FRANKINCENSE vs CANCER
http://news.bbc.co.uk/2/hi/middle_east/8505251.stm
Frankincense: Could it be a cure for
cancer?
by Jeremy Howell
The gift given by the wise men to the baby Jesus probably came
across the deserts from Oman. The BBC's Jeremy Howell visits the
country to ask whether a commodity that was once worth its weight
in gold could be reborn as a treatment for cancer.
Oman's Land of Frankincense is an 11-hour drive southwards from
the capital, Muscat.
Most of the journey is through Arabia's Empty Quarter - hundreds
of kilometres of flat, dun-coloured desert. Just when you are
starting to think this is the only scenery you will ever see
again, the Dhofar mountains appear in the distance.
On the other side are green valleys, with cows grazing in them.
The Dhofar region catches the tail-end of India's summer monsoons,
and they make this the most verdant place on the Arabian
peninsula.
Warm winters and showery summers are the perfect conditions for
the Boswellia sacra tree to produce the sap called frankincense.
These trees grow wild in Dhofar. A tour guide, Mohammed Al-Shahri
took me to Wadi Dawkah, a valley 20 km inland from the main city
of Salalah, to see a forest of them.
"The records show that frankincense was produced here as far back
as 7,000 BC," he says. He produces an army knife. He used to be a
member of the Sultan's Special Forces. With a practised flick, he
cuts a strip of bark from the trunk of one of the Boswellia sacra
trees. Pinpricks of milky-white sap appear on the wood and, very
slowly, start to ooze out.
"This is the first cut. But you don't gather this sap," he says.
"It releases whatever impurities are in the wood. The farmers
return after two or three weeks and make a second, and a third,
cut. Then the sap comes out yellow, or bright green, or brown or
even black. They take this."
Shortly afterwards, a frankincense farmer arrives in a pick-up
truck. He is white-bearded, wearing a brown thobe and the
traditional Omani, paisley-patterned turban.
He is 67-year-old Salem Mohammed from the Gidad family. Most of
the Boswellia sacra trees grow on public land, but custom dictates
that each forest is given to one of the local families to farm,
and Wadi Dawkah is his turf.
He has an old, black, iron chisel with which he gouges out clumps
of dried frankincense.
"We learnt about frankincense from our forefathers and they learnt
it from theirs" he says. "The practice has been passed down
through the generations. We exported the frankincense, and that's
how the families in Dhofar made their livings."
And what an export trade it was. Frankincense was sent by camel
train to Egypt, and from there to Europe. It was shipped from the
ancient port of Sumharan to Persia, India and China. Religions
adopted frankincense as a burnt offering.
That is why, according to Matthew's Gospel in the Bible, the Wise
Men brought it as a gift to the infant Jesus. Gold: for a king.
Frankincense: for God. Myrrh: to embalm Jesus' body after death.
The Roman Empire coveted the frankincense trade. In the first
century BCE, Augustus Caesar sent 10,000 troops to invade what the
Romans called Arabia Felix to find the source of frankincense and
to control its production. The legions, marching from Yemen, were
driven back by the heat and the aridity of the desert. They never
found their Eldorado.
Oman's frankincense trade went into decline three centuries ago,
when Portugal fought Oman for dominance of the sea routes in the
Indian and the Pacific Oceans.
The Haffa souk in Salalah
Salalah's Haffa souk: The place to buy Omani brands such as Royal
Hougari
Nowadays, hardly any Omani frankincense is exported. Partly, this
is because bulk buyers, such as the Roman Catholic Church, buy
cheaper Somalian varieties. Partly, it is because Omanis now
produce so little.
"Years ago, 20 families farmed frankincense in this area," says
Salem Mohammed Gidad. "But the younger generation can get
well-paid jobs in the government and the oil companies, with
pensions. Now, only three people still produce frankincense around
here. The trade is really, really tiny!"
Cancer hope
But immunologist Mahmoud Suhail is hoping to open a new chapter in
the history of frankincense.
Scientists have observed that there is some agent within
frankincense which stops cancer spreading, and which induces
cancerous cells to close themselves down. He is trying to find out
what this is.
"Cancer starts when the DNA code within the cell's nucleus becomes
corrupted," he says. "It seems frankincense has a re-set function.
It can tell the cell what the right DNA code should be.
"Frankincense separates the 'brain' of the cancerous cell - the
nucleus - from the 'body' - the cytoplasm, and closes down the
nucleus to stop it reproducing corrupted DNA codes."
Working with frankincense could revolutionise the treatment of
cancer. Currently, with chemotherapy, doctors blast the area
around a tumour to kill the cancer, but that also kills healthy
cells, and weakens the patient. Treatment with frankincense could
eradicate the cancerous cells alone and let the others live.
The task now is to isolate the agent within frankincense which,
apparently, works this wonder. Some ingredients of frankincense
are allergenic, so you cannot give a patient the whole thing.
Dr Suhail (who is originally from Iraq) has teamed up with medical
scientists from the University of Oklahoma for the task.
In his laboratory in Salalah, he extracts the essential oil from
locally produced frankincense. Then, he separates the oil into its
constituent agents, such as Boswellic acid.
"There are 17 active agents in frankincense essential oil," says
Dr Suhail. "We are using a process of elimination. We have cancer
sufferers - for example, a horse in South Africa - and we are
giving them tiny doses of each agent until we find the one which
works."
"Some scientists think Boswellic acid is the key ingredient. But I
think this is wrong. Many other essential oils - like oil from
sandalwood - contain Boswellic acid, but they don't have this
effect on cancer cells. So we are starting afresh."
The trials will take months to conduct and whatever results come
out of them will take longer still to be verified. But this is a
blink of the eye in the history of frankincense.
Nine thousand years ago, Omanis gathered it and burnt it for its
curative and cleansing properties. It could be a key to the
medical science of tomorrow.
http://theresanoilforthat.blogspot.com/2012/02/frankincense-and-cancer.html
Frankincense and Cancer
Studies on Frankincense and Cancer
History:
Frankincense trees were considered extremely valuable during
ancient times and their location was often a matter of state
secret. Egyptians used the incense to fumigate their homes, for
ritual incense and the oil for cosmetics. It was used as a holy
anointing oil and as a general cure-all for all diseases. It was
also used to enhance meditation and elevate spiritual
consciousness. History shows it was used for embalming and as a
perfume AND formed an important part of the Sabbath day offering.
Frankincense or olibanum was mentioned inthe Scriptures over 50
times and is found in the books of Exodus, Leviticus, Numbers,
Chronicles, Nehemiah,Song of Solomon, Isaiah, Matthew, and
Revelations.
Actions:
The actions of frankincense include anti-inflammatory,
anti-tumoral, immune-stimulant, antidepressant and muscle
relaxing. It stimulates the limbic system as well as the
hypothalamus, pineal and pituitary glands. It is strongly
anti-viral, antioxidant, antifungal, antibacterial, antiseptic and
expectorant oil. Frankincense has the ability to relax and
revitalize at the same time.
Research:
Cancer Research Using Frankincense
There are a few researchers studying the effects of
frankincense on various cancers with some degree of success. In
vitro effects show inhibition or stimulation of cell proliferation
depending on the concentration of frankincense oil in the growth
media.
A recent study conducted at the University of Oklahoma showed that
frankincense kills bladder cancer cells without harming
surrounding tissue.
Studies are showing frankincense to be a strong immune-stimulant
with some claiming that frankincense has the ability to repair
DNA.
A Chinese study conducted in 2000, indicated that Boswellia has
“anti-carcinogenic and anti-tumor activities.” These boswellic
acids from frankincense inhibited “a variety of malignant cells”
in people suffering from leukemia and brain tumors.
The Cancer Research Institute of the University of Nevada treated
cervical cancer with frankincense, in which “there was 72%
inhibition and growth of non-cancerous cells.”
Other studies have shown that boswellic acids from frankincense
exert anti-prolifertive activity toward a variety of malignant
cells.
Another study showed that boswellic acids are potent apoptotic
agents to cancer cells and another one shows that Boswellic acids
from frankincense gum exhibit potent cytotoxic activity againstCNS
tumors.
Why Hasn’t the General Public Heard about This?
It sounds incredulous but the anti-cancerous effects of
frankincense has been known for thousands of years. Does it work
for everyone? No, but compared to the effects of chemotherapy,
frankincense DOES show great promise now and in the future.
Frankincense will never be promoted for the breakthrough that it
is because there is no money to be made in its promotion.
Frankincense is expensive in comparison to other therapeutic grade
oils but “cheap” in comparison to drugs like chemotherapy.
Scientists have observed and do agree that there is some agent
within frankincense which stops cancer spreading, and which
induces cancerous cells to close themselves down. Immunologist
Mahmoud Suhail is quoted "Cancer starts when the DNA code within
the cell's nucleus becomes corrupted. It seems frankincense has a
re-set function. It can tell the cell what the right DNA code
should be. Frankincense separates the 'brain' of the cancerous
cell - the nucleus - from the 'body' - the cytoplasm, and closes
down the nucleus to stop it reproducing corrupted DNA
codes."--Currently, with chemotherapy, doctors blast the area
around a tumour to kill the cancer, but that also kills healthy
cells, and weakens the patient. Treatment with frankincense could
eradicate the cancerous cells alone and let the others live.The
task now is to isolate the agent within frankincense which,
apparently, works this wonder
History Medical Research (Bosellia serrata)
In Ayurvedic medicine Indian frankincense (Boswellia serrata),
commonly referred to as "dhoop," has been used for hundreds of
years for treating arthritis, healing wounds, strengthening the
female hormone system, and purifying the atmosphere from
undesirable germs. The use of frankincense in Ayurveda is called
"dhoopan". In Indian culture, it is suggested that burning
frankincense everyday in house brings good health.
Standardized preparations of Indian frankincense from Boswellia
serrata are being investigated in scientific studies as a
treatment for chronic inflammatory diseases such as Crohn's
disease, ulcerative colitis, and osteoarthritis. Initial clinical
study results indicate efficacy of incense preparations for
Crohn's disease. For therapy trials in ulcerativecolitis, asthma,
and rheumatoid arthritis there are only isolated reports and pilot
studies from which there is not yet sufficient evidence of safety
and efficacy. Similarly, the long-term effects and side effects of
taking frankincense has not yet been scientifically investigated.
Boswellic acid in vitro antiproliferative effects on various tumor
cell lines (such as melanoma, glioblastomas, liver cancer) are
based on induction of apoptosis. A positive effect has been found
in the use of incense on the accompanying specimens of brain
tumors, although in smaller clinical trials. Some scientists say
the results are due to methodological flaws. The main active
compound of Indian incense is viewed as being boswellic acid.
As of May 2008 FASEB Journal announced that Johns Hopkins
University and the Hebrew University of Jerusalem have determined
that frankincense smoke is a psychoactive drug that relieves
depression and anxiety in mice. The researchers found that the
chemical compound in censole acetate is responsible for the
effects.
In a different study, an enriched extract of "Indian Frankincense"
(usually Boswellia serrata) was used in a randomized,
double-blinded, placebo-controlled study of patients with
osteoarthritis. Patients receiving the extract showed significant
improvement in their arthritis in as little as seven days. The
compound caused no major adverse effects and, according to the
study authors, is safe for human consumption and long-term use.
The study was funded by a company which produces frankincense
extract, and that the results have not yet been duplicated by
another study.
In a study published in March 2009 by the University of Oklahoma
Health Sciences Center it was reported that"Frankincense oil
appears to distinguish cancerous from normal bladder cells and
suppress cancer cell viability
Study: Frankincense may fight some cancers
January 31, 2006
A Virginia Tech scientist says frankincense oil might be
useful in treating malignant melanoma -- an aggressive cancer that
attacks humans and equines.
Approximately 54,000 malignant melanoma cases are diagnosed
annually, according to the American Cancer Society, and there are
many similarities between malignant melanoma in horses and
malignant melanoma in people.
