JPH11217338A - Agent for improving and enhancing effect of medicine using quinoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve the absorption at digestive tract to put a medicine having difficulty in development because of lacking in oral absorption to practical use, and to utilize the medicine administered only by intravenous injection or the like as a practical oral medicine by making the agent include a specific quinoline derivative. SOLUTION: This oral absorption improver contains a quinoline derivative of formula I A is nitrogen or carbon; B is a direct bond, C=O, (CH2 )m [(m) is 0-3]; C is formula II (R1 to R3 are each H or phenyl), formula III (D is (CH2 )n [(n) is 0-3]} or CH=CH}, (preferably a compound of formulas IV or V) or a biologically acceptable salt thereof. The daily dose is 10 mg to 2 g, and administered by dividing the dose into one to several times. The objective medicine the oral absorption of which can be improved is a medicine or a drug such as an anticancer agent, a cardiovascular agent, an antiviral agent and a central nervous system-acting drug, e.g. taxol, taxotere and adriamycin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for improving the absorption of a poorly orally absorbable drug and an agent for enhancing the effect of a taxane derivative in cancer chemotherapy in a therapeutic method using a pharmaceutical in the medical field.

[0002]

2. Description of the Related Art Among the administration methods of drugs for treating diseases, the oral administration method has a relatively small physical and mental burden on patients and is easy to administer, so that it is widely used for drug treatment for various diseases. It is used for

[0003] In the oral administration method, improving the oral absorbability of the administered drug is an important factor for exerting the effect of the drug. Poor oral absorptivity requires a large dose of the drug in order to sufficiently exert the effect of the drug, which is not preferable from the viewpoint of an increase in drug cost.

On the other hand, in cancer chemotherapy, taxane derivatives such as taxol and taxotere are greatly expected as new anticancer agents worldwide.

[0005] Taxol (Paclitaxel, generic name)
Is a plant alkaloid extracted from the bark of the yew tree, and promotes the polymerization of tubulin proteins that constitute intracellular microtubules, thereby causing stable microtubule hyperplasia and inhibiting cell division, It is thought to exert activity. Clinical trials began in the United States in 1983, and were approved and marketed by the FDA in 1992. In Japan, clinical trials of taxol were also conducted, and high efficacy was confirmed for ovarian cancer, breast cancer, lung cancer, and the like. Taxol has begun to be widely used clinically as a new anticancer drug.

[0006] Taxotere, a taxane derivative, is a semi-synthetic anticancer agent obtained by partially modifying a precursor extracted from needles of western yew. Like taxol, it promotes protein polymerization in intracellular microtubules, causes hyperplasia of stabilized microtubules, and is thought to have antitumor effects by inhibiting cell division. Taxotere's clinical application has advanced in the United States and Europe, with ovarian cancer, mainly breast cancer, non-small cell lung cancer,
It has been performed on head and neck cancer, colorectal cancer, stomach cancer and the like, and good effects have been confirmed respectively. In Japan, a clinical trial of taxotere was started in 1991, completed in 1996, and approved for the manufacture of two carcinomas, breast cancer and non-small cell lung cancer.

However, these drugs have many problems such as poor oral absorbability and reduced effects due to resistance to cancer cells.

[0008]

DISCLOSURE OF THE INVENTION The present invention relates to the practical use of drugs that are difficult to develop due to poor oral absorbability, and to the safer and practical use of drugs that can be administered only by intravenous administration or other routes. An object of the present invention is to provide an absorption-improving agent that improves the absorbability of a drug for oral administration in the digestive tract for the purpose of utilizing it as an oral preparation.

Further, the present invention is to provide an agent for enhancing the effect of improving the oral absorption and overcoming the tolerance of taxane derivatives, which is currently expected in the field of cancer chemotherapy worldwide.

[0010]

[Means for Solving the Problems] With the development of cancer chemotherapy, cases in which a plurality of anticancer drugs do not show a therapeutic effect on a certain cancer from the beginning, or cancer cells become resistant to a plurality of anticancer drugs during treatment. Cases that have acquired and reduced therapeutic effects have been found. Such a phenomenon is a very serious clinical problem.

[0011] Along with this, research on the mechanism by which such cancer cells acquire resistance has been advanced, and P-type cells having a pump function of excreting intracellular anticancer drugs outside the membrane in cancer cells have been developed.
It has been revealed that membrane proteins such as glycoproteins and MRP proteins are expressed from the beginning, and that they are induced and overexpressed during treatment with anticancer drugs, and that these are the main factors of resistance. .

