JP5511895B2 - Composition for improving the bioavailability of curcumin - Google Patents

Description

  The present invention relates to a composition of curcumin containing turmeric essential oil having Ar-turmerol as a main component in order to improve the bioavailability of curcumin and increase the biological activity of curcumin. Improved bioavailability was demonstrated by human experiments with volunteers.

  Curcumin [1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione is the main yellow pigment of turmeric, a commonly used spice, and medicinal It is derived from the rhizome of the plant Curcuma longa Linn. In the Indian subcontinent and Southeast Asia, turmeric has traditionally been used as a treatment for inflammation, skin wounds, and tumors. The clinical activity of curcumin has not been confirmed yet.

  However, in preclinical animal models, curcumin has shown cancer chemoprevention, anti-tumor and anti-inflammatory properties (review, reference, Kelloff, GI, et al, J. Cell Biochem. , 1996, 265: 54-71). Curcumin is a genetic model for familial neoplastic polyps of human disease (Rao, CV et al, Cancer Res., 1995, 55: 259-66; Kawamori, T. et al, Cancer). Res., 1999, 59: 597-601), and in complex tumorigenic (Min / +) mice (Mahmod, NN et al, Carcinogenesis, 2000, 31: 921-27), carcinogen-induced intestinal precancer. It is said to be capable of preventing the formation of sexual disorders and malignant tumors.

  Curcumin functions as a scavenger for oxygen species such as hydroxy radicals, superoxide anions and singlet oxygen (Subramanian, M. et al, Mutat. Res., 1994, 311: 249-55; Tonsen, H. H. et al. , Int. J. Pharm., 1992, 87: 79-87; Reddy, ACP et al, Mol. Cell Biochem., 1994, 137: 1-8), preventing lipid peroxidation. (Donatus, IA, Biochem. Pharmacol., 1990, 39: 1869-75; Sharma, SC et al, Biochem. Pharmacol., 1972, 21: 1214-14). Curcumin suppresses a number of important elements in the intracellular signal induction pathways for growth, differentiation and malignant transformation.

  During signal transduction events, protein kinases (Huang, TS et al, Proc. Natl. Acad. Sci., 1991, 88: 5292-96), c-Jun / AP-1 activation (Huang, T S. et al, Proc. Natul. Acad. Sci., 1991, 88: 5292-96), prostaglandin biosynthesis (Huang, MT et al, In L. W. Battenberg (ed.) Cancer. Chemovention, CRC Press, Boca Raton, 1992, pp 375-91) and the activity and expression of the enzyme cyclooxygenase-2 (Huang, MT, et al, Cancer Res., 1991, 51: 813-19; Zhang, F .; et al, arcinogenesis, 1999,20: 445-51) is inhibited by curcumin. This last property is probably due to the ability of curcumin to block activation of the transcription factor NF-κB at the level of the NF-κB-inducible kinase / IKKα / β signaling complex (Plummer, S. et al, Oncogene, 1999). , 18: 6013-20).

  Curcumin directly inhibits cyclooxygenase-2 and also inhibits transcription of genes involved in its production. Cyclooxygenase (COX) catalyzes the synthesis of multiple prostaglandins (PGs) from arachidonic acid. There are two isoforms of COX, called COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and is thought to be involved in the housekeeping function (Funk, CD et al, FASEB. J., 1991, 5-2304-12). . On the other hand, COX-2 is usually undetectable in normal tissues, but is induced by oncogenes, growth factors, expressed substances and tumor promoters (Subbaramiah, K. et al, 1996, Cancer Res., 1996, 56: 4424). -29; DuBois, RN et al, J. Clin. Invest., 1994, 93: 493-98; Kelley, D.J. et al, Carcinogenesis, 1997, 18: 795-99). There are several related mechanisms between COX-2 activity and carcinogenesis.

  Curcumin also has non-steroidal anti-inflammatory drugs (NSAIDS), anti-inflammatory and cancer chemopreventive properties, but is not simply a replacement. This is because COX is a bifunctional enzyme having cyclooxygenase and peroxidase activities. Except for its importance for PG synthesis, peroxidase function is responsible for the activation of procarcinogens. Therefore, if NSAIDS fails to inhibit the peroxidase function of COX, the effect as an anticancer agent may be limited. On the other hand, curcumin down-regulates the level of COX-2, thereby reducing both the cyclooxygenase and peroxidase activities of the enzyme.