Recognizing the opportunity for translational research, John
Robertson, a professor in the Virginia-Maryland Regional College
of Veterinary Medicine at Virginia Tech, has been studying the
disease and an experimental treatment involving frankincense oil.
Frankincense is a botanical oil distillate made from fermented
plants that contains boswellic acid, a component known to have
anti-neoplastic properties.
During a recent presentation before a regional meeting of the
American Cancer Society in Roanoke, Va., Robertson -- director of
the college's Center for Comparative Oncology -- said he's found
the oil has fairly selective anti-tumor activity and doesn't
appear to disrupt normal cells."I think this research on
frankincense oil suggests that this ancient medicine may have
significant modern uses for chemotherapy of non-resectable
malignancies," said Robertson.
http://gulfnews.com/news/gulf/oman/oman-researchers-find-cancer-treatment-in-frankincense-1.1251940
Muscat: Omani researchers at the University of Nizwa have
succeeded in producing a medicinally important compound from Omani
frankincense, luban, for breast cancer treatment.
Dr Ahmad Sulaiman Al Harrasi, holder of the University’s Chair of
Oman’s Medicinal Plants and Marine Natural Products, said
researchers have succeeded in isolating and enhancing the
percentage of AKBA found in the resin of Omani frankincense.
AKBA (beta-boswellic acid, keto-beta-boswellic acid, and
acetyl-keto-beta-boswellic acid) has been indicated in apoptosis,
or death of cancer cells, in particular brain tumours and cells
affected by leukaemia or colon cancer.
Dr Al Harrasi pointed out that the research was done under the
chairmanship of Oman Medicinal Plants and Marine Natural Products
at the Nizwa University and was funded jointly by the Oman
Research Council and Nizwa University,
This discovery, the Nizwa University scientist says, will play a
vital medicinal as well as economic role. “AKBA is very costly,”
he said, explaining the economic benefits to the country.
Omani media have claimed that a “cure” for cancer had been found,
which Al Harrasi denies.
“We would like to dispel certain misgivings regarding our
discovery,” Dr Al Harrasi told Gulf News over the phone from
Nizwa, about 160km northwest of Muscat.
“We have not discovered a breast cancer cure and it is not from
oil as reported in some media and being circulated on WhatsApp as
well as social media,” he added
The Assistant Dean for Scientific Studies and Research in Nizwa
University also clarified that the compound had not been tested on
humans. “We experimented on various cancer cell alliances for our
research,” he clarified, adding that their experiments on several
cancer cells showed positive results.
He also revealed that patent registration process was under
process and 60 to 70 per cent of work was done. “The draft [for
patent] has been accepted,” he said
http://ecancer.org/news/465.php
Frankincense oil derived from Boswellia
carteri induces bladder tumor cell specific cytotoxicity
18 Mar 2009
Frankincense oil - a potential treatment option for bladder
cancer
An enriched extract of the Somalian Frankincense herb Boswellia
carteri has been shown to kill off bladder cancer cells.
Frankincense oil is prepared from aromatic hardened gum resins
obtained by tapping Boswellia trees. One of the main components of
frankincense oil is boswellic acid, a component known to have
anti-neoplastic properties. Research presented in the peer
reviewed journal, BMC Complementary and Alternative Medicine found
that Frankincense oil might represent an alternative
intravesical agent for bladder cancer treatment.
HK Lin and his team, from the University of Oklahoma Health
Sciences Center and Oklahoma City VA Medical Center, set out to
evaluate frankincense oil for its anti-tumour activity in bladder
cancer cells. The authors investigated the effects of the oil in
two different types of cells in culture: human bladder cancer
cells and normal bladder cells. The team found that frankincense
oil is able to discriminate between normal and cancerous bladder
cells in culture, and specifically kill cancer cells.
Within a range of concentration, frankincense oil suppressed cell
viability in bladder transitional carcinoma J82 cells but not in
UROtsa cells. Comprehensive gene expression analysis confirmed
that frankincense oil activates genes that are responsible for
cell cycle arrest, cell growth suppression, and apoptosis in J82
cells. However, frankincense oil-induced cell death in J82 cells
did not result in DNA fragmentation, a hallmark of apoptosis.
Article: Frankincense oil derived from Boswellia carteri induces
tumor cell specific cytotoxicity
Mark Barton Frank, Qing Yang, Jeanette Osban, Joseph T Azzarello,
Marcia R Saban, Ricardo Saban, Richard A Ashley, Jan C Welter,
Kar-Ming Fung and Hsueh-Kung Lin
http://www.biomedcentral.com/bmccomplementalternmed/
VIDEO
http://www.youtube.com/watch?v=hsJg_kmvQDE?
FRANKINCENSE FOR CANCER - PRE CLINICAL RESULTS
http://qwww.kfor.com/2013/04/30/the-biblical-cure/
Frankincense: The Biblical cure? | KFOR.com
PATENTS
Novel Salts Of Boswellic Acids And
Selectively Enriched Boswellic Acids And Processes For The
Same
US2013116211
New salts or ion-pair complexes obtained by a reaction between
boswellic acids or selectively enriched
3-O-acetyl-11-keto-beta-boswellic acid (AKBA) or
11-keto-beta-boswellic acid (KBA) compounds obtained through a new
improved process, and an organic amine, more particularly with
glucosamine. These salts or ion pair complexes are useful in
nutraceuticals and in food supplements for anti-inflammatory and
analgesic treatment of joints and cancer prevention or cancer
therapeutic agents. These salts or ion pair complexes could also
be used in cosmetic or pharmaceutical composition for external
treatment of body parts or organs to treat inflammatory diseases
or cancer.
[0001] This invention relates to novel salts or ion pair complexes
of substituted/unsubstituted boswellic acid with certain organic
bases particularly though not exclusively with glucosamine. This
invention also includes an improved process for selectively
enriching 3-O-acetyl-11-keto-[beta]-boswellic acid and
11-keto-[beta]-boswellic acid hereinafter referred as (AKBA) and
(KBA) respectively from an extract containing a mixture of
boswellic acids.
BACKGROUND ART
[0002] Inflammation is a critical protective biological process
triggered by irritation, injury or infection, characterized by
redness and heat, swelling, loss of function and pain. In addition
to the foregoing induced conditions, inflammation can also occur
due to age related factors. Life expectancy of general population
has increased dramatically during the past few decades due to
efficient control of infectious diseases and better access to
nutritious food. This positive enhancement in life span coupled
with changing environmental conditions elevated the incidence of
chronic age-related diseases such as arthritis, diabetes, cancer,
cardiovascular diseases, etc. Chronic inflammatory condition and
cancer have become emerging health concerns in a number of
countries across the globe and for people among all cultures.
Arthritis is one of the most debilitating diseases of modem times.
The quality of life for sufferers of these two diseases and their
families is severely affected. Non-steroidal anti-inflammatory
drugs are most commonly used remedies for rheumatic diseases.
Presently, there has been a tremendous surge in demand for natural
non-steroidal anti-inflammatory drugs (NSAIDs) because of their
established safety and efficacy, through decades of usage by
various cultures.
[0003] The inflammatory and carcinogenesis processes are known to
be triggered by increased metabolic activity of arachidonic acid.
Arachidonic acid diverges down into two main pathways during this
process, the cyclooxygenase (COX) and lipoxygenase (LOX) pathways.
The COX pathways lead to prostaglandin and thromboxane production
and the LOX pathways leads to leukotrienes (LTS) and hydroxyl
eicosatetetraenoic acid (HETEs). These classes of inflammatory
molecules exert profound biological effects, which enhance the
development and progression of human cancers,
[0004] Leukotrienes and 5(S)-HETE are important mediators for
inflammatory, allergic and obstructive process. Leukotrienes
increase micro vascular permeability and are potent chemotactic
agents. Inhibition of 5-lipoxygenase indirectly reduces the
expression of TNF-[alpha] (a cytokine that plays a key role in
inflammation). 5-Lipoxygenase is therefore the target enzyme for
identifying inhibitors, which have potential to cope with a
variety of inflammations and hypersensitivity-based human diseases
including asthma, arthritis, bowel diseases such as ulcerative
colitis and circulatory disorders such as shock and ischaemia.
[0005] Similarly prostaglandins are intercellular messengers that
are produced in high concentration at the sites of chronic
inflammation and are capable of causing vasodilation, increased
vascular permeability and sensitizing pain receptors. The
pro-inflammatory prostaglandins (PGE2) are produced by inducible
isoform cyclooxygenase-2 (COX-2). The prostaglandins that are
important in gastrointestinal and renal function are produced by
the constitutively expressed isoform, cyclooxygenase-1 (COX-1).
COX-1 is the protective housekeeper isoform and it regulates
mucosal cell production of mucous that provides a barrier between
the acid and pepsin present in gastric secretions. Non-selective
COX inhibitors thus produce serious side effects. Scientists
around the world are thus investing a major effort in identifying
non-steroidal anti-inflammatory drugs that inhibit 5-lipoxygenase
and cyclooxygenase-2 enzymes. As both COX-2 and 5-LOX are commonly
expressed in any kind of inflammatory condition, efforts are
currently being focused to obtain the so called dual acting
anti-inflammatory drugs that are able to inhibit both COX-2 and
5-LOX enzymes. Unfortunately, the odds of finding a new dual
acting natural NSAID that can truly alleviate the symptoms of
inflammatory diseases are very thin. Hence, the researchers
conceived the idea that using a combination of drugs, one having
the COX-2 inhibitory activity and the other having 5-LOX
inhibitory activity, as the next best option.
[0006] Rheumatoid arthritis is a chronic inflammatory condition
that affects the lubricating mechanism and cushioning of joints.
As a result of this autoimmune disease the bone surfaces are
destroyed, which leads to stiffness, swelling, fatigue and
crippling pain. Osteoarthritis is the common form of arthritis and
results primarily from progressive degeneration of cartilage
glycoaminoglycons. The damage is often compounded by a diminished
ability to restore and repair joint structures including
cartilage. The smooth surface of the cartilage becomes hard and
rough creating friction. As a result of this the joint gets
deformed, painful and stiff. Studies have indicated that over 40
million Americans have osteoarthritis, including 80% of persons
over the age of 50. The major focus for osteoarthritis treatment,
should therefore involve agents that not only stimulate the
production of biological substances necessary for regeneration of
cartilage cells and proper joint function but also diminish pain
inflammation.
[0007] It is therefore an object of the present invention to
provide a salt or ion pair complex as a dietary supplement, that
exhibits anti-arthritic properties without deleterious side
effects.
[0008] Boswellic Acids
[0009] Gum resin of Boswellia species known as Indian frankincense
has been used as an anti-inflammatory agent in Traditional
Ayurvedic Medicine in India. Ancient Ayurvedic texts described its
therapeutic use. Clinical trails performed by CSIR laboratories in
India have shown fair to excellent results in 88% of the patients,
with no adverse side effects (Singh, G. B., Status report,
anti-inflammatory drugs from plant sources, 1982). A randomized,
double blind, placebo controlled clinical trials on patients with
osteo-arthritis of knee exhibited statistically significant
improvement in the pain, decreased swelling and increased knee
flexion etc. (Kimmatkar, Phytomedicine, 2003, 10, 3-7), The
therapeutic effects shown by Boswellia serrata extract were
comparable to those exhibited by sulfasalazine and mesalazine in
patients with ulcerative colitis. (Gupta, I., et al., Eur. J. Med.
Res., 1998, 3, 511-14 and Gerhardt, H., et. al., Gastroenterol.,
2001, 39, 11-17). The source of anti-inflammatory actions has been
attributed to boswellic acids (Safayhi, H., et al., Planta Medica,
1997, 63, 487-493 and J. Pharmacol. Exp. Ther., 1992, 261,
1143-46, both the journals published from USA), a group of
triterpene acids isolated from the Boswellia resin (Pardhy, R. S.,
et al., Indian J. Chem., 1978, 16B, 176-178). These compounds
exert anti-inflammatory activity by inhibiting 5-lipoxygenase
(5-LOX). The boswellic acids also gained prominence recently for
their antiproliferative actions. Boswellic acids inhibited several
leukemia cell lines in vitro and inhibited melanoma growth and
induced apoptosis (Hostanska, K., et al., Anticancer Res., 2002,
22(5), 2853 -62). The acetyl boswellic acids were found to be
unique class of dual inhibitors of human topoisomerases I and II a
(Syrovets, T. et al., Mol. Pharmacol., 2000, 58(1), 71-81).
