U.S. patent application number 12/515329 was filed with the patent office on 2010-03-04 for use of tricyclic diterpenes and their derivatives for the treatment, co-treatment or prevention of inflammatory disorders and/or joint disorders.
Invention is credited to Daniel Raederstorff, Goede Schueler, Joseph Schwager, Christof Wehrli.
Application Number | 20100056615 12/515329 |
Document ID | / |
Family ID | 37708418 |
Filed Date | 2010-03-04 |
United States Patent
Application |
20100056615 |
Kind Code |
A1 |
Raederstorff; Daniel ; et
al. |
March 4, 2010 |
USE OF TRICYCLIC DITERPENES AND THEIR DERIVATIVES FOR THE
TREATMENT, CO-TREATMENT OR PREVENTION OF INFLAMMATORY DISORDERS
AND/OR JOINT DISORDERS
Abstract
The present invention refers to the use of at least one
tricyclic diterpenes for the manufacture of a nutraceutical or
pharmaceutical for the treatment, co-treatment or prevention of
inflammatory disorders and/or joint disorders.
Inventors: |
Raederstorff; Daniel;
(Flaxlanden, FR) ; Schueler; Goede; (Wein Am
Rhein, DE) ; Schwager; Joseph; (Basel, CH) ;
Wehrli; Christof; (Witterswil, CH) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Family ID: |
37708418 |
Appl. No.: |
12/515329 |
Filed: |
November 21, 2007 |
PCT Filed: |
November 21, 2007 |
PCT NO: |
PCT/EP07/10071 |
371 Date: |
November 6, 2009 |
Current U.S.
Class: |
514/450 ;
514/510; 514/569; 514/680; 514/729; 560/56; 562/461; 568/326;
568/714 |
Current CPC
Class: |
A23K 50/40 20160501;
A61P 17/02 20180101; A61P 17/08 20180101; A23K 20/105 20160501;
A61P 17/18 20180101; A61Q 17/04 20130101; A61K 8/4973 20130101;
A61P 9/00 20180101; A61Q 19/08 20130101; A61P 25/00 20180101; A61P
17/16 20180101; A61K 8/35 20130101; A61P 19/02 20180101; A61Q
19/005 20130101; A61K 8/347 20130101; A61K 8/365 20130101; A61P
17/10 20180101; A61P 17/00 20180101; A61K 31/192 20130101; A61P
17/06 20180101; A23V 2002/00 20130101; A61P 29/00 20180101; A23L
33/105 20160801; A61P 9/10 20180101; A61K 8/37 20130101; A61P 19/10
20180101; A23V 2002/00 20130101; A23V 2200/324 20130101; A23V
2250/21 20130101 |
Class at
Publication: |
514/450 ;
562/461; 568/714; 560/56; 568/326; 514/569; 514/729; 514/510;
514/680 |
International
Class: |
A61K 31/335 20060101
A61K031/335; C07C 59/00 20060101 C07C059/00; C07C 35/42 20060101
C07C035/42; C07C 69/76 20060101 C07C069/76; C07C 49/403 20060101
C07C049/403; A61K 31/192 20060101 A61K031/192; A61K 31/045 20060101
A61K031/045; A61K 31/215 20060101 A61K031/215; A61K 31/122 20060101
A61K031/122; A61P 29/00 20060101 A61P029/00; A61P 17/00 20060101
A61P017/00; A61P 19/02 20060101 A61P019/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 24, 2006 |
EP |
06024382.1 |
Claims
1. Use of at least one tricyclic diterpene of formulae I and/or II
##STR00012## wherein R.sup.1 is hydrogen or C.sub.1-6-alkyl;
R.sup.2 is hydroxy, C.sub.3-5-acyloxy, hydroxymethyl,
1,3-dihydroxypropyl or C.sub.1-6-alkyl; R.sup.3 and R.sup.4 are
independently from each other hydrogen, hydroxy, hydroxymethyl
(--CH.sub.2--OH), C.sub.1-5-acyloxy or C.sub.1-6-alkoxy; R.sup.5 is
C.sub.1-6-alkyl, hydroxymethyl, carboxy (CO.sub.2H) or
methoxycarbonyl (CO.sub.2CH.sub.3); R.sup.6 is hydrogen, or R.sup.5
and R.sup.6 taken together form a double bond; R.sup.7 and R.sup.8
are independently from each other C.sub.1-6-alkyl, carboxy,
x-hydroxy-C.sub.x-alkyl (with x being an integer from 1 to 6), or
C.sub.1-6-alkoxycarbonyl (--CO.sub.2(C.sub.1-6-alkyl)) with the
proviso that at least one of R.sup.7 and R.sup.8 is
C.sub.1-6-alkyl; R.sup.9 is hydrogen, hydroxymethyl, methoxy, oxo
or C.sub.1-5-acyloxy; R.sup.10 is hydrogen or R.sup.5 and R.sup.10
taken together are --CO--O--, --O--CO--, --CH.sub.2--O--or
--O--CH.sub.2--; R.sup.11 and R.sup.12 are both hydrogen or
R.sup.11 and R.sup.12 together are oxo; R.sup.13 is
C.sub.1-6-alkyl, hydroxymethyl, carboxy (CO.sub.2H) or
methoxycarbonyl (CO.sub.2CH.sub.3) or R.sup.6 and R.sup.13 taken
together form a double bond with the further proviso for formula I
that if R.sup.2 is hydroxy R.sup.1 is C.sub.1-6-alkyl for the
manufacture of a nutraceutical or pharmaceutical for the treatment,
co-treatment or prevention of inflammatory disorders and/or joint
disorders.
2. The use according to claim 1, wherein the at least one tricyclic
diterpene is a compound of formulae I and/or II wherein R.sup.1 is
hydrogen or iso-propyl; R.sup.2 is hydroxy or iso-propyl; R.sup.3
and R.sup.4 are independently from each other hydrogen, hydroxy or
methoxy; R.sup.5 is methyl, carboxy (CO.sub.2H) or hydroxymethyl;
R.sup.6 is hydrogen, or R.sup.5 and R.sup.6 taken together form a
double bond; R.sup.7 and R.sup.8 are independently from each other
methyl, carboxy, hydroxymethyl or methoxycarbonyl with the proviso
that at least one of R.sup.7 and R.sup.8 is methyl; R.sup.9 is
hydrogen, oxo or methoxy; R.sup.10 is hydrogen or R.sup.5 and
R.sup.10 taken together are --CO--O--, --O--CO--, --CH.sub.2--O--
or --CH.sub.2--; R.sup.13 is carboxy with the further proviso for
formula I that if R.sup.2 is hydroxy R.sup.1 is iso-propyl.