Curcumin is one of the few drugs that blocks both the COX and LOX (lipoxygenase) pathways of inflammation and carcinogenesis by directly regulating arachidonic acid metabolism. Studies to evaluate the effect of curcumin on arachidonic acid metabolism and action in mouse epidermitis found that topical application of curcumin inhibits arachidonic acid-induced ear inflammation in mice (Huang M.T., et al Cancer Res., 1988, 48: 5941-46; 1991, 51: 813-19). Curcumin (10 μM) inhibits the conversion of arachidonic acid to 5- and 8-hydroxyeicosatetraenoic acid by 60% and 51%, respectively (LOX pathway), and metabolism to PGE ₂ , PGF _2a and PDG ₂ Inhibits 70%, 64% and 73%, respectively (COX pathway).

In another study, dietary administration of 0.2% curcumin to rats inhibited azoxymethane-induced colon cancer development and reduced colon and tumor phospholipase A ₂ , phospholipase Cγ1 and PGE ₂ levels (Rao, C.V. et al, Cancer Res., 1995, 55: 259-66). In this study, curcumin diet in the colonic mucosa and tumor, _{PGE 2,} PGF 2a via the COX system, _PGD 2, also the enzyme activity to form a 6-keto-PGF _2a and thromboxane _{B 2} is reduced, It also inhibits the production of 5 (S)-, 8 (S)-, 12 (S)-, and 15 (S) -hydroxyeicosatetraenoic acid via the LOX pathway.

  Despite excellent dressing of beneficial biological activity, the bioavailability of curcumin remains low in animals and humans. In rodents, curcumin has a low systemic bioavailability after oral administration (Ireson, CR et al, Cancer Res., 2001, 41: 1058-64). This may be related to poor absorption and fast metabolism. As can be seen from the results of recent pilot studies of standard turmeric extracts in patients with colon cancer, the bioavailability of curcumin may also be low in humans (Sharma, RA et al, Clin. Cancer Res. , 2001, 7: 1834-1900).

  Indirect evidence suggests that curcumin is metabolized in the intestine. In vivo rats and mice (Pan, MH et al, Drug Metabol. Dispos., 1999, 27: 486-94; Asai, A., et al, Life Sci. 2000, 67: 2785-93), in suspensions of human and rat hepatocytes (Ireson et al, Ioc. Cit) and in the intestines of humans and rats (Ireson, CR et al, Cancer Epidemiol. Biomark. Prev. , 2002, 11: 105-11), curcumin undergoes metabolic O-conjugation to curcumin glucuronide and curcumin sulfate and bioreduction to tetrahydrocurcumin, hexahydrocurcumin and hexahydrocurcuminol. There was more metabolic conjugation and reduction of curcumin in humans than intestinal tissues of rats.

It has been suggested that the intestinal tract plays an important role in the metabolic dynamics of curcumin. This is mainly based on experiments in which [ ³ H] -labeled curcumin was cultured with inverted rat gut sacs (Ravindranath, V. and Chanderaskhara, N., Toxicology, 1981, 20: 251-57). This was recently confirmed in intestinal fractions from humans and rats. The intestinal mucosa, like liver and kidney tissue from rats, oxidizes curcumin to glucuronidation, as determined by analyzing differences in the amount of curcumin present before and after treatment of tissue extracts with conjugated hydrolase. And can be sulfated (Asai et al, loc cit). Thus, gastrointestinal metabolism contributes substantially to the total metabolic output that results from curcumin in vivo. In human intestinal fractions, conjugation with active sulfate or glucuronic acid occurs more frequently than in rat tissue, but less in human liver tissue (Ireson, CR, et al. , Cancer Epidemiol. Biomark. Prev., 2002, 11: 105-11).