Immunomodulatory activity of boswellic acids had been reported by
Sharma et al. in Phytotheraphy Research, 1996, 10, 107-112,
published from USA. A detailed study on the structural
requirements for boswellic acids indicated that of all the six
acids, 3-O-acetyl-11-keto-[beta]-boswellic acid, hereinafter
referenced as AKBA shows most pronounced inhibitory activity
against 5-LOX (Sailer, E. R., et al., British J. Pharmacology,
1996, 117, 615-618). AKBA acts by unique mechanism, in which it
binds to 5-LOX in a calcium-dependent and reversible manner and
acts as a non-redox-type, non-competitive inhibitor (Sailer, E.
R., et al., Eur. J. Biochem., 1998, 256, 364-368). The AKBA or a
plant extract or composition containing it was reported to be
effective for topical application, as an agent to soften lines
and/or relax the skin (Alain, M., et. al., U.S. patent application
No. 2004/0166178, dated Aug. 26, 2004). AKBA has thus become the
subject of intensive research for its potential for the treatment
of chronic inflammatory disorders.
[0010] Glucosamine
[0011] Glucosamine is a natural substance found in high quantities
in joint structures. The main function of glucosamine in joint
structures is to produce cartilage components necessary for
maintaining and repair joint tissue. Glucosamine stimulates the
formation of joint structural components such as collagen, the
protein of the fibrous substances that holds the joints together
and helps to build-up the cartilage matrix, Collagen is the main
component of the shock-absorbing cushion called articular
cartilage. It is also a necessary nutrient in the production of
synovial fluid. Some people may lose the ability with age to
produce glucosamine, thereby inhibiting the grpwth of cartilage
destroyed during wear and tear in osteoarthritis patients
(Towheed, T. E., Arthritis and Rheumatism, 2003, 49, 601-604).
When taken orally as a dietary supplement in the form of
glucosamine sulfate, it has been shown to exert protective effect
against joint destruction and is selectively used by joint tissues
to promote healthy joint function and show potential therapeutic
effect in osteoarthritis (Perry, G. H., et al., Ann. Rheum. Dis.,
1972, 31, 440-448).
[0012] Several double-blind studies with glucosamine sulfate
showed therapeutic effects comparable to or even better than non
steroidal anti-inflammatory drugs in relieving the symptoms of
osteoarthritis (Vaz, A. L., Curr. Med, Res. Opin., 1982, 8,
145-149; D'Ambrosia, E. D., et al., Pharmatherapeutica, 1982, 2,
504-508 and Tapadinhas, M. J., et al., Pharmatherapeutica, 1982,
3, 157-168). The NSAIDs offer only symptomatic relief, whereas
glucosamine addresses the root cause of osteoarthritis disease. It
support body's natural ability to tackle the disease on its own by
providing the building blocks to many structural components such
as glucosaminoglycons to repair the damage caused by
osteoarthritis. Glucosamine hydrochloride is used for this study.
DISCLOSURE OF THE INVENTION
[0013] The organic solvent extract of the gum resin of Boswellia
serrata contain a total of six boswellic acids and two timcallic
acids. These acids are shown in FIG. 1, and are represented by B1,
B2, B3, B4, B5, B6, T1, T2 and T3. Studies have indicated AKBA as
the most potent an anti-inflammatory agent among all the boswellic
acids. The concentration of AKBA, indicated as B2 in the FIG. 1,
amounts only in the range of 1-10% in the extract, but most often
it is in the range of 2-3%. The potential usefulness of boswellic
acids in general and AKBA in particular can be a great incentive
to take-up further development of these compounds in all possible
aspects.
[0014] The present invention is aimed at selective enrichment of
active compounds, KBA and AKBA to a therapeutically useful range
such as 30% to 100% from natural Boswellia extract using a new
improved process and then converting the enriched compounds to a
salt or ion pair complex with enhanced solubility and improved
therapeutic efficacy for use as an anti-arthritic dietary
supplement. The salt or ion pair combination may be accomplished
by using an acid function of the boswellic acid and an amine
function from amino organic compounds, especially glucosamine.
[0015] The enrichment of AKBA from natural Boswellia extract was
already described in international patent application (PCT #WO
03/074063, dated. 12th September 2003) and also in US patents
(application #20030199581, publication dated 23 Oct. 2003 and
application #20040073060, publication dated 15 Apr. 2004). The
processes described in these patents involve multi-step procedures
and requires tedious work-up and chromatographic purifications.
The present invention is an improved method, where in the
acetylation and allylic oxidation steps are conducted in a single
pot. This process eliminates the need for labor-intensive work-up
following acetylation and time consuming product drying before
proceeding to the oxidation step, as required by the processes
reported in the patents and journal articles. This process also
efficiently utilizes the un-reacted pyridine and acetic anhydride
from the acetylation step to form highly active oxidizing systems
such as CrO3/pyridine and CrO3/acetic anhydride. The present
invention effectively reduces the overall reaction time for
peracetylation and the oxidation steps. The new process eliminates
the presence of possible chromium impurities in the KBA/AKBA
enriched (30-40%) product by acid/base treatment without any need
for chromatography.
[0016] A fraction enriched to 30-40% 11-keto-[beta]-boswellic acid
(KBA), can be accomplished by subjecting the crude mixture to
basic treatment, followed by filtration and acidification of the
mother liquor, and then separation of the white solid by
filtration and drying, It was then reacetylated to obtain 30-40%
AKBA enriched fraction, The fractions enriched to higher
percentage (40-100%) of KBA and AKBA can be obtained by applying
chromatographic methodology on hydrolysis mixture and
re-acetylation mixture, respectively.
[0017] An ionic salt or ion pair complex of boswellic acids
containing AKBA in the range of 5 to 100% can be obtained by using
appropriately enhanced boswellic compound and a suitable amine
compound and adopting the representative procedure given in the
examples.
[0018] This invention relates to novel salts or ion pair complexes
of boswellic acid and keto boswellic acid and acetyl keto
boswellic acid with glucosamine having the following general
formula.
wherein R1 and R2 are H or taken together to form a keto group;
R3 is H or acyl group;
X is an heterocyclic base or an organic bases represented by
NHR4R5R6:
wherein R4, R5 and R6, are H or substituted or unsubtituted lower
or higher
alkyl group or aryl group or cyclic alkyl group.
[0024] Wherein the organic bases are glucosamine
(2-amino-2-deoxy-D-glucose), nicotinamide (3-pyridinecarboxamide),
pyridoxins (5-hydroxy-6-methyl-3,4-pyridinedimethanol), caffeine
(3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dxone), creatine
(N-(aminoiminomethyl)-N-methylglycine), allantoin
(2,5-dioxo-4-imidazolidinyl)urea), Theobromine
(3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione), theophylline
(3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), mesalamine
(5-amino-2-hydroxybenzoic acid), enfenamic acid
(2-[(2-phenylethyl)amino]benzoic acid), etofenamate
(2-[[3-(trifluoromethyl)phenyl]-amino]benzoic acid
2-(2-hydroxyethoxyethyl ester), flufenamic acid
(2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid), meclofenamic
acid (2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid),
mefenamic acid (2-[(2,3-dimethylphenyl)-amino]benzoic acid),
niflumic acid
(2-[[3-(trifluoromethyl)phenyl]-amino]-3-pyridinecarboxylic acid),
talniflumate
(2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid
1,3-dihydro-3-oxo-1-isobenzofuranyl ester), terofenamate
(2-[(2,6-dichloro-3-methylphenyl)-amino]benzoic acid ethoxymethyl
ester), tolfenamic acid
(2-[(3-chloro-2-methylphenyl)-amino]benzoic acid),
S-adenosylmethionine
((3S)-5'-[(3-amino-3-carboxypropyl)methylsulfonio]-5'-deoxyadenosine
inner salt), 3-amino-4-hydroxybutyric acid, amixetrine
(1[2-(3-methylbutoxy)-2-phenylethyl]pyrrolidine), benzydamine
(N,N-dimethyl-3-[[1-(phenylmethyl)-1H-indazol-3-yl]oxy]-1-propanamine),
difenpiramide (N-2-pyridinyl-[1,1'-biphenyl]-4-acetamide), ditazol
(2,2'-[(4,5-diphenyl-2-oxazolyl)imino]-bisethanol), emorfazone
(4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone),
fepradinol ((+-)-[alpha]-[[(2-hydroxy-1,
1-dimethylethyl)-amino]methyl]benzeneniethanol), paranyline
(4-(9H-fluoren-9-ylidenemethyl)benzene-carboximidamide), perisoxal
([alpha]-(5-phenyl-3-isoxazolyl)-1-piperidineethanol).
[0025] We have disclosed a simple method by which salts or
ion-pair complexes of boswellic acids with hetero-atom bases (also
referred to as 'organic base') can be made for their inclusion in
dietary or pharmaceutical compositions that provide reduction in
inflammation and other health benefits. These salts or ion pair
complexes are made by simple acid-base reaction, as shown in eq,
1, between an organic acid (RCOOH) and an organic base (NR4R5R6).
RCOOH+NR4R5R6->RCOO<-+>NHR4R5R6 (equation 1)
[0026] The new composition according to this invention may be
prepared by the following processes:
(a) By reacting boswellic acids or ketoboswellic acid or acetyl
ketoboswellic acid with organic base.
(b) By in situ generation of organic free base and reacting with
boswellic acids or ketoboswellic acid or acetyl ketoboswellic
acid.
[0029] In the first process, stoichiometric equivalents of the
reactants are mixed to obtain the desired salts or ion pair
complexes. Preferably, the reaction is initiated by the slow
addition of organic free base, particularly, glucosamine free base
to an aqueous methanolic solution of boswellic acids. Boswellic
acids (48% by HPLC) may be obtained by a known process of
extraction from the gum resin of Boswellia serrata. Glucosamine
free base may be liberated from glucosamine hydrochloride by
anionic exchange resin treatment. The enriched 11-ketoboswellic
acid or 3-O-acetyl-11-ketoboswellic acid (30%-100%) was obtained
from the gum-resin of Boswellia serrata using an improved method
described herein.
[0030] The salts or pair complexes prepared by this process may
contain between 10 to 70% of boswellic acids. 5-40% of
glucosamine.
[0031] According to the second process of preparing the compounds
of this invention, stoichiometric quantities of boswellic acids,
potassium hydroxide and organic base salts, particularly,
glucosamine hydrochloride are reacted in aqueous methanol medium.
[0032] A further aspect of the present invention is a
pharmaceutical formulation comprising a compound as described
above in a pharmaceutically acceptable carrier (e.g., an aqueous
or a non aqueous carrier).
[0033] A still further aspect of the present invention is a method
of treating inflammatory diseases, comprising administering to a
human or animal subject in need thereof a treatment effective
amount (e.g., an amount effective to treat, slow the progression
of, etc.) of a compound as described above.
[0034] Preferred embodiments relating to the improved process of
enriching AKBA in natural Boswellia extract and making the salts
or ion pair complexes are presented in examples 1 to 6.
[0035] Though the following examples describe a specific
embodiment of this invention, obvious equivalents and
modifications known to persons skilled in the art are not excluded
from the scope of the appended claims.
