KR100670840B1 - Use of Bamboo Concentrate for Enhancing Bioavailability of Taxane Family Drug - Google Patents

Abstract

The present invention discloses the use of bamboo liquor as a potency increasing agent of Taxane based drugs. Specifically, the present invention discloses a pharmaceutical composition comprising a taxane-based drug as an active ingredient and comprising bamboo herb solution as an efficacy increasing agent of the taxane-based drug, and a composition for increasing the efficacy of a taxane-based drug comprising bamboo-vinegar solution as an active ingredient. .

Taxane-based drugs, bamboo liquor, pharmaceutical compositions

Description

Use of Bamboo Concentrate for Enhancing Bioavailability of Taxane Family Drug}

1 is a graph showing the average plasma concentration of paclitaxel upon oral administration of paclitaxel and bamboo vinegar to rats.

Figure 2 is a graph showing the average plasma concentrations of paclitaxel upon oral administration of paclitaxel after oral administration of bamboo vinegar to rats.

Figure 3 is a simultaneous oral administration of paclitaxel and bamboo vinegar to rats or pretreatment with oral administration of bamboo vinegar to rats to show changes in the expression of anticancer metabolizing enzymes CYP3A1 and CYP3A2 in the liver Picture of electrophoresis.

Figure 4 is to show the changes in the expression of the anti-cancer metabolizing enzymes CYP3A1 and CYP3A2 in the kidney when paclitaxel and bamboo vinegar at the same time or pretreatment with oral administration of paclitaxel to rats Picture of electrophoresis.

The present invention relates to the use of bamboo liquor as an efficacy increasing agent of a taxane-based drug, specifically, a pharmaceutical composition comprising a taxane-based drug as an active ingredient and bamboo shoot liquor as an efficacy increasing agent of the taxane-based drug, and It relates to a composition for increasing the efficacy of a taxane-based drug comprising as an active ingredient.

Examples of the taxane-based drugs include paclitaxel (taxol) and docetaxel (taxetatel).

Among these, paclitaxel refers to an extremely complex diterpene-based compound having 20 or more asymmetric centers.

The study of paclitaxel began in the 1960s with a large-scale screening program of anticancer active substances conducted by the National Cancer Institute of the United States on 35,000 plant species, with extracts from the Pacificus bark (Taxus brevifolia) bark including leukemia and lung cancer. After being reported to have strong activity against branch tumors, the active substance was isolated in 1969 and the structure of paclitaxel as the body of the active substance was revealed in 1971 (Eric K. Rowinsky et al., J. National Can.Inst., 82 , 11247 (1990)).

Unlike conventional anticancer drugs, Colchicine or Vinca alkaloid, which decompose microtubules and exhibit anticancer activity, paclitaxel promotes the microtubule polymerization and the next step, As it is known that it exhibits a specific mechanism of action that inhibits the degradation of tubulin (Schiff, PB, J. Fant and SB Horwitz, Nature, 277 , 665 (1979)), studies on paclitaxel have been actively conducted.

Paclitaxel was licensed as an anticancer drug by the US Food and Drug Administration in 1993 and is currently reported to have anti-cancer activity against ovarian cancer, breast cancer, leukemia, melanoma, and prostate cancer. In particular, ovarian cancer 30% and breast cancer 50 %, And 20% lung cancer (David, G., et al., J. Nat. Prod., 53 , 1 (1990)).

Meanwhile, another taxane-based drug, docetaxel, has a similar mechanism of action with paclitaxel. That is, it promotes the polymerization of microtubules and inhibits the subsequent step of tubulin degradation. As a result, cells are detained at the M stage to inhibit cell division (Katzung's Pharmacology, 9th Edition (2004)).

Docetaxel also has anti-cancer effects such as lung and breast cancer (Piccart, M. Anticancer Drugs. 1995 Suppl 4: 7-11).

On the other hand, bamboo vinegar liquid refers to a reddish brown transparent liquid prepared by cooling the smoke generated during the carbonization process of bamboo and then policing and filtration and refinement.

