U.S. patent application number 13/645031 was filed with the patent office on 2014-10-02 for formulation of curcumin with enhanced bioavailability of curcumin and method of preparation and treatment thereof.
The applicant listed for this patent is Benny Antony. Invention is credited to Benny Antony.
Application Number | 20140295005 13/645031 |
Document ID | / |
Family ID | 50432846 |
Filed Date | 2014-10-02 |
United States Patent
Application |
20140295005 |
Kind Code |
A9 |
Antony; Benny |
October 2, 2014 |
Formulation of Curcumin With Enhanced Bioavailability of Curcumin
and Method of Preparation and Treatment Thereof
Abstract
Disclosure provides a formulation of curcuminoid with essential
oil of turmeric to enhance the bioavailability of curcumin and to
augment the biological activity of curcumin, wherein curcumin is
the main constituent of curcuminoid and wherein Ar-turmerone is the
main constituent of the essential oil of turmeric. An application
of curcuminoid with essential oil of turmeric to enhance the
bioavailability of curcumin for oral supplementation against a
variety of diseases and method of doing the same is provided.
Inventors: |
Antony; Benny; (Kochi,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Antony; Benny |
Kochi |
|
IN |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20140099390 A1 |
April 10, 2014 |
|
|
Family ID: |
50432846 |
Appl. No.: |
13/645031 |
Filed: |
October 4, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13385717 |
Mar 5, 2012 |
8623431 |
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13645031 |
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12926985 |
Dec 21, 2010 |
8153172 |
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13385717 |
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12662740 |
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7879373 |
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12926985 |
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11635599 |
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7736679 |
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12662740 |
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PCT/IN05/00176 |
May 30, 2005 |
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11635599 |
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PCT/IN2011/000232 |
Apr 4, 2011 |
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PCT/IN05/00176 |
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13506572 |
Apr 30, 2012 |
8329233 |
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PCT/IN2011/000232 |
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12926980 |
Dec 21, 2010 |
8197869 |
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13506572 |
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12073864 |
Mar 11, 2008 |
7883728 |
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12926980 |
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11635599 |
Dec 8, 2006 |
7736679 |
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12073864 |
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PCT/IN05/00176 |
May 30, 2005 |
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11635599 |
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Current U.S.
Class: |
424/756 |
Current CPC
Class: |
A61K 36/9066 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/12 20130101;
A61K 36/9066 20130101; A61K 31/12 20130101 |
Class at
Publication: |
424/756 |
International
Class: |
A61K 36/9066 20060101
A61K036/9066; A61K 31/12 20060101 A61K031/12 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 5, 2010 |
IN |
950CHE2010 |
Claims
1. A method of treating rheumatoid arthritis comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
2. A method of reducing visual analogue scale for pain comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
3. A method of decreasing disease activity score comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
4. A method of improving patient response to ACR criteria
comprising administering a composition of a curcuminoid mixture and
added essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
5. A method of reducing C-reactive protein levels comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
6. A method of reducing rheumatoid Arthritis Factor comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
7. A method of decreasing joint pain comprising administering a
composition of a curcuminoid mixture and added essential oil of
turmeric, wherein the weight ratio of the curcuminoid mixture to
the added essential oil of turmeric ranges from about 1:3 to about
99:1, wherein the curcuminoid mixture comprises curcumin,
demethoxycurcumin and bisdemethoxycurcumin, and wherein the
essential oil of turmeric comprises ar-turmerone.
9. A method of improving walking distance scores comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
10. A method of treating osteoarthritis comprising administering a
composition of a curcuminoid mixture and added essential oil of
turmeric, wherein the weight ratio of the curcuminoid mixture to
the added essential oil of turmeric ranges from about 1:3 to about
99:1, wherein the curcuminoid mixture comprises curcumin,
demethoxycurcumin and bisdemethoxycurcumin, and wherein the
essential oil of turmeric comprises ar-turmerone.
11. A method of treating Alzheimer's disease comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
12. A method of improving mini mental state exam scores comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
13. A method of increasing Vitamin E levels comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
14. A method of increasing serum amyloid beta levels comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
15. A method of disaggregating amyloid beta comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
16. A method of lowering plasma isoprostane levels comprising
administering a composition of a curcuminoid mixture and added
essential oil of turmeric, wherein the weight ratio of the
curcuminoid mixture to the added essential oil of turmeric ranges
from about 1:3 to about 99:1, wherein the curcuminoid mixture
comprises curcumin, demethoxycurcumin and bisdemethoxycurcumin, and
wherein the essential oil of turmeric comprises ar-turmerone.
17. A method of treating depression comprising administering a
composition of a curcuminoid mixture and added essential oil of
turmeric, wherein the weight ratio of the curcuminoid mixture to
the added essential oil of turmeric ranges from about 1:3 to about
99:1, wherein the curcuminoid mixture comprises curcumin,
demethoxycurcumin and bisdemethoxycurcumin, and wherein the
essential oil of turmeric comprises ar-turmerone.
18. A method of improving response rate on Hamilton Depression rate
scale comprising administering a composition of a curcuminoid
mixture and added essential oil of turmeric, wherein the weight
ratio of the curcuminoid mixture to the added essential oil of
turmeric ranges from about 1:3 to about 99:1, wherein the
curcuminoid mixture comprises curcumin, demethoxycurcumin and
bisdemethoxycurcumin, and wherein the essential oil of turmeric
comprises ar-turmerone.
19. A method if improving clinical global impression by Global
Severity comprising administering a composition of a curcuminoid
mixture and added essential oil of turmeric, wherein the weight
ratio of the curcuminoid mixture to the added essential oil of
turmeric ranges from about 1:3 to about 99:1, wherein the
curcuminoid mixture comprises curcumin, demethoxycurcumin and
bisdemethoxycurcumin, and wherein the essential oil of turmeric
comprises ar-turmerone.
20. A method of improving clinical global impression by Global
Change scale comprising administering a composition of a
curcuminoid mixture and added essential oil of turmeric, wherein
the weight ratio of the curcuminoid mixture to the added essential
oil of turmeric ranges from about 1:3 to about 99:1, wherein the
curcuminoid mixture comprises curcumin, demethoxycurcumin and
bisdemethoxycurcumin, and wherein the essential oil of turmeric
comprises ar-turmerone.
Description
[0001] This application is a continuation-in-part of PCT
Application Serial No. PCT/IN2011/000232, filed Apr. 4, 2011, which
claims priority of Indian Provisional Application Serial No.
950/CHE/2010, filed Apr. 5, 2010, and a continuation-in-part of
co-pending U.S. application Ser. No. 13/385,717, filed Mar. 5,
2012, which is a divisional of Ser. No. 12/926,985 filed Dec. 21,
2010, which is a divisional of Ser. No. 12/662,740 filed Apr. 30,
2010, which is a divisional of U.S. application Ser. No. 11/635,599
filed Dec. 8, 2006, which is a continuation of PCT Application
Serial No. PCT/IN05/00176, filed May 30, 2005, and a
continuation-in-part of co-pending U.S. application Ser. No.
13/506,572, filed Apr. 30, 2012, which is a divisional of Ser. No.
12/926,980, filed Dec. 21, 2010, which is a divisional of Ser. No.
12/073,864, filed Mar. 11, 2008, which is a continuation-in-part of
Ser. No. 11/635,599, filed Dec. 8, 2006, which is a continuation of
PCT Application Serial No. PCT/IN05/00176, filed May 30, 2005, all
of which applications are incorporated in entirety by
reference.
OBJECTIVE OF THE INVENTION
[0002] The following specification describes an invention which
relates to a formulation of curcuminoid with essential oil of
turmeric to enhance the bioavailability of curcumin and to augment
the biological activity of curcumin, wherein curcumin is the main
constituent of curcuminoid and wherein Ar-turmerone is the main
constituent of the essential oil of turmeric. Such enhanced
bioavailability of curcumin has been demonstrated in human
volunteers. The present invention also relates to an application of
curcuminoid with essential oil of turmeric to enhance the
bioavailability of curcumin for oral supplementation against a
variety of diseases and method of doing the same. In particular the
present invention relates to oral supplementation of curcuminoid
with essential oil of turmeric to enhance the bioavailability of
curcumin for the prophylaxis, treatment, maintenance therapy and as
add on therapy for disease conditions such as cancer, heart
diseases, diabetes, rheumatoid arthritis, osteoarthritis,
alzheimer's disease, inflammatory bowel diseases, liver fibrosis
and cirrhosis, abdominal aortic aneurysms, HIV, pancreatitis,
drug-resistant malaria, psoriasis, cystic fibrosis, epilepsy, wound
healing, diseases of the central nervous system, chronic
degenerative diseases and potentially many other diseases where
better delivery of curcumin from the supplement to the blood and
tissues is critical for the enhanced therapeutic benefit and an
improved method of delivering curcumin and ensuring bioavailability
in humans.
BACKGROUND OF THE INVENTION
Curcumin
[1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione]
##STR00001##
[0003] is the major yellow pigment of turmeric, a commonly used
spice, derived from the rhizome of the herb Curcima longa Linn. In
the Indian subcontinent and Southeast Asia, turmeric has
traditionally been used as a treatment for inflammation, skin
wounds, and tumors. Clinical activity of curcumin is yet to be
confirmed; however, in preclinical animal models, curcumin has
shown cancer chemo preventive, antineoplastic and anti-inflammatory
properties.sup.1. Especially interesting is its ability to prevent
the formation of carcinogen-induced intestinal premalignant lesions
and malignancies in rat.sup.2, 3 and in the multiple neoplasia
(Min/+) mouse.sup.4, a genetic model of the human disease familial
adenomatous polyposis. Curcumin acts as a scavenger of oxygen
species such as hydroxyl radical, superoxide anion and singlet
oxygen.sup.5,6,7 and interferes with lipid peroxidation.sup.8,9.
Curcumin suppresses a number of key elements in cellular signal
induction pathways pertinent to growth, differentiation and
malignant transformations. Among signaling events inhibited by
curcumin are protein kinases.sup.10, c-Jun/AP-1 activation.sup.11,
prostaglandin biosynthesis.sup.12 and activity and expression of
the enzyme cyclooxygenase-2.sup.13,14. This latter property is
probably mediated by the ability of curcumin to block activation of
the transcription factor NF-.kappa.B at the level of the
NF-.kappa.B inducing kinase/IKK.alpha./.beta. signalling
complex.sup.15.
[0004] Curcumin directly inhibits cyclooxygenase-2 and also
inhibits the transcription of the gene responsible for its
production. Cyclooxygenases (COX) catalyze the synthesis of
prostaglandins (PGs) from arachidonic acid. There are two isoforms
of COX, designated COX-1 and COX-2. COX-1 is expressed
constitutively in most tissues and appears to be responsible for
housekeeping functions.sup.16 while COX-2 is not detectable in most
normal tissues but is induced by oncogenes, growth factors,
carcinogens and tumor promoters.sup.17,18,19. Several different
mechanisms account for the link between COX-2 activity and
carcinogenesis.
[0005] Curcumin is not simply an alternative to non-steroidal
anti-inflammatory drugs (NSAIDS), which also have anti-inflammatory
and cancer chemopreventive properties. This is so because COX is a
bifunctional enzyme with cyclooxygenase and peroxidase activities.
Aside from being important for PG synthesis, the peroxidase
function contributes to the activation of procarcinogens.
Therefore, the failure of NSAIDS to inhibit the peroxidase function
of COX potentially limits their effectiveness as anticancer agents.
Curcumin, in contrast, down-regulates levels of COX-2 and thereby
decreases both the cyclooxygenase and peroxidase activities of the
enzyme.
[0006] Curcumin is among the few agents to block both the COX and
LOX (lipoxygenase) pathways of inflammation and carcinogenesis by
directly modulating arachidonic acid metabolism. In a study to
evaluate the effect of curcumin on the metabolism and action of
arachidonic acid in mouse epidermis, it was found that topical
application of curcumin inhibited arachidonic acid-induced ear
inflammation in mice.sup.20. Curcumin (10 .mu.M) inhibited the
conversion of arachidonic acid to 5- and 8-hydroxyeicosatetraenoic
acid by 60% and 51%, respectively (LOX pathway) and the metabolism
to PGE2, PGF2.alpha. and PGD2 by 70%, 64% and 73%, respectively
(COX pathway). In another study, dietary administration of 0.2%
curcumin to rats inhibited azoxymethane-induced colon
carcinogenesis and decreased colonic and tumor phospholipase A2,
phospholipase C.gamma.1, and PGE2 levels.sup.21. In this study,
dietary curcumin also decreased enzyme activity in the colonic
mucosa and tumors for the formation of PGE2, PGF2.alpha., POD2,
6-keto-PGF2.alpha. and thromboxane B2 via the COX system and
production of 5(S)-, 8(S)-, 12(S)-, and
15(S)-hydroxy-eicosatetraenoic acid via the LOX pathway was also
inhibited.
[0007] Despite this impressive array of beneficial bioactivities,
the bioavailability of curcumin in animals and man remains low. In
rodents, curcumin demonstrates poor systemic bioavailability after
p.o. dosing.sup.22 which may be related to its inadequate
absorption and fast metabolism. Curcumin bioavailability may also
be poor in humans as seen from the results of a recent pilot study
of a standardized turmeric extract in colorectal cancer
patients.sup.23. Indirect evidence suggests that curcumin is
metabolized in the intestinal tract. Curcumin undergoes metabolic
O-conjugation to curcumin glucuronide and curcumin sulfate and
bioreduction to tetrahydrocurcumin, hexahydrocurcumin and
hexahydrocurcuminol in rats and mice in vivo.sup.24,25 in
suspensions of human and rat hepatocytes.sup.26 and in human and
rat intestine.sup.27. Metabolic conjugation and reduction of
curcumin was more in human than in rat intestinal tissue. It has
been suggested that the intestinal tract plays an important role in
the metabolic disposition of curcumin. This is based predominantly
on experiments in which [.sup.3H] labeled curcumin was incubated
with inverted rat gut sacs.sup.28. This was later confirmed in
intestinal fractions from humans and rats. Intestinal mucosa, as
well as liver and kidney tissue from the rat, can glucurodinate and
sulfate curcumin, as judged by the analysis of differential amounts
of curcumin present before and after treatment of tissue extracts
with conjugate-hydrolyzing enzymes.sup.29. Thus, gut metabolism
contributes substantially to the overall metabolic yield generated
from curcumin in vivo. In human intestinal fractions, conjugation
with activated sulfuric or glucuronic acids was much more abundant,
whereas conjugation in human hepatic tissues was less extensive,
than in the rat tissues.sup.30.