Under these circumstances, the present inventors have conducted intensive studies on a method for improving the absorption of an orally-administered drug having poor intestinal absorption. As a result, the above-mentioned cancer chemotherapy was used to treat multidrug-resistant cancer. P-glycoprotein, MR, which is expected to be effective
It has been found that a protein inhibitor having a drug efflux pump function such as P is effective for improving oral absorption. Furthermore,
These same inhibitors have been found to have, in particular, an improvement in oral absorption of taxane derivatives and a potent anticancer effect by overcoming the resistance of the taxane derivatives, thereby completing the present invention.

That is, the present invention is as follows. [1] An oral absorption improving agent characterized by using a quinoline derivative represented by the following formula (1) or a biologically acceptable salt thereof,

[0014]

Embedded image (Where A represents a nitrogen atom or a carbon atom, B represents a direct bond, CＣO or — (CH ₂ ) _m —, C represents the following structure (Formula 10),

[0015]

Embedded image D is - (CH _{2) n} - or represents a -CH = CH-. Here, R ₁ , R ₂ and R ₃ independently represent a hydrogen atom or a phenyl group, and m and n each represent an integer of 0 to 3. [2] an anticancer effect enhancer of a taxane derivative, characterized by using a quinoline derivative represented by the following formula (1) or a biologically acceptable salt thereof;

[0016]

Embedded image (Wherein A represents a nitrogen atom or a carbon atom, B represents a direct bond, CＣO or — (CH ₂ ) _m —, C represents the following structure (Formula 12)

[0017]

Embedded image D is - (CH _{2) n} - or represents a -CH = CH-. Here, R ₁ , R ₂ and R ₃ independently represent a hydrogen atom or a phenyl group, and m and n each represent an integer of 0 to 3. )

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. Anti-cancer drugs are not effective from the beginning in the treatment with the anti-cancer drug, or become ineffective during the treatment, and the phenomenon of resistance progression, in which the cancer progresses, has been frequently observed clinically, and has become a serious problem in cancer chemotherapy. Among the resistance phenomena, a phenomenon called multidrug resistance is also observed at the cellular level, and the structure also functions as an anthracycline anticancer drug, vinca alkaloid anticancer drug, actinomycin D, and taxane derivatives such as taxol and taxotere. Also simultaneously become resistant to different anticancer agents. In such a multidrug-resistant cell, a membrane protein having an action of excreting an anticancer drug is present in the membrane, and since its pumping action has low selectivity to the anticancer drug, many anticancer drugs are excreted in the same manner and exhibit resistance. This causative protein is considered to be a P-glycoprotein or a multidrug resistance-related protein (MRP). Therefore, by inhibiting this protein, it is considered that the above-mentioned resistance to the anticancer drug is released and the effect is enhanced. This approach has been studied worldwide, and many compounds having an effect-enhancing effect are known, such as verapamil, a calcium antagonist, cyclosporine, an immunosuppressant, and FK506. Among them, the present inventors have previously reported (Japanese Unexamined Patent Application Publication No.
-101662, JP-A-6-1768), compounds of the present invention represented by formula (1), especially compounds represented by formulas (2) (13) and (3) (14) and biological compounds thereof. Salts that strongly inhibit the function of this drug excreted protein, and have low side effects such as calcium antagonism,
It is expected in clinical practice as an anti-cancer drug effect enhancer.

[0019]

Embedded image

[0020]

Embedded image

In the present invention, the salt which is biologically acceptable is not particularly limited, but salts with inorganic acids such as hydrochloric acid and sulfuric acid and salts with organic acids such as acetic acid, oxalic acid, fumaric acid, maleic acid and tartaric acid are exemplified. No. Further, the compound of the present invention has an asymmetric carbon and has optical isomers, and all of these are included in the present patent.

On the other hand, P-glycoprotein is not only cancer cells,
It has been clarified that it is expressed in various normal tissues. According to Pastan et al., MRNA for the P-glycoprotein gene (mdr) is found in human adrenal gland, kidney, lung, liver, small intestine, colon, pancreas, etc. (Proc. Natl. Acad. Sci. USA, vol.
84, p.7735, (1987)). The function of P-glycoprotein in these normal cells is considered to be a function of excreting chemicals and chemotherapeutic agents including metabolites and toxic substances out of cells and tissues.