Carbonization of the bamboo and cooling the smoke generated there is left to separate into three layers, the upper layer is a light oil layer, such as derpin oil, the middle layer is bamboo shoot liquid layer, the lower layer is a tar layer. This middle layer of bamboo vinegar is strictly called crude bamboo vinegar. The bamboo vinegar is currently distributed or used in the market is those that are politically aged, filtered, purified or distilled.

Bamboo vinegar is strongly acidic (pH 2.8 ~ 3.1), and its main component is organic acid such as acetic acid and formic acid, and contains other phenols.

Such bamboo vinegar is currently used as a bactericidal aid, insecticide aid, plant growth inhibitor, etc., and its new use is continuously being studied.

The present inventors expect that bamboo liquor may have several other uses in addition to the above uses, and while experimenting with different uses of bamboo liquor, bamboo liquor was orally administered in experimental animals with paclitaxel, a drug of taxane system. The present invention was completed by confirming that the plasma concentration of paclitaxel was increased.

Therefore, it is an object of the present invention to provide the use of bamboo liquor as a potency increasing agent of taxane-based drugs.

Specifically, it is an object of the present invention to provide a pharmaceutical composition comprising a taxane-based drug as an active ingredient and bamboo shoot liquid as its potency increasing agent, and a composition for increasing the efficacy of a taxane-based drug containing bamboo shoot liquid as an active ingredient. .

In one aspect, the present invention relates to a pharmaceutical composition comprising a taxane-based drug as an active ingredient and bamboo shoot liquid as its potency increasing agent.

The present inventors compared oral administration of paclitaxel and paclitaxel alone with oral administration of paclitaxel, which is a taxane-based drug, and bamboo herb solution to experimental animals, that is, rats, or pretreatment with oral treatment of bamboo herb solution. It was confirmed that the plasma concentration of Litaxel significantly increased. Additionally, pharmacokinetic analysis parameters, the plasma concentration curve enemy (AUC), maximum plasma concentration was (C _max) is also increased elimination rate constant (Kel) with the reduction, elimination half-life (t _1/2) is It was extended, it was confirmed that the absolute bioavailability (AB%) was increased (see Examples, Table 1, Table 2, Figure 1 and Figure 2).

The above results show that bamboo liquor increases the plasma concentration of paclitaxel or prolongs the time it is maintained in the plasma, thereby increasing the bioavailability.

On the other hand, the present inventors attempted an experiment to confirm what mechanism it is due to the increase in the plasma concentration of paclitaxel or prolong the retention time in the plasma. As a result, when oral administration of bamboo liquor simultaneously with paclitaxel or oral administration of paclitaxel after oral administration of bamboo liquor solution, the efficacy in vivo is reduced by decomposing various drugs including paclitaxel. (Sonnichsen DS, Liu Q, Schuetz EG, Schuetz JD, Pappo A, Relling MV, J. Pharmacol.Exp. Ther., 275 , 566-571 (1995)) Cytochrome-P450 3A series (Cytochrome P450 3A It was confirmed that the amount of expression of CYP3A4 and CYP3A1 enzymes among the enzymes of the family) was reduced. Paclitaxel is known to be degraded by enzymes of the CYP3A family (Katzung's Pharmacology, 9th Edition (2004); Dorr RT, Pharmacotherapy, 17, 96S-104S (1997)), in particular paclitaxel by the CYP3A4 enzyme Although it is degraded, it is known to increase the expression of the enzyme (Monsarrat B., et al., Drug Metab Dispos, 26, 229-233 (1998)). It can be clearly seen that by affecting the expression of these enzymes to inhibit the paclitaxel target process increases the plasma concentration of paclitaxel or prolongs the retention time in the plasma.

Therefore, the pharmaceutical composition of the present invention is characterized by including bamboo liquor as its potency increasing agent in addition to including taxane-based drugs such as paclitaxel as an active ingredient.