[0008] Although p.o. administered curcumin has poor bioavailability
and only low or non-measurable blood levels were observed.sup.31,
this route of administration inhibits chemically induced skin and
liver carcinogenesis.sup.32, 33. Oral administration of curcumin
also inhibits the initiation of radiation-induced mammary and
pituitary tumors.sup.34. Similarly, in a study to assess the
curcumin levels in the colorectum, a daily dose of 3.6 g curcumin
achieves pharmacologically effective levels in the colorectum with
negligible distribution of curcumin outside the gut.sup.35.
[0009] Earlier Shobha et al.sup.36 had observed that administering
piperine along with curcumin enhances the bioavailability of
curcumin. However, the level of enhancement was only modest and no
curcumin could be detected after 3 hours even when supplemented
with piperine.
[0010] Although some questions remain unanswered regarding the
pharmacokinetics of curcumin in humans, there is no denying the
fact that considerable proportion of ingested curcumin is excreted
through feces and at least about one-half of absorbed curcumin is
metabolized. The quantity of curcumin that reaches tissues outside
the gut is probably pharmacologically insignificant. Several
studies have failed to demonstrate the positive in vitro results
with curcumin in in vivo animal and human studies due to lack of
absorption of curcumin after oral administration. To provide the
clinical benefits, curcumin must be absorbed from its oral route of
administration at a suitable rate, be distributed in adequate
concentration in the blood and remain in the system for a
sufficient period at an effective concentration level.
SUMMARY
[0011] Some embodiments provide a composition of a curcuminoid
mixture and added essential oil of turmeric. In some embodiments,
the weight ratio of the curcuminoid mixture to the added essential
oil of turmeric ranges from about 1:3 to about 99:1. In some
embodiments, the curcuminoid mixture includes curcumin,
demethoxycurcumin and bisdemethoxycurcumin. In some embodiments,
the essential oil of turmeric includes ar-turmerone. In some
embodiments, the essential oil of turmeric includes about 40-50%
ar-turmerone.
[0012] Some embodiments provide a method of treating rheumatoid
arthritis by administering a composition having a curcuminoid
mixture and added essential oil of turmeric.
[0013] Some embodiments provide a method of reducing visual
analogue scale for pain by administering a composition having
curcuminoid mixture and added essential oil of turmeric.
[0014] Some embodiments provide a method of decreasing disease
activity score by administering a composition having the
curcuminoid mixture and added essential oil of turmeric. Some
embodiments provide a method of improving patient response to ACR
criteria by administering composition of a curcuminoid mixture and
added essential oil of turmeric. Some embodiments provide a method
of reducing C-reactive protein levels by administering a
composition of a curcuminoid mixture and added essential oil of
turmeric. Some embodiments provide a method of reducing rheumatoid
Arthritis Factor by administering a composition of a curcuminoid
mixture and added essential oil of turmeric. Some embodiments
provide a method of decreasing joint pain by administering a
composition of a curcuminoid mixture and added essential oil of
turmeric. Some embodiments provide a method of improving walking
distance scores by administering a composition of a curcuminoid
mixture and added essential oil of turmeric. Some embodiments
provide a method of treating osteoarthritis by administering a
composition of a curcuminoid mixture and added essential oil of
turmeric. Some embodiments provide a method of treating Alzheimer's
disease by administering a composition of a curcuminoid mixture and
added essential oil of turmeric. Some embodiments provide a method
of improving mini mental state exam scores by administering a
composition of a curcuminoid mixture and added essential oil of
turmeric. Some embodiments provide a method of increasing Vitamin E
levels by administering a composition of a curcuminoid mixture and
added essential oil of turmeric. Some embodiments provide a method
of increasing serum amyloid beta levels by administering a
composition of a curcuminoid mixture and added essential oil of
turmeric. Some embodiments provide a method of disaggregating
amyloid beta by administering a composition of a curcuminoid
mixture and added essential oil of turmeric. Some embodiments
provide a method of lowering plasma isoprostane levels by
administering a composition of a curcuminoid mixture and added
essential oil of turmeric. Some embodiments provide a method of
treating depression by administering a composition of a curcuminoid
mixture and added essential oil of turmeric. Some embodiments
provide a method of improving response rate on Hamilton Depression
rate scale by administering a composition of a curcuminoid mixture
and added essential oil of turmeric. Some embodiments provide a
method if improving clinical global impression by Global Severity
comprising administering a composition of a curcuminoid mixture and
added essential oil of turmeric. Some embodiments provide a method
of improving clinical global impression by Global Change scale by
administering a composition of a curcuminoid mixture and added
essential oil of turmeric.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The above objectives and advantages of the disclosed
teachings will become more apparent by describing in detail
preferred embodiments thereof with reference to the attached
drawings in which:
[0016] FIG. 1 provides a graph showing the bioavailability of
curcumin in humans upon administration of (1) gelatin capsules,
which were prepared by admixing curcuminoid isolated from turmeric
with essential oil of turmeric, and, (2) gelatin capsules of
curcuminoid alone, which were prepared without adding essential oil
of turmeric to the curcuminoid isolated from turmeric. The x-axis
shows time in hours following administration of the gelatin
capsules. The y-axis shows the concentration of curcumin (ng/g) in
blood
[0017] FIG. 2 provides a graph showing the bioavailability of
curcumin in human upon administration of 1) gelatin capsule, which
were prepared by admixing curcuminoid with added essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio, 2) gelatin capsules
of curcuminoid alone, which were prepared without adding essential
oil of turmeric to the curcuminoid isolated from turmeric, 3)
gelatin capsules of raw turmeric powder alone, 4) gelatin capsules
of Essential oil of turmeric with 45% Ar-turmerone alone, 5)
gelatin capsules of essential oil of turmeric with 10-15%
Ar-turmerone alone, 6) gelatin capsule, which were prepared by
admixing curcuminoid with added essential oil of turmeric with 45%
Ar-turmerone in 12:1 ratio, The x-axis shows time in hours and
y-axis shows the concentration of curcumin (ng/g) in blood
[0018] FIG. 3 provides a comparison of the bioavailability of
curcumin from the curcuminoid mixture without added essential oil
of turmeric group and the curcuminoid mixture with added essential
oil of turmeric with 45% Ar-turmerone in a weight ratio ranging
from about 1:3 to 99:1. The x-axis shows the ratio of curcumin to
essential oil of turmeric and y-axis shows the AUC value of
curcumin
[0019] FIG. 4 provides a comparison of curcumin bioavailability
from 10:1 and 1:10 weight ratios of 1) curcuminoid (454.55 mg) with
added essential oil of turmeric (45.45 mg) with 45% Ar-turmerone in
10:1 ratio, 2) curcuminoid (20 mg) with added essential oil of
turmeric (2 mg) with 45% Ar-turmerone in 10:1 ratio, 3) curcuminoid
(20 mg) with added essential oil of turmeric (200 mg) with 45%
Ar-turmerone in 1:10 ratio, 4) curcuminoid (20 mg) with added
essential oil of turmeric (200 mg) with 10-15% Ar-turmerone in 1:10
ratio, 5) curcuminoid alone (454.55 mg), 6) curcuminoid alone (20
mg), 7) Essential oil of turmeric with 45% Ar-turmerone alone
(45.45 mg), 8) Essential oil of turmeric with 10-15% Ar-turmerone
alone (200 mg). The x-axis shows time in hours and y-axis shows the
concentration of curcumin (ng/g) in blood
[0020] FIG. 5 provides Method of preparation of Essential oil of
turmeric with varying concentration of Ar-turmerone.
[0021] FIG. 6 provides Table 9 (ACR response of different
groups)
[0022] FIG. 7 provides Table 12 (Joint pain measurements and %
response of patients in each group over 3 months)
[0023] FIG. 8 provides Table 13 (Joint line tenderness and %
response of patients in each group over 3 months)
[0024] FIG. 9 provides Table 14 (Walking distance scores and %
response of patients in each group over 3 months)
DETAILED DESCRIPTION
[0025] The disclosure relates to a product to enhance the
bioavailability of curcumin by mixing a suitable portion of the
volatile oil obtained from turmeric with the curcuminoids isolated
from turmeric.
[0026] As disclosed herein the term "curcuminoid" is a mixture of
curcumin, demethoxycurcumin and bisdemethoxycurcumin. In some
embodiments, curcumin is the major component of the curcuminoid
mixture. In some embodiments, demethoxycurcumin and
bisdemethoxycurcumin are minor components of the curcuminoid
mixture. In some embodiments, 95% of the crystals having
curcuminoid mixture are composed of curcumin, demethoxycurcumin and
bisdemethoxycurcumin.
[0027] The term "essential oil" or "essential oil of turmeric" is
also referred to as "volatile oil" or "volatile oil of turmeric."
The essential oil of turmeric is a mixture of oils. Essential oil
is obtained as a by-product during the extraction of curcumin or
curcuminoids from turmeric. In some embodiments, Ar-turmerone,
which is also referred to as turmerone, is the main constituent of
essential oil. In some embodiments, Ar-turmerone constitutes about
40-50% of the essential oil of turmeric. In some embodiments,
Ar-turmerone comprises about 45% of the essential oil of
turmeric.
[0028] As stated herein, the term "a" or "an" refers to one or
more.
[0029] As stated herein, the terms "isolated" and "purified" are
referred to interchangeably.
[0030] The volatile oil of turmeric was isolated by conventional
methods of steam distillation to isolate essential oils and is well
known in the art.
[0031] Curcumin is isolated from the de-oiled turmeric by solvent
extraction. Suitable solvents for this purpose include acetone,
hexane, ethyl acetate, dichloroethane, chloroform, etc. The
extraction is conveniently carried out at moderate temperatures
(40-55.degree. C.) and the solvent is partially removed to yield a
concentrate containing 30-60% solids. This solution is cooled to
obtain crystals of curcuminoid which are isolated by any suitable
method such as filtration or centrifugation. Analysis of this
product, which is composed of the isolated crystals of curcumoid
mixture, showed that, in some embodiments, 95% of the product was
composed of curcumin, demethoxycurcumin and
bisdemethoxycurcumin.
[0032] The disclosure provides a composition having curcuminoid and
an essential oil of turmeric. Curcumin and the volatile oils of
curcumin are mixed and blended to get a uniform product. If small
percentages (.about.5%) of the essential oil of turmeric are added
to the curcuminoid, then the bioavailability of curcumin is
significantly enhanced. Accordingly, a composition of curcuminoid
admixed with a suitable proportion of Ar-turmerone (the main
component of the turmeric essential oil) is provided.
[0033] In some embodiments, the weight ratio of the curcuminoid to
the essential oil of turmeric ranges from about 1:1 to about 90:1.
In some embodiments, the weight ratio of the curcuminoid to the
essential oil of turmeric ranges from about 1:1 to about 3:1. The
weight ratio of the curcuminoid to the essential oil of turmeric
can be varied from about 3:1 to about 99:1. In some embodiments,
the weight ratio of the curcuminoid to the essential oil of
turmeric ranges from about 1:1 to about 70:1. In some embodiments,
the weight ratio of the curcuminoid to the essential oil of
turmeric ranges from about 1:1 to about 45:1. In some embodiments,
the weight ratio of the curcuminoid to the essential oil of
turmeric ranges from about 3:1 to about 50:1. In some embodiments,
the weight ratio of the curcuminoid to the essential oil of
turmeric ranges from about 8:1 to about 25:1. In some embodiments,
the weight ratio of the curcuminoid to the essential oil of
turmeric is about 90:7. In some embodiments, the weight ratio of
the curcuminoid to the essential oil of turmeric is about 90:8. In
some embodiments, the weight ratio of the curcuminoid to the
essential oil of turmeric is about 90:9. In some embodiments, the
weight ratio of the curcuminoid to the essential oil of turmeric is
about 89:9. In some embodiments, the weight ratio of the
curcuminoid to the essential oil of turmeric is about 89:8. In one
embodiment, the ratio is about 85:15. In another embodiment, the
ratio is about 92:8. In another embodiment, the ratio is about
95:5. In another embodiment the weight ratio is about 10:1. In some
embodiments, the weight ratio is about 12:1. In some embodiments,
the weight ratio of the curcuminoid to the essential oil of
turmeric is about 1:2. In some embodiments, the weight ratio of the
curcuminoid to the essential oil of turmeric is about 2:1. In some
embodiments, the weight ratio of the curcuminoid to the essential
oil of turmeric ranges from about 1:3 to about 99:1.
[0034] In some embodiments of the composition having curcuminoid
and added essential oil of turmeric, the curcuminoid ranges, by
weight, from about 24% to about 96%. In some embodiments of the
composition having curcuminoid and added essential oil of turmeric,
the curcuminoid ranges, by weight, from about 30% to about 96%. In
some embodiments of the composition of curcuminoid and added
essential oil of turmeric, the curcuminoid ranges, by weight, from
about 40% to about 75%. In some embodiments of the composition
having curcuminoid and added essential oil of turmeric, the
curcuminoid ranges, by weight, from about 50% to about 60%.
[0035] In some embodiments of the composition having curcuminoid
and added essential oil of turmeric, the demethoxycurcumin ranges,
by weight, from about 5% to about 25%. In some embodiments of the
composition having curcuminoid and added essential oil of turmeric,
the demethoxycurcumin ranges, by weight, from about 10% to about
20%.
[0036] In some embodiments of the enhanced curcumin bioavailability
composition having curcuminoid and added essential oil of turmeric,
the bisdemethoxycurcumin ranges, by weight, from about 2% to about
7%.
[0037] In some embodiments of the enhanced curcumin bioavailability
composition having curcuminoid and added essential oil of turmeric,
the essential oil of turmeric ranges, by weight, from about 4% to
about 50%. In some embodiments, of the composition of curcuminoid
and added essential oil having turmeric, the essential oil of
turmeric ranges, by weight, from about 15% to about 50%. In some
embodiments of the composition having curcuminoid and added
essential oil of turmeric, the essential oil of turmeric ranges, by
weight, from about 20% to about 50%. In some embodiments of the
composition having curcuminoid and added essential oil of turmeric,
the essential oil of turmeric ranges, by weight, from about 25% to
about 40%.
