WO2006019272A1 - Use of bamboo smoke distillate for enhancing bioavailability of taxane family drug - Google Patents

Use of bamboo smoke distillate for enhancing bioavailability of taxane family drug Download PDF

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Publication number
WO2006019272A1
WO2006019272A1 PCT/KR2005/002721 KR2005002721W WO2006019272A1 WO 2006019272 A1 WO2006019272 A1 WO 2006019272A1 KR 2005002721 W KR2005002721 W KR 2005002721W WO 2006019272 A1 WO2006019272 A1 WO 2006019272A1
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Prior art keywords
paclitaxel
composition
bamboo
taxane family
distillate
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PCT/KR2005/002721
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French (fr)
Inventor
Jun-Shik Choi
Keon-Wook Kang
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Damyanggun
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/12—Chewing gum characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention is related to a use of bamboo concentrate (bamboo smoke distillate, Bambusae Caulis in Liquamen, jukcho solution; 'BSD') for enhancing bioavailability of a drug in the taxane family. More specifically, the present invention relates to a pharmaceutical composition comprising a drug in the taxane family as an effective agent and bamboo smoke distillate as an enhancer for its bioavailability or a composition for enhancing bioavailability of a drug in the taxane family comprising bamboo smoke distillate as an effective agent.
  • bamboo concentrate biboo smoke distillate, Bambusae Caulis in Liquamen, jukcho solution
  • 'BSD' bamboo smoke distillate
  • Paclitaxel is a member of a family of diterpene with a very complex structure having more than 20 chiral centers. Since research on paclitaxel was begun by National Cancer Institute (US), which performed a large-scale screening program about 35,000 kinds of plants in 1960, it has been reported that extracts from Taxus brevifolia have activity on various tumors including leukemia and lung cancer. In 1969, an active ingredient was separated into paclitaxel and its structure was verified in 1971 (Eric K. Rowinsky et al., J. National Can. Inst., 82, 11247 (1990)).
  • paclitaxel is reported to follow a different mechanism, i.e. expediting microtubule assembly and inhibiting degradation of tubuline (Schiff, P. B., J. Fant and S. B. Horwitz, Nature, 277, 665 (1979)).
  • Paclitaxel was approved by FDA as an anticancer agent in 1993, and has been reported to an anticancer activity on ovarian cancer, breast cancer, leukemia, melanoma and prostate cancer, and especially to have high cure rate of 30%, 50% and 20% about ovarian cancer, breast cancer and lung cancer, respectively (David, G., et al., J. Nat. Prod.,
  • docetaxel also expedites microtubule assembly and inhibits degradation of tubuline, thereby keeping cells in M step and inhibiting cell division (Katzung's Pharmacology, 9th Edition (2004)).
  • Docetaxel a drug noted as a next generation anticancer agent, has been also reported to have an anticancer activity on lung cancer and breast cancer (Piccart, M. Anticancer Drugs. 1995 Suppl 4:7-11).
  • 'Bambusae Caulis in Liquamen' or 'jukcho solution' or abbreviated 'BSD' refers to transparent reddish brown liquid prepared by condensation of smoke generated during carbonization of bamboo, followed by settling down and aging, or filtrating and purifying, or distilling the condensates.
  • Upper layer is light oil layer comprising terpene oil
  • middle layer is crude bamboo vinegar layer
  • lower layer is tar layer.
  • Commercially available bamboo smoke distillate is obtained by settling down and aging, or filtrating and purifying, or distilling this crude bamboo vinegar solution.
  • the bamboo smoke distillate is currently used for an antibacterial enhancer, an insecticide enhancer, or an inhibitor for plant growth, and is still being attempted for a new use.
  • the present inventors have made extensive and intensive researches and have found that the plasma concentrations of paclitaxel, a drug in the taxane family, was remarkably enhanced when orally administered with or pretreated with bamboo smoke distillate.
  • One aspect of the present invention is related to a use of bamboo smoke distillate for enhancing bioavailability of a drag in the taxane family.
  • Another aspect of the present invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising a drug in the taxane family as an effective agent and bamboo smoke distillate as an enhancer for its bioavailability.
  • Still another aspect of the present invention is related to a composition for enhancing bioavailability of a drag in the taxane family comprising bamboo smoke distillate as an effective agent.
  • TECHNICAL SOLUTION One aspect of the present invention is related to a pharmaceutical composition comprising a drug in the taxane family as an effective agent and bamboo smoke distillate as an enhancer for its bioavailability.
  • the present inventors verified that the paclitaxel plasma concentration in rats was significantly enhanced by oral co-administration of paclitaxel together with bamboo smoke distillate or oral pretreatment of bamboo smoke distillate followed by oral administration of paclitaxel, as compared with administration of paclitaxel alone. Further, according to analysis of pharmacokinetic parameters, area under plasma concentration-time curves (AUC), peak concentration (Cmax), absolute bioavailability (AB%) and elimination half life (t 1 /.) increased in groups with such co-treatment or pretreatment, while elimination rate constant (KeI) decreased (Examples, Tables 1 & 2, Figures 1 & 2 herein).
  • bamboo smoke distillate has an activity of elevating plasma concentration or extending plasma residence time of paclitaxel, thereby enhancing bioavailability of paclitaxel.
  • bamboo smoke distillate elevates plasma concentration or extends plasma residence time of paclitaxel.
  • it was found that such oral co-treatment or pretreatment of bamboo smoke distillate decreases the expression levels of CYP3A4 and CYP3A1 among enzymes in cytochrome P450 3 A family, which were known to degrade various drugs including paclitaxel and weaken their activity in a body (Sonnichsen DS, Liu Q, Schuetz EG, Schuetz JD, Pappo A, Relling MV, J. Pharmacol. Exp. Ther., 275, 566-571 (1995)).
  • Paclitaxel is known to be degraded by enzymes in CYP3A family (Katzung's Pharmacology, 9th Edition (2004); Dorr RT, Pharmacotherapy, 17, 96S-104S (1997)), specifically by enzymes in CYP3A4, while enhancing the expression of such enzymes (Monsarrat B., et al., Drug Metab Dispos, 26, 229-233 (1998)). From the aforementioned results and prior reports, it is certain that bamboo smoke distillate elevates plasma concentration or extends plasma residence time of paclitaxel by affecting the expression of such enzyme and inhibiting metabolism of paclitaxel.