EXAMPLE 1
Isolation of 11-keto-[beta]-boswellic acid and
3-O-acetyl-11-keto-[beta]-boswellic acid
[0036] 1a). Single Pot Conversion of Boswellia Extract into AKBA
Enriched Fraction:
[0037] To a solution of Boswellia serrata extract (85%, 10 kg,) in
pyridine (5.4 L), in a 100 L all glass reactor equipped with a
water-cooled reflux condenser, was added acetic anhydride (4.2 L)
at room temperature and the mixture was subjected to heating at
60-65[deg.] C. under stirring. After 3 h, the mixture was cooled
to ambient temperature and diluted with acetic acid (24 L) and
acetic anhydride (24 L). The contents were cooled and treated
slowly with chromium trioxide (6.4 kg) while maintaining the
temperature under 40[deg.] C. The stirring was continued for
another 2 h after the addition, and then the mixture was poured
into ice water and the contents were mixed thoroughly. The solid
was filtered, washed with water and dried in a vacuum oven to
obtain a residue (14 kg). The HPLC analysis of the crude product
showed complete conversion of boswellic acids B1, B4 and B6 to B2
(AKBA).
[0038] 1b). Isolation of 30-40%
3-O-acetyl-11-keto-[beta]-boswellic acid: The above crude reaction
mixture (5 kg) was added to 4N hydrochloric acid (45 L) and heated
at 60[deg.] C. for 4 h. The mixture was cooled to ambient
temperature and filtered. The precipitate was washed with 4N HCl,
followed by water and dried in a vacuum oven to obtain AKBA
enriched to 30-40% (2.8 kg).
[0039] 1c). Isolation of 3-O-acetyl-11-keto-[beta]-boswellic acid:
The above, enriched compound (500 g) was subjected to silica
column chromatography using 5% to 30% ethyl acetate/hexane
mixtures. The fractions were monitored by TLC and those containing
AKBA (30%-60%) were combined and subjected crystallization in
hexane and ethyl acetate mixtures to obtain fractions enriched up
to 85% AKBA, Repeated crystallization in the same solvent system
yielded AKBA enriched up to 100%.
[0040] 1d). Isolation of 11-keto-[beta]-bowellic acid:
Alternatively, the crude mixture was dissolved in methanol and
subjected to base treatment (8N KOH), The precipitate was
separated by filtration and discarded. The mother liquor was
acidified and the off-white precipitate was filtered, washed with
water and dried under vacuum to obtain 30-40% ketoboswellic acid
(KBA). The 11-keto-[beta]-boswellic acid mixture (200 g) obtained
was adsorbed on 250 g of silica gel and subjected column
chromatography over 500 g of silica. The column was eluted with
hexane, 10% ethyl acetate/hexane, 20% ethyl acetate/hexane and 30%
ethyl acetate/hexane mixtures. The fractions were monitored by TLC
and the fractions containing 11-keto-p-boswellic acid were
combined and evaporated and the residue was subjected to repeated
crystallization from ethyl/hexane mixtures to obtain pure
11-keto-[beta]-boswellic acid (45 g, 95-100%. purity).
[0041] 1e). In a further variation of the process mentioned in
example 1a, the addition of acetic anhydride was eliminated.
Instead the peracetylated mixture was diluted with 20 L of acetic
acid and treated with CrO3 (6.4 kg) in 100 L of acetic acid. The
reaction mixture was quenched with excess water after 24 h, and
processed as described in example 1a,
EXAMPLE 2
[0042] Glucosamine salt of boswellic acids; To a solution of
boswellic acids (2 g, 48% boswellic acids) in 95% aqueous methanol
(50 mL) was added glucosamine free base solution (8.6 mL, 0.4 g)
and stirred at rt for 1 h. Then the solvent was evaporated under
reduced pressure and dried to give glucosamine salt or ion pair
complex of boswellic acids as gray colour powder (2.3 g), pH, 6,3,
soluble in 90% aqueous methanol.
[0043] The analytical characteristics of the glucosamine salt or
ion pair complex of boswellic acids thus obtained are, B1, 4.75%,
B2, 2,10%, B3, 5.44%, B4, 14.91%, B5, 2.18%, B6, 8.66%; total:
38.04%; glucosamine (as free base) is 8.52%.
EXAMPLE 3
[0044] Glucosamine salt of boswellic acids (KCl): To a solution of
boswellic acids (5 g, 48% boswellic acids) in methanol (125 mL)
was added a solution of glucosamine hydrochloride (2 g) in water
(8 mL) and stirred at rt for 15 min. Then potassium hydroxide
(0.52 g, 20% aqueous solution, 2.6 mL) was charged slowly for 10
min and the solution was stirred at rt for 1 h. The solvent was
evaporated under reduced pressure and dried to give glucosamine
salt or ion pair complex of boswellic acids as gray colour powder
(7.5 g), pH, 6.8, soluble in 90% aqueous methanol.
[0045] The analytical characteristics of the glucosamine salt or
ion pair complex of boswellic acids thus obtained are, B1, 4.04%,
B2, 1.86%, B3, 4.65%, B4, 12.73%, B5, 1.76%, B6, 7.34%; total:
32.38%; glucosamine (as free base) is 12.44%.
EXAMPLE 4
[0046] Glucosamine salt of boswellic acids (KCl): To a solution of
boswellic acids (5 g, 48% boswellic acids) in methanol (125 mL)
was added a solution of glucosamine hydrochloride (4g) in water
(11 mL) and stirred at rt for 15 min. Then potassium hydroxide
(0.52 g, 20% aqueous solution, 2.6 mL) was charged slowly for 10
min and the solution was stirred at rt for 1 h. The solvent was
evaporated under reduced pressure and dried to give glucosamine
salt or ion pair complex of boswellic acids as gray colour powder
(9.6 g), pH, 6.6, soluble in 90% aqueous methanol.
[0047] The analytical characteristics of the glucosamine salt or
ion pair complex of boswellic acids thus obtained are, B1, 3.14%,
B2, 1.37%, B3, 3.36%, B4, 9.75%, B5, 0.93%, B6, 4.76%; total:
23.31%; glucosamine (as free base) is 27.16%.
EXAMPLE 5
[0048] Glucosamine salt of Acetyl ketoboswellic acid (KCl); To a
solution of acetyl ketoboswellic acid (5 g, 30% AKBA) in methanol
(100 mL) was added a solution of glucosamine hydrochloride (0.63
g) in water (3 mL) and stirred at rt for 15 min. Then potassium
hydroxide (0.164 g, 20% aqueous solution, 0,82 mL) was charged
slowly for 10 min and the solution was stirred at rt for 1 h. The
solvent was evaporated under reduced pressure and dried to give
glucosamine salt or ion pair complex of acetyl ketoboswellic acid
as gray colour powder (4.8 g), pH, 6.7, soluble in 90% aqueous
methanol.
[0049] The analytical characteristics of the glucosamine salt or
ion pair complex of acetyl ketoboswellic acid thus obtained are,
AKBA is 27.68%; glucosamine (as free base) is 5.42%.
EXAMPLE 6
[0050] Glucosamine salt of Acetyl ketoboswellic acid (KCl): To a
solution of acetyl ketoboswellic acid (5 g, 30% AKBA) in methanol
(100 mL) was added a solution of glucosamine hydrochloride (5 g)
in water (15 mL) and stirred at rt for 15 min. Then potassium
hydroxide (0.2 g, 20% aqueous solution, 1.0 mL) was charged slowly
for 10 min and the solution was stirred at rt for 1 h. The solvent
was evaporated under reduced pressure and dried to give
glucosamine salt or ion complex of acetyl ketoboswellic acid as
gray colour powder (9.3 g), pH, 5.6, soluble in 90% aqueous
methanol.
[0051] The analytical characteristics of the glucosamine salt or
ion pair complex of acetyl ketoboswellic acid thus obtained are,
AKBA is 15.30%; glucosamine (as free base) is 39.44%.
Novel anti-cancer purely natural medicine
(11-carbonyl-beta-acetyl boswellic acid)
CN101724005
The invention relates to a novel broad spectrum purely natural
medicine that can specifically inhibit phosphorylation of protein
T-kappa-B to prevent nuclear transport of T-kappa-B so as to
inhibit the growth of cancer cell, thereby treating cancer. The
novel medicine is a natural extractive, and has the advantages of
low production cost, high curative effect and less side effect.
COMPOSITIONS AND METHODS FOR TREATING AND
PREVENTING INFLAMMATORY AND/OR DEGENERATIVE PROCESSES IN
HUMANS AND OTHER ANIMALS
WO2007011674
Disclosed are compositions useful for treating Alzheimer's
disease, atherosclerosis, arteriosclerosis, osteoarthritis and
other degenerative joint diseases, Huntington's chorea,
Parkinson's disease, optic atrophy, retinitis pigmentosa, macular
degeneration, muscular dystrophy, aging-associated degenerative
processes, asthma, dermatitis, laminitis, pemphigoid, pemphigus,
reactive airway disease (e.g., COPD, IAD), inflammatory bowel
disease (e.g., Crohn's disease, ulcerative colitis) , multiple
sclerosis, rheumatoid arthritis, periodontal disease, systemic
lupus erythematosus, sarcoidosis, psoriasis, type I diabetes,
ischemia-reperfusion injury, chronic inflammatory diseases,
geriatric wasting, cancer cachexia, cachexia associated with
chronic inflammation, sick feeling syndrome, and other
inflammatory and/or degenerative diseases, disorders, conditions,;
and processes in humans and other animals. In one embodiment, the
compositions include at least 4 of the following: a MMPl
inhibitor, a MMP2 inhibitor, a MMP3 inhibitor, a MMP7 inhibitor, a
MMP9 inhibitor, an ADAMTS-4 inhibitor, a MMP13 inhibitor, and a
MMP14 inhibitor. In another embodiment, the compositions include a
curcuminoid, a polymethoxylated flavone, a catechin, and a
boswellic acid.
WATER SOLUBLE BOSWELLIC ACIDS, THEIR
PREPARATION AND USE FOR TREATING IMFLAMMATORY
CONDITION
WO02066491
A new composition which can be formed through a method comprising:
(a) dissolving mixtures of boswellic acids in a water and alcohol
solution to form a mixture; (b) adding one or more alkali salts to
the mixture to form a salt solution; (c) filtering the solution to
separate un-reacted alkali salt from a filtrate; and (d)
recovering the soluble boswellic acid mixture from the filtrate.
Additionally, the new composition can be formed by using super
critical carbon dioxide. The new composition can be used to
alleviate numerous inflammatory conditions, including, but not
limited to, rheumatoid arthritis and osteoarthritis, colon cancer,
prostate cancer and breast cancer, and a broad range of
neurodegenerative conditions, such as Alzheimer's disease and
Parkinson's disease. The composition can be administered
parenterally, orally, or topically.
BACKGROUND OF THE INVENTION :
[0003] Boswellia serrata is a large, branching, deciduous tree,
which grows abundantly in the dry, hilly parts of India. The gum
resin exudate of this tree, known in the vernacular as"Salai
guggal", has been used in the Ayurvedic system of medicine for the
management of arthritis, respiratory diseases, and liver
disorders.
The major use of Boswellia serrata in modern medicine is as an
anti-arthritic and anti-inflammatory pharmacological agent.
[0004] The active principles found in the gum resin, specifically
a combination of boswellic acids, have emerged as effective
non-steroidal anti-inflammatory compounds (NSAID's) with broad
biological activities and also a low ulcerogenic index. Compared
experimentally with the anti-inflammatory drug phenylbutazone,
boswellic acids did not produce injury to the gastrointestinal
mucosa. The most popular NSAID, aspirin, although much better
tolerated than its parent compound salicylates, still has serious
side effects, e. g. gastrointestinal irritation and bleeding which
limit its long-term use. In addition, aspirin is contraindicated
in patients who have experienced asthma, urticaria (in general
allergic reactions), and should be administered with caution in
children and teenagers due to the risk of Reye syndrome.
[00005] One way in which to explain how boswellic acids function
as NSAIDs in the treatment of inflammatory conditions is to
compare these natural compounds to aspirin without the typical
gastrointestinal irritation. Similar to aspirin, boswellic acids
inhibit the pathway leading from arachidonic acid (a derivative of
our body's phospholipids) to its metabolic derivatives called
leukotrienes and prostaglandins.