Although orally administered curcumin has low bioavailability and is only low or unmeasurable in blood concentration (Perkins, S. et al, Cancer Epidemiol. Biomark. Prev., 2002, 11: 535-40), this The route of administration inhibits chemically induced skin and liver cancer development (Limtrakul, P., et al, Cancer Lett., 1997, 116: 197-203; Chiang, SE et al, Carcinogenesis, 2000 21: 331-35). Oral administration of curcumin also inhibits the development of radiation-induced mammary and pituitary tumors (Inano, H. et al, Carcinogenesis, 2000, 21: 1835-41; Int. J. Rediat. Oncol. Biol. Phys., 2002. , 52: 212-23; ibid, 2002, 53: 735-43). Similarly, in studies evaluating colorectal curcumin levels, a daily dose of 3.6 g of curcumin reaches a pharmaceutically effective level in the colorectal with a small distribution of curcumin outside the gastrointestinal tract ( Garcea, G. et al, Cancer Epidemiol. Biomark. Prev., 2005, 14: 120-25). Earlier Shobha et al. (Plant Med., 1998, 64: 353-56) found that administration of piperine with curcumin improved the bioavailability of curcumin. However, the level of improvement was negligible and curcumin could not be detected after 3 hours, even when supplemented with piperine.
Kelloff, G.M. I. Et al, J. et al. Cell Biochem. , 1996, 265: 54-71. Rao, C.I. V. et al, Cancer Res. , 1995, 55: 259-66. Kawamori, T .; et al, Cancer Res. 1999, 59: 597-601. Mahmood, N .; N. et al, Carcinogenesis, 2000, 31: 921-27. Subramanian, M.M. et al, Mutat. Res. 1994, 311: 249-55. Tonsen, H.C. H. et al, Int. J. et al. Pharm. , 1992, 87: 79-87. Reddy, A.M. C. P. et al, Mol. Cell Biochem. , 1994, 137: 1-8. Donatus, I.D. A. Biochem. Pharmacol. , 1990, 39: 1869-75. Sharma, S .; C. et al, Biochem. Pharmacol. 1972, 21: 1210-14. Huang, T .; S. et al, Proc. Natl. Acad. Sci. 1991, 88: 5292-96. Huang, T .; S. et al, Proc. Natul. Acad. Sci. 1991, 88: 5292-96. Huang, MT. et al, In L. et al. W. Battenberg (ed.) Cancer Chemoprevention, CRC Press, Boca Raton, 1992, pp 375-91 Huang, M .; T. T. et al. , Et al, Cancer Res. 1991, 51: 813-19. Zhang, F.M. et al, Carcinogenesis, 1999, 20: 445-51. Plummer, S.M. et al, Oncogene, 1999, 18: 6013-20. Funk, C.I. D. et al, FASEB. J. et al. 1991, 5-2304-12. Subbaramiah, K .; et al, 1996, Cancer Res. , 1996, 56: 4424-29. DuBois, R.M. N. et al, J. et al. Clin. Invest. , 1994, 93: 493-98. Kelly, D.C. J. et al. et al, Carcinogenesis, 1997, 18: 795-99. Huang, M .; T. T. et al. Et al Cancer Res. , 1988, 48: 5941-46; 1991, 51: 813-19. Rao, C.I. V. etal, Cancer Res. , 1995, 55: 259-66. Ireson, C.I. R. et al, Cancer Res. , 2001, 41: 1058-64. Sharma, R .; A. et al, Clin. Cancer Res. , 2001, 7: 1834-1900. Pan, M.C. H. et al, Drug Metabol. Dispos. 1999, 27: 486-94; Asai, A .; , Et al, Life Sci. 2000, 67: 2785-93 Ireson, C.I. R. et al, Cancer Epidemiol. Biomark. Prev. , 2002, 11: 105-11. Ravindranath, V.M. and Chandrasekhara, N .; , Toxiology, 1981, 20: 251-57. Perkins, S .; et al, Cancer Epidemiol. Biomark. Prev. , 2002, 11: 535-40 Limtrakul, P.M. , Et al, Cancer Lett. 1997, 116: 197-203. Chiang, S.H. E. et al, Carcinogenesis, 2000, 21: 331-35. Inano, H.C. et al, Carcinogenesis, 2000, 21: 1835-41. Int. J. et al. Rediat. Oncol. Biol. Phys. 2002: 52: 212-23. ibid, 2002, 53: 735-43 Garcea, G .; et al, Cancer Epidemiol. Biomark. Prev. , 2005, 14: 120-25. Earlier Shobha. et al, Planta Med. 1998, 64: 353-56.

  Thus, in order to obtain sufficient effects from the administration of curcumin to human subjects, it is necessary to search for means for improving the bioavailability. The present invention is a result in this direction.

When turmeric essential oil was added to curcumin, the bioavailability of curcumin was significantly improved. Accordingly, a composition of curcumin mixed with turmerone (the main component of turmeric essential oil) in appropriate proportions is provided.

  Hereinafter, the best mode for carrying out the present invention will be described based on examples.

  The present invention relates to a product that improves the bioavailability of curcumin by mixing an appropriate amount of curcuminoids separated from turmeric and volatile oil obtained from turmeric. For this purpose, turmeric volatile oils are separated by a conventional method called steam distillation to separate essential oils, which is well known in the art. Curcumin is separated from the deoiled turmeric by solvent extraction. Suitable solvents for this purpose include acetone, hexane, ethyl acetate, dichloroethane, chloroform and the like. Extraction is suitably performed at a moderate temperature (40-55 ° C.) and the solvent is partially removed to yield a concentrate containing 30-60% solids. The solution is cooled to obtain curcumin crystals and the curcumin crystals are separated by any suitable method such as filtration or centrifugation. Analysis of this product contained 95% curcumin. Curcumin and its volatile oil are mixed and blended to obtain a uniform product. The ratio of curcumin to oil may vary between 3: 1 and 99: 1, preferably a ratio of 85:15. A more preferred ratio is 95: 5. Gelatin capsules containing 500 mg of the blend were prepared. Essential oil-free curcumin capsules were similarly prepared.