  • one aspect of the present invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising a drug in taxane family as an effective agent and also bamboo smoke distillate as an enhancer for its bioavailability.
  • the bamboo smoke distillate herein is preferred to be the one prepared by the aforementioned method (i.e. by settling down and aging, or filtering and purifying, or distilling the crude bamboo vinegar), the crude bamboo vinegar per se may also satisfy the object of the present invention.
  • the crude bamboo vinegar may also show a desired activity of the present invention, be it different in its degree, based on Examples 1 & 2 herein and the results (Tables 1 & 2 and Figures 1-4).
  • 'Bambusae Caulis in Liquamen', or 'bamboo concentrate' or 'jukcho solution' is meant to include liquid prepared by condensation of smoke generated during carbonization followed by settling down and aging, or filtering and purifying, or distilling the condensate; the crude bamboo vinegar per se; and bamboo smoke distillate prepared from the crude bamboo by any other methods.
  • Representative examples of the drug in the taxane family include, but are not limited to, docetaxel as well as paclitaxel.
  • drugs in the taxane family is known to be absorbed very insufficiently (less than 1%) when administered orally.
  • paclitaxel has 0% (zero percent) bioavailability after oral intake (Eiseman et al. 2nd NCI Workshop on Taxol and Taxus (1992)).
  • paclitaxel may not be orally administered because there is no evidence that it has no anti-inflammation activity up to 160 mg/kg (Eiseman et al. 2nd NCI Workshop on Taxol and Taxus (1992); Suffiiess et al. in Taxol Science and Applications (CRC Press 1995)).
  • paclitaxel has usually been administered by intravenous injection.
  • a biological activity of a pharmaceutical composition herein should be understood to include any other activity of a drug in the taxane family as well as anticancer activity. Further, a biological activity of a pharmaceutical composition herein should also be understood to include any other activity of such a drug to be verified in the future, let alone already known activity. Because the present invention is related to a composition comprising bamboo smoke distillate as an enhancer of an activity of drugs in the taxane family, such incorporation of activity to be verified in the future does not excessively extend the scope of the present invention.
  • a biological activity of a pharmaceutical composition herein is preferred to be anticancer activity, when considering that drugs in the taxane family are currently used as an anticancer agent for ovarian cancer, breast cancer, lung cancer, etc.
  • Another aspect of the present invention is related to a composition for enhancing bioavailability of a drug in the taxane family comprising bamboo smoke distillate as an effective agent.
  • the composition for enhancing bioavailability of a drug in the taxane family is preferred to be an additive composition for a drug in taxane family.
  • composition for enhancing bioavailability of a drug in the taxane family may be usefully used as an additive composition for such a drug in taxane family.
  • the composition for enhancing bioavailability of a drug in the taxane family is preferred to be a pharmaceutical composition.
  • the pretreatment of bamboo smoke distillate herein or the co-treatment of bamboo smoke distillate along with paclitaxel increased plasma concentration of paclitaxel. This result shows that the composition for enhancing bioavailability of a drug in the taxane family may be administered before the administration of the taxane family drug in the form of a pharmaceutical composition.
  • composition for enhancing bioavailability of a taxane family drug is preferred to be for oral administration.
  • paclitaxel are has been prepared as formulations for intravenous injection instead of oral formulations.
  • plasma concentration of paclitaxel is maintained very high by oral co-administration along with bamboo smoke distillate or oral pre-treatment of bamboo smoke distillate as in Figure 1.
  • the pharmaceutical composition for enhancing bioavailability of a taxane family drug is also preferred to be for oral administration.
  • the composition for enhancing bioavailability of a taxane family drug is preferred to be a food composition.
  • Representative examples of a food composition of the present invention include, but are not limited to, chewing gum, vitamin complex, health supplemental food, nutrient-promoting composition and preferably functional drink.
  • the food composition may further comprise monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose and polysaccharides such as dextrin and cyclodextrin, sugar alcohol such as xylitol, sorbitol and erythritol, a sweetening agent such as taurin and stevia extract, and other food additives.
  • monosaccharides such as glucose and fructose
  • disaccharides such as maltose and sucrose
  • polysaccharides such as dextrin and cyclodextrin
  • sugar alcohol such as xylitol
  • sorbitol and erythritol sorbitol and erythritol
  • a sweetening agent such as taurin and stevia extract
  • a pharmaceutical composition herein may be administered by various routes such as oral, transdermal, subcutaneous, intranasal, intravenous and intramuscular route. Further, a pharmaceutical composition herein may be prepared into various formulations by incorporating pharmaceutically or pharmacologically acceptable conventional additives such as a filler, a bulking agent, a binder, a moistening agent, a disintegrating agent, a diluent such as a surfactant, and an excipient.
  • Representative examples of solid formulations for oral administration include, but are not limited to, a tablet, a pill, powder, granule and a capsule. The solid formulations are prepared by admixing at least one excipient such as starch, calcium carbonate, sucrose, lactose and gelatin, and a lubricant may also be included.
  • liquid formulations for oral administration include, but are not limited to, a suspension form, an internal solution form, an emulsion form and a syrup.
  • the liquid formulations may be prepared by adding widely used simple diluent such as water and liquid paraffin, and other excipients such as an moistening agent, an sweetening agent, fragrance and preservative may also be included.
  • non-oral formulations include, but are not limited to, a sterilized aqueous solution, a non-aqueous form, a suspension form, an emulsion form, a freeze-dried form and a suppository form.
  • Propylene glycol, poly(ethylene glycol), vegetable oil such as olive oil and injectable ester such as ethyl oleate may be used for non-aqueous form and suspension form.
  • As suppository bases Witepsol, macrogol, Tween 61, cacao paper, laurin paper, glycerol and gelatin may be used. Drugs in the taxane family may be administered according to appropriate dosage level as already known.
  • bamboo smoke distillate is preferred to be administered once or several times a day within a dose of 0.5-30 mg/kg body-weight.
  • appropriate dosage level of the pharmaceutical composition herein may be determined by considering various information such as formulation method, administration type, age, body weight, sex, physical conditions food, administration time and route, excretion and reaction sensitivity. Physicians with average skill may easily determine and diagnose dosage level of medicine effective for treating or preventing target disorders or diseases. Therefore, the aforementioned dose should be understood, in no way, to limit the scope of the present invention.