3. The use according to claim 1 wherein the at least one tricyclic
diterpene of formulae I and/or II is 7-oxodehydroabietic acid,
totarol, hydroxytotarol, totarol-19-carboxylic acid methyl ester,
sageone, 8,11,13-abietatriene-11,12,20-triol, royleanoic acid,
ferruginol, carnosic acid 12-methylether and/or
7-methylrosmanol.
4. The use according to claim 1, wherein the at least one tricyclic
diterpene of formulae I and/or II is comprised in a plant extract
in an amount of at least 30 weight-%.
5. The use according to claim 1, wherein the inflammatory disorder
is arthritis.
6. A nutraceutical comprising at least one tricyclic diterpene of
formulae I and/or II as defined in claim 1 and a nutraceutically
acceptable carrier for the treatment, co-treatment or prevention of
inflammatory disorders and/or joint disorders.
7. The nutraceutical according to claim 6 which is a food product,
foodstuff, dietary supplement, nutritional supplement or a
supplement composition for a food product or a foodstuff.
8. The nutraceutical according to claims 6 in which the amount of
the at least one tricyclic diterpene of formulae I and/or II is in
the range of 0.01 mg to 1000 mg, preferably in the range of 2.0 mg
to 300 mg per serving.
9. A pharmaceutical comprising at least one tricyclic diterpene of
formulae I and/or II as defined in claim 1 and a pharmaceutically
acceptable carrier for the treatment, co-treatment or prevention of
inflammatory disorders and/or joint disorders.
10. A cosmetic or dermatological composition comprising at least
one tricyclic diterpene of formulae I and/or II as defined in claim
1 and a cosmetically acceptable carrier.
11. The cosmetic composition or dermatological according to claim
10 which is a skin care preparation.
12. The cosmetic or dermatological composition according to claim
10 for the treatment, co-treatment or prevention of sunburn and/or
impure skin.
13. The tricyclic diterpene of formulae I and/or II as defined in
claim 1 for use as a medicament for the treatment, co-treatment or
prevention of inflammatory disorders and/or joint disorders.
14. Use of at least one tricyclic diterpene of formulae I and/or II
as defined in claim 1 for the treatment, co-treatment or prevention
of inflammatory disorders of the skin such as sunburn, impure skin
or the results of chronic skin inflammation such as
photoageing.
15. Use of at least one tricyclic diterpene of formulae I and/or II
as defined in claim 1 for the treatment, co-treatment or prevention
of cartilage degradation or cartilage damage in joints, for
cartilage regeneration or cartilage maintenance, or for maintenance
of joint health.
16. A method for treatment, co-treatment or prevention of
inflammatory disorders and/or joint disorders in animals including
humans said method comprising the step of administering an
effective amount of at least one tricyclic diterpene of formulae I
and/or II according to claim 1 to animals including humans, which
are in need thereof.
17. Method according to claim 16, wherein the inflammatory disorder
is arthritis.
18. Method according to claim 16, wherein the inflammatory disorder
is inflammation of the skin, in particular sunburn or impure
skin.
19. The method according to claim 16 wherein the at least one
tricyclic diterpene of formulae I and/or II as defined in any one
of claims 1- to 3 are comprised in a plant extract in an amount of
at least 30 weight-%.
Description
[0001] The present invention refers to the use of at least one
tricyclic diterpenes for the manufacture of a nutraceutical or
pharmaceutical for the treatment, co-treatment or prevention of
inflammatory disorders and/or joint disorders.
[0002] Inflammatory disorders are one of the most important health
problems in the world. Inflammation is in general a localized
protective response of the body tissues to invasion of the host by
foreign material or injurious stimuli. The causes of inflammation
can be infectious agents such as bacteria, viruses, and parasites;
or physical agents such as burns or radiation; or chemicals like
toxins, drugs or industrial agents; or immunological reactions such
as allergies and autoimmune responses or conditions associated with
oxidative stress.
[0003] Inflammation is characterized by pain, redness, swelling,
heat, and eventual loss of function of the affected area. These
symptoms are the results of a complex series of interactions taking
place between the cells of the immune system. The response of the
cells results in an interacting network of several groups of
inflammatory mediators: Proteins (e.g. cytokines, enzymes (e.g.
proteases, peroxydase), major basic protein, adhesion molecules
(ICAM, VCAM), lipid mediators (e.g. eicosanoids, prostaglandins,
leukotrienes, platelet activating factor (PAF)), reactive oxygen
species (e.g. hydroperoxides, superoxyde anion O.sub.2.sup.-,
nitric oxide (NO) etc). However, many of those mediators of
inflammation are also regulators of normal cellular activity. Thus,
deficiencies of inflammatory reactions lead to a compromised host
(i.e. infection) while uncontrolled and thus chronic inflammation
leads to inflammatory diseases mediated in part by the excessive
production of several of the above mentioned mediators.
[0004] Joint disorders are leading causes of disability and
dysfunction in the elderly; almost 80% of people over age 60 show
some evidence of these disorders. Age, genetic factors, muscle
disuse and weakness, trauma, obesity and anatomical abnormalities
contribute to the development of the disorder. Joint disorders can
e.g. be caused by (chronic) inflammatory diseases of the joints as
well as by cartilage degradation of one or several joints or a
combination thereof. Cartilage degradation is defined within the
framework of the invention as a metabolic disorder of joint
cartilage characterized by increased production of
cartilage-degrading enzymes such as matrix metalloproteases.
[0005] Acute and chronic inflammation resulting from an excessive
biosynthesis of inflammatory mediators is involved in numerous
inflammatory disorders such as arthritis (e.g. osteoarthritis,
rheumatoid arthritis), asthma, inflammatory bowel diseases,
inflammatory diseases of the skin (e.g. contact dermatitis
[particularly diaper area dermatitis], atopic dermatitis, xerosis,
eczema, rosacea, seborrhea, psoriasis, neurodermitis, acne, thermal
and radiation burns such as sunburn, other types of skin
inflammation, and the tissue-degenerating effects of aging) and
chronic inflammatory disorders, such as atherosclerosis, heart
diseases, metabolic syndrome X, osteoporosis, cancer, Alzheimer's
disease and pre-stages thereof such as mild cognitive impairment or
photoageing which is a result of chronic skin inflammation.