  Nine healthy human volunteers aged 25-45 were selected for this study. Volunteers were given curcumin and the composition of the invention in capsules at a dose of 50 mg / kg body weight. Advised volunteers to drink curcumin first. Blood samples were taken periodically for 8 hours at intervals of 0 hours and 1 hour or 30 minutes. After a one week washout period, the same clinical protocol was followed with the composition of the present invention. Whole blood was extracted completely with ethyl acetate. Recovery was in the range of 80.12 to 86.49. The ethyl acetate extract was analyzed by HPLC with a RO-C18 column (25 × 4.5 mm) using methanol as solvent and UV detection at 420 nm. The elution flow rate was 1 ml / min.

  The composition of the present invention was administered to 9 human volunteers, and blood samples were collected at 0 hours and then at 1 hour or 30 minute intervals for up to 8 hours. As a result, maximum absorption was observed 3 hours after administration. It also resulted in curcumin levels that were 5 to 16 times higher than when curcumin alone was administered.

  Earlier Shobha et al. (Plant Med., 1998, 64: 353-56) have observed that the administration of piperine with curcumin improves the bioavailability of curcumin. However, the level of improvement was negligible and curcumin could not be detected after 3 hours, even when supplemented with piperine. With turmerone as an adjunct as in the present invention, peak absorption occurred at 3 hours and continued at low levels for at least 8 hours. It was not measured for 8 hours or more.

Representative results are shown in the table below.

  The results are shown graphically in FIG. The peak absorption of curcumin occurred in 3 hours, and in the case of the composition of the present invention, a small amount remained in the blood for 8 hours. Measurement was not performed after 8 hours. This data has significant significance. The increase in bioavailability at peak absorption was 5-16 times among 9 people, with an average of 10.62 times.

  The composition of the present invention is biologically active in its essential oil component itself (see, eg, Yue, A et al, Int. J. Mol. Med., 2002, 9: 481-84; Jayaprakasha, GK et al. , Z. Natureforsch., 2002, 57: 828-35) and thus have the additional benefit expected to synergistically improve the biological activity of curcumin.

  The present invention relates to a composition of curcumin containing turmeric essential oil having Ar-turmerol as a main component in order to improve the bioavailability of curcumin and increase the biological activity of curcumin.

FIG. 1 is a graph instead of a drawing showing the transition of the blood concentration of curcumin.

Claims (7)

A composition for oral administration comprising curcuminoids and turmeric essential oil,
The turmeric essential oil is separated from the turmeric,
The curcuminoid is separated from the deoiled turmeric from which the turmeric essential oil has been removed,
The curcuminoid and the turmeric essential oil were mixed and prepared so that the ratio was in the range of 3: 1 to 85:15 or 95: 5 to 99: 1 .
Composition for oral administration. The composition for oral administration according to claim 1, wherein the ratio of the curcuminoid to the turmeric essential oil is 95: 5 to 99: 1.   The composition for oral administration according to claim 1, wherein the ratio of the curcuminoid to the turmeric essential oil is 3: 1 to 85:15.   The composition for oral administration according to claim 1, wherein the turmeric essential oil comprises Ar-turmerone. A method for producing a composition for oral administration comprising curcuminoid and turmeric essential oil, comprising:
Isolating said turmeric essential oil using steam distillation to obtain said turmeric essential oil and deoiled turmeric;
Isolating the curcuminoid from the deoiled turmeric using a solvent;
Removing the solvent to produce a curcuminoid concentrate and including from 30% to 60% solids in the concentrate;
Cooling the concentrated solution to obtain curcuminoid crystals from the concentrate;
Isolating the curcuminoid crystals from the cooled solution; and mixing the isolated curcuminoid crystals and the turmeric essential oil such that the ratio of the curcumin to the turmeric volatile oil is 3: 1 to 85: Adjusting the ratio from 15 or 95: 5 to 99: 1 . 6. The method of claim 5, wherein the ratio of the curcuminoid to the turmeric essential oil is 95: 5 to 99: 1. 6. The method of claim 5, wherein the ratio of the curcuminoid to the turmeric essential oil is from 3: 1 to 85:15.

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