  • the present invention provides a pharmaceutical composition comprising a drug in taxane family, as an effective agent, and bamboo smoke distillate as an enhancer for its bioavailability, along with a composition for enhancing bioavailability of a drug in taxane family comprising bamboo smoke distillate as an effective agent.
  • bamboo smoke distillate extends maintenance time of a taxane family drug in plasma, thus having an activity of enhancing the bioavailability of a taxane family drug.
  • Figure 1 is a graph showing plasma concentration of paclitaxel in rats (oral co-treatment with paclitaxel and bamboo smoke distillate).
  • Figure 2 is a graph showing plasma concentration of paclitaxel in rats (oral pretreatment with bamboo smoke distillate followed by oral administration of paclitaxel).
  • Figure 3 is an electrophoresis photograph showing expression levels of CYP3A1 and CYP3A4 in liver of rats (oral co-treatment & oral pretreatment).
  • Figure 4 is an electrophoresis photograph showing expression levels of CYP3A1 and CYP3A4 in kidney of rats (oral co-treatment & oral pretreatment).
  • Example 1-1 Experiment methods
  • Rats in a control group were orally administered with suspension comprising 50 mg/kg of paclitaxel and tween 80.
  • Rats in three co-treatment groups were orally administered with suspension admixed with 50 mg/kg of paclitaxel, tween 80 and 0.75, 1.5 and 3.0 mL/kg of bamboo smoke distillate, respectively.
  • rats in the three pretreatment groups were orally administered with suspension of tween 80 and 0.75, 1.5 and 3.0 mL/kg of bamboo smoke distillate, respectively, followed by oral administration of suspension of 50 mg/kg of paclitaxel and tween 80 after 1 hour. 0, 0.25, 0.5, 1, 2, 3, 4, 8, 12 and 24 hours after the administration, blood samples
  • Concentration of paclitaxel in plasma was measured according to a revised method based on Catalin et al. (N. Manrin, J. Catalin, M.F. Blachon, A. Durand, J. Chromato. B., 709, 281-288 (1998)) and Mase et al. (H. Mase, M. Hiraoka, F. Suzuki, Yakugaku. Zasshi., 114, 351-355 (1994).
  • Calibration curve was established by adding 20, 50, 100, 200 and 500 ng/niL of paclitaxel and i ⁇ m/mL of butylparaben to 0.25 mL of plasma, followed by vortex for 1 minute and quantification as set forth above.
  • LAGRAN computer program according to Lagrange et al. (M.L. Rocci, WJ. Jusko, LAGRAN program for area and monents in pharmacokinetic analysis, Computer Program in
  • AUCs area under plasma concentration-time curves
  • Example 1-2 Experiment Results 1. Plasma concentration of paclitaxel
  • Plasma concentrations in Figures 1 & 2 are average values of concentrations of 6 rats in each group. However, plasma concentrations were not measured in 0.75 mL/kg pretreatment group.
  • the o-curve is a plasma concentration curve of a control group administered with 50 mg/kg paclitaxel alone;
  • the ⁇ -curve is a plasma concentration curve of a co-treatment group (0.75 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel);
  • the B-curve is a plasma concentration curve of a co-pretreatment group (1.5 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel);
  • the ⁇ -curve is a plasma concentration curve of a co-treatment group (3 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel).
  • the • -curve is a plasma concentration curve of a co-treatment group (1.5 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel), which corresponds to the ⁇ -curve in Figure 1;
  • the o-curve is a plasma concentration curve of a pretreatment group (pretreatment of 1.5 mL/kg bamboo smoke distillate for 1 hour, followed by oral administration of 50 mg/kg paclitaxel;
  • the ⁇ -curve is a plasma concentration curve of a pretreatment group (1-hour pretreatment of 3 mL/kg bamboo smoke distillate, followed by oral administration of 50 mg/kg paclitaxel;
  • the ⁇ -curve is a plasma concentration curve of a pretreatment group (pretreatment of 1.5 mL/kg bamboo smoke distillate for 3 days, followed by oral administration of 50 mg/kg paclitaxel);
  • the ⁇ -curve is a plasma concentration curve of a pretreatment group (3 -day pretreatment of 3 mL/kg bamboo smoke distillate,
  • the two co-treatment groups (0.75 mL/kg and 1.5 mL/kg of bamboo smoke distillate, respectively) showed no significant difference in paclitaxel plasma concentration.
  • the co-treatment group (3.0 mL/kg of bamboo smoke distillate) showed significant difference from 1 hour to 24 hours (p ⁇ 0.05).
  • the two pretreatment groups (1-hour and 3-day pretreatment, respectively) also showed significant difference from 1 hour to 24 hours (p ⁇ 0.05, 1-hour pretreatment, p ⁇ 0.01 3-day pretreatment).
  • Pharmacokinetic parameters are provided in Tables 1 & 2. Especially, bioavailability was compared between intravenous injection and oral administration. As compared with the control group, among co-treatment groups, only the co-treatment group (3 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel) showed a significant increase in AUC up to 2351 ⁇ 639 ng/mL-hr (p ⁇ 0.05). The two pretreatment groups (1-hour and 3 -day pretreatment of 3 mL/kg bamboo smoke distillate, respectively) also showed significant increases in AUC up to 2639 ⁇ 659 ng/mL-hr and 3398 ⁇ 853 ng/mL-hr, respectively (p ⁇ 0.05, 1-hour pretreatment, p ⁇ 0.01, 3-day pretreatment).
  • KeI decreased and X 1 A was extended with statistical significance in groups administered with bamboo smoke distillate showed a possibility that bamboo smoke distillate may act on cytochrome P450 monoxidase, especially CYP3A4. Therefore, a combinatory administration of bamboo smoke distillate may be applied to a patient who is under anticancer treatment with paclitaxel, thereby enhancing bioavailability of paclitaxel.
  • AUC Area under the plasma concentration-time curve Cmax: Peak concentration Tmax: Time to reach peak concentration KeI: Elimination rate constant
  • Tissues from liver and kidney of rats in each group were separated, washed twice with sterilized phosphate-buffered saline and ground with tissue grinder, followed by centrifuge, and then cytoplasm and microsome were separated. SDS-polyacrylaminde gel electrophoresis and immunoblot analysis were performed according to known methods. After each protein was separated with 10% gel electrophoresis, transferred to nitrocellulose paper, followed by blocking with skim milk, the nitrocellulose paper was reacted with CYP3A1 and 3A4 antibodies and also with selective secondary antibody, and then developed by ECL chemillumiescence.