[0006] Arthritis is a chronic (inflammatory) disease of the joints
and encompasses many different forms. For example, arthritis
includes rheumatoid arthritis, spondyloarthopathies, gouty
arthritis, osteoarthritis, systemic lupus erythematosus and
juvenile arthritis. Like asthma, rheumatoid arthritis is
characterized at the molecular level by chronically unbalanced
expression of cytokines, chemokines, kinins and their receptors,
adhesion molecules and their respective receptors, as well as
inflammatory enzymes.
[0007] Osteoarthritis is a joint disease caused by the breakdown
and loss of the cartilage of one or more joints which develops by
wear and tear of the joints during aging and results in pain and
diminished joint function. Symptoms of osteoarthritis include pain,
stiffness and loss of mobility in one or more joints. Excessive
joint loading increases the risk of osteoarthritis, hence
osteoarthritis mostly affects the weight-bearing joints such as
spine, knees and hips, but thumb and finger joints may also be
affected. Joint disorders can also results from injury, i.e.
microdamage or blunt trauma, fractures, damage to tendons, menisci
or ligaments or can be the result of excessive mechanical stress or
other biomechanical instability resulting from for example an
injury or obesity.
[0008] Psoriasis is one of the most common skin problems, affecting
1-3% of the human population. Inflammatory bowel disease is a
general term used to describe gastrointestinal tract diseases and
includes disorders such as ulcerative colitis and Crohn's
disease.
[0009] Beside the process of intravascular lipid deposition,
inflammatory reactions of the endothelial (i.e. blood vessel) wall
are considered to critically contribute to atherosclerosis i.e.
atheroma formation. Atherosclerosis results from vascular injury
which triggers inflammation. Activated macrophages, T-lymphocytes,
and eventually smooth muscle cells are present in atherosclerotic
plaques. Monocyte/macrophage and lymphocyte activation leads to the
release of eicosanoids, cytokines and matrix metalloproteinases
(MMPs) which are implicated in endothelial damage, as well as in
the formation and eventually the rupture of atherosclerotic
plaques. Finally, circulating inflammatory markers such as
C-reactive protein (CRP), fibrinogen, and interleukins are
increased or altered in groups at high-risk of coronary artery
diseases (CAD). Several clinical trials indicate that elevated CRP
concentration correlates with increased risk of coronary, and
vascular, events. Thus inflammation appears to play an important
role in the initiation and progression of atheroma formation.
[0010] Inflammatory processes are also associated with the
pathophysiology of Alzheimer's disease. There is evidence of
inflammation in the brain of patients with Alzheimer's disease, as
it is characterized by increased levels of cytokines and activated
microglial cells. Thus, inflammation is not only involved in the
classical inflammatory disorders (e.g., arthritis, asthma, bowel
diseases) but is also associated with many chronic inflammatory
disorders (e.g., atherosclerosis, heart diseases, metabolic
syndrome X, osteoporosis, cancer, Alzheimer disease).
[0011] Inflammatory events are also associated with the
pathophysiology of different types of cancers (e.g. gastric and
intestinal cancers, melanomas). Increased levels of inflammatory
mediators such as prostaglandins have been found in cancers of
breast, colon, lung and pancreas in humans.
[0012] Currently, two main classes of drugs, the corticosteroid and
the nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat
inflammatory disorders and/or joint disorders. NSAIDs and
corticosteroids provide essentially symptomatic relief. Use of
corticosteroids has declined due to a growing concern about the
serious side effects of prolonged use.
[0013] NSAIDs are among the most widely used drugs, primarily for
the treatment of pain and inflammatory disorders, in particular for
the treatment of arthritis (i.e. pain relief) but also for the
treatment of cartilage degradation such as osteoarthritis. However,
in the latter case, the drugs are given to control the pain and to
restrain swelling, but do not prevent or treat damage to the
cartilage.
[0014] Epidemiological studies have suggested that patients taking
NSAIDs have a lower risk of developing Alzheimer's disease than
those not taking NSAIDs. A protective effect of NSAIDs suggests
that the cyclooxygenases might be involved in the neurodegenerative
process.
[0015] Epidemiological studies showed a significant reduction in
the risk of colorectal, gastric, esophageal, and breast cancers
among people who take NSAIDs compared with those not taking NSAIDs.
In animal models, NSAIDs significantly reduced tumor
development.
[0016] However, long-term use of NSAIDs when treating chronic
diseases such as arthritis or osteoarthritis is limited by severe
side-effects like serious gastrointestinal complications, renal
toxicity or asthmatic reactions.
[0017] For these reasons patients with inflammatory diseases and/or
joint disorders have a special interest in a type of treatment
considered as "natural" with mild anti-inflammatory effects and
without major side effects, which can be used for disease
prevention and as adjuvant treatment. Even though there are
examples of "natural" agents with shown anti-inflammatory action
these "natural" compounds often have an inadequate biological and
thus inhibitory activity.
[0018] For the reasons outlined above, there is a great need for
new anti-inflammatory agents and agents that treat joint disorders
e.g. caused by cartilage degradation.
[0019] Surprisingly it has been found that tricyclic diterpenes of
formulae I and/or II have an anti-inflammatory activity and are
suitable to treat or prevent cartilage loss and damage and can
consequently be used as an agent suitable for the treatment,
co-treatment or prevention of inflammatory disorders and/or joint
disorders.