An excess of leukotrienes and prostaglandins may be responsible,
directly or indirectly, for the classic signs of inflammation ;
redness (due to dilated vessels), swelling (due to the blood
vessels leaking out), pain (due to activation of the pain
receptors) and increased heat over the affected part of the body.
The specific biochemical mechanism of boswellic acids differs from
that of aspirin, however both compounds result in the diminishment
of the mediators of inflammation, leukotrienes or prostaglandins,
and the inflammation is subdued.
[0006] Studies designed to determine the anti-inflammatory
mechanism of boswellic acids indicate that their primary mode of
action involves the inhibition of 5lipoxygenase, the key enzyme
responsible in the formation of leukotrienes.
Additionally, boswellic acids do not appear to impair the
peroxidation of arachidonic acid by iron and ascorbate. These
results suggest that boswellic acids are safe, specific, non-redox
inhibitors of leukotriene synthesis that operate through a well
defined mechanism.
[0007] One of the most interesting properties of boswellic acids
is their anticomplementary activity. In in vitro experiments
boswellic acids prevented a wellknown
inflammatory"chain-reaction"involving several protein compounds
collectively known as"complement". This is due to the inhibition
of an enzyme that activates one of the components of complement,
C3 convertase. The domino effect of the complement in the course
of rheumatoid arthritis (or a similar chronic inflammatory
process) leads to a subsequent elevation of the enzymes (e. g.
cathepsins, glucuronidase and human leukocyte elastase (HLE))
causing excessive catabolism (wasting) of the joint-forming
glycoproteins and glycosaminoglycans.
This tissue destructive process leads to continuously worsening
joint disfigurement, pain, and limited mobility. As a consequence
of complement-mediated tissue destruction, there is an increased
release of markers (metabolites) of the connective tissue, e. g.
hydroxyproline, hexosamine and uronic acid. Boswellic acids have
been found to decrease the levels of tissue destructive enzymes
and also of the levels of urinary hydroxyproline, hexosamine and
uronic acid in the acute and chronic phases of experimental
arthritis.
[0008] There are four major b-boswellic acids involved in the
inhibition of 5lipoxygenase and related anti-inflammatory events.
These are: b-Boswellic Acid (BBA), Acetyl-b-Boswellic Acid (ABBA),
11-keto-b-Boswellic Acid (KBBA), Acetyl-11- keto-b-Boswellic
(AKBBA), listed here in the order of increasing anti-inflammatory
properties.
[0009] Boswellic acids have been found to be effective in
alleviation of numerous inflammatory conditions, including,
rheumatoid arthritis and osteoarthritis.
[0010] A standardized extract of boswellic acids (200 mg tid) was
evaluated in a four week double blind, cross-over trial in 30
patients suffering from rheumatoid arthritis. The mean arthritic
score (sum of symptoms) and the biochemical index of inflammation
in the group receiving boswellic acids came down significantly
after the treatment. However, when the placebo was substituted
(crossover), the subjective and objective indices of arthritis
rose again. (See Majeed, M, Badmaev, V, Gopinathan, S, Rajendran,
R, Norton, T. Boswellin The Anti-inflammatory Phytonutrient.
Nutriscience Publishers, Inc. Piscataway, N. J. 1996. pp. 78.)
[0011] In another 20 patient, double blind, crossover study a
boswellia gum resin extract (200 mg tid) combined in an
herbomineral formula was evaluated in the treatment of rheumatoid
arthritis and separately in osteoarthritis. Active and placebo
treatments were given for a period of three months. After a
washout period of two weeks, the regimens were crossed-over. The
three month active therapy resulted in a significant decrease in
severity of pain, morning stiffness, improved joint mobility
score, grip strength score and the overall disability score
compared to the placebo group. The biochemical index of
inflammation was also significantly improved due to the treatment.
(See Kulkarni, RR, Patki, PS, Jog, VP, Patwardhan, G & B.
Efficacy Of An Ayurvedic Formulation In Rheumatoid Arthritis: A
Double-Blind, Placebo Controlled, Cross-Over Study. Ind J
Pharmacol. 1992 ; 24: 98-101.) [0012] Ulcerative colitis is an
example of a chronic inflammatory process in the bowel, which may
be caused and/or aggravated by excessive leukotriene production.
Effects of Boswellia serrata gum resin (350 mg thrice daily for 6
weeks) vs. the NSAID sulfasalazine was studied in patients with
ulcerative colitis. The tested parameters, including stool
properties, istolopathology of rectal biopsies, and blood
biochemistry improved after treatment with the gum resin. As a
result of the treatment, 82% of patients went into remission, as
compared to a 75% remission rate obtained with sulfasalazine. (See
Gupta, 1, Parihar, A, Malhotra, P, Singh, GB, Ludtke, R, Safayhi,
H, Ammon, HP. Effects of Boswellia serrata gum resin in patients
with ulcerative colitis. Eur J Med Res. 1997 Jan; 2 (1) : 37-43.)
[0013] Boswellic acids were also tested in the management of
asthma, since a new generation of anti-asthmatic drugs is based on
the premise of being leukotriene inhibitors. In a double blind,
placebo-controlled study 40 patients with a several years'history
of bronchial asthma were treated with 300 mg tid of boswellia gum
resin for a period of six weeks. Seventy percent of the patients
responded to the treatment as evidenced by a reduction in dyspnea,
ronchi, and number of attacks, improvement in lung tests and blood
biochemistry. Only 27% of the patients receiving placebo showed
clinical improvement. (See Gupta, 1, Gupta, V, Parihar, A, Gupta,
S, Ludtke, R, Safayhi, H, Ammon, HP. Effects Of Boswellia Serrata
Gum Resin In Patients With Bronchial Asthma: Results Of A
Double-Blind, Placebo
Controlled, 6-Week Clinical Study. Eur J Med Res. 1998; 3:
511-514.) [0014] Finally, boswellic acids also have use in the
veterinary field. Several veterinarians found success using
boswellic acids in the treatment of chronic inflammatory
conditions in horses such as stifle problems, sore backs, bowed
tendons and bone spurs. In addition, a preliminary study of
boswellic acids in aging pet dogs and cats showed beneficial
effects in alleviating arthritic conditions. (See Majeed, M,
Badmaev, V, Gopinathan, S, Rajendran, R, Norton, T. Boswellin The
Anti-inflammatory Phytonutrient. Nutriscience Publishers, Inc.
Piscataway, N. J. 1996. pp. 78.) [0015] Sabinsa Corporation
manufactures different grades of Boswellic acids known under the
trademark Boswellin@, two of these are Boswellin (standardized for
25% boswellic acids) and Boswellin Forte (standardized for 40%
boswellic acids).
More specifically, the minimum amount of each boswellic acid that
must be present in these grades is:
Boswellin Forte Boswellin BBA min. 11.0% 6.0% ABBA min. 8.0% 4.0%
KBBA min. 7.0% 3.0% AKBBA min. 4.0% 1.5% [0016] Please note that,
of course, every acid may not be present in its minimum amount as
the required total percentages of boswellic acids (40% and 25%)
would not be met if this occurred.
[0017] Such non-water soluble mixtures of BBA, ABBA, KBBA, and
AKBBA boswellic acids can be used as a pharmaceutical. Since the
ancient times, frankincense has been used in the preparation of
cosmetics and perfumes, and also as a fixative in perfumes, soaps,
creams, lotions and detergents. Frankincense is a common name for
Boswellia gum resin, and Boswellia gum resin is a raw source from
which boswellic acids are extracted. The stabilizing effect of
frankincense in cosmetic preparations is directly related to the
biological properties of boswellic acids. The anti-inflammatory
properties of boswellic acids can also yield an interesting
applications for topical and cosmetic use of the extract of
Boswellia serrata. Boswellia cream for the management of
inflammatory conditions has been available for several years in
the US market. Its therapeutic composition includes, roughly 5 wt.
% boswellic acids, 0.025 wt. % capsaicin, an extract of Capsicum
annum fruits, and 10 wt. % methyl salicylate.
[0018] However, a problem associated with these formulations is
that they are not soluble in water. Therefore, there is a great
need in the field for water soluble boswellic acid mixtures and
salts.
SUMMARY OF THE INVENTION :
[0019] The new water-soluble composition can be formed through a
method comprising the steps of: (a) dissolving mixtures of
boswellic acids in a water and alcohol solution to form a mixture;
(b) adding one or more alkali salts to the mixture to form a salt
solution; (c) filtering the solution to separate un-reacted alkali
salt from a filtrate; and (d) recovering the soluble boswellic
acid mixture from the filtrate.
[0020] Additionally, the new composition can be formed by using
super critical carbon dioxide. The new composition can be used to
alleviate numerous inflammatory conditions, including, but not
limited to, rheumatoid arthritis and osteoarthritis, colon cancer,
prostate cancer and breast cancer, and a broad range of
neurodegenerative conditions, such as Alzheimer's disease and
Parkinson's disease. It can also be used in the prevention and
treatment of cardiovascular conditions such as stroke, coronary
artery disease or thrombophlebitis. The composition can be
administered parenterally, orally, or topically.
DETAILED DISCLOSURE :
[0021] As stated above, the composition can be formed by (a)
dissolving mixtures of boswellic acids in a water and alcohol
solution to form a mixture, (b) adding one or more alkali salts to
the mixture to form a salt solution, (c) filtering the salt
solution to separate un-reacted alkali salt from a filtrate, and
(d) recovering the soluble boswellic acid mixture from the
filtrate.
[0022] Preferably, though, the method involves (a) dissolving
boswellin forte in a water and 5% methanol solution to form a
mixture, (b) adding one or more potassium salts to the mixture to
form a salt solution and then stirring the salt solution at room
temperature, (c) filtering the solution with a nutsche filter to
separate un-reacted potassium salts from a filtrate, (d)
recovering the soluble boswellic acid mixture from the filtrate,
(e) drying the filtrate with a vacuum drier at a temperature of no
more than 50 C, and (f) powdering the filtrate.
[0023] More preferably, the filtrate can be dried through
concentrating the filtrate free of the solvent to obtain a solid,
wherein this step also further comprises dissolving the obtained
solid in water to obtain a secondary mixture, charcoalizing the
secondary mixture, filtering the charcoalized secondary mixture
and spray-drying the resulting product.
[0024] Additionally, it is also possible to use the super critical
carbon dioxide method of obtaining the boswellic acid mixture.
Such a process would comprise the steps of (a) dissolving a
mixture of boswellic acids, preferably boswellin forte, in a water
and alcohol solution to form a mixture, (b) adding one or more
alkali salts to the mixture to form a salt solution, (c) treating
the salt solution with supercritical carbon dioxide, (d) allowing
the supercritical carbon dioxide to evaporate to leave an
oleoresin, (e) passing an alcohol solution of the oleoresin
through a column packed with an anion exchange resin, and (f)
collecting the soluble boswellic acid mixture from the eluent.
Furthermore, it is preferred that the treatment of the salt
solution take place for at least 10 hours and that the alcohol
solution be 5% methanol and 95% water. Suitable resins include
Amberjet 4200 (cl), Amberlite IRA 410, Amberlite IRA 900, Dowex
1x2-100, Dowex 22cl, Dowex Marathon A2, Dowex MSA 1, Dowex 550 A,
all of which are Rohm-Haas or Dow products. The oleoresin is
preferably passed through the resin at a rate of 20-50 L per hour.
[0025] The processes described above produce a water soluble
composition, preferably comprising at least 12.5% by weight of the
alkali salt of BBA, at least 9.57% by weight of the alkali salt of
ABBA, at least 8.15% by weight of the alkali salt of KBBA, and at
least 3.72% by weight of the alkali salt of AKBBA, the remainder
of the water soluble composition being organic acids or matter,
and the alkali salts thereof. This composition of boswellic acids
is suitable for the treatment of many inflammatory conditions
including rheumatoid arthritis and osteoarthritis, colon cancer,
prostate cancer and breast cancer, and a broad range of
neurodegenerative conditions, such as Alzheimer's disease and
Parkinson's disease. It can also be used in the prevention and
treatment of cardiovascular conditions such as stroke, coronary
artery disease or thrombophlebitis.
