Showed availability. Under fasting conditions, bioavailability was approximately 7-fold. In Example 6, the oily composition for oral administration of the present invention showed stable bioavailability of probucol without being affected by diet as compared to a commercially available formulation. Under fasting conditions, it showed an AUC value of about 170-fold.

(3) Stability of a poorly water-soluble drug which is susceptible to (oxidative) decomposition In Example 7, the oily composition for oral administration of the present invention comprises a compound A containing a solid general-purpose preparation and other surfactants. Compared to the case of the used oily solution, the formation of the oxidized product at the time of preparation of the preparation was suppressed, and the storage stability was excellent. In Example 8,
The oily composition for oral administration of the present invention showed high storage stability with respect to probucol.

[0060]

The oily composition for oral administration of the present invention can be prepared by dissolving a poorly water-soluble drug in medium-chain fatty acid triglyceride in the presence of a small amount of lecithin, using only a very simple formulation technique, or , Can be administered by filling into soft capsules or hard capsules, ensuring high bioavailability that could not be achieved even with conventional solid formulation technologies, and suppressing fluctuations in bioavailability due to the presence or absence of food intake Can be. Furthermore, the oily composition for oral administration of the present invention prevents oxidation of poorly water-soluble drugs which are easily oxidized in the air, and is excellent in storage stability.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) A61K 31/435 A61K 31/095 A61K 47/14 A61K 47/24 CA (STN)

Claims (6)

(57) [Claims] 1. A method comprising: at least one poorly water-soluble drug selected from the group consisting of a dihydrothienopyridine derivative and probucol; a medium-chain fatty acid triglyceride having 8 to 12 carbon atoms; and lecithin. Oily composition for oral administration. 2. The oily composition for oral administration according to claim 1, wherein the poorly water-soluble drug is a dihydrothienopyridine derivative. 3. A poorly water-soluble drug in an amount of 0.1 to 200 parts by weight, a medium-chain fatty acid triglyceride having a carbon number of 8 to 12 and 100 to 30.
The oily composition for oral administration according to claim 1 or 2, comprising 0 parts by weight and 0.1 to 100 parts by weight of lecithin. 4. A medium-chain fatty acid triglyceride having 8 to 12 carbon atoms in an amount of 100 parts by weight and a dihydrothienopyridine derivative 0.1.
4. The oily composition for oral administration according to claim 1, comprising 1 to 10 parts by weight and 0.1 to 10 parts by weight of lecithin. 5. The method according to claim 1, further comprising an antioxidant.
5. The oily composition for oral administration according to 2, 3 or 4. 6. A capsule preparation comprising the oily composition for oral administration according to claim 1, 2, 3, 4, or 5.