On the other hand, drugs administered orally are almost always
Since the drug is absorbed from the small intestine, the bioavailability of the drug largely depends on the amount of the drug absorbed from the small intestine. Therefore, it is considered that the ability of the small intestinal mucosa to block the permeation of villus cells is an important factor affecting drug absorption.
Thus, the present inventors have conducted intensive studies based on the above findings, and as a result, the absorption of orally administered drugs has been improved by inhibiting drug excretion function proteins that are thought to be present in villous cells of the small intestinal mucosa. I found something.

Examples of the drug efflux function protein include the same P-glycoprotein, MRP and its family proteins as described above for the anticancer drug. Examples of the drug efflux function protein inhibitor include a group of compounds represented by the formula (1) which are quinoline derivatives, in particular, compounds represented by the formula (2) (hereinafter referred to as MS-2).
09 in some cases) or the compound represented by the formula (3) (hereinafter sometimes abbreviated as MS-073)
Has a strong inhibitory effect on P-glycoprotein and MRP, has low toxicity, and is most preferable as a drug for clinical use. Also,
The present inventors have previously reported (Suzuki, Fukasawa, et al., J. Me.
d. Chem. 40 p. 2047 (1997)) Naturally, compounds expected from the correlation between the structure and activity of the compound group are naturally included in the present invention.

In addition, many other inhibitors with similar effects, namely SDZ-PSC-833 (Novatis), LY-335979 (Eli Lilly), V
It is easily inferred from the present invention that X-710 (Vertex) and the like also have the same action.

The agent for improving absorption of an orally-administered drug of the present invention is in the form of an orally administrable substance of the above-mentioned drug efflux function protein inhibitor. The formulation is a formulation containing commonly used excipients and other additives, such as crystalline cellulose, light silicic anhydride, corn starch, lactose, calcium phosphate, magnesium stearate, etc., tablets, granules, powders , Capsules, suspensions, etc., as long as they can be administered orally. The dose is also a symptom,
The dose may be appropriately selected depending on the usage, the condition of the patient, the age, the sex, and the like. Usually, 10 mg to 2 g can be administered once or several times a day.

As a specific method for improving absorption using the absorption improving agent of the present invention, the above-mentioned inhibitor is directly or formulated before, simultaneously with or after oral administration of a target drug whose absorption is to be improved. Can be achieved by oral administration as a mixture with the target drug. The target drug can be a wide range of drugs or drugs having a problem with oral absorption, such as anticancer drugs such as taxol, taxotere, and adriamycin, cardiovascular drugs, antiviral drugs, and centrally acting drugs, and is not particularly limited.

Further, as a specific method for enhancing the anticancer effect of the taxane derivative of the present invention, the above-mentioned inhibitor is directly or formulated before, simultaneously with or after administration of an anticancer agent such as taxol, taxotere, etc. It can be achieved by oral administration as a mixture with a drug. The formulation method, dosage, etc. are the same as described above. The type of cancer to be treated can be applied to various cancers for which taxane derivatives are expected to be effective, such as breast cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, gastric cancer, and colon cancer, but is not particularly limited.

[0029]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. Example 1 Taxol (Paclitaxel), which has low oral absorbability because it is excreted by the action of P-glycoprotein expressed in the gastrointestinal tract, is used as an oral drug to be subjected to improvement in absorption, and is digested in rats during oral administration. The effect of the absorption improver of the present invention on tube absorption was examined. (1) Method: d1-5- [3- {4- (2,2-diphenylacetyl) piperazin-1-yl} -2-hydroxypropyl] quinoline fumarate, molecular formula C ₃₀ H ₃₁ N
_{3 O 3 · 3 / 2C 4} H 4 O 4, molecular weight 655.7 (equation (2)
Aqueous suspension of 0.1% Tween 80 containing compound (MS-209) at a concentration of 10 mg / ml was taken as the absorption improving agent of the present invention. Radiolabeled ³ H-Paclitaxel was used to facilitate measurement of the absorbability of the drug of interest. ³ H-Paclit
After axel was dissolved in ethanol, it was adjusted to a concentration of 1 mg / ml using Cremophor EL and physiological saline, and used in experiments. ³ H-Paclitaxel was administered by gavage at a dose of 4 mg / kg. The agent of the present invention was orally administered by gavage at a dose of 100 mg / kg 30 minutes before administration of Paclitaxel. Blood was collected from the carotid artery using heparin-treated syringes over time without anesthesia after administration of ³ H-Paclitaxel. Immediately after blood collection, centrifugation was performed to collect plasma. To the obtained plasma, a liquid scintillation cocktail was added, and the radioactivity was measured with a liquid scintillation counter. Pharmacokinetic parameters were calculated for each individual. The measured values of the maximum blood concentration (Cmax) and the time to reach the maximum blood concentration (Tmax) were used. AU
C was calculated from 0 to 24 hours by the trapezoidal method. Absorbency was evaluated from the measured values of these parameters.