[0026] The composition may be administered to the subject orally,
parenterally, or topically. For preparing pharmaceutical
compositions containing compounds of the invention, inert,
pharmaceutical acceptable carriers are used. The pharmaceutical
carrier can be either solid or liquid. Solid form preparations
include, for example, powders, tablets, dispersible granules,
capsules, creams, and cachets.
[0027] A solid carrier can be one or more substances which can
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or tablet disintegrating agents; it
can also be an encapsulating material. In powders, the carrier is
generally a finely divided solid which is in a mixture with the
finely divided active component. In tablets, the active compound
is mixed with the carrier having the necessary binding properties
in suitable proportions and compacted in the shape and size
desired.
[0028] Powders and tablets preferably contain between about 5% to
about 70% by weight of the active ingredient. Suitable carriers
include, for example, magnesium carbonate, magnesium stearate,
talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl
cellulose, sodium carboxymethyl cellulose, a low-melting wax,
cocoa butter and the like. The pharmaceutical compositions can
include the formulation of the active compound with encapsulating
material as a carrier providing a capsule in which the active
component (with or without other carriers) is surrounded by a
carrier, which is thus in association with it. In a similar
manner, cachets are also included. Tablets, powders, cachets, and
capsules can be used as solid dosage forms suitable for oral
administration.
[0029] Liquid pharmaceutical compositions include, for example,
solutions suitable for oral or parenteral administration, or
suspensions, and emulsions suitable for oral administration.
Sterile water solutions of the active component or sterile
solutions of the active component in solvents comprising water,
ethanol, or propylene glycol are examples of liquid compositions
suitable for parenteral administration.
[0030] Sterile solutions can be prepared by dissolving the active
component in the desired solvent system, and then passing the
resulting solution through a membrane filter to sterilize it or,
alternatively, by dissolving the sterile compound in a previously
sterilized solvent under sterile conditions.
[0031] Aqueous solutions for oral administration can be prepared
by dissolving the active compound in water or other appropriate
solvents and adding suitable flavorants, coloring agents,
stabilizers, and thickening agents as desired. Aqueous suspensions
for oral use can be made by dispersing the finely divided active
component in water together with a viscous material such as
natural or synthetic gums, resins, methyl cellulose, sodium
carboxymethyl cellulose, and other suspending agents known to the
pharmaceutical formulation art. Preferably, the pharmaceutical
composition is in unit dosage form. In such form, the composition
is divided into unit doses containing appropriate quantities of
the boswellic acid mixtures. The unit dosage form can be
a-packaged preparation, the package containing discrete quantities
of the preparation, for example, packeted tablets, capsules, and
powders in vials or ampules. The unit dosage form can also be a
capsule, cachet, or tablet itself, or it can be the appropriate
number of any of these packaged forms.
[0032] The specific dosages employed, however, can be varied
depending upon the requirements of the patient, and the severity
of the condition being treated. The preferred dosage of the alkali
boswellic acid salts given is 50-800 mg per day. More preferably,
the dosage is 100-600 mg per day. Even more preferred is a dosage
of 150-300 mg per day. Most preferred is a dosage of about 200 mg
per day, which is preferably administered by doses of 200 mg of
the boswellic acid salt composition 3 times a day. The
determination of optimum dosages for a particular situation is
within the skill of the art.
BRIEF DESCRIPTION OF DRAWINGS :
[0033] Figure 1: This diagram reflects the boswellic acid
composition of the Potassium Boswellin used in Example 1 and the
composition of the Boswellin forte used to create the Potassium
Boswellin used in Example 1.
[0034] Figure 2: This diagram reflects the presence of the four
boswellic acids in the serum of Individual A at 5,10,20,40,80, and
160 minutes.
[0035] Figure 3: This diagram reflects the presence of the four
boswellic acids in the serum of Individual B at 5,10,20,40,80, and
160 minutes [0036] Figure 4: This diagram is a graph charting the
serum levels of the various four boswellic acids in the serum of
Individual A at the 5,10,20,40,80, and 160 minute intervals.
[0037] Figure 5: This diagram is a graph charting the serum levels
of the various four boswellic acids in the serum of Individual B
at the 5,10,20,40,80, and 160 minute intervals
EXAMPLES
Example 1:
An initial batch of 1 kg Potassium Boswellin was prepared using
40% Boswellin Forte material (see Figure 1).
Potassium Boswellin and Boswellin 40% were then orally
administered to two human volunteers who had spent the previous 16
hours fasting. 1 gram of Potassium Boswellin was given to
Individual A and 1 gram of Boswellin 40% was given to Individual
B. Both the Potassium Boswellin and the Boswellin 40% were
suspended in 35 mi of milk and given to the subjects to consume. 5
ml of blood was withdrawn from the volunteers at intervals of
5,10,20,40,80, and 160 minutes.
The blood samples were collected into sterile centrifuge tubes and
left for 120 minutes to retract the clot. The samples were then
centrifuged to separate the serum. The serum was transferred to
sterile 2 mi vials and stored at 0 C-4 C overnight.
The serum samples were then brought to room temperature. 1 ml of
the serum was placed into a 10 ml stoppered volumetric flask and 1
ml of 3 N HCI was added to it. This mixture was then sonicated for
20 minutes to free the boswellic acid. The volume of the mixture
was then brought to 10 ml with methanol and the resulting solution
was sonicated for 10 minutes to extract the boswellic acids and to
precipitate the serum proteins. This prepared sample was then
transferred into capped centrifuge tubes and centrifuged at 4,000
rpm for 10 minutes. The serum proteins were precipitated as
sediment and the clear supernatant was filtered through No. 1
filter paper.
The clear supernatants were then subjected to a HPLC assay, the
results of which are shown in Figures 2-5. As can be plainly seen,
the serum with Potassium Boswellin shows that a greater amount of
boswellic acids have been absorbed by the subject's bloodstream,
thereby demonstrating the efficacy of the present invention.
EXTRACT OF OLIBANUM (FRANKINCENSE GUM) IN
THE FORM OF NANOPARTICLES, AND USE THEREOF
WO2006128634
[ Machine translation ]
The invention relates to a novel and improved nanoparticulate form
of a frankincense gum extract, containing, inter alia, Boswellic
acids and/or their derivatives. The nanoparticles have
advantageous properties for use in the treatment of inflammatory
diseases. Surprisingly, these advantages are obtained both in
topical application and oral administration. When used in topical
formulations, the nanoparticles are better absorbed by the skin
than are known, tacky extracts, and they are thus suitable for the
treatment, for example, of neurodermatitis and/or actinic
keratosis and/or basal cell carcinoma and/or epithlioma and/or
squamous cell carcinoma of the skin. For example, in soft gel
capsules that dissolve in the small intestine, the nanoparticles
have much improved bioavailability, which also considerably
improves oral administration for treatment of inflammatory
conditions. Finally, the nanoparticles can also be used for
coating stents and implants.
0001] extract from olibanum (incense) in the form of nanoparticles
and
[0002] using the same
[0003] The invention relates to a new and improved nanoparticulate
form of a Olibanumextraktes (incense extract) containing, among
other boswellic acids and / or derivatives thereof.
The dissolved Olibanumextrakt embedded in spherical particles
having a three-dimensional size in the nanometer (nm) range.
The so-called nanoparticles have advantageous properties in terms
of a use for treating inflammatory diseases.
Surprisingly these advantages are obtained both for a topical, an
oral administration as well as a surface coating of implants.
The nanoparticles are absorbed better when used in topical
formulations of the skin known as sticky extracts and thus
suitable for the treatment of, for example, atopic dermatitis and
/ or actinic keratosis and / or basal cell carcinoma and / or
squamous and / or squamous cell carcinoma of the skin.
For example, in enteric softgels show the olibanum nanoparticles
significantly improved bioavailability, which also improves oral
use in the treatment of inflammatory conditions significantly.
Finally, Olibanum nanoparticles can also be used for coating of
implants (vessel joint, bone, tooth) and surgical sutures.
[0004] state of the art early in oriental folk medicine is the use
of incense, primarily in India and in the Near East, for the
treatment of various diseases, especially inflammation and
rheumatic joint diseases known.
Even in recent times several medical applications have been found
for incense or Olibanumextrakte and especially for boswellic acids
and their derivatives.
Inflammatory responses are measures of the organism, which serve
to remove the damaging tissue damages by causing foreign bodies or
the damaged part of the tissue repair and replace tissue.
Hence, inflammation is a physiological process.
However, there are a number of situations in which functions of
organs are disturbed by inflammatory processes, especially when
they are shooting or chronic.
Inflammation is triggered by the release of so-called biochemical
mediators of inflammation.
There are two types of different inflammatory mediators that are
involved in the formation and maintaining inflammatory
prostaglandins and leukotrienes.
The current therapy of inflammation occurs with drugs that are
predominantly in a position called the arachidonic acid cascade,
namely to block the part of the leads to the formation of
Prostaglandiene.
The drugs used are among the steroidal and non-steroidal
anti-inflammatory drugs.
The anti-inflammatory effects of these drugs is associated with
significant side effects.
[0005] The anti-inflammatory effect of boswellic acids has been
repeatedly published (Safayhi, H., et.
AI, Planta Medica 63, 487-493, 1997. J. Pharmacol. And Exp Ther,
261, 1143-46, 1992). Sashwati et al investigated by screening the
human genome, the genetic basis of the anti-inflammatory effect of
Boswellia in microvascular endothelial cells and found an
inhibition of 5 -lipoxygenase, a key enzyme in the biosynthesis of
leukotrienes. The research revealed that
3-O-acetyl-11-keto-boswellic acid is the most potent as
5-lipoxygenase inhibitor among the boswellic acids.
In addition, the boswellic acids prevented the TNF-alpha-induced
expression of metalloproteinases and of mediators of apoptosis.
It was also the expression of VCAM-1 and ICAM-1 suppresses
Olibanumextrakte.
This research showed that Olibanumextrakt by influencing the
mechanisms of inflammation Signalmecha anti-inflammatory effect
(Sashwati, R., et al, DNA AND CELL BIOLOGY:. VoI 24, Number 4,
2005).
[0010] EP 552 657 A1 discloses that pure boswellic acid, the
physiologically compatible salts borrowed, derivatives thereof and
salts of derivatives or a herbal preparation containing boswellic
acid can fight inflammation, caused by increased leukotriene
formation.
It is suggested in the treatment of inflammatory joint diseases,
epidermal lesions, allergic and chronic asthma, Endoxinschock,
inflammatory bowel disease and chronic hepatitis with these
compounds.
[0011] WO 90/01937 reports that a-and ss-Boswelliaacetat
Boswelliaacetat and its analogs inhibit topoisomerase I and
topoisomerase II.
Therefore, this document proposes to use the compounds for the
treatment of various cancers.
[0012] WO 97/07796 uses boswellic acid, a physiologically
acceptable salt, derivative, a salt of said derivative or a
boswellic acid-containing herbal preparation for the prophylaxis
and / or the control of diseases that are caused by increased
Leukozytenelastaseoder Piasminaktivität.
Therefore, this document proposes to use the compounds in the
treatment of diseases such as emphysema, acute respiratory
distress syndrome, adult respiratory distress syndrome, cystic
fibrosis, chronic bronchitis, glomerulonephritis and rheumatoid
arthritis, and also to inhibit the growth and metastasis of many
cancers.
[0013] WO 02/15916 discloses Dihydroboswelliasäuren,
physiologically acceptable salts thereof, and hydrogenated
extracts of boswellia.
It is proposed to use these compounds for prophylactic and / or
therapeutic treatment of adverse physical and psychological
conditions, especially of somatic, psychosomatic and mental
disorders such as inflammatory processes, which are caused by
increased leukotriene formation, Leukozytenelastaseoder
Piasminaktivität.