[0038] Some embodiments include a composition having a curcuminoid
and an added amount of essential oil of turmeric, wherein the
essential oil is present in an amount sufficient to cause an
enhancement of bioavailability of the curcumin when administered to
a human as compared to the bioavailability of curcumin upon
administration of a composition prepared using curcuminoid alone
without adding essential oil. Curcumin levels in blood samples is
greater following administration of a composition having
curcuminoid and added essential oil of turmeric as compared to a
composition of curcuminoid alone. In some embodiments, the
enhancement of bioavailability of curcumin following administration
of a composition of curcuminoid and added essential oil of turmeric
ranges from about 5-fold to about 16-fold. Enhancement of
bioavailability of curcumin from a composition prepared by mixing
curcuminoid and essential oil of turmeric is provided in FIG. 1 and
Example 1.
[0039] In some embodiments, a composition of a curcuminoid and
added essential oil of turmeric is orally administered to a
human.
[0040] A method of extraction of curcuminoids includes treating
dried and powdered rhizomes of turmeric with a solvent, followed by
solvent stripping, and steam distilling to obtain an essential-oil
free extract. The essential oil-free extract is cooled to about
4.degree. C. to allow the curcuminoids to crystallize. The
curcuminoids are then separated by filtration, centrifugation or
any other method of solid-liquid separation well-known in the art.
In some embodiments, 95% of the separated crystals are composed of
curcumin, demethoxycurcumin and bisdemethoxycurcumin.
[0041] Curcumin is isolated from the de-oiled turmeric by solvent
extraction. Suitable solvents for this purpose include acetone,
hexane, ethyl acetate, dichloroethane, chloroform, etc. The
extraction is conveniently carried out at moderate temperatures
(about 40.degree. C. to about 55.degree. C.) and the solvent is
partially removed to yield a concentrate containing 30-60% solids.
This solution is cooled to obtain crystals having curcuminoid
mixture which are isolated by any suitable method such as
filtration or centrifugation. 95% of this product (crystals) was
composed of the curcuminoid mixture. The remaining may contain
traces of essential oil plus other constituents such as
carbohydrates, etc, which were not characterized.
[0042] The disclosure provides a method of extracting a curcuminoid
from turmeric including:
drying rhizomes of turmeric to form a dried turmeric; powdering the
dried turmeric to form a powdered turmeric; treating the powdered
turmeric with a solvent selected from the group consisting of ethyl
acetate, acetone, hexane, ethylene dichloride, ethyl alcohol, and
combinations thereof to form a solution; stripping the solvent from
the solution to form an extract; cooling the extract to about
4.degree. C. to form crystals and a liquid, wherein the liquid
comprises the essential oil of turmeric and a resin; and separating
the crystals from the liquid to obtain the curcuminoid
crystals.
[0043] In some embodiments, curcumin, demethoxycurcumin and
bisdemethoxycurcumin comprise 95% of the curcuminoid crystals.
[0044] Some embodiments include a method of extracting a
curcuminoid from turmeric by drying rhizomes of turmeric to form
dried turmeric. The dried turmeric is powdered to form powdered
turmeric. The powdered turmeric is treated with a solvent selected
from the group consisting of ethyl acetate, acetone, hexane, and
combinations thereof to form a solution. The solvent is stripped
from the solution to form an extract. The extract is cooled to
about 4.degree. C. to form crystals having curcuminoid mixture,
and, a liquid. The liquid comprises the essential oil of turmeric
and a resin. The crystals having the curcuminoid mixture are
separated from the liquid. In some embodiments, 95% of the crystals
having the curcuminoid mixture is composed of the curcuminoid
mixture, namely, curcumin, demethoxycurcumin and
bisdemethoxycurcumin.
[0045] The volatile oil of turmeric was isolated by conventional
methods of steam distillation to isolate essential oils and is well
known in the art.
[0046] Curcuminoid and the essential oil are blended in a suitable
proportion by a process including, suspending the curcuminoid in
about 3 to 5 times its quantity of water, mixing in the essential
oil, pulverizing in a colloidal mill into fine slurry, and
stripping the slurry off water under heat and vacuum to obtain a
uniform blend. Five hundred milligram capsules are made from this
blend for human consumption.
[0047] The disclosure provides a method of preparing a composition
including a curcuminoid and an essential oil of turmeric
including:
suspending the curcuminoid in water to form a suspension: adding
the essential oil to the suspension to form a mixture; homogenizing
the mixture to obtain a fine slurry; and drying the fine slurry
under heat and vacuum to form a uniform blend of a composition
including the curcuminoid and the essential oil of turmeric. Drying
of the fine slurry under heat and vacuum can be performed using a
vaccumized desolventiser with a stirrer.
[0048] A composition of curcuminoid and added essential oil of
turmeric can be prepared by suspending the curcuminoid in water to
form a suspension. Essential oil is added to the suspension to form
a mixture. The mixture is homogenized to form fine slurry. The fine
slurry is dried under heat and vacuum to form a uniform blend of a
composition of curcuminoid and an essential oil of turmeric. The
fine slurry can be dried under heat and vacuum using, for example,
a vaccumized desolventiser having a stirrer.
[0049] In one embodiment, a homogeneous mixture of curcuminoid and
water is prepared by suspending the curcuminoid in water to form a
suspension. The suspension is homogenized to obtain fine slurry.
The fine slurry is dried under heat and vacuum to form a
composition having a homogeneous mixture of the curcuminoid and
water.
[0050] The disclosure provides a method of preparing a homogeneous
mixture having a curcuminoid and water by,
suspending a curcuminoid in water to form a suspension;
homogenizing the suspension to obtain a fine slurry; and drying the
suspension under heat and vacuum to form a composition including a
homogeneous mixture of the curcuminoid and water.
[0051] Hard gelatin capsules, which contain about 500 mg of a blend
of curcuminoid and essential oil of turmeric, are prepared. A 500
mg capsule for enhanced bioavailability of curcumin, having the
curcuminoid mixture and essential oil of turmeric in a weight ratio
of about 95:5 is expected to contain about 460 mg of curcuminoid
and about 40 mg of essential oil. The curcuminoid mixture is
composed of curcumin, demethoxycurcumin and bisdemethoxycurcumin.
In terms of active constituents, the respective figures would be
about 437 mg of curcumin and about 18 mg of Ar-turmerone. In some
embodiments, the gelatin capsules have about 300 mg to about 460 mg
of curcuminoid and about 40 mg to about 375 mg of essential oil of
turmeric. In some embodiments of the composition having curcumin
and added essential oil of turmeric, wherein the gelatin capsule
comprises 500 mg of a blend including the curcuminoid and the
essential oil, the curcuminoid in the blend ranges from about 300
mg to about 485 mg, and the Ar-turmerone in the blend ranges from
about 5 mg to about 200 mg.
[0052] Gelatin capsules with curcuminoid alone but without added
essential oil were similarly prepared to study the comparative
efficacies of the capsule containing added essential oil versus the
capsule prepared without adding essential oil.
[0053] The disclosure provides a method of preparing a gelatin
capsule having a curcuminoid and an essential oil of turmeric by
suspending a curcuminoid in water to form a suspension. Then adding
an essential oil to the suspension to form a mixture. Then
homogenizing the mixture to obtain a fine slurry. Then drying the
slurry under heat and vacuum to form a uniform blend of a
composition having the curcuminoid and the essential oil of
turmeric. Then compressing the blend into the hard gelatin
capsule.
[0054] Hard gelatin capsules of a composition having a curcuminoid
and an added essential oil of turmeric can be prepared by
compressing a uniform blend of the composition into a capsule.
Gelatin capsules are prepared by standard methods using instrument
such as a capsule tilling machine manufactured by Pam
Pharmaceuticals, Mumbai, India.
[0055] The disclosed compositions can be administered to a human
for treating conditions including various human cancers such as
colon cancer, prostate cancer, breast cancer, lung cancer, oral
cancers, leukemias, etc, diabetes, depression, epilepsy, and
various chronic inflammatory diseases such as rheumatoid arthritis,
Alzheimer's disease, inflammatory bowel diseases (Crohn's disease,
ulcerative colitis), coronary artery diseases, fibrosis and
cirrhosis of liver, pancreatitis, abdominal aortic aneurysms,
drug-resistant malaria, psoriasis, cystic fibrosis, HIV, wound
healing, central nervous system disorders and potentially many
other diseases. Another embodiment of the present invention
provides for an application of a formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio for
oral supplementation against rheumatoid arthritis and an improved
method of delivering curcumin in human blood and tissues and
ensuring better bioavailability in humans for the prophylaxis and
treatment for active rheumatoid arthritis patients, maintenance
therapy for preventing flare up of symptoms and as add on therapy
with antiarthritic medications. In some embodiments, the ratio of
curcuminoid mixture to essential oil of turmeric is 12:1 ratio for
oral supplementation against rheumatoid arthritis and an improved
method of delivering curcumin in human blood and tissues and
ensuring better bioavailability in humans for the prophylaxis and
treatment for active rheumatoid arthritis patients, maintenance
therapy for preventing flare up of symptoms and as add on therapy
with antiarthritic medications. Raw turmeric powder, essential oil
of turmeric with 45% Ar-turmerone, essential oil of turmeric with
10-15% Ar-turmerone, curcuminoid with essential oil of turmeric
with 45% Ar-turmerone in 1:10 ratio, curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 1:1 ratio, curcuminoid 24%
with essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio,
curcuminoid with essential oil of turmeric with 10-15% Ar-turmerone
in 10:1 ratio, formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio or
curcuminoids 95% were given to patients with active rheumatoid
arthritis for 2 months duration in a dose of 500 mg capsules twice
daily. Formulation of curcuminoid with essential oil of turmeric
with 45% Ar-turmerone in 10:1 and 12:1 ratios were able to
significantly decrease disease activity score, total number of
swollen and painful joints and erythrocyte sedimentation rate. The
patients administered formulation of Curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 10:1 and 12:1 ratios, also
showed significant improvement when assessed according to the
American College of Rheumatology criteria, functional status and
pain score. The inflammatory marker C reactive protein (CRP), anti
streptolysin O (ASO) values and rheumatoid arthritis factor (RA)
also drastically decreased in patients taking formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratios. Similar benefits were not evidenced in any of
the patients given curcuminoids 95% alone in similar dose. The
patients who were given maintenance therapy of formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratios alone after 2 months continued to be
asymptomatic during the follow up phase of 4 more months.
[0056] Another embodiment of the present invention provides for
application of a formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio for oral
supplementation against osteoarthritis and an improved method of
delivering curcumin in the human blood and tissues and ensuring
bioavailability in humans for the prophylaxis and treatment for
osteoarthritic patients, maintenance therapy for preventing flare
up of symptoms and as add on therapy with antiarthritic
medications. In some embodiments, the ratio of curcuminoid mixture
to essential oil of turmeric is 12:1 ratio for oral supplementation
against osteoarthritis and an improved method of delivering
curcumin in the human blood and tissues and ensuring
bioavailability in humans for the prophylaxis and treatment for
osteoarthritic patients, maintenance therapy for preventing flare
up of symptoms and as add on therapy with antiarthritic
medications. Osteoarthritic patients were given Raw turmeric
powder, essential oil of turmeric with 45% Ar-turmerone, essential
oil of turmeric with 10-15% Ar-turmerone, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:1 ratio, curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio, formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 ratio, Curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 12:1 ratio, and curcuminoids 95% in a dose of 500
mg twice daily for 3 months. Almost all patients in formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratio group had significant improvement in the joint
tenderness, crepitus, joint swelling, range of movements and gait.
In the group given curcuminoids 95%, majority of patients remained
symptomatic throughout the study and had to be started on analgesic
drugs and antiarthritic medications before the end of the
study.
[0057] Another embodiment of the present invention provides for
application of formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio for oral
supplementation in patients with Alzheimers disease and an improved
method of delivering curcumin in the human blood and tissues and
ensuring bioavailability in humans to delay the onset of
neurodegenerative diseases like Alzheimers disease, for treatment
and symptomatic improvement in patients with Alzheimers disease. In
some embodiments, the ratio of curcuminoid mixture to essential oil
of turmeric is 12:1 ratio for oral supplementation in patients with
Alzheimers disease and an improved method of delivering curcumin in
the human blood and tissues and ensuring bioavailability in humans
to delay the onset of neurodegenerative diseases like Alzheimers
disease, for treatment and symptomatic improvement in patients with
Alzheimers disease. Alzheimers disease patients were given raw
turmeric powder, essential oil of turmeric with 45% Ar-turmerone,
essential oil of turmeric with 10-15% Ar-turmerone, curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:1 ratio, curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio, formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 ratio, Curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 12:1 ratio or curcuminoids 95% in a dose of 3
gm/day. The patients on curcuminoid with essential oil of turmeric
with 45% Ar-turmerone in 10:1 and 12:1 ratio formulations
significantly benefitted cognitive performance, functional
impairment, behavior and global function compared with commercial
curcumin formulation in the same dose. The serum level of Amyloid
beta increased significantly in group taking the formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratios reflecting the ability of formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratios to disaggregate Amyloid beta deposits in the
brain compared to curcuminoids 95%. It was also associated with an
increase in the Vitamin E content between curcuminoids 95% and
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 and 12:1 ratios, the values being
significantly higher for the formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 and 12:1
ratio groups. Another human study which supplemented formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratios to patients with mild cognitive impairment
over a period of 2 years showed that the risk of development of
dementia and Alzheimers disease is reduced drastically in all
patients on formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 and 12:1 ratios therapy
while majority of the patients in curcuminoids 95% progressed to
dementia and 50% to Alzheimers disease within 2 years.
[0058] Another embodiment of the present invention provides for
application of a formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 and 12:1 ratios for oral
supplementation in patients with depression and an improved method
of delivering curcumin in the human blood and tissues and ensuring
bioavailability in humans for treatment of patients with
depression. Patients with depression were given raw turmeric
powder, essential oil of turmeric with 45% Ar-turmerone, essential
oil of turmeric with 10-15% Ar-turmerone, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:1 ratio, curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio, formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 ratio, curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 12:1 ratio and curcuminoids 95% in a dose of 500 mg
twice daily for 8 weeks. Almost all patients in formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratio groups had significant reduction in the
severity of depression as assessed by the Hamilton depression scale
and showed significant reduction in severity of illness and
improvement and response to treatment as assessed by the clinical
global impression scale.