In the pharmaceutical composition of the present invention, the bamboo vinegar is preferably bamboo vinegar, that is, the aging, filtration, purified or distilled from the bamboo vinegar as described above, but may be crude bamboo vinegar. If the bamboo vinegar is purified from the crude bamboo vinegar, if the bamboo vinegar has the effect of increasing the efficacy of taxane-based drugs such as paclitaxel, even if there is a difference in the degree of effect, those skilled in the art will practice the following As long as it is based on Examples 1 and 2 and the results (see Table 1, Table 2, Figures 1 to 4), it can be expected that the crude vinegar solution will also have the above effects, as long as it utilizes its usual ability. You will see the above effect.

In addition, although bamboo liquor may show a difference in the effect of the taxane-based drug such as paclitaxel as an effect increasing agent depending on the manner of purification in the crude bamboo liquor, those skilled in the art can adjust the bamboo liquor in some way as long as it is based on the disclosure of the present invention. Whether purified from bamboo liquor, it will be predicted that all bamboo liquor has the potential to be effective in increasing the efficacy of taxane-based drugs such as paclitaxel. Those skilled in the art will also appreciate the use of taxane-based drugs, such as paclitaxel, within their usual capabilities, based on the following examples of the present invention and the results (see Table 1, Table 2, FIGS. 1 to 4). It is possible to identify and select bamboo liquor that has an effect of increasing potency.

Therefore, above and below, including the claims, the term "bamboo vinegar" should be understood as including not only those that have been politically aged, filtered, purified, or distilled from the crude bamboo vinegar, but also the crude bamboo vinegar of the previous stage, furthermore, If it is purified from bamboo liquor and has an effect of increasing the efficacy of taxane-based drugs such as paclitaxel, it should be understood as a meaning including such bamboo liquor.

In the pharmaceutical composition of the present invention, the taxane-based drug is meant to include docetaxel as well as parixtaxel. Although the following example of the present invention shows that the bamboo vinegar solution shows an increase in the efficacy of paclitaxel, docetaxel has a similar pharmacological effect as paclitaxel, and its in vivo reaction or pharmacological mechanism is reported to be similar (Crown J. , et al., Oncologist, 9 suppl2, 24-32 (2004)), and both paclitaxel and docetaxel are known to be mainly metabolized by the CYP3A family of enzymes, especially CPA 3A4 (Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, Gueritte F. Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship.Drug Metab Dispos. 2002 Apr; 30 (4): 438-45 ; Marre F, Sanderink GJ, de Sousa G, Gaillard C, Martinet M, Rahmani R. Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans.Cancer Res. 1996 Mar 15; 56 (6): 1296-302 ; Baker SD., Pharmacotherapy, 17 , 126S-132S (1997)) ; Shou M., et al., Pharmacogenetics, 8, 391-401 (1998), which references are hereby incorporated by reference), since both drugs are known to have the effect of inducing CYP3A4. (Nallani SC., Et al., Cancer Chemotherap Pharmacol, 48, 115-122 (2001)), those skilled in the art can predict that bamboo liquor will increase the efficacy of taxane-based drugs, including docetaxel, as well as paclitaxel, Based on Examples 1 and 2 and the results, it can be seen that bamboo liquor increases the efficacy of docetaxel as well as paclitaxel within its usual capacity. Therefore, in the pharmaceutical composition of the present invention, the taxane-based drug should be understood as meaning including docetaxel, although the following examples of the present invention target paclitaxel.

Taxane based drugs, in particular paclitaxel, have been reported to be absorbed very poorly (less than 1%) upon oral administration. Oral administration of paclitaxel has been reported to have a bioavailability of 0% (Eiseman et al. Second NCI Workshop on Taxol and Taxus (1992)), even when administered orally up to 160 mg / kg daily It has been reported that paclitaxel cannot be administered orally because no evidence of tumor activity is found (Eiseman et al. Second NCI Workshop on Taxol and Taxus (1992); Suffness et al. In Taxol Science and Applications (CRC Press 1995)). ). Thus paclitaxel has been used almost exclusively for intravenous injections. The present invention can be confirmed that the plasma concentration of paclitaxel is maintained very high when paclitaxel was orally coadministered with bamboo liquor solution or orally after administration of bamboo liquor pretreatment in the following examples (<Table 1>, <Table 1). 2>, see FIGS. 1 and 2).