The above diseases are, for example inflammatory joint diseases,
epidermal lesions, allergic and chronic asthma, endotoxin,
inflammatory bowel disease, chronic hepatitis, pulmonary
emphysema, acute respiratory distress syndrome, shock lung, cystic
fibrosis, chronic bronchitis, glomerulonephritis and rheumatoid
arthritis as well as specific tumors and tumor metastases.
[0015] DE 101 21 252 A1 describes the treatment of acne, a
hormone-induced inflammatory skin disease, the use of lipoxygenase
inhibitors alone or in combination with other lipoxygenase
inhibitors or with other anti-acne agents in a suitable
pharmaceutical composition, in particular by oral and / or
locally-applied topically.
[0016] In the publication U.S. 2004/0166178 A1 discloses the use
of 3-O-acetyl-11-keto-boswellic acid is described in a formulation
for topical application for relaxation of the skin and for the
treatment of facial wrinkles.
[0017] In summary it can be said that incense and Olibanumextrakte
is known as a traditional natural remedies or medicines to treat
various physical and mental conditions.
Because of the versatility of the applicability of the good effect
coupled with reduced side effects, there is a great need to
provide Olibanumextrakte in an improved form, and this improved
formulation for as many applications, such as topical and oral
administration as well as for coating implants and should be
suitable for surgical sutures.
To skin diseases
[0018] In the case of eczema (including atopic dermatitis, eczema
atopic, eczema diffusa, eczema disseminated, eczema
constitutionalis, endogenous eczema Besnier-prurigo) is a chronic
or chronically relapsing, in their morphological aspect and
overall process quite different types of inflammatory skin disease
which is accompanied by severe itching.
The eczema is hereditary and often occurs together with other
atopic diseases such as allergic rhinitis, allergic conjunctivitis
and allergic bronchial asthma on.
Biochemically is neurodermatitis a fault in the humoral and
cellular immunity, the infection is associated with a high
activity of the skin.
The current treatment of these inflammatory skin disorder is often
performed by means of the external application of glucocorticoids
in the form of ointments or creams.
This inflammatory activity is indeed reduced, but the treatment is
associated with significant side effects with cortisone.
[0019] The incidence of "light skin cancer," meaning Kanzerosen as
actinic keratoses, basal cell carcinomas, squamous cell carcinomas
and squamous fall, takes explosively in the temperate latitudes.
The "light skin cancer" is ten times more common than melanoma,
the skin cancer known as black. Every seven years, double the
number of cases. One of the causes is sun exposure and skin damage
caused by UV radiation and the frequent use of tanning beds.
The actinic keratoses are now no longer classified as a
precancerous condition, but as an early cancer.
Approximately every second German has over 60 years due to many
years of UV light exposure to actinic keratoses.
Most actinic keratoses persist as long Carinoma in situ, whereas
20% show spontaneous remission or develop into invasive carcinomas
spinozelläre.
There are now following therapeutic options: 1 Surgical removal
(eg As excision, curettage, cryosurgery), with mostly 100%
remissions are obtained. However, there remain scars and
surrounding skin areas that were indeed exposed to the same UV
exposure, remain untreated.
2 Chemotherapies (eg As 5-fluorouracil or podophyllin) reach
up to 85% remissions and can be applied areally.
However, they must be carried out over weeks, are painful and can
leave scars and pigmentation.
[0021] 3 Photodynamic Therapy: After photosensitization by 5 -
aminolevulinic acid cream light to destroy the tumor cells.
Remissions and good cosmetic results can be achieved. For this,
the procedure is painful phototoxic reactions are possible.
[0022] 4 Immunomodulators: For example, with imiquimod or
diclofenac as a cream or gel remissions in up to 80% of cases can
be achieved and the actinic keratoses can be removed without
leaving any scars. The treatment is repeated, but it takes at
least 12 weeks and requires a high level of patient compliance.
[0023] In the above-mentioned skin diseases is a high inflammatory
activity with activation of inflammatory mediators, such as
prostaglandins and the 5-lipoxygenase. In the skin lesions can be
as in the basal cell carcinoma, squamous and squamous skin cells
degenerate prove. By antiphlogistic drugs that interfere with the
prostaglandin, such as diclofenac, remission can be achieved, but
these drugs are known side effects.
Boswellic acids that occur from Olibanumharz in the extract have
anti-inflammatory, antiproliferative and cytostatic effects.
The anti-inflammatory action based on inhibition of
5-lipoxygenase, in an essential enzyme for the synthesis of
leukotrienes (see, for B. Safayhi et al., Mol Pharm 47, 1212-1216,
1995. Sailer et al, Arch Pharm 329, 54-56, 1996) and the
inhibition of leukocyte elastase, as described in EP 854 709th
Furthermore, boswellic acids have a cytostatic effect.
It is reported more recently, of chemopreventive and therapeutic
effects of acetyl-keto-boswellic acids in the treatment of various
cancers.
This seems to be the inhibition of topoisomerase-1, alpha
TopoisomeraseIl and induction of apoptosis through activation of
caspase-3 and -8 play a key role by boswellic acids (Jian-Jun Liu,
et. AI., Intern. J. of Molecular Medicine 10:. 501-505, 2002, Shao
et al, Planta Medica 64, 328-331, 1998). These effects appear to
be suitable as boswellic acids for treatment of tumors, as
described in EP 871 437
[0024] Treatment of inflammatory and malignant skin diseases
Olibanumextrakten and / or boswellic acids and derivatives thereof
is generally known in the prior art. However, arises with the
topical use of the extracts, the problem that they are typically
sticky and thus have the property not to be absorbed by the skin
and therefore can not operate in the deeper skin layers.
[0025] There is therefore a need, extracts of frankincense in a
form more available for topical applications to provide that
optimally penetrate into the skin to the skin in order to be
pharmacologically active either topically or systemically.
Vascular disease
[0026] Atherosclerosis is the cause of heart attacks, strokes and
peripheral vascular occlusive disease of the extremities and is a
chronic inflammatory fibroproliferative disease of the arterial
wall, which is associated with an impaired immune response.
Inflammatory processes, the inner wall of arteries, the intima,
disturbed in their integrity and particularly loaded vessel
sections, for example on vessel bifurcations occur injuries and
lacerations of the intima.
Inflammatory cells in the lesions themselves are deposited as
monocytes, macrophages, dendritic cells, mast cells and
neutrophils.
Mast cells are transformed by taking up oxidized low-density
lipoproteins (LDL) in foam cells and to form the "lipid core" of
the so-called plaques, inflammatory ulcers in the vessel wall.
Reduce by chronic inflammation with activation of
metalloproteinases, enzymes, connective tissue and collagen, the
connective tissue sheath layer of the plaques is injured and the
lipid-containing core of the plaques come in contact with the
coagulation system of the blood, it forms very quickly
Gerinnungspfropf which closes the vessel .
This process occurs in a coronary artery that supplied by the
vascular portion of the heart muscle dies from lack of oxygen. A
heart attack is the result. Atherosclerotic processes in the brain
that trigger strokes.
[0027] The inflammation of the vessel wall are activated by
inflammatory mediators, such as prostaglandins and leukotrienes
released. Leukotrienes are formed via the 5-lipoxygenase cascade
of inflammation. It has been shown that 5-lipoxygenase expressed
in increasing concentrations at various stages of atherosclerosis
in the arterial wall (Spanbroek, R.; PNAS, Vol 100, No. 3,
1238-1243, 2003). The authors proposed a new model of
atherosclerosis in which mediated by the 5-lipoxygenase
inflammatory activity in the vessel wall is the cause of the
progression of atherosclerotic lesions.
[0028] Inflammatory markers in the blood of patients with
atherosclerosis have elevated levels of C-reactive protein,
interleukin 116, tumor necrosis factor alpha (TNF-alpha), a
reduced antioxidant capacity, increased lipid peroxidation and
increased homocysteine ??concentrations.
In the treatment of patients with coronary heart disease with
statins, that lipid-lowering drugs, in addition to a reduction of
the anti-inflammatory effects LDLCholesterinspiegels a reduction
was observed with the C-reactive protein concentration.
This effect was accompanied by a significant reduction in the risk
of sudden cardiac death and stroke and the significant decrease in
the lipid core forming lipoproteins (LDL) and inflammatory
activity has been attributed.
[0029] The treatment of atherosclerosis, coronary heart disease is
classically with medications such as statins, beta-blockers, ACE
inhibitors, and acetylsalicylic acid, which all require
considerable side effects.
[0030] Olibanumextrakte point, as explained in detail above,
anti-inflammatory and antiproliferative effects on cytostatic,
which is also known from the prior art.
These effects make the extracts useful in the treatment of
inflammatory processes and vascular proliferative diseases,
arteriosclerosis, and side effects of conventional drugs can be
avoided.
[0031] However, there is a need, extracts of frankincense in a
more bioavailable form for oral administration to provide.
implants
[0032] As an example, stents: percutaneous transluminal
angioplasty (PTA) of blood vessels, especially the coronary artery
angioplasty (PTCA) is a very common way to eliminate strictures or
stenoses, which obstruct the blood supply of human organs.
Endovascular stents are used as a scaffold in order to prevent a
sudden arterial occlusion in the angioplasty.
Stents may also reduce the restenosis rates as compared with a
conventional balloon angioplasty.
Restenosis after stent implantation, however, provide at rates
20-30% remains a Problern in coronary arteries dar.
Restenosis is the result of massive blood vessel damage with
induction of inflammation and endothelial cell proliferation
stimuli for the use of a stent.
Rates of restenosis following stent implantation are also from the
stent design and material dependent.
From WO 90/13332 and WO 91/12779 stent has become known, which are
coated with anti-inflammatory drugs gerinnungsund to reduce
restenosis rates.
The erfolgversprechensten drugs that may reduce restenosis rates
effective agents include rapamycin (sirolimus (R)) and paclitacel
(Taxol (R)).
[0033] Rapamycin is a macrolide antibiotic which has both
anti-inflammatory and antiproliferative properties.
It prevents smooth muscle cell proliferation and reduces the
inflammatory response induced by stent implantation by inhibition
of proinflammatory cytokines (Suzuki et al., Circulation 104 (10),
1188-1193, 2001).
[0034] One of the disadvantages of the currently discussed eluting
stents is the delayed epithelialization of the stent inner
surface, so that the antithrombotic therapy to prevent must be
in-stent thrombosis significantly prolonged time. There is thus a
need to provide an alternative means which is suitable to coat
stents.
[0035] The object of the invention is therefore to provide
Olibanumextrakt in a form which can be used in pharmaceutical and
/ or cosmetic and / or for the coating of the implant surface, and
thereby improves the corresponding means.
This improvement should be guaranteed for different application
forms such as topical and oral administration.
In the area of ??topical application is to be achieved in that the
or can be absorbed by the skin, the active compounds of the
Olibanumextrakts better.
In the oral administration of Olibanumextrakt the active
ingredient to be more bioavailable.
In the application for the coating of surfaces of implant
treatment of vascular disease is to be provided for example by
means of a stent in the form Olibanumextrakt within which makes
the coating of the stent with the active compound or compounds of
Olibanumextrakt possible.
[0036] These objects are achieved by the subject matter of the
claims.
[0037] Surprisingly it was found that Olibanumextrakte in
nanoparticulate form are perfectly suitable, on the one hand in
formulations for topical administration and the other in
formulations for oral administration significantly improve their
properties.
When applied topically, the active ingredient (or active
ingredients) is much better absorbed by the skin than is the case
with the use of conventional extracts.
For oral administration, preferably in enteric soft gel capsules,
the bioavailability of the active substance (or substances) is
considerably improved.
It was also found that Olibanumextrakte in nanoparticulate form
are an excellent way to coat implants such as stents or other
(port system, joint prostheses, Herzschrittmaeher, dental pins,
screws, plates, Kirschner wires).
Also has been found out that surgical sutures (eg As
polyethylene), and indwelling indwelling, vascular catheters can
be coated with Olibanumextrakt-Nanopartikenl.