[0059] The inventive compositions have the additional benefit that
the essential oil components are themselves bioactive (for example,
see Yue, A et al, Int. J. Mol. Med., 2002, 9:481-84; Jayaprakasha,
G. K. et al, Z. Naturforsch., 2002, 57:828-35) and thus are
expected to synergistically enhance the bioactivity of
curcumin.
[0060] It will be readily understood by the skilled artisan that
numerous alterations may be made to the examples and instructions
given herein. These and other objects and features of present
invention will be made apparent from the following examples. The
following examples as described are not intended to be construed as
limiting the scope of the present invention.
EXAMPLES
Example 1
[0061] Nine healthy human volunteers aged between 25 and 45 years
of age were selected for the study. They were given capsules of
curcuminoid mixture alone and capsules of enhanced curcumin
capsules at the dosage of 50 mg curcuminoid/kg body weight.
Enhanced curcumin is a composition having curcuminoid and added
essential oil of turmeric. In the enhanced curcumin capsules the
weight ratio of curcuminoid to essential oil of turmeric was 10:1.
The subjects were advised to take curcuminoid capsules first. Blood
samples were collected at zero hour and periodically at one-hour or
half-hour intervals for 8 hours. After a washout period of one
week, the same protocol was repeated with enhanced curcumin
bioavailability capsules. The whole blood was extracted
exhaustively with ethyl acetate to recover curcumin. The ethyl
acetate extract was analyzed by HPLC on a RP-C18 column
(25.times.4.5 mm) using tetrahydrofuran (THF) as solvent and UV
detection at 420 nm. The eluant flow rate was 1 ml/min. Efficiency
of the extraction procedure for recovering curcumin from blood
samples was determined by measuring recovery of curcumin upon
extraction of normal blood samples. Normal blood samples were
collected by adding curcumin to normal blood (of persons not
consuming curcumin or enhanced curcumin capsules). Curcumin was
extracted from the normal blood samples by the above procedure. The
efficiency of recovery of curcumin by the above extraction
procedure was estimated to range between 80.12% and 86.49%.
[0062] A Typical Result is Given in Table 1.
TABLE-US-00001 TABLE 1 Curcumin content in blood (ng/g) Enhanced
curcumin Curcumin bioavailability Time (h) composition composition
0.0 0.0 0 0.5 3.17 7.85 1.0 7.57 6.23 1.5 4.42 4.84 2.0 13.81 11.95
2.5 9.61 19.22 3.0 5.67 92.59 4.0 8.2 24.33 6.0 1.62 8.43 8.0 1.11
5.09
[0063] The results are also graphically represented in FIG. 1.
Following administration of capsules having a 10:1 weight ratio of
curcuminoid to essential oil of turmeric, the peak absorption of
curcumin occurred at 3 hr. Furthermore, curcumin persisted in small
amounts in the blood till 8 hr beyond which measurements were not
made. At peak absorption the enhancement of bioavailability ranged,
among the 9 persons, between 5 and 16-fold with a mean value of
10.62.
Example 2
[0064] Human subjects were administered capsule (4.times.500 mg)
prepared with curcuminoids and without added essential oil of
turmeric (curcuminoids group in Table 2). Blood was drawn at
different intervals (one hour) and tested for curcumin content.
After two weeks the same groups were administered an enhanced
curcumin bioavailability composition (4.times.500 mg). The varying
ratios of curcuminoids and added essential oil of turmeric are as
provided in Table 2. Blood from the enhanced curcumin group was
drawn at different intervals and tested for curcumin content. As
seen in Table 2, bioavailability of curcumin was greater when
enhanced curcumin capsules were administered as compared to
administration of capsule containing curcuminoids without added
essential oil of turmeric.
TABLE-US-00002 TABLE 2 Analysis of curcumin content in blood. Ratio
of curcuminoids Curcumin content in blood (AUC) to added essential
oil of Curcuminoid mixture Enhanced turmeric alone group curcumin
group 90:4 725 5147.5 90:5 820 5904 90:6 750 5475 90:7 900 6300.0
90:8 752 5367.6 90.9 782 5552.2 89.9 696 5080.8 90:10 760 5320 80:9
726 5227.2 80:20 754 5315.7 90:20 765 5469.75 70:20 810 5147.5
[0065] The ratios of curcuminoids to added essential oil of
turmeric in the enhanced curcumin bioavailability composition
provided in Table 2 can also be represented as shown in Table 3.
The unit of curcumin content in blood is provided as area under the
curve (AUC).
TABLE-US-00003 TABLE 3 Ratio of curcuminoids to added essential oil
in compositions for enhanced curcumin bioavailability Ratio of
Ratio of Curcuminoids to added curcuminoids to added essential oil
of turmeric essential oil of turmeric 90:4 22.5:1 90:5 18:1 90:6
15:1 90:7 12.9:1 90:8 11.25:1 90:9 10:1 90:10 9:1 80:9 8.9:1 80:20
4:1 90:20 4.5:1 70:20 3.5:1
Example 3
[0066] Bioavailability of curcumin from essential oil of turmeric
alone, raw turmeric powder, curcuminoid alone, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio and
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
12:1 ratio etc.
[0067] Nine healthy human volunteers were given capsules containing
475 mg of curcuminoid mixture without added essential oil of
turmeric (the capsule was made up to 500 mg by addition of rice
powder) at a dosage of 50 mg curcuminoid/kg body weight. Blood was
drawn from the subjects at baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6
and 8 hours post drug. The same subjects after a washout period of
one week were given 500 mg capsule having 454.55 mg curcuminoid
mixture with 45.45 mg essential oil of turmeric, wherein the
essential oil of turmeric had about 45% Ar-turmerone (the weight
ratio of curcuminoid mixture to added essential oil of turmeric was
10:1) at a dosage of 50 mg curcuminoid/kg body weight of the
subject. Blood was drawn from the subjects at baseline, 0.5, 1,
1.5, 2, 2.5, 3, 4, 6 and 8 hours post drug. Table 4 provides the
amount of curcumin in nanograms per gram of blood for the subjects,
which was averaged for each time point.
[0068] The above protocol was repeated with the following three
formulations:
(1) A capsule having 500 mg of essential oil of turmeric, wherein
the essential oil of turmeric had 10-15% Ar-turmerone, was
administered at a dosage of 50 mg of essential oil of turmeric per
kg body weight of the human subject: (2) A capsule having 500 mg of
essential oil of turmeric, wherein the essential oil of turmeric
had 45% Ar-turmerone, administered at a dosage of 50 mg of
essential oil of turmeric per kg body weight of the human subject;
and (3) A capsule having 500 mg of raw turmeric powder was
administered at a dosage of 50 mg of raw turmeric powder/kg body
weight of the human subject. (4) A capsule having 500 mg of 461.5
mg curcuminoid mixture with 38.45 mg essential oil of turmeric,
wherein the essential oil of turmeric had about 45% Ar-turmerone
(the weight ratio of curcuminoid mixture to added essential oil of
turmeric was 12:1)
[0069] Whole blood drawn from the subjects was extracted
exhaustively with ethyl acetate to recover curcumin. The ethyl
acetate extract was analyzed by HPLC on a RP-C18 column
(25.times.4.5 mm) using tetrahydrofuran (THF) as solvent and UV
detection at 420 nm. The eluent flow rate was 1 ml/min. As seen in
Table 4 and FIG. 2, curcumin bioavailability in human subjects
following administration of raw turmeric was low. Curcumin
bioavailability following administration of negative controls,
namely, essential oil fractions having 10-15% or 45% Ar-turmerone
was not detectable (referred to as Nd in Table 4). Whereas,
curcumin was detectable in human subjects following administration
of curcuminoid mixture without added essential oil of turmeric, the
bioavailability of curcumin was enhanced by 6.7 fold upon
administration of a composition having curcuminoid mixture and
essential oil of turmeric with 45% Ar-t in 10:1 ratio and the
bioavailability of curcumin was enhanced by 8.3 fold upon
administration of a composition having curcuminoid mixture and
essential oil of turmeric with 45% Ar-t in 12:1 ratio.
[0070] As seen in FIG. 2, the maximum concentration of curcumin in
blood (Cmax of curcumin) was 13.81 ng/g upon administration of the
negative control capsule having curcuminoid mixture without the
added essential oil of turmeric, whereas, the Cmax of curcumin was
92.59 ng/g upon administration of the positive control capsule
having curcuminoid mixture and added essential oil of turmeric with
45% Ar-t in 10:1 ratio. The Cmax of curcumin was 114.59 ng/g upon
administration of the positive control capsule having curcuminoid
mixture and added essential oil of turmeric with 45% Ar-t in 12:1
ratio. Therefore, comparison of the Cmax values shows that
bioavailability of curcumin upon oral administration of the claimed
composition having curcuminoid mixture and added essential oil of
turmeric with 45% Ar-t in 10:1 was 6.7 times greater than
bioavailability of curcumin upon oral administration of curcuminoid
mixture without the added essential oil of turmeric.
Bioavailability of curcumin upon oral administration of the claimed
composition having curcuminoid mixture and added essential oil of
turmeric with 45% Ar-t in 12:1 ratio was 8.3 times greater than
bioavailability of curcumin upon oral administration of curcuminoid
mixture without the added essential oil of turmeric.
TABLE-US-00004 TABLE 4 Negative and Positive Control experiments
Curcumin content in blood (ng/g) Curcuminoid Curcuminoid mixture
with mixture with Essential Curcuminoid added added Essential oil
of mixture essential oil essential oil oil of turmeric without of
turmeric of turmeric Time Raw turmeric (10-15% added (45% Ar- (45%
Ar- in turmeric (45% Ar- Ar- Essential oil turmerone) turmerone)
hours powder turmerone) turmerone) of turmeric 10:1 12:1 0 0 0 0 0
0 0 0.5 Nd Nd Nd 3.17 7.85 15.2 1 1.05 Nd Nd 7.57 6.23 23.4 1.5 Nd
Nd Nd 4.42 4.84 32.8 2 2.1 Nd Nd 13.81 11.95 69.8 2.5 Nd Nd Nd 9.61
19.22 114.59 3 Nd Nd Nd 5.67 92.59 88.5 4 Nd Nd Nd 8.2 24.33 49.4 6
Nd Nd Nd 1.62 8.43 20.74 8 Nd Nd Nd 1.11 5.09 10.8
Example 4
[0071] Bioavailability of curcumin from capsules having a weight
ratio of curcuminoid mixture to essential oil of turmeric ranging
from about 1:3 to 99:1
[0072] Human volunteers aged between 25 and 45 years were
randomized into separate groups having 3 subjects each (Groups A
through W). For control experiment, at the initial time point,
subjects in all the groups were four 500 mg capsules of C without
added E having about 475 mg of curcuminoid mixture. Then blood was
drawn from the subjects at different time periods (0.5, 1, 1.5, 2,
2.5, 3, 4, 6 and 8 hours post drug) and the amount of curcumin in
blood (in nanograms per gram of blood) was determined. The average
values of curcumin in blood at each time period was plotted in
separate graphs for each of the groups (A to W). For each of the
groups, the area under the curve (AUC) of curcumin was calculated
from the figure. In Table 5 and FIG. 3, AUC is provided as
nanograms of curcumin per gram of blood.
[0073] After a wash out period of 2 weeks, subjects in groups A
through W were given four 500 mg capsules each, wherein set of 4
capsules had varying ratios of curcuminoid mixture to added
essential oil of turmeric (referred to as C with added E capsule in
Table 5), and wherein the essential oil of turmeric in the capsules
had 45% Ar-turmerone. The ratio of curcuminoid mixture to essential
oil of turmeric in the capsules ranged from about 99:1 to about
1:3. Some of the could be expressed as more than one type of ratio,
for example, as 95:5 or 19:1; 90:4 or 22.5:1; 90:5 or 18:1; 90:6 or
15:1; 90:7 or 12.9:1; 90:8 or 11.3:1; 90:9 or 10:1; 90:10 or 9:1;
90:20 or 4.5:1; 89:9 or 9.8:1; 80:9 or 8.8:1; 80:20 or 4:1; 70:20
or 3.5:1; 75:25 or 3:1; 60:30 or 2:1; 50:50 or 1:1, 30:60 or 1:2
and 25:75 or 1:3 and therefore the ratios are referred to
accordingly in Table 5.
[0074] As shown in Table 5, each of the groups was administered a
capsule having a different weight ratio of curcuminoid mixture to
essential oil of turmeric (referred to as C:E). Blood was drawn
from the subjects and the AUC was calculated as described above.
The curcumin content in the blood for each group was expressed as
AUC, which was used to compare the bioavailability of curcumin from
the different treatment groups.
[0075] Table 5 and FIG. 3 provide a comparison of the
bioavailability of curcumin from the curcuminoid mixture without
added essential oil of turmeric as the control group and the
curcuminoid mixture with added essential oil of turmeric with 45%
Ar-turmerone.
[0076] As seen in Table 5 and FIG. 3, curcumin bioavailability upon
administration of capsules having curcuminoid mixture with added
essential oil of turmeric with 45% Ar-turmerone resulted in an
enhancement of bioavailability ranging from 1.8 to 7.3 fold over
the curcumin bioavailability that was observed when negative
control capsules having curcuminoid mixture without added essential
oil of turmeric were administered. The results in Table 5 further
show that the enhancement of bioavailability was observed over the
entire claimed range of the ratio about 1:3 to about 99:1 of
curcuminoid mixture to essential oil of turmeric.