This may mean that the pharmaceutical composition of the present invention can be orally administered while containing a taxane-based drug as an active ingredient.

Therefore, the pharmaceutical composition of the present invention is preferably for oral administration.

Taxane-based drugs have generally been used as anticancer drugs, but in recent years Alzheimer's disease (Michaelis ML., Et al., J Mol Neurosci, 19, 101-105 (2002)) or Restenosis (Herdeg) C., et al., J Am Coll Cardiol, 35, 1969-1979 (2000)).

For this reason, above and below, including the claims, the pharmacological effect in the pharmaceutical composition of the present invention should be understood to include not only the pharmacological effect as an anticancer agent, but also all the pharmacological effects of other taxane-based drugs. .

In addition, such a pharmacological effect should be understood as a meaning including not only the pharmacological effect known to date as a pharmacological effect of the taxane-based drug, but also the pharmacological effect of the above-described drug.

Since the pharmaceutical composition of the present invention is characterized by including bamboo vinegar as an efficacy increasing agent of the taxane-based drug, the pharmaceutical composition of the present invention may not only reveal the pharmacological effect known to the present drug but also the pharmacological effect which will be revealed later. Even if included, the scope of the present invention is not unreasonably expanded.

Nevertheless, the pharmacological effect is preferably a pharmacological effect as an anticancer agent in that taxane drugs are still used as anticancer agents such as ovarian cancer, breast cancer, and lung cancer.

In another aspect, the present invention relates to a composition for increasing the efficacy of a taxane-based drug comprising bamboo vinegar.

In one specific aspect, the composition for increasing the efficacy of the taxane-based drug of the present invention is preferably an additive composition of the taxane-based drug.

As confirmed in the following examples of the present invention, when paclitaxel and bamboo vinegar were mixed and orally administered to rats, which are experimental animals, the plasma concentration of paclitaxel increases.

This can be said that the composition for increasing the efficacy of the taxane-based drug containing the bamboo vinegar of the present invention can be usefully used as an additive composition of the taxane-based drug.

On the other hand, the composition for increasing the efficacy of the taxane-based drug of the present invention is preferably a pharmaceutical composition in another specific embodiment.

As shown in the following examples of the present invention, bamboo liquor is shown to increase the plasma concentration of paclitaxel not only when co-administered orally with paclitaxel but also when pretreated orally before paclitaxel is administered.

This means that the composition for increasing the efficacy of the taxane-based drug of the present invention may be administered as a pharmaceutical composition before the taxane-based drug such as paclitaxel is administered.

In addition, the composition for increasing the efficacy of the taxane-based drug of the present invention is preferably for oral administration. As mentioned above, taxane-based drugs, especially paclitaxel, have been formulated almost exclusively by intravenous injection, not by oral preparation. However, in the following examples of the present invention, when paclitaxel was orally coadministered with bamboo liquor or orally after administration of bamboo liquor pretreatment, the plasma concentration of paclitaxel was maintained very high as shown in FIG. 1. This can be said that the pharmaceutical composition for increasing the efficacy of the taxane-based drug of the present invention enables oral administration of the taxane-based drug. For this reason, the pharmaceutical composition for increasing the efficacy of the taxane-based drug of the present invention is also preferably for oral administration.

In another specific embodiment, the composition for increasing the efficacy of the taxane-based drug of the present invention is preferably a food composition.

The food composition of the present invention may be prepared from gums, vitamin complexes, dietary supplements, special nutritional supplements, functional drinks, and the like, and particularly preferably from functional drinks.