The devices mentioned can cause foreign body reactions in the
human body, which may be associated with inflammation and even
with Granulombildungen.
Surprisingly, it has been found that the coating of the device
with OlibanumNanopartikeln prevent foreign body reaction or can be
counteracted.
Ultimately, it has proved advantageous to add as additive to
Olibanumextrakt storage solutions for biological materials in
nanoparticulate form.
These can be used in transport solutions for organs, as used for
example in organ transplantation.
[0038] Olibanumextrakt can be obtained by, for example, ethanol,
methanol, ether or chloroform extraction extraction of resin of
olibanum. Preferably, such extracts are lipophilic.
[0039] According to a preferred embodiment of the invention the
Olibanumextrakt with acetyl-11-keto-boswellic acid is enriched ss.
Optionally, the hydrogenation of incense, and the physiologically
acceptable salts and derivatives, as well as hydrogenated
Olibanumextrakte can be used.
Suitable [0040] According to the invention as an additive
containing boswellic acids are also herbal extracts, their
hydrogenation, boswellic acids, physiologically acceptable salts
of the boswellic acids, derivatives of boswellic acids, herbal
preparations containing boswellic acid or acetyl-11-keto-boswellic
acid ss-containing plant extracts.
Also suitable are hydrogenation products of other ingredients of
the incense, such as from the other Tirucallensäure or
triterpenoid compounds, salts or derivatives thereof as well as
plant extracts containing these compounds.
According to the invention are suitable as an additive continue
the hydrogenation of acetyl-11-keto-boswellic acid or
ss-ss-11-keto-boswellic acid or ss-boswellic acid, the latter may
contain small amounts of alpha or gammaBoswelliasäure.
Also suitable are hydrogenation of ss-boswellic acid,
Boswelliasäureformiat ss, ss-boswellic acid, acetyl-ss-boswellic
acid, but also of the boswellic acids and derivatives of boswellic
acids, which are described in DE-A 42 01 903, of which reference
is made to the will.
[0041] boswellic acids, in particular acetyl-11-keto-boswellic ss
can, in a known manner to be obtained from boswellic
acid-containing plants.
Suitable Boswelliaarten are: Boswellia serrata, Boswellia carteri,
Boswellia sacra, Boswellia papyrifera, Boswellia frereana,
boswellia or Boswellia thurifera glabra, but also other members of
the Boswellia family, or Commiphora family can be used.
[0042] As inventive hydrogenation can Dihydroboswelliasäuren,
their physiologically acceptable salts, derivatives thereof, and
physiological salts of derivatives, in particular
ss-dihydro-boswellic acid acetate, ss Dihydroboswelliasäure
formate, ss Dihydroboswelliasäure methyl ester,
acetyl-ss-dihydroboswelliasäure, alpha dihydro-boswellic acid,
acetyl-a-formyl-a-dihydroboswelliasäure and dihydroboswelliasäure
be used.
[0043] According to the invention are also suitable keto
Dihydroboswelliasäuren their physiologically acceptable salts,
derivatives thereof and physiological salts of the derivatives,
especially acetyl-11-keto-ss-dihydroboswelliasäure,
11-keto-ss-dihydroboswelliasäure or formyl-11-keto-ss
-dihydroboswelliasäure.
The compounds useful according to the invention can be obtained by
hydrogenation, preferably by catalytic hydrogenation.
The hydrogenation of these compounds is carried out in a manner
known in the art, preferably so that the backbone of the compound
is selectively hydrogenated.
Such a method is described for example in WO 02 / 15916th
[0044] For the preparation of the inventive pharmaceutical
composition may further contain a hydrated plant extract is from
incense, for example, ethanol, methanol, chloroform extraction,
ether extraction, or obtained may be used.
[0045] The Olibanumextrakte used in the invention include, in
particular ss-boswellic acid and / or acetyl-ss-boswellic acid and
/ or acetyl-11-keto-ss-boswellic acid and / or
11-keto-ss-boswellic acid and optionally with acetyl-11-
beta.-keto-boswellic acid at levels higher than the natural
content enriched.
[0046] In accordance with the invention physiologically acceptable
salts, especially the sodium, potassium, ammonium, magnesium and
calcium salts of the above compounds are understood.
Derivatives such as in particular Ci-C6 - alkyl esters of
Dihydroboswelliasäure understood, in which the carboxyl group of
the Dihydroboswelliasäure was esterified with a corresponding
alcohol.
Such Dihydroboswelliasäurealkylester are for example the methyl
ester, ethyl ester, n-propyl, iso-propyl, n-butyl, iso-butyl
esters and the tertButylester Dihydroboswelliasäuren.
It is also possible that the hydroxyl group of the
Dihydroboswelliasäure is esterified with a physiologically
acceptable carboxylic acid, for B. a dbis C2o, in particular
having a CRC8 carboxylic acid, in particular formic acid or acetic
acid.
Herbal preparations that can be used for the preparation of the
novel Olibanumextrakte are commercially available, for example
from the company PL-Thomas, New Jersey under the name 5-Loxin
(TM).
This is a standardized Olibanumextrakt of Boswellia serrata, at
least 30% of the acetyl-11-keto-ss-boswellic acid contains.
[0047] According to the invention, however, can also
Olibanumextrakte and their hydrogenation products are used by
other preparations, in particular according to the invention can
also hydrogenation synthetically manufactured or natural way
derived ingredients of incense, especially
acetyl-11-keto-ss-boswellic acid and / or 11 -
beta.-keto-boswellic acid and / or ss-boswellic acid, optionally
in admixture with a-und/oder yBoswelliasäure and / or several of
the derivatives according to the invention are preferably used the
boswellic acid, as described above, to produce the drug.
[0048] According to the invention, the medicament in addition to
the herein defined, based on incense ingredients or other active
ingredients, especially other herbal ingredients contained.
[0049] According to the invention is brought into a
nanoparticulate form with one or more of the optional additives
described above, the Olibanumextrakt.
Preferably, the nanoparticles have a size in the range of 30 to
400 nm, preferably 60 to 200 nm, more preferably from 100 to 200
nm.
Those skilled in the art will vary depending on use of the
medicine anvisierter known per se and suitably produce
nanoparticles.
[0050] Since the Olibanumextrakt, especially the hydrogenated
Olibanumextrakt and especially the hydrogenated boswellic acids
and their derivatives and salts have a very low toxicity, their
compatibility is generally good.
Your dosage can be easily selected by the treating physician
according to the severity of the condition being treated and other
factors such as the duration of the disease, possible known
incompatibilities of the patient's general condition of the
patient, etc..
The drug according to the invention can be formulated so that it
is in unit doses one or more times daily, in particular mono-to
four times a day can be administered.
[0051] For topical application, the inventive nanoparticles can be
incorporated into dermatocosmetic ointment bases, which can be
applied several times daily to the affected skin.
The inventive pharmaceutical compositions may be, for example, in
solid, semisolid, or liquid form.
Suitable creams, ointments, gels, lotions, etc.
[0052] For oral administration come into consideration tablets,
granules, capsules, solutions, etc., which include
pharmaceutically acceptable additives in addition to the invention
nanoparticles.
Furthermore, the pharmaceutical compositions may be in a manner
known in the art as liquid compositions for oral administration.
Preference for oral administration enteric softgels are thin.
[0053] The invention is not to be bound by the following
statement, but probably have the novel nanoparticles of the active
substance (or substances) in enteric softgels to a significantly
improved bioavailability, since the nanoparticles probably similar
transport mechanisms in the intestine as the
Phosphatidylcholinmatrix triglycerides are absorbed via
chylomicrons.
Other examples of suitable formulations and methods for their
preparation can be found in DE-A 44 44 288 and DE-A 44 45 728, to
the extent fully incorporated herein by reference.
[0054] Finally, the invention nanoparticles of the active
ingredient (or ingredients) for coating medikamenteneluierenden
implants, such as stents, are suitable.
By the inhibitory effect on the proliferation of smooth muscle
cells in the vessel wall and by inhibiting the inflammatory
processes counteract the novel nanoparticles of in-stent
restenosis.
According to the international medical literature, it comes with
the conventional stent within the first six months in 30% of cases
a stent closure or to an in-stent stenosis.
For nanoparticles coated with the inventive stent is a high
probability that this closure rate can be significantly reduced.
[0055] By inhibiting effect on the proliferation of connective
tissue cells, and by inhibiting the inflammatory processes as an
additive to implant erfindungsmässen OlibanumNanopartikel Cement
(bone cement) act against the surface of implants of
Fremdkörpergranulombildung and loosening of joint implants by
Entzündungsund against degeneration processes.
[0056] Examples
[0057] Example 1:
[0058] Use of the nanoparticles according to the invention as a
topical cream to treat inflammatory skin diseases,
[0059] 1-5% (relative to the ointment base) of the novel
nanoparticles are applied morning and evening to the affected skin
and gently massaged.
Inflammation is a visible reduction in pilot studies in actinic
keratosis, eczema and psoriasis already detectable after one week.
For example, the inflammatory lesions were completely healed after
a treatment period of 6 weeks at a cohort of 5 patients with
actinic keratoses in 3 patients.
In one patient the result was confirmed histologically.
In 2 patients, the skin lesions were significantly improved.
[0060] Example 2:
[0061] possibility of enhancing the effect of
[0062] In inflammatory skin diseases according to the invention
nanoparticles were prepared as described in Example 1 above, is
applied. In addition, activation was:
[0063] 1 A soft laser, 785 nm, laser shower (from MKW Laser
System) with 14 x 10 mW power, 5 minutes in direct skin contact
times per two weeks and
[0064] 2 With water-filtered infrared-A (from Hydrosun) for 20 min
at 30 cm distance, two per week, performed once. The infrared
activation of nanoparticles according to the invention was carried
out 2 times a week.
By activation with infrared led to a much faster effect.
The postulated mechanism could be a direct activation of boswellia
triterpenes by energy absorption and improve the penetration
properties of the skin by a low-thermal radiation.
Optimized frankincense and myrrh treating
process
CN1349813
[ Machine translation ]
The optimization treatment process of the Chinese medicinal
materials of frankincense and myrrh includes the following steps:
pulverizing, dissolving and extracting to obtain volatility
component, then using beta-CD to make mixing and inclusion,
cooling and filtering to obtain the invented frankincense and
myrrh extract. Before inclusion and after one combined image
structure of the volatile oil and beta-CD gets obviously change,
so that when the frankincense and myrrh are used, it can reduce
irritation to gastrointestinal tract, and can reduce production of
adverse reactions of abdominal pain, nausea, vomiting, diarrhea,
dyspepsia and anoraxia, etc. to further raise medicine effect of
frankincense and myrrh and raise the preparation quality.
The invention relates to the field of medicine, in particular to a
frankincense, myrrh optimization processes...
The object of the present invention can be achieved by the
following measures:
One kind of frankincense, myrrh optimized treatment process is
frankincense, myrrh become crushed particles With petroleum ether,
dissolved, extracted until a colorless, volatile petroleum ether
and volatile oil obtained, and then With ß-CD solution mixing,
cooling, filtration can be.
The invention will be further described in detail with reference
to Examples:
process: take frankincense, myrrh, to crush a particle with
petroleum ether
Solvent dissolved, extracted with Soxhlet extractor pumping until
colorless, and then in a water bath hood
Within volatile petroleum ether to obtain volatile oil and seal it
back; Another ß-CD was dissolved in distilled
Water and placed DF-101 collector-type magnetic stirrer, adding
essential oil dissolved in ethanol,
Maintaining a predetermined temperature, mixing a predetermined
time, and make up water, then in the refrigerator to
Chilled for 24 hours, with a dry pump suction filter, washed with
a small amount of ethanol, 60 ? dried for 2
Hours, weighing, measuring oil content, and calculate the oil
utilization and yield...
The results show that the temperature of the oil contained
utilization rate and the oil has a significant impact on the yield
of No significant effects feed ratio and stirring time of oily
rate has a significant impact on oil profits With a yield rate and
a significant effect
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