TABLE-US-00005 TABLE 5 Bioavailability of curcumin from
compositions having weight ratios of curcuminoid mixture to added
essential oil of turmeric ranging from 1:3 to 99:1 C without added
E C with added E C (ng) C (ng) Dosage C (mg) per gm C (mg) E (mg)
per gm of 4 caps per of blood per per blood Group Ratio of C:E each
capsule (AUC) capsule capsule (AUC) A 99:1 500 mg 475 771 495 5
3855 B 95:5 or 19:1 500 mg 475 786 475 25 5515 C 90:4 or 22.5:1 500
mg 475 725 478.72 21.28 5147.5 D 90:5 or 18:1 500 mg 475 820 473.68
26.32 5904 E 90:6 or 15:1 500 mg 475 750 468.75 31.25 5475 F 90:7
or 12.9:1 500 mg 475 900 463.77 36.23 6300 G 90:8 or 11.3:1 500 mg
475 752 459.35 40.65 5367.6 H 90:9 or 10:1 500 mg 475 782 454.55
45.45 5552.2 I 90:10 or 9:1 500 mg 475 760 450 50 5320 J 90:20 or
4.5:1 500 mg 475 765 409.1 90.9 5469.75 K 89:9 or 9.8:1 500 mg 475
696 453.7 46.3 5080.8 L 80:9 or 8.8:1 500 mg 475 726 448.98 51.02
5227.2 M 80:20 or 4:1 500 mg 475 754 400 100 5315.7 N 70:20 or
3.5:1 500 mg 475 810 388.89 111.11 5147.5 O 70:1 500 mg 475 769 493
7 5124 P 60:1 500 mg 475 725 491.8 8.2 5200 Q 50:1 500 mg 475 749
490.2 9.8 5284 R 40:1 500 mg 475 737 487.8 12.2 5310 S 75:25 or 3:1
500 mg 475 756 375 125 4158 T 60:30 or 2:1 500 mg 475 742 333.3
166.6 3635.8 U 50:50 or 1:1 500 mg 475 788 250 250 2537 V 30:60 or
1:2 500 mg 475 715 166.6 333.3 1651 W 25:75 or 1:3 500 mg 475 726
125 375 1276
Example 5
[0077] Comparison of curcumin bioavailability from 10:1 and 1:10
weight ratios of curcuminoid mixture to essential oil of
turmeric.
[0078] Nine healthy human volunteers were given four 500 mg
capsules having 20 mg curcuminoid mixture without added essential
oil of turmeric (referred to as 20 mg C in Table 6). Blood was
drawn from the subjects at baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6
and 8 hours post drug. Following one week washout period, the same
nine subjects were given four 500 mg capsules having 200 mg of
essential oil of turmeric having 10 to 15% Ar-turmerone. Blood was
drawn from the subjects at baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6
and 8 hours post drug.
[0079] With one week washout period between treatments, the
subjects were tested for the following treatments, wherein four of
500 mg capsules were administered to each subject. If any of the
capsules had less than 500 mg of the test component such as
curcuminoid mixture or essential oil or the combination of
curcuminoid mixture and essential oil, then the capsules were made
up to 500 mg by addition of a placebo, e.g., rice powder. In one
treatment, each capsule had a 1:10 ratio of curcuminoid mixture to
added essential oil of turmeric. Each capsule contained 20 mg
curcuminoid and 200 mg essential oil of turmeric, wherein the
essential oil of turmeric had 10 to 15% Ar-turmerone (referred to
as Ar-t in Table 6).
[0080] In another treatment, each capsule had a 1:10 ratio of
curcuminoid mixture to added essential oil of turmeric, wherein the
essential oil had 45% Ar-turmerone. Each capsule contained 20 mg
curcuminoid and 200 mg essential oil of turmeric. The capsule is
referred to as 20 mg C: 200 mg E=1:10 (E had 10-15% Ar-t) in Table
6.
[0081] In another treatment, the capsule had a 10:1 ratio of
curcuminoid mixture to added essential oil of turmeric, wherein the
essential oil had 45% Ar-turmerone. Each capsule contained 20 mg
curcuminoid and 2 mg essential oil of turmeric. The capsule is
referred to as 20 mg C: 2 mg E=10:1 (E had 45% Ar-t) in Table
6.
[0082] In another treatment, each capsule had curcuminoid mixture
without the added essential oil of turmeric. Each capsule contained
454.55 mg curcuminoids. The capsule is referred to as 454.55 mg C
without added E in Table 6.
[0083] In another treatment, each capsule had essential oil of
turmeric having 45% Ar-turmerone. Each capsule contained 45.45 mg
essential oil of turmeric. The capsule is referred to as 45.45 mg E
(45% Ar-t) in Table 6.
[0084] In another treatment, each capsule had curcuminoid mixture
along with added essential oil of turmeric with 45% Ar-turmerone at
a 10:1 ratio. Each capsule contained 454.55 mg curcuminoids and
45.45 mg of essential oil of turmeric. The essential oil of
turmeric had 45% Ar-turmerone. The capsule is referred to as 454.55
mg C: 45.45 mg E=10:1 (E had 45% Ar-t) in Table 6.
[0085] Whole blood from the subjects was extracted exhaustively
with ethyl acetate to recover curcumin. The ethyl acetate extract
was analyzed by HPLC on a RP-C18 column (25.times.4.5 mm) using
tetrahydrofuran (THF) as solvent and UV detection at 420 nm. The
eluent flow rate was 1 ml/min. Curcumin content in the blood was
determined for each group at each time point and the average value
of curcumin in blood (in nanogram per gram of blood) was
calculated. The average value of curcumin at each time point for
various the treatment protocols is provided in Table 6 and in FIG.
4.
[0086] As seen in Table 6, low bioavailability of curcumin of about
1.05 ng curcumin per gm of blood was observed from the negative
control having 20 mg of curcuminoid mixture without added essential
oil of turmeric. In the negative controls having essential oil of
turmeric alone, with either 10-15% Ar-turmerone or 45%
Ar-turmerone, the bioavailability of curcumin was not detectable
(referred to as Nd in Table 6). Further, bioavailability of
curcumin from the capsule prepared and having a 1:10 ratio of
curcuminoid mixture to essential oil of turmeric, wherein the
essential oil had either a 10-15% Ar-turmerone content or 45%
Ar-turmerone content, showed poor bioavailability of curcumin.
[0087] An experimental capsule prepared at the ratio of 10:1 of
curcuminoid mixture to essential oil of turmeric, wherein the
essential oil had a 45% Ar-turmerone content, having 20 mg
curcuminoid mixture and 2 mg essential oil of turmeric showed
greater than 2-fold enhanced bioavailability over the negative
control of 20 mg curcuminoid mixture without the added essential
oil of turmeric. On the other hand the positive control having
454.55 mg curcuminoid mixture and 45.55 mg essential oil of
turmeric, wherein the essential oil of turmeric had a 45%
Ar-turmerone content, i.e., a 10:1 ratio of curcuminoid mixture to
essential oil of turmeric, showed a 6.97 fold enhancement of
bioavailability of curcumin as compared to the bioavailability of
curcumin from the negative control capsule having 454.55 mg
curcuminoid mixture without the added essential oil of
turmeric.
TABLE-US-00006 TABLE 6 Comparison of curcumin bioavailability from
10:1 and 1:10 weight ratios of curcuminod mixture to essential oil
of turmeric Nanograms of curcumin per gram of blood 20 mg 20 mg 20
mg C:200 mg E = C:200 mg C:2 mg 454.55 mg C:45.45 mg 200 mg E 1:10
E = E = E = alone (E had 1:10 (E 10:1, (E 454.55 mg C 45.45 mg E
10:1 (E Time (10-15% 10-15% had 45% had 45% without (45% had 45%
(h) 20 mg C Ar-t) Ar-t) Ar-t) Ar-t) added E Ar-t) Ar-t) 0 0 0 0 0 0
0 0 0 0.5 Nd Nd Nd Nd 1.1 3.02 Nd 7.45 1 Nd Nd Nd Nd 1 7.27 Nd 5.81
1.5 Nd Nd Nd Nd 1.05 4.11 Nd 4.52 2 1.05 Nd 1.1 1.3 1.3 13.18 Nd
11.46 2.5 Nd Nd Nd 1.1 1.7 9.17 Nd 15.66 3 Nd Nd Nd Nd 2.67 5.21 Nd
91.9 4 Nd Nd Nd Nd 1.34 7.82 Nd 22.44 6 Nd Nd Nd Nd 1.1 1.54 Nd
8.01 8 Nd Nd Nd Nd 1.05 1.05 Nd 6.18
Example 6
Method of Preparation of Curcuminoid Mixture with 95%
Curcuminoids
[0088] The rhizomes of turmeric (300 Kg) were dried. The dried
turmeric rhizomes were powdered to form powdered turmeric. The
powdered turmeric was treated with ethyl acetate (900 L) to form a
solution. The extraction was carried out at 78.degree. C.
temperature for 1 hr. After initial extraction, the extraction
process was repeated 4 more times and the resultant solution was
filtered and the solvent was stripped from the filtered solution to
form an extract. This extract was cooled to about 4.degree. C. to
obtain crystals of curcuminoid (12 Kg) and a liquid. The crystals
of curcuminoid were isolated from the liquid by filtration. The
crystals were powdered to form powdered curcuminoid mixture with
95% curcuminoids.
Example 7
Method of Preparation of Curcuminoid Mixture with 24%
Curcuminoids
[0089] The rhizomes of turmeric (50 Kg) were dried and flaked into
required size. The flakes of turmeric was filled in the soxhlet
apparatus and extracted with ethylene dichloride (EDC). The
extraction was carried out for 5 his at a temperature of about
83.degree. C. After the completion of extraction, the solvent was
filtered. The solvent was removed by distillation and mild vacuum
was applied to get an oleoresin which contains essential oil of
turmeric and curcuminoid. The oleoresin was steam distilled to get
essential oil and a residue. The residue was dried under vacuum to
form a powder (10 Kg) with 24% curcuminoid content.
Example 8
Method of Analysis of Total Curcuminoids by HPLC Method
[0090] From 500 mg capsule, 25 mg was accurately weighed and
transferred into a 50 ml standard flask and made up to a 50 ml
solution with methanol. From this pipette out 2 ml into 50 ml
standard flask and made up to a 50 ml solution with methanol.
Filter through 0.2 .mu.m membrane filter before injection. Standard
was prepared by weighing accurately 25 mg standard [Curcumin
Standard: --99% Total Curcuminoids (Sigma)] and transferred into a
50 ml standard flask and made up to a 50 ml solution with methanol.
From this pipette out 2 ml into 50 ml standard flask and made up to
a 50 ml solution with methanol. Filter through 0.2 .mu.m membrane
filter before injection.
[0091] The total Curcuminoids was analyzed by high performance
liquid chromatography (HPLC) on a C18 column ((250.times.4.6 mm
Shimadzu Co., Japan.) using tetrahydrofuran (THF) as the mobile
phase and UV detection at 420 nm. The eluent flow rate was 1
ml/min.
[0092] By comparing the area of standard and sample, the percentage
of total curcuminoids was calculated using the formula
% of total Curcuminoid = Area of sample .times. amount of std
.times. Purity of std Area of Std .times. weight of the sample
##EQU00001##
Example 9
Method of Preparation of Essential Oil of Turmeric with Varying
Concentration of Ar-Turmerone
[0093] The rhizomes of turmeric (500 Kg) were dried. The dried
turmeric rhizomes were powdered to form powdered turmeric. The
powdered turmeric was treated with ethyl acetate (1500 L) to form a
solution. The extraction was carried out at 78.degree. C.
temperature for 1 hr. After initial extraction, the extraction
process was repeated 4 more times and the resultant solution was
filtered and the solvent was stripped from the filtered solution to
form an extract. This extract was cooled to about 4.degree. C. to
obtain crystals of curcuminoid (20 Kg) and a liquid. The crystals
of curcuminoid were isolated from the liquid by filtration.
[0094] The remaining liquid comprises the essential oil of turmeric
and a resin. The liquid was then steam distilled to isolate
essential oil of turmeric with 10-15% Ar turmerone (25 Kg). After
fractionating this oil, essential oil with 45% Ar turmerone (7.5
Kg) was obtained as fraction 3, essential oil of turmeric with 4-5%
Ar turmerone (8.3) was obtained as fraction 2 and essential oil of
turmeric with 2-3% Ar turmerone (9.3 Kg) was obtained as fraction
1. (FIG. 5)
Example 10
Method of Preparation of Combination of Curcuminoids and Essential
Oil of Turmeric with 45% Ar Turmerone in 10:1 Ratio
[0095] The curcuminoid powder prepared as per Example 6 (2.7 Kg)
was suspended in water (12 L) to form a suspension. Fraction of
essential oil containing 45% Ar-turmerone prepared as per Example 9
(0.27 Kg) was added to the suspension in 10:1 ratio. The mixture is
pulverized in a colloidal mill to form fine slurry. Water is
stripped from the slurry under heat and vacuum to form a uniform
blend. (3 Kg).
[0096] A 500 mg capsule containing 454.55 mg of curcuminoid and
45.45 mg of Essential oil with 45% Ar-turmerone in a weight ratio
of about 90:9 (10:1) was prepared by encapsulating the above
blended extract powder in hard gelatin capsules done in an
air-conditioned at 21.degree. C. and de-humidified room. 3 kg of
extract powder was charged into the hopper of a semi-automatic
capsule filling machine. `0` size hard gelatin capsule shell was
loaded to the tray and the blended extract powder was filled into
the shell. The filled weight of capsules were checked
simultaneously and these capsules were sorted by a sorting machine
and polished with the help of a polishing machine to give 6000
capsules of 500 mg each.
Example 11
Method of Preparation of Combination of Curcuminoids and Essential
Oil of Turmeric with 45% Ar-Turmerone in 1:10 Ratio
[0097] The powdered curcuminoid mixture prepared as per Example 6
(0.27 Kg) was suspended in water (1 L) to form a suspension.
Fraction of essential oil of turmeric containing 45% Ar-turmerone
prepared as per Example 9 (2.7 Kg) was added to the suspension in
1:10 ratio. The mixture is pulverized in a colloidal mill to form
fine slurry. Water was stripped from the slurry under heat and
vacuum to form a uniform blend (3 Kg).
[0098] Capsule containing curcuminoid and Essential oil of turmeric
with 45% Ar-turmerone in a weight ratio of about 1:10 was prepared
by encapsulating the above blended extract powder in soft gelatin
capsules done in an air-conditioned at 21.degree. C. and
de-humidified room. 3 kg of extract powder was charged into the
hopper of a semi-automatic capsule tilling machine. `0` size soft
gelatin capsule shell was loaded to the tray and the blended
extract powder was filled into the shell. The filled weights of
capsules were checked simultaneously and these capsules were sorted
by a sorting machine and polished with the help of a polishing
machine.