##STR00001##
wherein R.sup.1 is hydrogen or C.sub.1-6-alkyl; R.sup.2 is hydroxy,
C.sub.3-5-acyloxy, hydroxymethyl, 1,3-dihydroxypropyl or
C.sub.1-6-alkyl; R.sup.3 and R.sup.4 are independently from each
other hydrogen, hydroxy, hydroxymethyl (--CH.sub.2--OH),
C.sub.1-5-acyloxy or C.sub.1-6-alkoxy; R.sup.5 is C.sub.1-6-alkyl,
hydroxymethyl, carboxy (CO.sub.2H) or methoxycarbonyl
(CO.sub.2CH.sub.3); R.sup.6 is hydrogen, or R.sup.5 and R.sup.6
together form a double bond; R.sup.7 and R.sup.8 are independently
from each other C.sub.1-6-alkyl, carboxy, x-hydroxy-C.sub.x-alkyl
(with x being an integer from 1 to 6), or C.sub.1-6-alkoxycarbonyl
(--CO.sub.2(C.sub.1-6-alkyl)) with the proviso that at least one of
R.sup.7 and R.sup.8 is C.sub.1-6-alkyl; R.sup.9 is hydrogen,
hydroxymethyl, methoxy, oxo or C.sub.1-5-acyloxy; R.sup.10 is
hydrogen or R.sup.5 and R.sup.10 taken together are --CO--O--,
--O--CO--, --CH.sub.2--O-- or --O--CH.sub.2--; R.sup.11 and
R.sup.12 are both hydrogen or R.sup.11 and R.sup.12 together are
oxo; R.sup.13 is C.sub.1-6-alkyl, hydroxymethyl, carboxy
(CO.sub.2H) or methoxycarbonyl (CO.sub.2CH.sub.3) or R.sup.6 and
R.sup.13 taken together form a double bond with the further proviso
for formula I that if R.sup.2 is hydroxy R.sup.1 is
C.sub.1-6-alkyl.
[0020] Thus, the invention relates to the use of at least one
tricyclic diterpenes of formulae I and/or II with the definitions
of R.sup.1 to R.sup.13 as given above for the manufacture of a
nutraceutical or pharmaceutical in particular for the manufacture
of a nutraceutical or pharmaceutical for the treatment,
co-treatment or prevention of inflammatory disorders such as heart
disease, multiple sclerosis, osteo- and rheumatoid arthritis,
atherosclerosis, and osteoporosis, preferably of arthritis, in
particular of osteoarthritis and rheumatoid arthritis.
[0021] Also, the tricyclic diterpenes of the present invention are
suitable for treatment, co-treatment and prevention of joint
disorders in particular for reduction of joint inflammation,
maintenance and/or improvement of joint health, prevention of joint
stiffness, increase of joint mobility, providing supple and/or
flexible joints, lubrication of the joints, relief of pain
associated with joint inflammation, decrease of joint swelling,
lessening joint problems, and providing joint care. Thus, the
invention also relates to the use of at least one tricyclic
diterpenes of formulae I and II with the definitions of R.sup.1 to
R.sup.13 as given above for the manufacture of a nutraceutical or
pharmaceutical for the treatment, co-treatment or prevention of
joint disorders.
[0022] Further objects of the present invention are the use of at
least one tricyclic diterpenes of formulae I and/or II with the
definitions of R.sup.1 to R.sup.13 as given above as
cartilage-regenerating and -maintaining agent as well as the use of
at least one tricyclic diterpenes of formulae I and/or II with the
definitions of R.sup.1 to R.sup.13 as given above (for the
manufacture of a composition) for the maintenance and regeneration
of articular cartilage.
[0023] Preferred in all embodiments of the invention are tricyclic
diterpenes of formulae I and/or II wherein [0024] R.sup.1 is
hydrogen or iso-propyl; [0025] R.sup.2 is hydroxy or iso-propyl;
[0026] R.sup.3 and R.sup.4 are independently from each other
hydrogen, hydroxy or methoxy; [0027] R.sup.5 is methyl, carboxy
(CO.sub.2H) or hydroxymethyl; [0028] R.sup.6 is hydrogen, or
R.sup.5 and R.sup.6 taken together form a double bond; [0029]
R.sup.7 and R.sup.8 are independently from each other methyl,
carboxy, hydroxymethyl or methoxycarbonyl with the proviso that at
least one of R.sup.7 and R.sup.8 is methyl; [0030] R.sup.9 is
hydrogen, oxo or methoxy; [0031] R.sup.10 is hydrogen or R.sup.5
and R.sup.10 taken together are --CO--O--, --O--CO--,
--CH.sub.2--O-- or --O--CH.sub.2--; [0032] R.sup.13 is carboxy;
[0033] with the further proviso for formula I that if R.sup.2 is
hydroxy R.sup.1 is iso-propyl, even more preferred are the
tricyclic diterpenes 7-oxodehydroabietic acid (III), totarol (IV),
hydroxytotarol (V), totarol-19-carboxylic acid methyl ester (VI),
sageone (VII), 8,11,13-abietatriene-11,12,20-triol (VIII),
royleanoic acid (IX), ferruginol (X), carnosic acid 12-methylether
(XI), most preferred are sageone (VII),
8,11,13-abietatriene-11,12,20-triol (VIII) carnosic acid
12-methylether (XI) and/or 7-methylrosmanol (XII), in particular
carnosic acid 12-methylether (XI).
[0034] The structures of the compounds (III) to (XII) are listed in
table 1.
TABLE-US-00001 TABLE I tricyclic diterpenes ##STR00002##
7-Oxodehydroabietic acid (III) (CAS 18684-55-4) ##STR00003##
Totarol (IV) ##STR00004## 16-Hydroxytotarol (V) (CAS 2288-33-7)
##STR00005## Totarol-19-carboxylic acid methyl ester (VI) (Methyl
13-hydroxy-14- isopropyl-9(11),12,14(8)- podocarpatrienoate) (CAS
24035-62-9) ##STR00006## Sageone (VII) (CAS 142546-15-4)
##STR00007## 8,11,13-abietatriene- 11,12,20-triol (VIII)
##STR00008## Royleanoic acid (IX) ##STR00009## Ferruginol (X) (CAS
514-62-5) ##STR00010## Carnosic acid 12- methylether (XI)
##STR00011## 7-Methylrosmanol (XII)
[0035] In all embodiments of the invention the term "tricyclic
diterpene of formulae I and/or II" also encompasses any material or
extract of a plant containing at least one tricyclic diterpene of
formulae I and II in an amount of at least 30 weight-% (i.e. from
30 to 100 weight-%), preferably in an amount of at least 50
weight-% (i.e. from 50 to 100 weight-%), more preferably in an
amount of at least 70 weight-% (i.e. from 70 to 100 weight-%), most
preferably in an amount of at least 90 weight-% (i.e. from 90 to
100 weight-%), based on the total weight of the plant material or
extract. The terms "material of a plant" and "plant material" used
in the context of the present invention mean any part of a
plant.