Abstract

Disclosed is the use of bamboo smoke distillate for enhancing bioavailability of a taxane family drug. Particularly, this invention discloses a pharmaceutical composition comprising a taxane family drug as an effective agent and bamboo smoke distillate as an enhancer for its bioavailability, and a composition for enhancing bioavailability of a taxane family drug comprising bamboo smoke distillate as an effective agent.

Description

SPECIFICATION
USE OF BAMBOO SMOKE DISTILLATE
FOR ENHANCING BIOAVAILABILITY OF TAXANE FAMILY DRUG
TECHNICAL FIELD
The present invention is related to a use of bamboo concentrate (bamboo smoke distillate, Bambusae Caulis in Liquamen, jukcho solution; 'BSD') for enhancing bioavailability of a drug in the taxane family. More specifically, the present invention relates to a pharmaceutical composition comprising a drug in the taxane family as an effective agent and bamboo smoke distillate as an enhancer for its bioavailability or a composition for enhancing bioavailability of a drug in the taxane family comprising bamboo smoke distillate as an effective agent.
RELATED PRIOR ART
Representative examples of drugs in the taxane family include paclitaxel (taxol) and docetaxel (taxotere). Paclitaxel is a member of a family of diterpene with a very complex structure having more than 20 chiral centers. Since research on paclitaxel was begun by National Cancer Institute (US), which performed a large-scale screening program about 35,000 kinds of plants in 1960, it has been reported that extracts from Taxus brevifolia have activity on various tumors including leukemia and lung cancer. In 1969, an active ingredient was separated into paclitaxel and its structure was verified in 1971 (Eric K. Rowinsky et al., J. National Can. Inst., 82, 11247 (1990)).
While other anticancer agents such as colchicines and vinca alkaloid shows an anticancer activity by degrading microtubule, paclitaxel is reported to follow a different mechanism, i.e. expediting microtubule assembly and inhibiting degradation of tubuline (Schiff, P. B., J. Fant and S. B. Horwitz, Nature, 277, 665 (1979)).
Paclitaxel was approved by FDA as an anticancer agent in 1993, and has been reported to an anticancer activity on ovarian cancer, breast cancer, leukemia, melanoma and prostate cancer, and especially to have high cure rate of 30%, 50% and 20% about ovarian cancer, breast cancer and lung cancer, respectively (David, G., et al., J. Nat. Prod.,
53, 1 (1990)).
Meanwhile, docetaxel also expedites microtubule assembly and inhibits degradation of tubuline, thereby keeping cells in M step and inhibiting cell division (Katzung's Pharmacology, 9th Edition (2004)). Docetaxel, a drug noted as a next generation anticancer agent, has been also reported to have an anticancer activity on lung cancer and breast cancer (Piccart, M. Anticancer Drugs. 1995 Suppl 4:7-11).
Meanwhile, as used herein, 'bamboo smoke distillate' or 'bamboo concentrate' or
'Bambusae Caulis in Liquamen' or 'jukcho solution' or abbreviated 'BSD' refers to transparent reddish brown liquid prepared by condensation of smoke generated during carbonization of bamboo, followed by settling down and aging, or filtrating and purifying, or distilling the condensates.
The smoke generated during carbonization of bamboo, after condensation, becomes separated into three layers. Upper layer is light oil layer comprising terpene oil, middle layer is crude bamboo vinegar layer, and lower layer is tar layer. Commercially available bamboo smoke distillate is obtained by settling down and aging, or filtrating and purifying, or distilling this crude bamboo vinegar solution. The bamboo smoke distillate is strong acid (pH = 2.8-3.1), and comprises, as a main ingredient, organic acids such as acetic acid and formic acid, and may further comprises phenols. The bamboo smoke distillate is currently used for an antibacterial enhancer, an insecticide enhancer, or an inhibitor for plant growth, and is still being attempted for a new use.
Under such circumstances, the present inventors have made extensive and intensive researches and have found that the plasma concentrations of paclitaxel, a drug in the taxane family, was remarkably enhanced when orally administered with or pretreated with bamboo smoke distillate.
DISCLOSURE
TECHNICAL PROBLEM One aspect of the present invention is related to a use of bamboo smoke distillate for enhancing bioavailability of a drag in the taxane family.
Another aspect of the present invention is related to a pharmaceutical composition comprising a drug in the taxane family as an effective agent and bamboo smoke distillate as an enhancer for its bioavailability. Still another aspect of the present invention is related to a composition for enhancing bioavailability of a drag in the taxane family comprising bamboo smoke distillate as an effective agent.
TECHNICAL SOLUTION One aspect of the present invention is related to a pharmaceutical composition comprising a drug in the taxane family as an effective agent and bamboo smoke distillate as an enhancer for its bioavailability.
The present inventors verified that the paclitaxel plasma concentration in rats was significantly enhanced by oral co-administration of paclitaxel together with bamboo smoke distillate or oral pretreatment of bamboo smoke distillate followed by oral administration of paclitaxel, as compared with administration of paclitaxel alone. Further, according to analysis of pharmacokinetic parameters, area under plasma concentration-time curves (AUC), peak concentration (Cmax), absolute bioavailability (AB%) and elimination half life (t1/.) increased in groups with such co-treatment or pretreatment, while elimination rate constant (KeI) decreased (Examples, Tables 1 & 2, Figures 1 & 2 herein).
These results showed that bamboo smoke distillate has an activity of elevating plasma concentration or extending plasma residence time of paclitaxel, thereby enhancing bioavailability of paclitaxel.