Example 12
Method of Preparation of Combination of Curcuminoids and Essential
Oil of Turmeric with 45% Ar Turmerone in 1:1 Ratio
[0099] The powdered curcuminoid mixture prepared as per Example 6
(1.5 Kg) was suspended in water (6 L) to form a suspension.
Fraction of essential oil of turmeric containing 45% Ar-turmerone
prepared as per Example 9 (1.5 Kg) was added to the suspension in
1:1 ratio. The mixture was pulverized in a colloidal mill to form
fine slurry. Water was stripped from the slurry under heat and
vacuum to form a uniform blend. (3 Kg).
[0100] A 500 mg capsule containing 250 mg of curcuminoid and 250 mg
of Essential oil of turmeric with 45% Ar-turmerone in a weight
ratio of about 1:1 was prepared by encapsulating the above blended
extract powder in hard gelatin capsules done in an air-conditioned
at 21.degree. C. and de-humidified room. 3 kg of extract powder was
charged into the hopper of a semi-automatic capsule filling
machine. `0` size hard gelatin capsule shell was loaded to the tray
and the blended extract powder was filled into the shell. The
filled weight of capsules were checked simultaneously and these
capsules were sorted by a sorting machine and polished with the
help of a polishing machine to give 6000 capsules of 500 mg
each.
Example 13
Method of Preparation of Combination of Curcuminoids and Essential
Oil of Turmeric with 10-15% Ar Turmerone in 10:1 Ratio
[0101] The powdered curcuminoid mixture prepared as per Example 6
(2.7 Kg) was suspended in water (12 L) to form a suspension.
Fraction of essential oil of turmeric containing 10-15%
Ar-turmerone prepared as per Example 9 (0.27 Kg) was added to the
suspension in 10:1 ratio. The mixture was pulverized in a colloidal
mill to form fine slurry. Water was stripped from the slurry under
heat and vacuum to form a uniform blend (3 Kg).
[0102] A 500 mg capsule containing 454.55 mg of curcuminoid and
45.45 mg of Essential oil of turmeric with 10-15% Ar-turmerone in a
weight ratio of about 90:9 (10:1) was prepared by encapsulating the
above blended extract powder in hard gelatin capsules done in an
air-conditioned at 21.degree. C. and de-humidified room. 3 kg of
extract powder was charged into the hopper of a semi-automatic
capsule filling machine. `0` size hard gelatin capsule shell was
loaded to the tray and the blended extract powder was filled into
the shell. The filled weight of capsules were checked
simultaneously and these capsules were sorted by a sorting machine
and polished with the help of a polishing machine to give 6000
capsules of 500 mg each.
Example 14
Method of Preparation of Capsules Containing Essential Oil of
Turmeric with 45% Ar-Turmerone
[0103] A 500 mg capsule with essential oil of turmeric containing
45% Ar-turmerone was prepared by encapsulating the essential oil of
turmeric with 45% Ar-turmerone prepared as per example 9 (2.5 kg)
in soft gelatin capsules done in an air-conditioned at 21.degree.
C. and de-humidified room. 2.5 kg essential oil of turmeric with
45% Ar-turmerone was charged into the hopper of a semi-automatic
capsule filling machine. `0` size soft gelatin capsule shell was
loaded to the tray and the blended extract powder was filled into
the shell. The filled weight of capsules were checked
simultaneously and these capsules were sorted by a sorting machine
and polished with the help of a polishing machine to give 5000
capsules of 500 mg each.
Example 15
Method of Preparation of Capsules Containing Essential Oil of
Turmeric with 10-15% Ar-Turmerone
[0104] A 500 mg capsule with essential oil of turmeric containing
10-15% Ar-turmerone was prepared by encapsulating the essential oil
with 10-15% Ar-turmerone prepared as per example 9 (2.5 kg) in soft
gelatin capsules done in an air-conditioned at 21.degree. C. and
de-humidified room. 2.5 kg essential oil of turmeric with 10-15%
Ar-turmerone was charged into the hopper of a semi-automatic
capsule filling machine. `0` size soft gelatin capsule shell was
loaded to the tray and the blended extract powder was filled into
the shell. The filled weight of capsules were checked
simultaneously and these capsules were sorted by a sorting machine
and polished with the help of a polishing machine to give 5000
capsules of 500 mg each.
Example 16
Method of Preparation of Capsules Containing Curcuminoids 95%
[0105] A 500 mg capsule containing curcuminoids 95% was prepared by
encapsulating the curcuminoid powder with 95% curcuminoids in hard
gelatin capsules done in an air-conditioned at 21.degree. C. and
de-humidified room. 3 kg of powder was charged into the hopper of a
semi-automatic capsule filling machine. `0` size hard gelatin
capsule shell was loaded to the tray and the powder was filled into
the shell. The filled weight of capsules were checked
simultaneously and these capsules were sorted by a sorting machine
and polished with the help of a polishing machine to give 6000
capsules of 500 mg each.
Example 17
Method of Preparation of Combination of Curcuminoids with 24%
Curcuminoids and Essential Oil of Turmeric with 45% Ar-Turmerone in
10:1 Ratio
[0106] The powdered curcuminoid prepared as per Example 7 (2.7 Kg)
was suspended in water (12 L) to form a suspension. Fraction of
essential oil containing 45% Ar-turmerone prepared as per Example 9
(0.27 Kg) was added to the suspension in 10:1 ratio. The mixture
was pulverized in a colloidal mill to form fine slurry. Water was
stripped from the slurry under heat and vacuum to form a uniform
blend (3 Kg).
[0107] A 500 mg capsule containing 454.55 mg of curcuminoid and
45.45 mg of Essential oil with 45% Ar-turmerone in a weight ratio
of about 90:9 (10:1) was prepared by encapsulating the above
blended extract powder in hard gelatin capsules done in an
air-conditioned at 21.degree. C. and de-humidified room. 3 kg of
extract powder was charged into the hopper of a semi-automatic
capsule filling machine. `0` size hard gelatin capsule shell was
loaded to the tray and the blended extract powder was filled into
the shell. The filled weight of capsules were checked
simultaneously and these capsules were sorted by a sorting machine
and polished with the help of a polishing machine to give 6000
capsules of 500 mg each.
Example 18
Method of Preparation of Raw Turmeric Powder
[0108] The raw turmeric rhizomes (10 Kg) were collected and
cleaned. The rhizomes were dried and pulverized to get turmeric
powder (2.5 Kg). The turmeric powder was sieved through 20 meshes.
A 500 mg capsule with raw turmeric powder (curcuminoids 5%) was
prepared by encapsulating the powder in hard gelatin capsules done
in an air-conditioned at 21.degree. C. and de-humidified room. 2.5
kg raw turmeric powder is charged into the hopper of a
semi-automatic capsule filling machine. `0` size hard gelatin
capsule shell was loaded to the tray and the blended extract powder
was filled into the shell. The filled weight of capsules were
checked simultaneously and these capsules were sorted by a sorting
machine and polished with the help of a polishing machine to give
5000 capsules of 500 mg each.
Example 19
Method of Preparation of Combination of Curcuminoids and Essential
Oil of Turmeric with 45% Art Turmerone in 12:1 Ratio
[0109] The curcuminoid powder prepared as per Example 6 (3.5 Kg)
was suspended in water (15 L) to form a suspension. Fraction of
essential oil containing 45% Ar-turmerone prepared as per Example 9
(0.29 Kg) was added to the suspension in 12:1 ratio. The mixture is
pulverized in a colloidal mill to form fine slurry. Water is
stripped from the slurry under heat and vacuum to form a uniform
blend. (3.8 Kg).
[0110] A 500 mg capsule containing 461.5 mg of curcuminoid and
38.45 mg of Essential oil with 45% Ar-turmerone in a weight ratio
of about 12:1 (curcumin 69.5%, demethoxy curcumin 17% and
bisdemethoxy curcumin 4% and Essential oil of turmeric 7.5%) was
prepared by encapsulating the above blended extract powder in hard
gelatin capsules done in an air-conditioned at 21.degree. C. and
de-humidified room. 3 kg of extract powder was charged into the
hopper of a semi-automatic capsule filling machine. `0` size hard
gelatin capsule shell was loaded to the tray and the blended
extract powder was filled into the shell. The filled weight of
capsules were checked simultaneously and these capsules were sorted
by a sorting machine and polished with the help of a polishing
machine to give 6000 capsules of 500 mg each.
Example 20
Human Clinical Study of Different Turmeric Extracts in Patients
with Rheumatoid Arthritis
[0111] In a human clinical study to assess the efficacy of
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio compared to raw turmeric powder,
essential oil of turmeric with 45% Ar-turmerone, essential oil of
turmeric with 10-15% Ar-turmerone, curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 1:10 ratio, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 1:1 ratio,
curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio, Curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio, and
curcuminoids 95% in patients with rheumatoid arthritis, 50 patients
diagnosed with rheumatoid arthritis were randomized into 10 groups
viz.,
Group1: Subjects receiving raw turmeric powder 500 mg capsules
prepared as described in Example 18 twice daily Group2: Subjects
receiving essential oil of turmeric with 45% Ar-turmerone (EOT with
45% Ar-t) 500 mg capsules prepared as described in Example 14 twice
daily Group3: Subjects receiving essential oil of turmeric with
10-15% Ar-turmerone (EOT with 10-15% Ar-t) 500 mg capsules prepared
as described in Example 15 twice daily Group4: Subjects receiving
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:10 ratio (C+E with 45% Ar-t in 1:10 ratio), 500 mg capsules
prepared as described in Example 11 twice daily. Group5: Subjects
receiving curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 1:1 ratio (C+E with 45% Ar-t in 1:1 ratio), 500 mg
capsules prepared as described in Example 12 twice daily Group6:
Subjects receiving curcuminoid 24% with essential oil of turmeric
with 45% Ar-turmerone in 10:1 ratio (C 24%+E with 45% Ar-t in 10:1
ratio), 500 mg capsules prepared as described in Example 17 twice
daily. Group7: Subjects receiving curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio (C+E with 10-15%
Ar-t in 10:1 ratio), 500 mg capsules prepared as described in
Example 13 twice daily Group8: Subjects receiving curcuminoids 95%
500 mg capsules prepared as described in Example 16, twice daily.
Group9: Subjects receiving formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio (C+E
with 45% Ar-t in 10:1 ratio) 500 mg capsules prepared as described
in Example 10, twice daily dose after food with water for a period
of 8 weeks. Group10: Subjects receiving formulation of curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio
(C+E with 45% Ar-t in 12:1 ratio) 500 mg capsules prepared as
described in Example 19, twice daily dose after food with water for
a period of 8 weeks.
[0112] Subjects aged 18-65 years of either sex diagnosed to have
rheumatoid arthritis (RA) according to the revised 1987 ACR
criteria for the classification of rheumatoid arthritis Class I or
II, with Disease Activity Score (DAS)>5, receiving treatment on
an outpatient basis were included in the study. Patients with
inflammatory joint disease other than RA and having concurrent
treatment with any NSAID, DMARD or any anti-TNF-.alpha. therapy or
other anti arthritic therapy were excluded. The study examinations
included general and clinical examination, evaluation of disease,
recording of vital signs, X-ray AP view of chest/hands/wrist/foot,
ECG, Haematology. Blood chemistry and Urine Pregnancy Test for
women of child bearing potential.
[0113] Efficacy and safety evaluations were performed at biweekly
intervals. Patients were assessed for the primary efficacy
endpoints disease activity score (DAS) 28 and ACR criteria. DAS is
the numerical sum of four outcome parameters: tender and swollen
joint count (28-joint assessment), patient's global assessment of
disease on a visual analog scale (VAS; 0, no pain and 100, severe
pain); and erythrocyte sedimentation rate. The ACR criteria are
indicated as ACR 20, ACR 50, and ACR 70. ACR criteria measures
improvement in tender or swollen joint counts and improvement in
three of the following five parameters: patient global
assessment-global assessment of disease activity on a 0-100 scale
(0, best; 100, worst); physician assessment-global assessment of
disease activity on a 0-100 scale (0, best; 100, worst); pain scale
disability-visual analogue scale for pain (VAS; 0, no pain and 100,
severe pain); functional questionnaire-HAQ (Health Assessment
Questionnaire) includes four categories: dressing and grooming,
arising, eating, and walking, on a 0-3 scale (0, best; 3, worst);
acute phase reactant (such as sedimentation rate). ACR20 is defined
as a reduction in tender and swollen joint counts of 20%, ACR 50 of
50% and ACR 70 of 70%, from baseline. Monitoring of vital signs,
physical examinations, laboratory parameters (hematology, blood
chemistry, C-reactive protein (CRP), antistreptolysin-O (ASO),
rheumatoid factor and blood sugar) were performed biweekly for
safety evaluation. The occurrence of adverse events was the primary
safety variable.
[0114] Treatment with formulation of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 12:1 ratio showed decrease in
disease activity score from 6.5 at baseline to 3 at the end of
treatment.
[0115] Treatment with formulation of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 10:1 ratio showed decrease in
disease activity score from 6.5 at baseline to 3.5 at the end of
treatment. The results are summarized in Table 7. Mean VAS scores
for pain in all the groups were comparable at baseline, and
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio group showed significant reduction (65%)
in VAS score from 79 mm at baseline to 27.5 mm at the end of
treatment. Mean VAS scores for pain in the group with formulation
of curcuminoid with essential oil of turmeric with 45% Ar-turmerone
in 12:1 ratio group also showed significant reduction (69%) in VAS
score from 78 mm at baseline to 24 mm at the end of treatment. The
results are summarized in Table 8. All components of ACR response
criteria viz., Total Painful Joints, Total Swollen Joints,
Patient's GA, Physician's GA, Disability Index and HAQ showed a
significant reduction from baseline to end of study in the
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 12:1 and 10:1 ratios. The results are summarized in
Table 9 (FIG. 6). Treatment with formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio group
showed decreased C reactive protein from 12 mg/L at baseline to 5.3
mg/L at the end of treatment and formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio
showed decreased C reactive protein from 12 mg/L at baseline to 5.7
mg/L at the end of treatment. The results are summarized in Table
10. Treatment with formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 12:1 ratio group showed decrease
in Rheumatoid Arthritis factor from 23 IU/L at baseline to 13 IU/L
at the end of treatment. Formulation of curcuminoid with essential
oil of turmeric with 45% Ar-turmerone in 10:1 ratio showed decrease
in Rheumatoid Arthritis factor from 24 IU/L at baseline to 15 IU/L
at the end of treatment. The results are summarized in Table 11.