[0036] "Carnosic acid 12-methyl ether" means the racemic mixture as
well as pure (4aR,10aS)-carnosic acid 12-methyl ether or pure
(4aS,10aR)-carnosic acid 12-methyl ether or any mixture or
diastereoisomer of them. Carnosic acid 12-methyl ether can be
isolated from plants like sage, rosemary, Hyptis martiusii, but not
limited to it. Therefore, any material or extract of these plants
or any other plant material or extract containing carnosic acid
12-methyl ether in an amount of at least 30 weight-% (i.e. from 30
to 100 weight-%), preferably in an amount of at least 50 weight-%
(i.e. from 50 to 100 weight-%), more preferably in an amount of at
least 70 weight-% (i.e. from 70 to 100 weight-%), most preferably
in an amount of at least 90 weight-% (i.e. from 90 to 100
weight-%), based on the total weight of the plant material or
extract, is also encompassed by this expression. "Carnosic acid
12-methyl ether" means both "natural" (isolated) and "synthetic"
(manufactured) carnosic acid 12-methyl ether.
[0037] "7-oxodehydroabietic acid" means the racemic mixture as well
as pure (1S,4aS,10aR)-7-oxodehydroabietic acid or pure
(1R,4aR,10aS)-7-7-oxodehydroabietic acid or any mixture or
diastereoisomer of them. 7-oxodehydroabietic acid can be isolated
from plants like the following, but not limited to Cynara
cardunculus ssp. cardunculus and Juniperus chinensis. Therefore,
any material or extract of these plants or any other plant material
or extract containing 7-oxodehydroabietic acid in an amount of at
least 30 weight-% (i.e. from 30 to 100 weight-%), preferably in an
amount of at least 50 weight-% (i.e. from 50 to 100 weight-%), more
preferably in an amount of at least 70 weight-% (i.e. from 70 to
100 weight-%), most preferably in an amount of at least 90 weight-%
(i.e. from 90 to 100 weight-%), based on the total weight of the
plant material or extract, is also encompassed by this expression.
"7-oxodehydroabietic acid" means both "natural" (isolated) and
"synthetic" (manufactured) 7-oxodehydroabietic acid.
[0038] "Totarol" means the racemic mixture as well as pure
(4bS,8aS)-totarol ((+)-totarol, trans-totarol) or pure
(4bR,8aR)-totarol or any mixture or diastereoisomer of them.
Totarol can be isolated from plants like the following, but not
limited to sage, juniper and podocarpus sp. Therefore, any material
or extract of these plants or any other plant material or extract
containing totarol in an amount of at least 30 weight-% (i.e. from
30 to 100 weight-%), preferably in an amount of at least 50
weight-% (i.e. from 50 to 100 weight-%), more preferably in an
amount of at least 70 weight-% (i.e. from 70 to 100 weight-%), most
preferably in an amount of at least 90 weight-% (i.e. from 90 to
100 weight-%), based on the total weight of the plant material or
extract, is also encompassed by this expression. "Totarol" means
both "natural" (isolated) and "synthetic" (manufactured) totarol.
Totarol's synthesis is described in several articles, i.e. in
Tetrahedron Letters 2003, 44(49), 8831-8835.
[0039] "16-Hydroxytotarol" means the racemic mixture as well as
pure (1S,4aS,10aR)-16-hydroxytotarol or pure
(1R,4aR,10aS)-16-hydroxytotarol or any mixture or diastereoisomer
of them. 16-Hydroxytotarol can be isolated from the wood of
Podocarpus species and other plants. Therefore, any material or
extract of these plants or any other plant material or extract
containing 16-hydroxytotarol in an amount of at least 30 weight-%
(i.e. from 30 to 100 weight-%), preferably in an amount of at least
50 weight-% (i.e. from 50 to 100 weight-%), more preferably in an
amount of at least 70 weight-% (i.e. from 70 to 100 weight-%), most
preferably in an amount of at least 90 weight-% (i.e. from 90 to
100 weight-%), based on the total weight of the plant material or
extract, is also encompassed by this expression.
"16-Hydroxytotarol" means both "natural" (isolated) and "synthetic"
(manufactured) 16-hydroxytotarol. 16-Hydroxytotarol's synthesis is
described in several articles, i.e. in Journal of the Chemical
Society, Abstracts 1963, 1553-1560 and in Chemistry & Industry
(London, United Kingdom) 1963, 44, 1760-1761.
[0040] "Totarol-19-carboxylic acid methyl ester" means the racemic
mixture as well as pure (4aR,10aS)-totarol-19-carboxylic acid
methyl ester or pure (4aR,10aS)-totarol-19-carboxylic acid methyl
ester or any mixture or diastereoisomer of them.
Totarol-19-carboxylic acid methyl ester can be isolated from the
wood of Podocarpus species and other plants. Therefore, any
material or extract of these plants or any other plant material or
extract containing totarol-19-carboxylic acid methyl ester in an
amount of at least 30 weight-% (i.e. from 30 to 100 weight-%),
preferably in an amount of at least 50 weight-% (i.e. from 50 to
100 weight-%), more preferably in an amount of at least 70 weight-%
(i.e. from 70 to 100 weight-%), most preferably in an amount of at
least 90 weight-% (i.e. from 90 to 100 weight-%), based on the
total weight of the plant material or extract, is also encompassed
by this expression. "Totarol-19-carboxylic acid methyl ester" means
both "natural" (isolated) and "synthetic" (manufactured)
totarol-19-carboxylic acid methyl ester. Totarol-19-carboxylic acid
methyl ester can be prepared according to the process described in
Chemistry & Industry (London, United Kingdom) 1963, 44,
1760-1761.
[0041] Sageone can be isolated from plants like the following, but
not limited to sage, and other salivia sp. Therefore, any material
or extract of these plants or any other plant material or extract
containing sageone in an amount of at least 30 weight-% (i.e. from
30 to 100 weight-%), preferably in an amount of at least 50
weight-% (i.e. from 50 to 100 weight-%), more preferably in an
amount of at least 70 weight-% (i.e. from 70 to 100 weight-%), most
preferably in an amount of at least 90 weight-% (i.e. from 90 to
100 weight-%), based on the total weight of the plant material or
extract, is also encompassed by this expression. "Sageone" means
both "natural" (isolated) and "synthetic" (manufactured) sageone.
Sageone's synthesis is described e.g. in Journal of Organic
Chemistry 1997, 62(20), 6928-6951.
[0042] "8,11,13-Abietatriene-11,12,20-triol" means the racemic
mixture as well as pure
(4bR,8aS)-8,11,13-abietatriene-11,12,20-triol or pure
(4bS,8aR)-8,11,13-abietatriene-11,12,20-triol or any
diastereoisomer or mixture of them.