In addition to the addition of bamboo vinegar as an active ingredient to the food composition of the present invention, disaccharides such as glucose, monosaccharides such as fructose, maltose, sucrose, or polysaccharides such as dextrin and cyclodextrin may be added, and xylitol, sorbitol, Sugar alcohols such as erythritol may also be added, and sweeteners such as taurine, stevia extract and the like may also be added, and other food additives may be added.

On the other hand, in the above and below, including the claims, the "porridge solution" or "taxane-based drug" should be understood in the same sense as described above for the same reason as described above.

On the other hand, the pharmaceutical compositions of the present invention can be administered orally as described above or via various routes including other transdermal, subcutaneous, intravenous or muscle. In addition, the pharmaceutical compositions of the present invention may be formulated in various formulations, and when formulated, they may be formulated using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants. have. Solid preparations for oral administration include tablets, pills, powders, granules and capsules, and the like, which are prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose and gelatin. . Lubricants may also be used in addition to simple excipients. Liquid preparations for oral administration include suspensions, solvents, emulsions and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances and preservatives May be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol and gelatin may be used.

In the daily dosage of the pharmaceutical compositions of the present invention, a taxane-based drug may be administered at a known dose, and in the case of bamboo vinegar, it is usually divided into one or several times in the range of 0.5 to 30 mg / kg body weight. May be administered. However, since the actual dosage of the pharmaceutical composition of the present invention is determined in view of various related factors such as the route of administration, the age, sex and weight of the patient, and the severity of the patient, the dosage is in any aspect the scope of the present invention. It should not be understood as limiting.

Hereinafter, the present invention will be described with reference to Examples. However, these examples do not limit the scope of the present invention.

<Example 1> Determination of Paclitaxel Blood Concentration by Administering Bamboo Vinegar

Example 1-1 Experimental Method

(1) Sampling Process of Plasma from Experimental Animal

In order to confirm that bamboo liquor solution increases the blood concentration of paclitaxel, the experiment was conducted as follows.

In this experiment, Park Litaxel was supplied and used by Samyang Genex (Daejeon, South Korea), and bamboo liquor was supplied and used by Damyang Tech (Damyang, South Korea).

First, Sprague-Dawley (Sunrise Science, South Korea), weighed around 300 g, was anesthetized with ether, fixed on a stator, and then anesthetized by subcutaneous injection of 4 ml / kg of 25% urethane.

The control group was orally administered suspension prepared by mixing tween 80 in 50 mg / kg of paclitaxel, and in the simultaneous oral group, 0.75, 1.5, 3.0 ml / kg and tween 80 of bamboo liquor solution in 50 mg / kg of paclitaxel. The mixed suspension was orally administered. On the other hand, in the pretreatment oral administration group, 0.75, 1.5, 3.0 ml / kg of bamboo vinegar and tween 80 were respectively mixed and prepared by suspending agent orally, respectively, and after 1 hour, tween 80 was mixed with 50 mg / kg of paclitaxel. Suspension was orally administered, followed by oral administration of a suspension prepared by mixing bamboo vinegar solution 0.75, 1.5, 3.0 ml / kg and tween 80, twice a day for 3 days, and after 1 hour, the paclitaxel of the suspension was administered. Oral administration.

All the above administration groups consisted of 6 rats.

After administration as described above, the polyethylene tube was inserted into the rat femoral artery at 0, 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24 hours, and blood 0.6 ml was collected. At this time, heparin (75 U / ml) was injected into the tube to prevent blood coagulation. The collected blood was centrifuged at 3000 rpm for 5 minutes to collect plasma and stored frozen at -40 ° C until analysis.

(2) Paclitaxel Plasma Concentration Analysis Method

The concentration of paclitaxel in plasma was determined by catharine et al. (N. Manrin, J. Catalin, MF Blachon, A. Durand, J. Chromato. B., 709 , 281-288 (1998)). (H. Mase, M. Hiraoka, F. Suzuki, Yakugaku. Zasshi., 114 , 351-355 (1994)).