The study shows that formulation of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 10:1 and 12:1 ratios can
provide significant improvement in treatment efficacy in active RA.
All the patients who were given raw turmeric powder, essential oil
of turmeric with 45% Ar-turmerone, essential oil of turmeric with
10-15% Ar-turmerone, curcuminoid with essential oil of turmeric
with 45% Ar-turmerone in 1:10 ratio, curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 1:1 ratio, curcuminoid 24%
with essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio,
curcuminoid with essential oil of turmeric with 10-15% Ar-turmerone
in 10:1 ratio or curcuminoids 95% capsules showed no significant
improvement with treatment and some of the patients even showed
worsening of their symptoms with time even with treatment.
TABLE-US-00007 TABLE 7 Treatment efficacy results - Disease
Activity Score End of % Group Baseline Treatment Change Raw
turmeric Mean 6 6.5 8% EOT with 45% Mean 6.5 6.5 0 Ar-t EOT with
10-15% Mean 6.5 7 7% Ar-t C + E with Mean 7 7.5 6.6% 45% Ar-t in
1:10 ratio C + E with Mean 7.5 7.5 0 45% Ar-t in 1:1 ratio C 24% +
E Mean 7 7 0 with 45% Ar- t in 10:1 ratio C + E with 10-15% Mean 6
6 0 Ar-t in 10:1 ratio C + E with Mean 6.5 3.5 46% 45% Ar-t in 10:1
ratio Curcuminoids Mean 6.5 6 8% 95% C + E with Mean 6.5 3 54% 45%
Ar-t in 12:1 ratio
TABLE-US-00008 TABLE 8 Treatment efficacy results - VAS End of
Treatment Group Baseline (mm) (mm) % Change Raw turmeric Mean 80 78
2.5% EOT with 45% Ar-t Mean 75 77 2.6% EOT with 10-15% Ar-t Mean 77
78 1.3% C + E with 45% Ar-t Mean 79 77 2.5% in 1:10 ratio C + E
with 45% Ar-t Mean 78 76 2.6% in 1:1 ratio C 24% + E with 45% Mean
76 74 2.6% Ar-t in 10:1 ratio C + E with 10-15% Mean 75 71 5.3%
Ar-t in 10:1 ratio C + E with 45% Ar-t Mean 79 27.5 65% in 10:1
ratio Curcuminoids 95% Mean 77 70 9% C + E with 45% Ar-t Mean 78 24
69% in 12:1 ratio
TABLE-US-00009 TABLE 10 Treatment efficacy results - CRP End of
Baseline Treatment % Group (mg/L) (mg/L) Change Raw turmeric Mean
13 13 0 EOT with Mean 11 11.5 4% 45% Ar-t EOT with 10-15% Mean 12.5
13.5 7% 15% Ar-t C + E with 45% Mean 12 12.5 4% Ar-t in 1:10 ratio
C + E with 45% Mean 13 13 0 Ar-t in 1:1 ratio C 24% + E Mean 12 12
0 with 45% Ar-t in 10:1 ratio C + E with 10-15% Mean 11.5 11.5 0
Ar-t in 10:1 ratio C + E with 45% Mean 12 5.7 53% Ar-t in 10:1
ratio Curcuminoids Mean 11.5 11.4 1% 9.5% C + E with 45% Mean 12
5.3 56% Ar-t in 12:1 ratio
TABLE-US-00010 TABLE 11 Treatment efficacy results - Rheumatoid
Arthritis Factor End of Baseline Treatment % Group (IU/L) (IU/L)
Change Raw turmeric Mean 23 25 8% EOT with 45% Mean 26 28 7% Ar-t
EOT with 10-15% Mean 25 26 3.8% Ar-t C + E with 45% Mean 23 24 4%
Ar-t in 1:10 ratio C + E with 45% Mean 22 22 0 Ar-t in 1:1 ratio C
24% + E with Mean 21 21 0 45% Ar-t in 10:1 ratio C + E with 10-15%
Mean 24 24 0 Ar-t in 10:1 ratio C + E with 45% Mean 24 15 38% Ar-t
in 10:1 ratio Curcuminoids Mean 22 24 9% 95% C + E with 45% Mean 23
13 39% Ar-t in 12:1 ratio
Example 21
Human Clinical Study of Different Turmeric Extracts in Patients
with Osteo Arthritis
[0116] In a human clinical trial to determine the effectiveness of
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio in relieving symptoms and clinical
conditions of osteoarthritic patients compared with raw turmeric
powder, essential oil of turmeric with 45% Ar-turmerone, essential
oil of turmeric with 10-15% Ar-turmerone, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:1 ratio, curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio, formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
12:1 ratio and curcuminoids 95% capsules, patients of either sex
diagnosed to have osteoarthritis according to ACR criteria were
selected for the study. The patients were divided into nine groups
of 5 patients each.
Gr 1: Oral administration of raw turmeric powder 500 mg capsules,
prepared as described in Example 18, in twice daily dosage Gr 2:
Oral administration of essential oil of turmeric with 45%
Ar-turmerone (EOT with 45% Ar-t) 500 mg capsules prepared as
described in Example 14, in twice daily dosage. Gr3: Oral
administration of essential oil of turmeric with 10-15%
Ar-turmerone (EOT with 10-15% Ar-t) 500 mg capsules prepared as
described in Example 15, in twice daily dosage. Gr4: Oral
administration of curcuminoid with essential oil of turmeric with
45% Ar-turmerone in 1:10 ratio (C+E with 45% Ar-t in 1:10 ratio),
500 mg capsules prepared as described in Example 11, in twice daily
dosage. Gr5: Oral administration of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 1:1 ratio (C+E with 45% Ar-t
in 1:1 ratio), 500 mg capsules prepared as described in Example 12,
in twice daily dosage. Gr6: Subjects receiving curcuminoid 24% with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio (C
24%+E with 45% Ar-t in 10:1 ratio), 500 mg capsules prepared as
described in Example 17 twice daily Gr7: Oral administration of
curcuminoid with essential oil of turmeric with 10-15% Ar-turmerone
in 10:1 ratio (C+E with 10-15% Ar-t in 10:1 ratio), 500 mg capsules
prepared as described in Example 13, in twice daily dosage. Gr8:
Oral administration of formulation of curcuminoid with essential
oil of turmeric with 45% Ar-turmerone in 10:1 ratio (C+E with 45%
Ar-t in 10:1 ratio), 500 mg capsule prepared as described in
Example 10, in twice daily dosage Gr 9: Oral administration of
curcuminoids 95% 500 mg capsule prepared as described in Example
16, in twice daily dosage. Gr10: Oral administration of formulation
of curcuminoid with essential oil of turmeric with 45% Ar-turmerone
in 12:1 ratio (C+E with 45% Ar-t in 12:1 ratio), 500 mg capsule
prepared as described in Example 19, in twice daily dosage
[0117] Each patient was given treatment for 12 weeks. The efficacy
of the use of the study drugs over the treatment period was
evaluated by symptom scoring and clinical examination. Symptom
refers to the complaints expressed by the patient and scored
depending on severity. Symptom scoring includes joint pain
measurements and walking distance measurements. Joint pain in
osteoarthritis is a deep pain localized to the joint and is
measured by querying the patient and scoring it as
No/mild/moderate/severe during each visit. Results of this analysis
for the eight treatment groups are presented in Table 12 (FIG. 7).
Walking distance refers to the maximum distance a person is able to
walk at a stretch without limiting pain. Walking distance
measurements were recorded and are given Table 13 (FIG. 8). Joint
line tenderness was elicited by palpating along the joint line and
was measured by querying the patient and recording the response as
No/mild/moderate/severe and was recorded and results are presented
in Table 14 (FIG. 9).
[0118] Crepitus (crackling or grating feeling or sound in joints)
is elicited by palpating the joint on movement and scoring it as
No/Mild/Moderate/Severe. Range of movement of the knee is measured
for flexion/extension movement and the normal range is from 0 to
135 degrees (0 being neutral position and increasing flexion of the
joint is normally up to 135 degrees). It is measured using a
Goniometer and is measured by asking the patient to flex the joint
to the maximum extent possible and the maximum value was
recorded.
[0119] The results showed that the % response of patients taking
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 and 12:1 ratios were significantly better than
patients taking raw turmeric powder, essential oil of turmeric with
45% Ar-turmerone, essential oil of turmeric with 10-15%
Ar-turmerone, curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 1:10 ratio, curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 1:1 ratio, curcuminoid 24% with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio,
curcuminoid with essential oil of turmeric with 10-15% Ar-turmerone
in 10:1 ratio and curcuminoids 95% capsules. At the beginning of
study all patients had joint pain and after treatment with
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 12:1 ratio, 19% patients did not have any joint
pain. The percentage of patients with moderate joint pain decreased
from 80% at baseline to 29% at the end of treatment and majority of
the patients (52%) had only mild pain at the end of 3 months of
treatment in patients given formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio.
Before the treatment 7% of patients had severe joint pain and after
treatment none of the patients given formulation of curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio
had severe joint pain.
[0120] At the beginning of study all patients had joint pain and
after treatment with formulation of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 10:1 ratio, 17% patients did
not have any joint pain. The percentage of patients with moderate
joint pain decreased from 78% at baseline to 30% at the end of
treatment and majority of the patients (53%) had only mild pain at
the end of 3 months of treatment in patients given formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 ratio. Before the treatment 7% of patients had severe joint
pain and after treatment none of the patients given formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 ratio had severe joint pain.
[0121] Before the treatment 87% of patients given formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
12:1 ratio had joint line tenderness and after treatment 52% of
patients no longer had pain and the remaining 48% patients showed
improvement and none of the patient's condition worsened or
remained same without change.
[0122] Before the treatment 86% of patients given formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 ratio had joint line tenderness and after treatment 50% of
patients no longer had pain and the remaining 50% patients showed
improvement and none of the patient's condition worsened or
remained same without change.
[0123] Before the treatment with formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio 8% of
patients could not walk even up to 100 meters. And after the
treatment 75% of patients could walk over 1000 meters and 22% could
walk 500-1000 meters.
[0124] Before the treatment with formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio 7% of
patients could not walk even up to 100 meters. And after the
treatment 72% of patients could walk over 1000 meters and the
remaining 28% could walk 500-1000 meters.
[0125] The safety of the test drug was evaluated by measuring vital
signs (systolic and diastolic blood pressure, pulse rate,
respiratory rate), haemogram measurement (Hb, TC, DC, ESR), liver
function tests (SGOT, SGPT, SAP, bilirubin), renal function tests
(blood urea, serum creatinine). None of these parameters were
adversely modified by the study drugs. There were also no adverse
events reported in the study.
[0126] In conclusion, formulation of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 10:1 and 12:1 ratios were
significantly effective compared to raw turmeric powder, essential
oil of turmeric with 45% Ar-turmerone, essential oil of turmeric
with 10-15% Ar-turmerone, curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 1:10 ratio, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 1:1 ratio,
curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio and curcuminoids
95% capsules in relieving symptoms and clinical conditions of
osteoarthritic patients when given over a period of 3 months. There
was significant improvement in pain scores, walking distance, joint
line tenderness, crepitus, range of movement of the knee and joint
swelling measurements in osteoarthritic patients receiving
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 and 12:1 ratios for 3 months compared to
patients receiving raw turmeric powder, essential oil of turmeric
with 45% Ar-turmerone, essential oil of turmeric with 10-15%
Ar-turmerone, curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 1:10 ratio, curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 1:1 ratio, curcuminoid 24% with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio,
curcuminoid with essential oil of turmeric with 10-15% Ar-turmerone
in 10:1 ratio and curcuminoids 95% capsules in the similar dosage.
The study drugs were well tolerated and no dose-related toxicity
was found.
Example 22
Human Clinical Study in Patients with Alzheimers Disease
[0127] A double-blind, placebo-controlled, pilot clinical trial
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 and 12:1 ratio capsules compared with raw
turmeric powder, essential oil of turmeric with 45% Ar-turmerone,
essential oil of turmeric with 10-15% Ar-turmerone, curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:1 ratio, curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio and curcuminoids
95% capsules was done in patients with progressive decline in
memory or cognitive function and diagnosed with probable or
possible Alzheimer's disease (AD). Patients were randomized to 10
groups to receive 3.0 grams of each study drug capsules twice daily
for 12 months.
[0128] Parameters measured at baseline and end of study include
plasma isoprostanes, Vit E, A.beta. and clinical assessment with
Mini-Mental State Examination Scores (MMSE). Isoprostanes are the
products of non-enzymatic oxidation of arachidonic acid and so
this, along with the antioxidant Vit E levels is indicative of the
level of oxidative stress. A.beta. are a 39-43 amino acid peptide
fragment derived from the f-amyloid precursor protein (APP) and are
the predominant component of the neuritic plaques, an invariant
pathological hallmark of AD. Aggregated forms of A.beta. are
believed to be the real culprits of the disease. Mini-Mental State
Examination Scores (MMSE) is a measure of cognitive function. The
pharmacokinetics of curcumin from the ingested drugs and adverse
events, if any, associated with the drug were also recorded.