Meanwhile, the present inventors have performed experiments to determine the mechanism, based on which bamboo smoke distillate elevates plasma concentration or extends plasma residence time of paclitaxel. As a result, it was found that such oral co-treatment or pretreatment of bamboo smoke distillate decreases the expression levels of CYP3A4 and CYP3A1 among enzymes in cytochrome P450 3 A family, which were known to degrade various drugs including paclitaxel and weaken their activity in a body (Sonnichsen DS, Liu Q, Schuetz EG, Schuetz JD, Pappo A, Relling MV, J. Pharmacol. Exp. Ther., 275, 566-571 (1995)). Paclitaxel is known to be degraded by enzymes in CYP3A family (Katzung's Pharmacology, 9th Edition (2004); Dorr RT, Pharmacotherapy, 17, 96S-104S (1997)), specifically by enzymes in CYP3A4, while enhancing the expression of such enzymes (Monsarrat B., et al., Drug Metab Dispos, 26, 229-233 (1998)). From the aforementioned results and prior reports, it is certain that bamboo smoke distillate elevates plasma concentration or extends plasma residence time of paclitaxel by affecting the expression of such enzyme and inhibiting metabolism of paclitaxel.
Therefore, one aspect of the present invention is related to a pharmaceutical composition comprising a drug in taxane family as an effective agent and also bamboo smoke distillate as an enhancer for its bioavailability.
Although the bamboo smoke distillate herein is preferred to be the one prepared by the aforementioned method (i.e. by settling down and aging, or filtering and purifying, or distilling the crude bamboo vinegar), the crude bamboo vinegar per se may also satisfy the object of the present invention. Thus, as long as bamboo smoke distillate is prepared by purifying crude bamboo vinegar and exhibits an activity of enhancing bioavailability of paclitaxel, one skilled in the art may expect and easily verify that crude bamboo vinegar may also show a desired activity of the present invention, be it different in its degree, based on Examples 1 & 2 herein and the results (Tables 1 & 2 and Figures 1-4).
Further, one skilled in the art may also expect and easily verify, from the disclosure herein, that the effect of the present invention may be accomplished by using bamboo smoke distillate prepared from the crude bamboo vinegar by other methods than the aforementioned ones. Furthermore, one skilled in the art may easily determine and select an appropriate bamboo smoke distillate having a desired activity of the present invention based on the disclosure herein. Therefore, despite the earlier definitions, the terms of 'bamboo smoke distillate' or
'Bambusae Caulis in Liquamen', or 'bamboo concentrate' or 'jukcho solution', as used herein, is meant to include liquid prepared by condensation of smoke generated during carbonization followed by settling down and aging, or filtering and purifying, or distilling the condensate; the crude bamboo vinegar per se; and bamboo smoke distillate prepared from the crude bamboo by any other methods. Representative examples of the drug in the taxane family include, but are not limited to, docetaxel as well as paclitaxel. Although the following Examples showed only the enhancement of paclitaxel by bamboo smoke distillate, one skilled in the art may expect and easily verify that the effect of the present invention may be also accomplished by using docetaxel instead of paclitaxel, based on Examples herein and common knowledge in the art, because it is known that docetaxel shows similar biological activity, response and mechanism in a body to those of paclitaxel (Crown J., et al., Oncologist, 9 suppl2, 24-32 (2004)), both paclitaxel and docetaxel are metabolized mainly enzymes in the CYP3A family, especially CYA3A4, (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), and both paclitaxel and docetaxel have activity of inducing CYP3A4 (Nallani SC, et al., Cancer Chemotherap Pharmacol, 48, 115-122 (2001)), which documents were incorporated herein by reference. Therefore, the drug in the taxane family herein should be understood to include docetaxel as well, although the non-liming Examples herein use only paclitaxel. Meanwhile, drugs in the taxane family, especially paclitaxel, is known to be absorbed very insufficiently (less than 1%) when administered orally. For example, it was reported that paclitaxel has 0% (zero percent) bioavailability after oral intake (Eiseman et al. 2nd NCI Workshop on Taxol and Taxus (1992)). Further, it has also been reported that paclitaxel may not be orally administered because there is no evidence that it has no anti-inflammation activity up to 160 mg/kg (Eiseman et al. 2nd NCI Workshop on Taxol and Taxus (1992); Suffiiess et al. in Taxol Science and Applications (CRC Press 1995)). For this reason, paclitaxel has usually been administered by intravenous injection.
However, in the following Examples herein, it was verified that plasma concentration of paclitaxel is maintained very high by oral co-administration along with bamboo smoke distillate or oral pre-treatment of bamboo smoke distillate (Tables 1 & 2, Figures 1 & 2). This result shows that n comprising drugs in the taxane family may be orally administered. Therefore, a pharmaceutical composition according to the present invention is preferred to be for oral administration. Meanwhile, drugs in the taxane family have been used for an anticancer agent, and have recently been reported to have an activity on Alzheimer's disease (Michaelis ML., et al, J MoI Neurosci, 19, 101-105 (2002)) or restenosis (Herdeg C, et al.s J Am Coll Cardiol, 35, 1969-1979 (2000)).
Therefore, a biological activity of a pharmaceutical composition herein should be understood to include any other activity of a drug in the taxane family as well as anticancer activity. Further, a biological activity of a pharmaceutical composition herein should also be understood to include any other activity of such a drug to be verified in the future, let alone already known activity. Because the present invention is related to a composition comprising bamboo smoke distillate as an enhancer of an activity of drugs in the taxane family, such incorporation of activity to be verified in the future does not excessively extend the scope of the present invention.
Nevertheless, a biological activity of a pharmaceutical composition herein is preferred to be anticancer activity, when considering that drugs in the taxane family are currently used as an anticancer agent for ovarian cancer, breast cancer, lung cancer, etc.
Another aspect of the present invention is related to a composition for enhancing bioavailability of a drug in the taxane family comprising bamboo smoke distillate as an effective agent. In one embodiment of the present invention, the composition for enhancing bioavailability of a drug in the taxane family is preferred to be an additive composition for a drug in taxane family.
As verified in the following Examples, mixture of paclitaxel and bamboo smoke distillate, when administered orally in a rat, increased plasma concentration of paclitaxel. This result showed that the composition for enhancing bioavailability of a drug in the taxane family may be usefully used as an additive composition for such a drug in taxane family. Meanwhile, in another embodiment of the present invention, the composition for enhancing bioavailability of a drug in the taxane family is preferred to be a pharmaceutical composition.
As shown in the following Examples, the pretreatment of bamboo smoke distillate herein or the co-treatment of bamboo smoke distillate along with paclitaxel increased plasma concentration of paclitaxel. This result shows that the composition for enhancing bioavailability of a drug in the taxane family may be administered before the administration of the taxane family drug in the form of a pharmaceutical composition.