(2) Results: Tables 1 to 3 (Tables 1 to 3) show Pacl
Oral administration of itaxel alone or 0.1% Tween
The pharmacokinetic parameters when Paclitaxel was orally administered after pre-administration of 80 or the absorption improving agent of the present invention were shown.
The plasma concentration in the single administration group showed a maximum value of 156 ng / ml at 2.9 hours after administration. In addition, the radioactivity concentration in plasma in the solvent-administered group showed a similar transition, and no difference was observed in the AUC between the two. As described above, no difference was observed between the single administration group and the solvent combination group, and oral administration of only 0.1% Tween 80, which is the solvent used in the present invention, had no effect on the plasma concentration of Paclitaxel. Had no effect. On the other hand, as compared with the single administration group, the plasma emission concentration of the group improved with the present invention was significantly increased from 1.5 to 12 hours after administration. As a result, the group of the present invention combined with the ameliorating agent had a Cmax of about 2 compared to the single administration group.
Tmax was delayed by a factor of 5.3 hours. AUC also significantly increased in the group of the present invention combined with the agent of the present invention as compared to the group administered alone.

[0031]

Table 1-1 Table 1-1 Oral Absorption of Paclitaxel in Rats (a) Paclitaxel administered alone ──────────────────────────── Animal number Cmax Tmax AUC (0-24h) (ng / ml) (h) (ng.h / ml) ───────────────────────── ─── 1 129 1 1066 2 98 0.5 1452 3 147 1 1568 4 250 9 4100 ──────────────────────────── Average 156 2.9 2047 SD 66 4.1 1386 ────────────────────────────

[0032]

[Table 2] Table 1-2 Oral Absorption of Paclitaxel in Rats (b) Paclitaxel + 0.1% Tween 80 administration ──────────────────────── ──── Animal number Cmax Tmax AUC (0-24h) (ng / ml) (h) (ng.h / ml) ───────────────────── ─────── 1 204 12 3954 2 116 1.5 1408 3 96 0.75 1273 4 124 1 1864 ─ Average 135 3.8 2 125 SD 47 5.5 1245 ────────────────────────────

[0033]

Table 1-3 Oral absorbability of Paclitaxel in rats (c) In the case of administration of Paclitaxel + the improving agent of the present invention ─── Animal number Cmax Tmax AUC (0-24h) (ng / ml) (h) (ng.h / ml) ────────────────────── ────── 1 362 4 3745 2 377 9 5222 3 368 4 3840 4 271 4 3163 ──────────────────────────── Average 345 5.3 3993 SD 49 2.5 873 ────────────────────────────

Example 2 The effect of the improving agent of the present invention on gastrointestinal absorption in mice after oral administration of taxol (Paclitaxel) was examined. (1) Method: The same improver used in Example 1 was used as the present invention. The radiolabeled ³ H-Paclitaxel was dissolved in ethanol, and then adjusted to a concentration of 1 mg / ml using Cremophor EL and physiological saline, and used in experiments. ³ H-Paclitaxel was administered by gavage at a dose of 8 mg / kg. 100 mg / kg of the improving agent of the present invention
Was administered by gavage 30 minutes before the administration of taxol. Blood collection was performed 1 to 2 hours after administration of ³ H-Paclitaxel under ether anesthesia using a syringe that had been treated with heparin from the heart. Immediately after blood collection, centrifugation was performed to collect plasma. To the obtained plasma, a liquid scintillation cocktail was added, and the radioactivity was measured with a liquid scintillation counter.