8,11,13-Abietatriene-11,12,20-triol can be isolated from plants
like Salivia sp. Without being limited thereto. Therefore, any
material or extract of these plants or any other plant material or
extract containing 8,11,13-abietatriene-11,12,20-triol in an amount
of at least 30 weight-% (i.e. from 30 to 100 weight-%), preferably
in an amount of at least 50 weight-% (i.e. from 50 to 100
weight-%), more preferably in an amount of at least 70 weight-%
(i.e. from 70 to 100 weight-%), most preferably in an amount of at
least 90 weight-% (i.e. from 90 to 100 weight-%), based on the
total weight of the plant material or extract, is also encompassed
by this expression. "8,11,13-Abietatriene-11,12,20-triol" means
both "natural" (isolated) and "synthetic" (manufactured)
8,11,13-abietatriene-11,12,20-triol.
[0043] "Royleanonic acid" means the racemic mixture as well as pure
(4aR,10aS)-royleanonic acid or pure (4aS,10aR)-royleanonic acid or
any diastereoisomer or mixture of them. Royleanonic acid can be
isolated from plants like sage (Salvia sp.), but not limited to it.
Therefore, any material or extract of these plants or any other
plant material or extract containing royleanonic acid in an amount
of at least 30 weight-% (i.e. from 30 to 100 weight-%), preferably
in an amount of at least 50 weight-% (i.e. from 50 to 100
weight-%), more preferably in an amount of at least 70 weight-%
(i.e. from 70 to 100 weight-%), most preferably in an amount of at
least 90 weight-% (i.e. from 90 to 100 weight-%), based on the
total weight of the plant material or extract, is also encompassed
by this expression. "Royleanonic acid" means both "natural"
(isolated) and "synthetic" (manufactured) royleanonic acid.
[0044] "Ferruginol" means pure (4bS,8aS)-ferruginol or pure
(4bR,8aR)-ferruginol or any stereoisomer or mixture of them.
Ferruginol can be isolated from plants like Cryptomeria sp.,
Juniperus sp., Salvia sp., but not limited to it. Therefore, any
material or extract of these plants or any other plant material or
extract containing ferruginol in an amount of at least 30 weight-%
(i.e. from 30 to 100 weight-%), preferably in an amount of at least
50 weight-% (i.e. from 50 to 100 weight-%), more preferably in an
amount of at least 70 weight-% (i.e. from 70 to 100 weight-%), most
preferably in an amount of at least 90 weight-% (i.e. from 90 to
100 weight-%), based on the total weight of the plant material or
extract, is also encompassed by this expression. "Ferruginol" means
both "natural" (isolated) and "synthetic" (manufactured)
ferruginol. Ferruginol's synthesis is described in Organic Letters
2001, 3(11), 1737-1740.
[0045] Beside the (pure) compounds carnosic acid 12-methyl ether,
7-oxocallitrisic acid, totarol, 16-hydroxytotarol,
totarol-19-carboxylic acid methyl ester, 20-deoxo-camosol,
7-methylrosmanol, sageone, 8,11,13-abietatriene-11,12,20-triol,
royleanonic acid and ferruginol especially preferred are plant
materials and plant extracts containing at least 30 weight-% (i.e.
from 30 to 100 weight-%), preferably at least 50 weight-% (i.e.
from 50 to 100 weight-%), more preferably at least 70 weight-%
(i.e. from 70 to 100 weight-%), most preferably at least 90
weight-% (i.e. from 90 to 100 weight-%), of these compounds, based
on the total weight of the plant material/extract.
[0046] In the context of this invention "treatment" also
encompasses co-treatment as well as prevention. "Prevention" can be
the prevention of the first occurrence (primary prevention) or the
prevention of a reoccurence (secondary prevention). In the context
of this invention the term "disorder" also encompasses
diseases.
[0047] The dosage and ratios of the at least one tricyclic
diterpene of formulae I and/or II with the definitions of R.sup.1
to R.sup.13 and preferences as given above to an animal including
humans may vary depending upon known factors, such as the
physiological characteristics of the particular composition and its
mode and route of administration; the age, health and weight of the
recipient; the nature and extent of the symptoms; the kind of
concurrent treatment; the frequency of treatment; and the effect
desired which can be determined by the expert in the field with
normal trials, or with the usual considerations regarding the
formulation of a nutraceutical. A suitable daily dosage of at least
one tricyclic diterpene of formulae I and/or II, with the
definitions of R.sup.1 to R.sup.13 and the preferences as given
above for humans may be within the range of from 0.001 mg per kg
body weight to about 40 mg per kg body weight per day. More
preferred is a daily dosage of from about 0.01 to about 10 mg per
kg body weight, and especially preferred is a daily dosage of from
about 0.05 to 5.0 mg per kg body weight. The amount of a plant
material or plant extract containing such tricyclic diterpene of
formulae I and II with the definitions of R.sup.1 to R.sup.13 and
the preferences as given above can be calculated accordingly. In
solid dosage unit preparations for humans, the tricyclic diterpene
of formulae I and/or II, with the definitions of R.sup.1 to
R.sup.13 and the preferences as given above, is suitably present in
an amount in the range of from about 0.1 mg to about 1000 mg,
preferably in the range of from about 1 mg to about 500 mg per
dosage unit.
[0048] In a different aspect, the invention also relates to
tricyclic diterpenes of formulae I and/or II with the definitions
of R.sup.1 to R.sup.13 and the preferences and definitions as given
above for use as a medicament/composition for the treatment,
co-treatment or prevention of inflammatory disorders such as
arthritis, in particular of osteoarthritis and rheumatoid arthritis
and/or for the treatment, co-treatment or prevention of joint
disorders.
[0049] In another aspect, the invention relates to a nutraceutical
comprising at least one tricyclic diterpene of formulae I and/or II
with the definitions of R.sup.1 to R.sup.13 and the preferences as
given above and a nutraceutically acceptable carrier. In particular
the invention relates to a nutraceutical comprising at least one
tricyclic diterpene of formulae I and/or II with the definitions of
R.sup.1 to R.sup.13 and the preferences as given above and a
nutraceutically acceptable carrier for the treatment, co-treatment
or prevention of inflammatory disorders such as arthritis, in
particular of osteoarthritis and rheumatoid arthritis and/or joint
disorders.