[0129] Serum A.beta. levels was significantly higher in formulation
of curcuminoid with essential oil of turmeric with 45% Ar-turmerone
in 10:1 and 12:1 ratio capsules compared to results following
administration of raw turmeric powder, essential oil of turmeric
with 45% Ar-turmerone, essential oil of turmeric with 10-15%
Ar-turmerone, curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 1:10 ratio, curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 1:1 ratio, curcuminoid 24% with
essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio,
curcuminoid with essential oil of turmeric with 10-15% Ar-turmerone
in 10:1 ratio and curcuminoids 95% capsules, reflecting the
increased ability of formulation of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 10:1 and 12:1 ratio capsules
to disaggregate A.beta. deposits in the brain. The MMSE scores of
patients given formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio capsules increased
significantly from baseline value at 16/30 to 23/30 at the end of
the study. The MMSE scores of patients given formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
12:1 ratio capsules increased significantly from baseline value at
17/30 to 25/30 at the end of the study and in patients given raw
turmeric powder, essential oil of turmeric with 45% Ar-turmerone,
essential oil of turmeric with 10-15% Ar-turmerone, curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:1 ratio, curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio and curcuminoids
95% capsules there was a marginal deterioration in the MMSE score
(Table 15). Isoprostanes arc products of non-enzymatic oxidation of
arachidonic acid and are indicative of oxidative stress. Plasma
isoprostane levels were significantly lowered between baseline and
at 12 months in patients taking formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 and 12:1
ratios. Vitamin E levels increased in the formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 and 12:1 ratio groups from baseline to end of treatment,
(Table 16). The curcumin level in patients taking formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
10:1 ratio (baseline at 12 to 653 at the end of treatment period)
was 15 times higher than patients taking curcuminoids 95% capsules
(baseline at 13 to 42 at the end of treatment) (Table 17). The
curcumin level in patients taking formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 12:1 ratio
(baseline at 14 to 875 at the end of treatment period) was 20 times
higher than patients taking curcuminoids 95% capsules (baseline at
13 to 42 at the end of treatment) (Table 17). In patients taking
raw turmeric powder, essential oil of turmeric with 45%
Ar-turmerone, essential oil of turmeric with 10-15% Ar-turmerone,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:10 ratio, curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 1:1 ratio, curcuminoid 24% with essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio, curcuminoid with
essential oil of turmeric with 10-15% Ar-turmerone in 10:1 ratio
and curcuminoids 95% capsules there was no decrease noticed in the
plasma isoprostane levels and Vitamin E levels remained more or
less the same in all the groups except in patients taking
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 and 12:1 ratios.
[0130] This study thus reveals that the formulation of curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 10:1 and
12:1 ratio capsules confer greater clinical benefits as observed by
significant increase in the MMSE score, increase in Vit E levels,
high levels of serum A.beta. levels, and lowered plasma isoprostane
levels in patients consuming formulation of curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 10:1 and 12:1
ratio capsules compared with patients consuming raw turmeric
powder, essential oil of turmeric with 45% Ar-turmerone, essential
oil of turmeric with 10-15% Ar-turmerone, curcuminoid with
essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:1 ratio, curcuminoid 24% with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio, curcuminoid with essential oil of
turmeric with 10-15% Ar-turmerone in 10:1 ratio and curcuminoid 95%
capsules for 12 months.
TABLE-US-00011 TABLE 15 MMSE levels of patients in each group over
12 months Baseline Study End Groups 0 month 12 months Raw turmeric
MMSE 16/30 14/30 EOT with 45% Ar-t MMSE 15/30 14/30 EOT with 10-15%
MMSE 18/30 16/30 Ar-t C + E with 45% Ar-t MMSE 16/30 15/30 in 1:10
ratio C + E with 45% Ar-t MMSE 18/30 17/30 in 1:1 ratio C 24% + E
with MMSE 16/30 16/30 45% Ar-t in 10:1 ratio C + E with 10-15% MMSE
17/30 17/30 Ar-t in 10:1 ratio C + E with 45% Ar-t MMSE 16/30 23/30
in 10:1 ratio Curcuminoids 95% MMSE 17/30 16/30 C + E with 45% Ar-t
MMSE 17/30 25/30 in 12:1 ratio
TABLE-US-00012 TABLE 16 Vitamin E levels of patients in each group
over 12 months Baseline Study End Groups 0 month 12 months Raw
turmeric Vit E in 0.4 0.4 mg % EOT with Vit E in 0.3 0.3 45% Ar-t
mg % EOT with 10-15% Vit E in 0.3 0.3 Ar-t mg % C + E with 45% Vit
E in 0.4 0.4 Ar-t in 1:10 ratio mg % C + E with 45% Vit E in 0.3
0.3 Ar-t in 1:1 ratio mg % C 24% + E with Vit E in 0.4 0.4 45% Ar-t
in 10:1 mg % ratio C + E with 10-15% Vit E in 0.3 0.4 Ar-t in 10:1
mg % ratio C + E with 45% Vit E in 0.30 2.1 Ar-t in 10:1 ratio mg %
Curcuminoids Vit E in 0.4 0.4 95% mg % C + E with 45% Vit E in 0.3
2.8 Ar-t in 12:1 ratio mg %
TABLE-US-00013 TABLE 17 Plasma level of curcumin in patients in
each group over 12 months Baseline Study End Groups 0 month 12
months Raw turmeric Curcumin in 11 20 nMol/L EOT with Curcumin in 9
11 45% Ar-t nMol/L EOT with 10-15% Curcumin in 12 11 Ar-t nMol/L C
+ E with 45% Curcumin in 10 13 Ar-t in 1:10 ratio nMol/L C + E with
45% Curcumin in 21 145 Ar-t in 1:1 ratio nMol/L C 24% + E with
Curcumin in 14 28 45% Ar-t in 10:1 nMol/L ratio C + E with 10-15%
Curcumin in 15 82 Ar-t in 10:1 nMol/L ratio C + E with 45% Curcumin
in 12 653 Ar-t in 10:1 ratio nMol/L Curcuminoids Curcumin in 13 42
95% nMol/L C + E with 45% Curcumin in 14 875 Ar-t in 12:1 ratio
nMol/L
Example 23
Human Clinical Study of Patients with Depression
[0131] In a randomized, double blind, active control, parallel
group study, formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 and 12:1 ratios were studied
against raw turmeric powder, essential oil of turmeric with 45%
Ar-turmerone, essential oil of turmeric with 10-15% Ar-turmerone,
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
1:10 ratio, curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 1:1 ratio, curcuminoid 24% with essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio, curcuminoid with
essential oil of turmeric with 10-15% Ar-turmerone in 10:1 ratio
and curcuminoid 95% capsules in patients with depression to compare
the efficacy and tolerability of the eight formulations. Patients
with a Score greater than 7 but less than 24 on the 17-item
Hamilton Depression (HAM-D) Scale and assessed by Structured
Clinical Interview or DSM-IV Axis I Disorders without any
concurrent treatment were selected for the study. 50 patients
selected were randomized into 10 groups and were given treatment
for 8 weeks.
Gr 1: raw turmeric powder 500 mg capsules prepared as described in
Example 18 twice daily Gr 2: essential oil of turmeric with 45%
Ar-turmerone (EOT with 45% Ar-t) 500 mg capsules prepared as
described in Example 14 twice daily. Gr3: essential oil of turmeric
with 10-15% Ar-turmerone (EOT with 10-15% Ar-t) 500 mg capsules
prepared as described in Example 15 twice daily Gr4: curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 1:10 ratio
(C+E with 45% Ar-t in 1:10 ratio), 500 mg capsules prepared as
described in Example 11 twice daily Gr5: curcuminoid with essential
oil of turmeric with 45% Ar-turmerone in 1:1 ratio (C+E with 45%
Ar-t in 1:1 ratio), 500 mg capsules prepared as described in
Example 12 twice daily. Gr6: Subjects receiving curcuminoid 24%
with essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio
(C 24%+E with 45% Ar-t in 10:1 ratio), 500 mg capsules prepared as
described in Example 17 twice daily. Gr7: curcuminoid with
essential oil of turmeric with 10-15% Ar-turmerone in 10:1 ratio
(C+E with 10-15% Ar-t in 10:1 ratio), 500 mg capsules prepared as
described in Example 13 twice daily. Gr 8: curcuminoids 95% (500
mg) capsules prepared as described in example 16 twice daily. Gr 9:
Formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 10:1 ratio (C+E with 45% Ar-t in 10:1 ratio) (500
mg) capsules prepared as described in Example 10 twice daily. Gr
10: Formulation of curcuminoid with essential oil of turmeric with
45% Ar-turmerone in 12:1 ratio (C+E with 45% Ar-t in 12:1 ratio)
(500 mg) capsules prepared as described in Example 19 twice
daily.
[0132] Efficacy was evaluated by using 17 point--Hamilton
depression scale and clinical global impression by Global Severity
(CGI-S) and Global change (CGI-I) scales. Tolerability of the drugs
was assessed clinically and by biochemical parameters like SGOT,
SGPT, Urea and Creatinine (measured at the start and at the end of
study).
[0133] Results: The proportion of responders as measured by the
HAM-D17 scale was significantly (97%) higher in the formulation of
curcuminoid with essential oil of turmeric with 45% Ar-turmerone in
12:1 ratio group than other groups (Table: 18). The proportion of
responders as measured by the HAM-D17 scale was significantly (93%)
higher in the formulation of curcuminoid with essential oil of
turmeric with 45% Ar-turmerone in 10:1 ratio group than other
groups (Table: 18). The change in HAM-D17 scores at the end of 8
weeks from baseline at 20 to 7 at the end of treatment was higher
for formulation of curcuminoid with essential oil of turmeric with
45% Ar-turmerone in 12:1 ratio group (65%) than other groups
(Table: 19). The change in HAM-D17 scores at the end of 8 weeks
from baseline at 21 to 10 at the end of treatment was also higher
for formulation of curcuminoid with essential oil of turmeric with
45% Ar-turmerone in 10:1 ratio group (52%) than other groups
(Table: 19). In Clinical Global Impression assessment scale, the
formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 12:1 ratio group showed a decrease in CGI-S score
from baseline at 4 to 1 at the end of treatment. That is 75%
improvement in CGI-S (Table: 20). In Clinical Global Impression
assessment scale, the formulation of curcuminoid with essential oil
of turmeric with 45% Ar-turmerone in 10:1 ratio group showed a
decrease in CGI-S score from baseline at 5 to 2 at the end of
treatment. That is 60% improvement in CGI-S (Table: 20).
Formulation of curcuminoid with essential oil of turmeric with 45%
Ar-turmerone in 12:1 ratio group showed a decrease in CGI-I score
from baseline 5 to 2 at the end of treatment. That is 60%
improvement in CGI-I scale (Table: 21). Formulation of curcuminoid
with essential oil of turmeric with 45% Ar-turmerone in 10:1 ratio
group showed a decrease in CGI-I score from baseline 4 to 2 at the
end of treatment. That is 50% improvement in CGI-I scale (Table:
21). Whereas the other groups showed no change at all at the end of
8 weeks of treatment. Overall the study medications were well
tolerated and there was no significant difference in vital signs,
physical examination, laboratory tests and electrocardiogram from
baseline and had `excellent` tolerability.
TABLE-US-00014 TABLE 18 Proportion of responders in each group over
2 months Raw turmeric % response rate on 6% HAM-D17 scale EOT with
45% Ar-t % response rate on 4% HAM-D17 scale EOT with 10-15% Ar-t %
response rate on 4% HAM-D17 scale c + E with 45% Ar-t in % response
rate on 7% 1:10 ratio HAM-D17 scale C + E with 45% Ar-t in %
response rate on 9% 1:1 ratio HAM-D17 scale C 24% + E with 45% %
response rate on 8% Ar-t in 10:1 ratio HAM-D17 scale C + E with
10-15% Ar- % response rate on 12% t in 10:1 ratio HAM-D17 scale C +
E with 45% Ar-t in % response rate on 93% 10:1 ratio HAM-D17 scale
Curcuminoids 95% % response rate on 10% HAM-D17 scale C + E with
45% Ar-t in % response rate on 97% 12:1 ratio HAM-D17 scale
TABLE-US-00015 TABLE 19 Hamilton Depression Scoring Scale - 17
point scale in patients in each group over 2 months Baseline Study
End Groups 0 month 2 months Raw turmeric HAM-D17 20 19 scale EOT
with 45% Ar-t HAM-D17 19 19 scale EOT with 10-15% HAM-D17 22 22
Ar-t scale C + E with 45% Ar- HAM-D17 18 18 t in 1:10 ratio scale C
+ E with 45% Ar- HAM-D17 20 19 t in 1:1 ratio scale C 24% + E with
HAM-D17 19 19 45% Ar-t in 10:1 scale ratio C + E with 10-15%
HAM-D17 19 16 Ar-t in 10:1 ratio scale C + E with 45% Ar- HAM-D17
21 10 t in 10:1 ratio scale Curcuminoids 95% HAM-D17 19 17 scale C
+ E with 45% Ar- HAM-D17 20 7 t in 12:1 ratio scale
TABLE-US-00016 TABLE 20 Clinical Global Impression - Severity Scale
in patients in each group over 2 months Baseline Study End Groups 0
month 12 months Raw turmeric CGI-S score 5 5 EOT with 45% Ar-t
CGI-S score 4 4 EOT with 10-15% Ar-t CGI-S score 4 4 C + E with 45%
Ar-t in CGI-S score 5 5 1:10 ratio C + E with 45% Ar-t in CGI-S
score 4 4 1:1 ratio C 24% + E with 45% CGI-S score 4 4 Ar-t in 10:1
ratio C + E with 10-15% Ar- CGI-S score 5 5 t in 10:1 ratio C + E
with 45% Ar-t in CGI-S score 5 2 10:1 ratio Curcuminoids 95% CGI-S
score 5 5 C + E with 45% Ar-t in CGI-S score 4 1 12:1 ratio
TABLE-US-00017 TABLE 21 Clinical Global Impression -
Improvement/Change Scale in patients in each group over 2 months
Baseline Study End Groups 0 month 12 months Raw turmeric CGI-I
score 4 4 EOT with 45% Ar-t CGI-I score 4 4 EOT with 10-15% Ar-t
CGI-I score 4 4 C + E with 45% Ar-t in CGI-I score 5 5 1:10 ratio C
+ E with 45% Ar-t in CGI-I score 4 4 1:1 ratio C 24% + E with 45%
CGI-I score 4 4 Ar-t in 10:1 ratio C + E with 10-15% Ar-t CGI-I
score 5 5 in 10:1 ratio C + E with 45% Ar-t in CGI-I score 4 2 10:1
ratio Curcuminoids 95% CGI-I score 4 4 C + E with 45% Ar-t in CGI-I
score 5 2 12:1 ratio
[0134] Other modifications and variations to the invention will be
apparent to those skilled in the art from the foregoing disclosure
and teachings. Thus, while only certain embodiments of the
invention have been specifically described herein, it will be
apparent that numerous modifications may be made thereto without
departing from the spirit and scope of the invention.
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