(2) Results: Table 4 (Table 4) shows 0.1% Tween80
Alternatively, the average plasma radioactivity concentration transition when Paclitaxel was orally administered with the compound of the present invention in advance was shown. As in the case of the rat, the radioactivity concentration in the plasma of the group of the compound of the present invention was significantly higher than that of the group administered alone.

[0036]

[Table 4] Table 4. Paclitaxel oral absorption in mice Pa Blood Paclitaxel concentration (ng / ml) ──── ────────────────── 0.1% Tween 80 Improvement agent of the present invention ────────────────────── Animal number 1h 2h 1h 2h ─────────────────────────────── 1 177.9 166.7 786.1 819.2 2 76.3 150.0 1230.5 755.9 3 223.5 102.7 409.1 575.2 4 268.5 218.0 364.3 741.3 ──────────────────────────────── Average 186.6 159.6 697.5 722.9 SD 82.3 47.6 402.5 104.1 ─── ─────────────────────────────

From the results of Examples 1 and 2, the combined use of the absorption-improving agent of the present invention increased the plasma concentration of Paclitaxel in oral administration and improved the absorption from the intestinal tract in both animal species of rats and mice. It became clear that it was done.

Example 3 The combined effect of the absorption-improving agent of the present invention on the anticancer effect of oral administration of Paclitaxel was evaluated. (1) Method: Mouse melanoma cell line B16 cells 1 × 10
^{Six of} them were implanted subcutaneously on the body side of BDF1 mice (day 0 of treatment), and the drug was administered for 5 consecutive days from day 3 of treatment. The agent of the present invention was the same as that used in Example 1.2. Paclitaxel is dissolved in ethanol,
1.25,2, using Cremophor EL and saline
It was dissolved in a concentration of 2.5, 5 mg / ml and used for the experiment (10/10/80; v / v / v). Paclitaxel single administration group, 25, 50, 100m above Paclitaxel solution
g / kg was administered by oral gavage. The group administered with Paclitaxel and the agent of the present invention at a dose of 100 mg /
Oral administration at a dose of kg, and 30 minutes later Paclitax
The el solution was administered by gavage at a dose of 25, 50, 100 mg / kg. The antitumor effect was determined by determining the tumor volume of the control group and the drug administration group (1/2 × L × W ² : L = tumor major axis, W
= Tumor minor axis).

(2) Results: Table 5 (Table 5) shows the tumor volume on day 17 in each group. In the paclitaxel single oral administration group, the tumor volume showed almost the same value as the non-administration group. On the other hand, in the combination administration group, the increase in tumor volume was suppressed depending on the dose of Paclitaxel.

[0040]

[Table 5] Table 5. Antitumor effect 薬 物 Administered drug Tumor volume T / C ^* (mm ³ ) (%) ─────────────────────────────────── Non-administration group 923 100 Paclitaxel (25 mg / kg) 1004 109 Paclitaxel (50 mg / kg) 973 105 Paclitaxel (100 mg / kg) 1032 112 Paclitaxel (25 mg / kg) + improver of the present invention (100 mg / kg) 851 92 Paclitaxel (50 mg / kg) + improver of the present invention (100 mg / kg ) 469 51 Paclitaxel (100 mg / kg) + improver of the present invention (100 mg / kg) 349 38 ────── *; tumor volume ratio compared to T / C non-administration group

Example 4 The enhanced taxol (Paclitaxel) effect of the agent of the present invention was demonstrated to be a mouse leukemia-derived cell line P388 and its multidrug resistance-acquiring cell line, and three lines (P388 / Taxol, P388 /
VCR, P388 / ADM) in vitro
The system was examined. After culturing each of the above cell lines in RPMI1640 medium (containing 10% fetal calf serum, 20 μM 2-mercaptoethanol, and 100 μM streptomycin), 0.75-1.5 × 1 was added to a 96-well plate.
Cells were seeded at a density of 0 ³ cells / 0.2 ml / well. Next, d1-5- [3- ｛4-
(2,2-diphenylacetyl) piperazin-1-yl} -2-hydroxypropyl] fumarate quinoline, molecular formula _{C 30 H 31 N 3 O 3} · 3 / 2C 4 H 4 O 4, molecular weight 655.7 ( Compound of formula (2), MS-209)
Alternatively, it was added to 3 μM. In addition, taxol
The solution dissolved in SO was added to a final concentration of 0.001 to 3000 n.
g / ml. After 72 hours of culture, MTT
Cytotoxicity was measured in the assay. Table 6 shows the results. Expressing the cytotoxicity of taxol on taxol-resistant cells (P388 / Taxol) by 50% growth inhibition rate (IC ₅₀ value) is 126 ng / ml, P388 / VCR and P
IC ₅₀ values for 388 / ADM are each 171 ng
/ Ml and 64.1 ng / ml. MS-20
9 at 3 μM, the effect of taxol was 36-fold in P388 / Taxol cells, P388 / VC
50 times for R cells and 34 for P388 / ADM cells.
Doubled.