100 μl of an internal standard (Butylparaben (Butylparaoxybenzoic Acid), Sigma) (1 μg / ml) was added to 0.25 ml of plasma and mixed for 1 minute with Vortex. Add 4 ml of Tert-Butylmethyl Ether, extract for 15 minutes, and centrifuge at 3000 rpm for 10 minutes. 3.5 ml of organic solvent layer was taken and evaporated under 40 degreeC nitrogen stream. After evaporation, 300 μl of the mobile phase was taken, vortex and sonication were performed for 2 minutes each, centrifuged for 5 minutes, filtered through a 0.22 μm filter paper, and 100 μl was injected into the HPLC.

The HPLC instrument used a Waters 1515 pump, a 717 Plus Autosampler, and a 2487 Dual λ Absorbance Detector, which was separated at room temperature at a wavelength of 227 nm. The column used was Symmetry® C18 5 μm, 4.6 * 150 mm. The composition of the mobile phase was ACN: MeOH: 0.05 mM Phosphoric acid = 45: 10: 45 v / v / v. The flow rate was 1.2 ml / min and the aufs was 0.01. Plasma chromatogram showed good separation of internal standard (Butylparaben) at 5.4 minutes and paclitaxel at 7.5 minutes.

Plasma calibration curve was added to 0.25 ml of plasma from 20, 50, 100, 200 and 500 ng / ml of paclitaxel, and 100 µl of 1 µg / ml of internal standard (Butylparaben) was added to the vortex. After mixing for 1 minute and quantified by the same method as above.

This calibration curve is drawn from the blood y = 100x-0.207 (r = 0.9973).

(3) pharmacokinetic analysis method

Pharmacokinetic parameter analysis was performed using the Lagrange method (ML Rocci, WJ Jusko, LAGRAN program for area and monents in pharmacokinetic analysis, Computer Program in Biomedicine., 16 , 203 (1983)). Program) was used. The area under the blood concentration curve (AUC) was applied to the Trapezoidal Rule. The loss rate constant (Kel) was obtained by regression of four blood concentrations in the lost phase, and the biological half-life (t½) was calculated as 0.693 / kel.

Peak blood concentration (Cmax) and peak blood concentration reaching time (Tmax) were used as actual measurements. The formula for calculating other parameters is as follows.

Absolute Bioavailability (AB%) = Oral AUC / 1V AUC x 1V dose / Oral dose x 100

* Relative Bioavailability = AUC codamin / AUC control x 100

Example 1-2 Experimental Results

(1) Plasma Concentration of Paclitaxel

The average plasma concentrations obtained after oral administration of paclitaxel alone, simultaneous oral administration of bamboo liquor and pretreatment for 1 hour and 3 days in rats are shown in FIGS. 1 and 2. The plasma concentration shown in FIG. 1 and FIG. 2 is an average plasma concentration which is the average of the plasma concentrations of six rats in each administration group. Here, the plasma concentration was not measured in the administration group administered orally administered 0.75 ml / kg of bamboo vinegar, and the plasma concentration was measured only in the remaining groups.

In Figure 1, ○ curve is the plasma concentration curve of the control group orally administered only paclitaxel (50 mg / kg), □ curve is a simultaneous oral administration of 0.75 ml / kg of bamboo vinegar solution and paclitaxel (50 mg / kg) Plasma concentration curve, ■ curve is the plasma concentration curve of oral administration group with 1.5 ml / kg and paclitaxel (50 mg / kg), △ curve 3 ml / kg and paclitaxel (50 mg / kg) Plasma concentration curve of the simultaneous oral administration group).