[0050] Also, the invention relates to a method for treatment,
co-treatment and prevention of inflammatory disorders such as
arthritis, in particular of osteoarthritis and rheumatoid arthritis
and/or joint disorders in animals including humans said method
comprising the step of administering an effective amount of at
least one tricyclic diterpenes of formulae I and II with the
definitions of R.sup.1 to R.sup.13 and the preferences as given
above to animals including humans, which are in need thereof.
Furthermore the invention relates to a method for the regeneration
and/or maintenance of (articular) cartilage in a mammal which
comprises administering to a mammal in need of such regeneration
and/or maintenance an effective amount of at least one tricyclic
diterpenes of formulae I and/or II with the definitions of R.sup.1
to R.sup.13 as given above.
[0051] The term `an effective amount` refers to an amount necessary
to obtain a physiological effect. The physiological effect may be
achieved by one single dose or by repeated doses. The dosage
administered may, of course, vary depending upon known factors,
such as the physiological characteristics of the particular
composition and its mode and route of administration; the age,
health and weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of
treatment; and the effect desired and can be adjusted by a person
skilled in the art.
[0052] In the framework of the invention, with animals is meant all
animals, including mammals, examples of which include humans.
Preferred examples of mammals beside humans are non-ruminant or
ruminant animals including cats, dogs, dromedaries, camels,
elephants, and horses.
[0053] The term nutraceutical as used herein include food product,
foodstuff, dietary supplement, nutritional supplement or a
supplement composition for a food product or a foodstuff.
[0054] Thus, in another embodiment the present invention relates to
a nutraceutical comprising at least one tricyclic diterpenes of
formulae I and/or II with the definitions of R.sup.1 to R.sup.13
and preferences as given above in particular for the treatment,
co-treatment or prevention of inflammatory disorders such as
arthritis, in particular of osteoarthritis and rheumatoid arthritis
and/or joint disorders wherein the nutraceutical is a food product,
foodstuff, dietary supplement, nutritional supplement or a
supplement composition for a food product or a foodstuff preferably
a dietary supplement, a nutritional supplement or a supplement
composition for a food or a foodstuff.
[0055] As used herein, the term food product refers to any food or
feed suitable for consumption by humans or animals. The food
product may be a prepared and packaged food (e.g., mayonnaise,
salad dressing, bread, or cheese food) or an animal feed (e.g.,
extruded and pelleted animal feed, coarse mixed feed or pet food
composition). As used herein, the term foodstuff refers to any
substance fit for human or animal consumption. The term dietary
supplement refers to a small amount of a compound for
supplementation of a human or animal diet packaged in single or
multiple dose units. Dietary supplements do not generally provide
significant amounts of calories but may contain other
micronutrients (e.g., vitamins or minerals). The term nutritional
supplement refers to a composition comprising a dietary supplement
in combination with a source of calories. In some embodiments,
nutritional supplements are meal replacements or supplements (e.g.,
nutrient or energy bars or nutrient beverages or concentrates).
[0056] Food products or foodstuffs are for example beverages such
as non-alcoholic and alcoholic drinks as well as liquid preparation
to be added to drinking water and liquid food, non-alcoholic drinks
are for instance soft drinks, sport drinks, fruit juices, such as
for example orange juice, apple juice and grapefruit juice;
lemonades, teas, near-water drinks and milk and other dairy drinks
such as for example yoghurt drinks, and diet drinks. In another
embodiment food products or foodstuffs refer to solid or semi-solid
foods comprising the composition according to the invention. These
forms can include, but are not limited to baked goods such as cakes
and cookies, puddings, dairy products, confections, snack foods, or
frozen confections or novelties (e.g., ice cream, milk shakes),
prepared frozen meals, candy, snack products (e.g., chips), liquid
food such as soups, spreads, sauces, salad dressings, prepared meat
products, cheese, yogurt and any other fat or oil containing foods,
and food ingredients (e.g., wheat flour).
[0057] The term food products or foodstuffs also includes
functional foods and prepared food products, the latter referring
to any pre-packaged food approved for human consumption.
[0058] Animal feed including pet food compositions advantageously
include food intended to supply necessary dietary requirements, as
well as treats (e.g., dog biscuits) or other food supplements. The
animal feed comprising the composition according to the invention
may be in the form of a dry composition (for example, kibble),
semi-moist composition, wet composition, or any mixture thereof.
Alternatively or additionally, the animal feed is a supplement,
such as a gravy, drinking water, yogurt, powder, suspension, chew,
treat (e.g., biscuits) or any other delivery form.
[0059] Dietary supplements of the present invention may be
delivered in any suitable format. In preferred embodiments, dietary
supplements are formulated for oral delivery. The ingredients of
the dietary supplement of this invention are contained in
acceptable excipients and/or carriers for oral consumption. The
actual form of the carrier, and thus, the dietary supplement
itself, is not critical. The carrier may be a liquid, gel, gelcap,
capsule, powder, solid tablet (coated or non-coated), tea, or the
like. The dietary supplement is preferably in the form of a tablet
or capsule and most preferably in the form of a hard (shell)
gelatin capsule. Suitable excipient and/or carriers include
maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium
phosphate, microcrystalline cellulose, dextrose, rice flour,
magnesium stearate, stearic acid, croscarmellose sodium, sodium
starch glycolate, crospovidone, sucrose, vegetable gums, lactose,
methylcellulose, povidone, carboxymethylcellulose, corn starch, and
the like (including mixtures thereof). Preferred carriers include
calcium carbonate, magnesium stearate, maltodextrin, and mixtures
thereof. The various ingredients and the excipient and/or carrier
are mixed and formed into the desired form using conventional
techniques. The tablet or capsule of the present invention may be
coated with an enteric coating that dissolves at a pH of about 6.0
to 7.0. A suitable enteric coating that dissolves in the small
intestine but not in the stomach is cellulose acetate phthalate.
Further details on techniques for formulation for and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0060] In other embodiments, the dietary supplement is provided as
a powder or liquid suitable for adding by the consumer to a food or
beverage. For example, in some embodiments, the dietary supplement
can be administered to an individual in the form of a powder, for
instance to be used by mixing into a beverage, or by stirring into
a semi-solid food such as a pudding, topping, sauce, puree, cooked
cereal, or salad dressing, for instance, or by otherwise adding to
a food e.g. enclosed in caps of food or beverage container for
release immediately before consumption. The dietary supplement may
comprise one or more inert ingredients, especially if it is
desirable to limit the number of calories added to the diet by the
dietary supplement. For example, the dietary supplement of the
present invention may also contain optional ingredients including,
for example, herbs, vitamins, minerals, enhancers, colorants,
sweeteners, flavorants, inert ingredients, and the like.