[0042]

Table 6 Taxol anticancer effect enhancing effect of MS-209 ────────────────────────────── IC50 value (ng / ml) ──────────────── Cell line MS-209 0μM 3μM ──────────────────────── ────── P388 3.28 1.46 (2.2 ^* ) P388 / Taxol 126 3.47 (36) P388 / VCR 171 3.43 (50) P338 / ADM 64.1 1.86 (34) ───────────── ───────────────── *: Numbers in parentheses indicate effect enhancement [IC ₅₀ (0 μM) / IC ₅₀ (3 μM)]

Example 5 The effect of the agent of the present invention on the effect of Taxotere, Docetaxel on the taxol-resistant strain of P388 (P388 / Taxol)
Was examined in an in vitro system using. The above two cells are expressed as R
PMI1640 medium (10% fetal calf serum, 20 μM 2
-Containing mercaptoethanol and 100 µM streptomycin), and inoculated to a 96-well plate at 1.5 x 10 ³ cells / 0.1 ml / well. MS or 209 (compound of formula (2)) was added to each well at 0 or 3 μM and taxotere at 0.0
After adding 0 to 3000 ng / ml and culturing at 37C for 72 hours, cytotoxicity was evaluated by MTT assay. The results are shown in Table 7 (Table 7). Taxotere cytotoxicity (IC ₅₀ value) against P388 / Taxol cells is 22.4 n
g / ml. When 3 μM of MS-209 was added, it became 3.9 ng / ml, and the effect of taxotere was 5.7.
Doubled.

[0044]

Table 7 Taxotere anticancer effect enhancing effect of MS-209 ─────────────────────────────── IC50 value ( ng / ml) ────────────────── Cell line MS-209 0μM 3μM ───────────────────── ────────── P388 / Taxol 22.4 3.91 (5.74 *) ─────────────────────────────── *; Numbers in parentheses indicate effect enhancement [IC ₅₀ (0 μM) / IC ₅₀ (3 μM)]

Example 6 The enhancement of the effect of the agent of the present invention on taxol (Paclitaxel) was examined using P388 / Taxol cell-transplanted mice. P388 / Taxol cells (10 ⁶ cells / m
ouse) was implanted intraperitoneally into CD2F1 mice (day 0). Taxol alone or MS daily on days 1-5
-209 was administered in combination. MS-209 is 0.1% T
It was suspended in an aqueous solution of ween 80 and orally administered. Taxol was dissolved in ethanol, diluted and adjusted with CremophorEL (manufactured by BASF) and saline, and administered into the tail vein. The antitumor activity was calculated from the median survival time of each experimental group.
/ C value (C is survival time of untreated control group). The results are shown in Table 8 (Table 8). Taxol alone did not increase survival at all. On the other hand, MS-2
When 09 was administered in combination with 200 mg / kg, the survival time was prolonged in a dose-dependent manner with taxol.

[0046]

Table 8 Taxol anticancer effect enhancing effect of MS-209 using P388 / Taxol-transplanted mice薬 物 Number of drugs administered Average number of surviving days T / C (days) (%) ──────────────────────── ──────────── Control 11 10 100 MS-209 (200mg / kg) 6 11 110 Taxol (7.5mg / kg) 6 10 100 Taxol (15mg / kg) 6 10 100 Taxol (7.5mg / kg) + MS-209 (200mg / kg) 6 10.5 105 Taxol (15mg / kg) + MS-209 (200mg / kg) 6 12 120 ───────────────── ───────────────────

Example 7 Formulation examples of the improving agent of the present invention are shown below. This tablet is a tablet containing 300 mg of MS-209 in one tablet. MS-209 (300 g), lactose (36.9 g),
Corn starch (15.9 g) was mixed well and a hydroxypropylcellulose aqueous solution (11.7 g / 201 m2) was added.
Granulate by wet granulation using L) and dry to obtain granules. Then, carmellose calcium (19.5 g),
Magnesium stearate (6 g) was sequentially added and mixed well, and the mixture was tableted using a tableting machine at a weight of 390 mg per tablet to give tablets.