In Fig. 2, the curve is the plasma concentration curve of oral administration group with 1.5 ml / kg of bamboo liquor and paclitaxel (50 mg / kg) (in Fig. 1, the curve corresponds), and the curve is 1.5 ml / kg of bamboo liquor. The plasma concentration curve of the pretreatment oral group administered orally with paclitaxel (50 mg / kg) after oral pretreatment for 1 hour, and □ curve after the oral administration of 3 ml / kg of bamboo liquor solution for 1 hour orally with paclitaxel (50 mg / kg) orally administered plasma concentration curve of pretreatment oral group. ■ Curves of pretreatment oral group administered oral administration of paclitaxel (50 mg / kg) after 1.5 ml / kg of bamboo liquor solution for 3 days. Plasma concentration curve, △ curve is the plasma concentration curve of the pretreatment oral administration group oral administration of paclitaxel (50 mg / kg) after oral administration of 3 ml / kg of bamboo vinegar for 3 days.

Compared with the control group, rats administered 0.75 ml / kg and 1.5 ml / kg of bamboo vinegar did not show significant changes in plasma concentrations of paclitaxel, but rats treated with 3.0 ml / kg of bamboo vinegar were 1 hour to 24 hours. Significantly increased by time (p <0.05). Plasma concentrations of paclitaxel increased significantly (p <0.05, 1 hour pretreatment, p <0.01 3 days pretreatment) from 1 hour to 24 hours in rats treated with 1 or 3 days pretreatment.

(2) pharmacokinetic parameters of paclitaxel

The analyzed pharmacokinetic parameters are shown in Table 1 and Table 2. The pharmacokinetic parameters and bioavailability of intravenous and oral administration were compared. The area under the plasma concentration curve (AUC) was significantly increased (p <0.05) to 2351 ± 639 ng / ml · hr only in the group orally administered 3 ml / kg of bamboo vinegar and paclitaxel (50 mg / kg). . Plasma concentration curve in 3 ml / kg 1-hour pretreatment oral administration of 2639 ± 659 ng / ml · hr, 3 ml / kg 3 seconds / day of bamboo liquor solution in 3398 ± 853 ng / Significantly increased in ml · hr (p <0.05, 1 hour pretreatment, p <0.01, 3 days pretreatment). The maximum plasma concentration (C _max ) in the pretreatment oral group was 137 ± 34 ng / ml in 3 ml / kg bamboo liquor 1 hour pretreatment oral group, and 153 ± 41 ng in 3 ml / kg bamboo liquor 3 day in pretreatment oral administration group. It increased to / ml, but significance (p <0.05) was verified only in the 3 days pretreatment oral group.

The loss rate constant (Kel) in the pretreatment group was 0.056 ± 0.014 hr ^-1 in 3 ml / kg bamboo vinegar 1 hour pretreatment oral group, and 0.049 ± 0.012 hr ^-1 in 3 days of pretreatment oral group in 3 ml / kg bamboo vinegar solution 3 Significant increase (p <0.05) was observed only in the daily pretreatment oral group.

The half-life (t½) was decreased in the pretreatment oral group compared to the control group. Only group was significantly extended (p <0.05).

Absolute bioavailability (AB%) in the control group was 2.1%, which was significantly (2.6%, p <0.05) increased only in the 3 ml / kg oral administration group. Compared with the control group, 3.2 ml of 3 ml / kg bamboo herb solution for 1 hour pretreatment orally treated group increased significantly to 3.2% and 3 ml / kg bamboo herb solution for 3 days pretreated orally group for 3.9% (p <0.05 1 hour treatment, p <0.01 3 days treatment). It became.

Significantly decreased loss rate constant (Kel) and significantly longer half-life (t½) in the group treated with bamboo liquor compared to the control group, suggesting that bamboo liquor may affect cytochrome P450 monooxinase, especially CYP3A4. This can be combined with the administration of bamboo liquor in patients receiving anti-cancer therapy of paclitaxel, and may be considered to increase the bioavailability of paclitaxel.