Further, the composition for enhancing bioavailability of a taxane family drug is preferred to be for oral administration. As mentioned previously, paclitaxel are has been prepared as formulations for intravenous injection instead of oral formulations. However, in the following Examples herein, it was verified that plasma concentration of paclitaxel is maintained very high by oral co-administration along with bamboo smoke distillate or oral pre-treatment of bamboo smoke distillate as in Figure 1. For this reason, the pharmaceutical composition for enhancing bioavailability of a taxane family drug is also preferred to be for oral administration.
In still another embodiment of the present invention, the composition for enhancing bioavailability of a taxane family drug is preferred to be a food composition.
Representative examples of a food composition of the present invention include, but are not limited to, chewing gum, vitamin complex, health supplemental food, nutrient-promoting composition and preferably functional drink.
The food composition may further comprise monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose and polysaccharides such as dextrin and cyclodextrin, sugar alcohol such as xylitol, sorbitol and erythritol, a sweetening agent such as taurin and stevia extract, and other food additives.
For the aforementioned reason, the terms of 'bamboo smoke distillate', 'drug in the taxane family', etc should be understood to have the same meanings defined above.
Meanwhile, a pharmaceutical composition herein may be administered by various routes such as oral, transdermal, subcutaneous, intranasal, intravenous and intramuscular route. Further, a pharmaceutical composition herein may be prepared into various formulations by incorporating pharmaceutically or pharmacologically acceptable conventional additives such as a filler, a bulking agent, a binder, a moistening agent, a disintegrating agent, a diluent such as a surfactant, and an excipient. Representative examples of solid formulations for oral administration include, but are not limited to, a tablet, a pill, powder, granule and a capsule. The solid formulations are prepared by admixing at least one excipient such as starch, calcium carbonate, sucrose, lactose and gelatin, and a lubricant may also be included.
Representative examples of liquid formulations for oral administration include, but are not limited to, a suspension form, an internal solution form, an emulsion form and a syrup. The liquid formulations may be prepared by adding widely used simple diluent such as water and liquid paraffin, and other excipients such as an moistening agent, an sweetening agent, fragrance and preservative may also be included.
Representative examples of non-oral formulations include, but are not limited to, a sterilized aqueous solution, a non-aqueous form, a suspension form, an emulsion form, a freeze-dried form and a suppository form. Propylene glycol, poly(ethylene glycol), vegetable oil such as olive oil and injectable ester such as ethyl oleate may be used for non-aqueous form and suspension form. As suppository bases, Witepsol, macrogol, Tween 61, cacao paper, laurin paper, glycerol and gelatin may be used. Drugs in the taxane family may be administered according to appropriate dosage level as already known. In an embodiment of the present invention, bamboo smoke distillate is preferred to be administered once or several times a day within a dose of 0.5-30 mg/kg body-weight. However, appropriate dosage level of the pharmaceutical composition herein may be determined by considering various information such as formulation method, administration type, age, body weight, sex, physical conditions food, administration time and route, excretion and reaction sensitivity. Physicians with average skill may easily determine and diagnose dosage level of medicine effective for treating or preventing target disorders or diseases. Therefore, the aforementioned dose should be understood, in no way, to limit the scope of the present invention. ADVANTAGEOUS EFFECTS
As set forth above, the present invention provides a pharmaceutical composition comprising a drug in taxane family, as an effective agent, and bamboo smoke distillate as an enhancer for its bioavailability, along with a composition for enhancing bioavailability of a drug in taxane family comprising bamboo smoke distillate as an effective agent.
Bamboo smoke distillate extends maintenance time of a taxane family drug in plasma, thus having an activity of enhancing the bioavailability of a taxane family drug.
BRIEF DESCRIPTION OF DRAWINGS Figure 1 is a graph showing plasma concentration of paclitaxel in rats (oral co-treatment with paclitaxel and bamboo smoke distillate).
Figure 2 is a graph showing plasma concentration of paclitaxel in rats (oral pretreatment with bamboo smoke distillate followed by oral administration of paclitaxel).
Figure 3 is an electrophoresis photograph showing expression levels of CYP3A1 and CYP3A4 in liver of rats (oral co-treatment & oral pretreatment).
Figure 4 is an electrophoresis photograph showing expression levels of CYP3A1 and CYP3A4 in kidney of rats (oral co-treatment & oral pretreatment).
MODE FOR THE INVENTION The present invention is described more specifically by the following Examples.
Examples herein are meant only to illustrate the present invention, but in no way to limit the claimed invention.
Example 1: Measurement of Paclitaxel Plasma Concentration after Bamboo Smoke Distillate Treatment
Example 1-1: Experiment methods
1. Separation of blood plasma from animal test subjects Paclitaxel and bamboo smoke distillate were provided by Samyang Genex Corp. (Taejon, KR) and Damyang Tech Coφ. (Damyang, KR), respectively.
After Sprague-Dawley rats (Ilchul Science?, KR), weighing around 300 g, were anesthetized with ether and immobilized in a stereotaxic frame, anesthesia was maintained by intravenous injection of 25% urethane (4 mL/kg). Rats were divided into a control group (n=6), a co-treatment group (n=6) and a pretreatment group (μ-6), and each of the latter two groups was divided into 3 groups depending on amounts of bamboo smoke distillate.
Rats in a control group were orally administered with suspension comprising 50 mg/kg of paclitaxel and tween 80. Rats in three co-treatment groups were orally administered with suspension admixed with 50 mg/kg of paclitaxel, tween 80 and 0.75, 1.5 and 3.0 mL/kg of bamboo smoke distillate, respectively. Likewise, rats in the three pretreatment groups were orally administered with suspension of tween 80 and 0.75, 1.5 and 3.0 mL/kg of bamboo smoke distillate, respectively, followed by oral administration of suspension of 50 mg/kg of paclitaxel and tween 80 after 1 hour. 0, 0.25, 0.5, 1, 2, 3, 4, 8, 12 and 24 hours after the administration, blood samples
(0.6 mL each) were collected through a polyethylene tube, which was inserted into thigh artery of the rats. 75 U/mL of heparin was injected into the tube to prevent blood coagulation. Blood plasma was separated from the collected blood samples by centrifuge at 3,000 rpm for 5 minutes, and stored at -40 0C until analysis.