Example 8 Formulation examples of the improving agent of the present invention, which is a combination of MS-209 and taxol which is a target drug for improving oral absorption, are shown below. In addition, this drug contains 100 mg of taxol per tablet and MS-20.
It is a tablet containing 9,300 mg. MS-209
(300 g), taxol (100 g), lactose (36.
9g) and corn starch (15.9 g) were mixed well and mixed with an aqueous solution of hydroxypropylcellulose (11.7 g / 2).
01 mL), and granulate and dry to obtain granules. Then, carmellose calsim (19.5)
g) and magnesium stearate (6 g) were sequentially added and mixed well, and the mixture was tableted using a tableting machine at a weight of 490 mg per tablet to obtain tablets.

[0049]

As is clear from the above examples, the oral absorption improving agent according to the present invention improves the absorbability of a drug having poor oral absorption, thereby providing a new clinically effective therapeutic agent or method. And to enhance the anti-cancer effect of taxane derivatives such as taxol and taxotere,
This is an invention that brings great benefits in the field of drug treatment.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Kyoko Nonomura 1900-1 Togo, Togo, Mobara City, Chiba Prefecture Inside (72) Inventor Jun Aoki 1900-1, Togo, Togo, Mobara City, Chiba Prefecture Mitsui Pharmaceutical Industry Co., Ltd. (72) Inventor Izumi Mita 1900-1, Togo, Mobara City, Chiba Prefecture Inside Mitsui Pharmaceutical Industry Co., Ltd. (72) Inventor Kazunori Mabuchi 1,900-1, Togo Togo, Mobara City, Chiba Prefecture, Japan

Claims (11)

[Claims] 1. An oral absorption improving agent characterized by using a quinoline derivative represented by the following formula (1) or a biologically acceptable salt thereof. Embedded image (Wherein, A represents a nitrogen atom or a carbon atom, B represents a direct bond, CＯO or — (CH ₂ ) _m —, C represents the following structure (Chemical Formula 2), D is - (CH _{2) n} - or represents a -CH = CH-. Here, R ₁ , R ₂ and R ₃ independently represent a hydrogen atom or a phenyl group, and m and n each represent an integer of 0 to 3. ) 2. The oral absorption improving agent according to claim 1, wherein the quinoline derivative or a biologically acceptable salt thereof is a compound represented by the following formula (2). Embedded image 3. The oral absorption improving agent according to claim 1, wherein the quinoline derivative or a biologically acceptable salt thereof is a compound represented by the following formula (3). Embedded image 4. The oral absorption improving agent according to claim 1, wherein the drug whose oral absorption is improved is an anticancer agent. 5. The oral absorption improving agent according to claim 4, wherein the drug whose oral absorption is improved is a taxane derivative. 6. The oral absorption improving agent according to claim 5, wherein the taxane derivative is taxol or taxotere. 7. The drug whose oral absorption is improved is a cardiovascular drug, a centrally acting drug or an antiviral drug.
The oral absorption improver according to any one of the above. 8. An agent for enhancing the anticancer effect of a taxane derivative, which comprises using a quinoline derivative represented by the following formula (1) or a biologically acceptable salt thereof. Embedded image (Wherein, A represents a nitrogen atom or a carbon atom, B represents a direct bond, C ま た は O or — (CH ₂ ) _m —, C represents the following structure (Chemical Formula 6), D is - (CH _{2) n} - or represents a -CH = CH-. Here, R ₁ , R ₂ and R ₃ independently represent a hydrogen atom or a phenyl group, and m and n each represent an integer of 0 to 3. ) 9. The anticancer effect enhancer according to claim 8, wherein the quinoline derivative or a biologically acceptable salt thereof is a compound represented by the following formula (2). Embedded image 10. The anticancer effect enhancer according to claim 8, wherein the quinoline derivative or a biologically acceptable salt thereof is a compound represented by the following formula (3). Embedded image 11. The method according to claim 8, wherein the taxane derivative is taxol or taxotere.