Mean ± S.D. (n = 6), * p <0.05 compared to control

AUC: Area Under the Plasma Concentration-time Curve

Cmax: Peak Concentration

Tmax: Time to Reach Peak Concentration

Kel: Elimination Rate Constant

t½: half-life

AB (%): Absolute Bioavailability

RB (%): Relative Bioavailability

Mean ± S.D. (n = 6), * p <0.05, ** p <0.01 compared to control

AUC: Area Under the Plasma Concentration-time Curve

Cmax: Peak Concentration

Tmax: Time to Reach Peak Concentration

Kel: Elimination Rate Constant

t½: half-life

AB (%): Absolute Bioavailability

RB (%): Relative Bioavailability

<Example 2> Change in the expression level of CYP3A protein by administration of bamboo vinegar

Example 2-1 Experimental Method

Liver and kidney tissues of rats were washed twice with sterile Phosphate-Buffered Saline in each administration group, crushed with a tissue mill and centrifuged with a centrifuge to separate cytoplasm and microsomes. SDS-polyacrylamide gel electrophoresis and immunological analysis (Immunoblot Analysis) were performed by previously reported methods. Each protein was separated by 10% gel electrophoresis, transferred to nitrocellulose paper, blocked with skimmed milk, and the nitrocellulose paper was reacted with CYP3A1 and 3A4 antibodies. It was reacted with the secondary antibody and developed by ECL chemiluminescence.

Example 2-2 Experimental Results

As a result of the above experiment, it was confirmed that the expression level of CYP3A4 in both liver and kidney was reduced by the administration of bamboo herb solution (FIGS. 3 and 4). In addition, the expression of CYP3A1 was decreased in the same manner by the administration of bamboo vinegar and the inhibitory effect was obvious in the simultaneous oral administration group (FIGS. 3 and 4). The amount of actin in each tissue was used as the loading control of the sample. This result clearly shows that administration of bamboo liquor affects the expression of cytochrome P450 3A family of enzymes, thereby inhibiting the metabolic process of paclitaxel and causing an increase in blood levels in FIGS. 1 and 2.

As described above, according to the present invention, a pharmaceutical composition comprising taxane-based drug as an active ingredient and comprising bamboo herb solution as an efficacy increasing agent of the taxane-based drug, and for increasing the efficacy of a taxane-based drug comprising bamboo-choice solution as an active ingredient A composition can be provided.

In the present invention, bamboo liquor has the effect of increasing the plasma concentration of the taxane-based drug and prolonging the time maintained in the plasma of the taxane-based drug to increase the efficacy in vivo of the carbonic acid-based drug.

Claims (14)

delete A pharmaceutical composition for preventing or treating cancer, comprising paclitaxel as an active ingredient and bamboo shoot liquid as an efficacy increasing agent of the paclitaxel. A pharmaceutical composition comprising docetaxel as an active ingredient, bamboo shoot liquid as an increase in potency of the docetaxel, and preventing or treating cancer. The method according to claim 2 or 3, The pharmaceutical composition is a pharmaceutical composition, characterized in that for oral administration. delete A composition for increasing the efficacy of paclitaxel or docetaxel, characterized in that it comprises bamboo herb solution. The method of claim 6, The composition is a composition for increasing the efficacy of paclitaxel or docetaxel, characterized in that the additive composition of paclitaxel or docetaxel. The method of claim 6, The composition for increasing the efficacy of paclitaxel or docetaxel, characterized in that the pharmaceutical composition The method of claim 6, The composition is a pharmaceutical composition, the pharmaceutical composition for increasing the efficacy of paclitaxel or docetaxel, characterized in that for oral administration. delete delete The method of claim 6, The composition is a composition for increasing the efficacy of paclitaxel or docetaxel, characterized in that the food composition. The method of claim 6, The composition is a food composition, the composition for increasing the efficacy of paclitaxel or docetaxel, characterized in that the food composition is a functional beverage. Includes paclitaxel as an active ingredient and bamboo shoot liquor as an potency increasing agent of paclitaxel, The bamboo vinegar solution is cooled and left to smoke the bamboo obtained by carbonization, and separated into the upper hard oil layer, the middle layer of bamboo vinegar liquid layer and the lower tar layer, and removes the upper hard oil layer and the lower tar layer from the three layers thus separated. And obtained by taking the middle layer of bamboo vinegar liquid, Pharmaceutical composition for preventing or treating cancer.

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