2. Measurement of paclitaxel plasma concentration
Concentration of paclitaxel in plasma was measured according to a revised method based on Catalin et al. (N. Manrin, J. Catalin, M.F. Blachon, A. Durand, J. Chromato. B., 709, 281-288 (1998)) and Mase et al. (H. Mase, M. Hiraoka, F. Suzuki, Yakugaku. Zasshi., 114, 351-355 (1994).
100 μL of internal standard material (butylparaben(butylparaoxybenzoic acid; Sigma) was added to 0.25 mL of blood plama, and admixed for 1 minute with vortex. 4 mL of tert-butylmethyl ether was added to the mixture for extraction and centrifuged at 3,000 for 10 minutes. 3.5 mL of organic layer was separated and dried at 40 °C under nitrogen. After 300 μL of mobile phase was extracted, it was vortexed and sonicated for 2 minutes, respectively, followed by centrifuge for 5 minutes. After the centrifuged mixture was filtered through 0.22 μm-thick filter paper, 100 μL was taken and incorporated into HPLC.
1515 Pump, 717 Plus Autosampler and 2487 Dual λ Absorbance Detector ((Waters Corp.) were used as HPLC devices, and separation was performed at 227 nm and at room temperature. Symmetry® Cl 8 (5 μm, 4.6x150 mm) was used as a column. The content of mobile phase was ACN:MeOH:0.05 mM Phosphoric acid = 45:10:45 v/v/v. Flow rate was 1.2 mL/min, and aufs? was 0.01. Internal standard material (butylparaben) and paclitaxel were separated in 5.4 minutes and 7.5 minutes, respectively. Calibration curve was established by adding 20, 50, 100, 200 and 500 ng/niL of paclitaxel and iμm/mL of butylparaben to 0.25 mL of plasma, followed by vortex for 1 minute and quantification as set forth above. The obtained calibration curve was y=100x-0.207 (r=0.9973).
3. Pharmacokinetic analysis
Analysis of pharmacokinetic parameters was performed by using (LAGRAN computer program according to Lagrange et al. (M.L. Rocci, WJ. Jusko, LAGRAN program for area and monents in pharmacokinetic analysis, Computer Program in
Biomedicine., 16, 203 (1983)). The area under plasma concentration-time curves (AUCs) and the biological half-life were calculated by using Trapezoidal rule and 0.693/kel equation, respectively.
The elimination rate constant (KeI) was obtained by regressing 4 points of plama concentration? Measured values were used for the peak concentration (Cmax) and the time required to reach the maximum plasma concentration (Tmax). Equations for other parameters were as follows:
* Absolute bioavailability (AB%) = Oral AUC/1V AUC x IV dose/Oral dose x 100
* Relative Bioavailability) = AUC co-admin/ AUC control x 100
Example 1-2: Experiment Results 1. Plasma concentration of paclitaxel
Average concentrations of paclitaxel in plasma of 3 groups of rats, which were treated with paclitaxel alone, co-treated with paclitaxel and bamboo smoke distillate (doses of bamboo smoke distillate: 0.75, 1.5 & 3 mL/kg), and pretreated with bamboo smoke distillate (0.75, 1.5 & 3 mL/kg), along with oral administration of paclitaxel (pretreatment time: 1 hour & 3 days), are provided in Figures 1 & 2.
Plasma concentrations in Figures 1 & 2 are average values of concentrations of 6 rats in each group. However, plasma concentrations were not measured in 0.75 mL/kg pretreatment group.
In Figure 1, the o-curve is a plasma concentration curve of a control group administered with 50 mg/kg paclitaxel alone; the α-curve is a plasma concentration curve of a co-treatment group (0.75 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel); the B-curve is a plasma concentration curve of a co-pretreatment group (1.5 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel); and the Δ -curve is a plasma concentration curve of a co-treatment group (3 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel).
In Figure 2, the • -curve is a plasma concentration curve of a co-treatment group (1.5 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel), which corresponds to the β-curve in Figure 1; the o-curve is a plasma concentration curve of a pretreatment group (pretreatment of 1.5 mL/kg bamboo smoke distillate for 1 hour, followed by oral administration of 50 mg/kg paclitaxel; the π-curve is a plasma concentration curve of a pretreatment group (1-hour pretreatment of 3 mL/kg bamboo smoke distillate, followed by oral administration of 50 mg/kg paclitaxel; the β-curve is a plasma concentration curve of a pretreatment group (pretreatment of 1.5 mL/kg bamboo smoke distillate for 3 days, followed by oral administration of 50 mg/kg paclitaxel); and the Δ -curve is a plasma concentration curve of a pretreatment group (3 -day pretreatment of 3 mL/kg bamboo smoke distillate, followed by oral administration of 50 mg/kg paclitaxel).
As compared with the control group, the two co-treatment groups (0.75 mL/kg and 1.5 mL/kg of bamboo smoke distillate, respectively) showed no significant difference in paclitaxel plasma concentration. However, the co-treatment group (3.0 mL/kg of bamboo smoke distillate) showed significant difference from 1 hour to 24 hours (p<0.05). The two pretreatment groups (1-hour and 3-day pretreatment, respectively) also showed significant difference from 1 hour to 24 hours (p<0.05, 1-hour pretreatment, p<0.01 3-day pretreatment).
2. Pharmacokinetic parameters of paclitaxel
Pharmacokinetic parameters are provided in Tables 1 & 2. Especially, bioavailability was compared between intravenous injection and oral administration. As compared with the control group, among co-treatment groups, only the co-treatment group (3 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel) showed a significant increase in AUC up to 2351±639 ng/mL-hr (p<0.05). The two pretreatment groups (1-hour and 3 -day pretreatment of 3 mL/kg bamboo smoke distillate, respectively) also showed significant increases in AUC up to 2639±659 ng/mL-hr and 3398±853 ng/mL-hr, respectively (p<0.05, 1-hour pretreatment, p<0.01, 3-day pretreatment).
Although Cmax values increased up to 137±34 ng/mL and 153±41 ng/niL in the 1-hour and 3-day pretreatment groups, respectively, the statistical significance was observed only in the 3-day pretreatment group (p<0.05). KeI values were determined to be 0.056±0.014 hr"1 and 0.049±0.012 hr'1 in 1-hour and 3-day pretreatment groups, respectively. However, the statistical significance was also observed only in the 3-day pretreatment group (p<0.05).
Likewise, although ti4 values were extended up to 12.38±2.98 hr and 14.14±3.48 hr in the 1-hour and 3-day pretreatment groups, respectively, the statistical significance was observed only in the 3-day pretreatment group (p<0.05).
Among co-treatment groups, only the co-treatment group (3 mL/kg of bamboo smoke distillate and 50 mg/kg of paclitaxel) showed a significant increase in AB% up to
2.6% (p<0.05), while AB% value of the control group was 2.1%. The two pretreatment groups (1-hour and 3 -day pretreatment of 3 mL/kg bamboo smoke distillate, respectively) also showed significant increases in AB% up to 3.2% and 3.9%, respectively (p<0.05, 1-hour pretreatment, p<0.01, 3-day pre treatment).
The results that KeI decreased and X1A was extended with statistical significance in groups administered with bamboo smoke distillate showed a possibility that bamboo smoke distillate may act on cytochrome P450 monoxidase, especially CYP3A4. Therefore, a combinatory administration of bamboo smoke distillate may be applied to a patient who is under anticancer treatment with paclitaxel, thereby enhancing bioavailability of paclitaxel.
Table 1. Pharmacokinetic parameters: oral co-administration of bamboo smoke distillate paclitaxel (50 mg/kg)
Paclitaxel Bamboo cqadmin.
Parameters -
IV Conh-ol 0.3 ml/kg 1.5 ml/kg 3,0 ml/kg
AUC
3631±9G7 1837+459 2030±50B (ns/mi - hr) 2279±569 2351-639*
CmwClIβ/ml) 115±29 122±31 132±34 135434
Tniax(hr) 2.0±0.6 2,Q±0.S i.€J±G.S 1.8*0.5
KelChr *) O,0S2±0.021 0.070±0,017 0.0S7±0.016 0.064±O.Q16 0.060iO.O14 t. (Iu-) HAQ±ZΛl 9.90±2.47 10.34±3-.Sa 10.72±2,63 11.55^2.68
ΛB(%) 2.1 2.2 2.5 2.6*
RB(%) 100 105 1 19 128
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 KeI: Elimination rate constant
AB(%): Absolute bioavailability RB(%):Relative bioavailability Table 2. Pharmacokinetic parameters: oral pre-treatment of bamboo smoke distillate followed by oral administration of paclitaxel (50 mg/kg)
Bfirn boo Pretreat.
Parameters cnadrπin. 1.0 h. 1.0 h 3 d«y« 3 days (1-5 .mJ/ki?) (1.5 IΓIIAΓK) (3.0 ml/kg) (1,5 ml/kg) (3.0 ml/kg]
JKX.ΪCZ f / T ^ Λ 2279*569 £443-1588* 2639*669* 3289±S24** 339S3:853**
Crostna/mU 132*34 134*34 137±34 149±38* I53±41*
Tm-«(hr) 1.9*0,5 1.9±0.S 1.8±0.5 3.6±0.4 1.7±0.4
KeKhr"1) 0,004i0.016 0.0β4i0,016 O.ϋS6±O.O14 0,050÷0.013* Q.U49±0.012»< ti Chr) 10.72±2.63 10.72*2.(53 12.38±2.98 13.86*3.34+ 14.14*3.48*
2.5 2.8* 3.2* 36** 3.9**
RB(SiS) 1 19 133 142 ITX 185
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 KeI: Elimination rate constant X1A: Half-life AB(%):Absolute bioavailability RB(%):Relative bioavailability
Example 2: Observation of Expression Level of CYP3A after Bamboo Smoke Distillate Treatment
Example 2-1: Experiment methods
Tissues from liver and kidney of rats in each group were separated, washed twice with sterilized phosphate-buffered saline and ground with tissue grinder, followed by centrifuge, and then cytoplasm and microsome were separated. SDS-polyacrylaminde gel electrophoresis and immunoblot analysis were performed according to known methods. After each protein was separated with 10% gel electrophoresis, transferred to nitrocellulose paper, followed by blocking with skim milk, the nitrocellulose paper was reacted with CYP3A1 and 3A4 antibodies and also with selective secondary antibody, and then developed by ECL chemillumiescence.
Example 2-2: Experiment results
Levels of CYP3A4 in liver and kidney were decreased by administration of bamboo smoke distillate (Figures 3 & 4). Likewise, levels of CYP3A1 were also decreased by administration of bamboo smoke distillate in the same manner (Figures 3 & 4), and this tendency was evident in oral co-treatment groups (Figures 3 & 4). From these results, it was evidently verified that the administration of bamboo smoke distillate acts on expression of enzymes in cytochrome P450 3A family and inhibits metabolism of paclitaxel, thereby serving as a cause of enhancement in plasma concentration of paclitaxel as set forth in Figures 1 & 2.

Claims

1. A pharmaceutical composition comprising (i) a drag in taxane family as an effective agent and (ii) bamboo smoke distillate as an enhancer for its bioavailability.
2. A pharmaceutical composition of claim 1, wherein the drag in taxane family is paclitaxel.
3. A pharmaceutical composition of claim 1, wherein the drug in taxane family is docetaxel.
4. A pharmaceutical composition of claim 1, wherein the composition is for oral administration.
5. A pharmaceutical composition of claim 1, wherein the drag in taxane family has an activity of preventing or treating cancer.
6. A composition for enhancing bioavailability of a drag in taxane family, the composition comprising bamboo smoke distillate as an effective agent.
7. A composition of claim 6, wherein the composition is an additive composition for a drag in taxane family.
8. A composition of claim 6, wherein the composition is a pharmaceutical composition.
9. A composition of claim 6, wherein the composition is a pharmaceutical composition for oral administration.
10. A composition of claim 6, wherein the drug in taxane family is paclitaxel.
11. A composition of claim 6, wherein the drug in taxane family is docetaxel.
12. A composition of claim 6, wherein the composition is a food composition.
13. A composition of claim 6, wherein the composition is a functional drink.
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Cited By (1)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1946747A1 (en) * 2007-01-17 2008-07-23 Sandoz AG Pharmaceutical composition of improved stability containing taxane derivatives
WO2008087076A1 (en) * 2007-01-17 2008-07-24 Sandoz Ag Pharmaceutical composition of improved stability containing taxane derivatives

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