[0061] In some embodiments, the dietary supplements further
comprise vitamins and minerals including, but not limited to,
calcium phosphate or acetate, tribasic; potassium phosphate,
dibasic; magnesium sulfate or oxide; salt (sodium chloride);
potassium chloride or acetate; ascorbic acid; ferric
orthophosphate; niacinamide; zinc sulfate or oxide; calcium
pantothenate; copper gluconate; riboflavin; beta-carotene;
pyridoxine hydrochloride; thiamin mononitrate; folic acid; biotin;
chromium chloride or picolonate; potassium iodide; sodium selenate;
sodium molybdate; phylloquinone; vitamin D3; cyanocobalamin; sodium
selenite; copper sulfate; vitamin A; vitamin C; inositol; potassium
iodide. Suitable dosages for vitamins and minerals may be obtained,
for example, by consulting the U.S. RDA guidelines.
[0062] In other embodiments, the present invention provides
nutritional supplements (e.g., energy bars or meal replacement bars
or beverages) comprising the composition according to the
invention. The nutritional supplement may serve as meal or snack
replacement and generally provides nutrient calories. Preferably,
the nutritional supplements provide carbohydrates, proteins, and
fats in balanced amounts. The nutritional supplement can further
comprise carbohydrate, simple, medium chain length, or
polysaccharides, or a combination thereof. A simple sugar can be
chosen for desirable organoleptic properties. Uncooked cornstarch
is one example of a complex carbohydrate. If it is desired that it
should maintain its high molecular weight structure, it should be
included only in food formulations or portions thereof which are
not cooked or heat processed since the heat will break down the
complex carbohydrate into simple carbohydrates, wherein simple
carbohydrates are mono- or disaccharides. The nutritional
supplement contains, in one embodiment, combinations of sources of
carbohydrate of three levels of chain length (simple, medium and
complex; e.g., sucrose, maltodextrins, and uncooked
cornstarch).
[0063] Sources of protein to be incorporated into the nutritional
supplement of the invention can be any suitable protein utilized in
nutritional formulations and can include whey protein, whey protein
concentrate, whey powder, egg, soy flour, soy milk, soy protein,
soy protein isolate, caseinate (e.g., sodium caseinate, sodium
calcium caseinate, calcium caseinate, potassium caseinate), animal
and vegetable protein and hydrolysates or mixtures thereof. When
choosing a protein source, the biological value of the protein
should be considered first, with the highest biological values
being found in caseinate, whey, lactalbumin, egg albumin and whole
egg proteins. In a preferred embodiment, the protein is a
combination of whey protein concentrate and calcium caseinate.
These proteins have high biological value; that is, they have a
high proportion of the essential amino acids. See Modern Nutrition
in Health and Disease, eighth edition, Lea & Febiger,
publishers, 1986, especially Volume 1, pages 30-32. The nutritional
supplement can also contain other ingredients, such as one or a
combination of other vitamins, minerals, antioxidants, fiber and
other dietary supplements (e.g., protein, amino acids, choline,
lecithin, omega-3 fatty acids). Selection of one or several of
these ingredients is a matter of formulation, design, consumer
preference and end-user. The amounts of these ingredients added to
the dietary supplements of this invention are readily known to the
skilled artisan. Guidance to such amounts can be provided by the
U.S. RDA doses for children and adults. Further vitamins and
minerals that can be added include, but are not limited to, calcium
phosphate or acetate, tribasic; potassium phosphate, dibasic;
magnesium sulfate or oxide; salt (sodium chloride); potassium
chloride or acetate; ascorbic acid; ferric orthophosphate;
niacinamide; zinc sulfate or oxide; calcium pantothenate; copper
gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride;
thiamin mononitrate; folic acid; biotin; chromium chloride or
picolonate; potassium iodide; sodium selenate; sodium molybdate;
phylloquinone; vitamin D3; cyanocobalamin; sodium selenite; copper
sulfate; vitamin A; vitamin C; inositol; potassium iodide.
[0064] The nutritional supplement can be provided in a variety of
forms, and by a variety of production methods. In a preferred
embodiment, to manufacture a food bar, the liquid ingredients are
cooked; the dry ingredients are added with the liquid ingredients
in a mixer and mixed until the dough phase is reached; the dough is
put into an extruder, and extruded; the extruded dough is cut into
appropriate lengths; and the product is cooled. The bars may
contain other nutrients and fillers to enhance taste, in addition
to the ingredients specifically listed herein.
[0065] It is understood by those of skill in the art that other
ingredients can be added to those described herein, for example,
fillers, emulsifiers, preservatives, etc. for the processing or
manufacture of a nutritional supplement.
[0066] Additionally, flavors, coloring agents, spices, nuts and the
like may be incorporated into the nutraceutical composition.
Flavorings can be in the form of flavored extracts, volatile oils,
chocolate flavorings, peanut butter flavoring, cookie crumbs, crisp
rice, vanilla or any commercially available flavoring. Examples of
useful flavoring include, but are not limited to, pure anise
extract, imitation banana extract, imitation cherry extract,
chocolate extract, pure lemon extract, pure orange extract, pure
peppermint extract, imitation pineapple extract, imitation rum
extract, imitation strawberry extract, or pure vanilla extract; or
volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood
oil, walnut oil, cherry oil, cinnamon oil, clove oil, or peppermint
oil; peanut butter, chocolate flavoring, vanilla cookie crumb,
butterscotch or toffee. In one embodiment, the dietary supplement
contains cocoa or chocolate.
[0067] Emulsifiers may be added for stability of the nutraceutical.
Examples of suitable emulsifiers include, but are not limited to,
lecithin (e.g., from egg or soy), and/or mono- and di-glycerides.
Other emulsifiers are readily apparent to the skilled artisan and
selection of suitable emulsifier(s) will depend, in part, upon the
formulation and final product. Preservatives may also be added to
the nutritional supplement to extend product shelf life.
Preferably, preservatives such as potassium sorbate, sodium
sorbate, potassium benzoate, sodium benzoate or calcium disodium
EDTA are used.
[0068] In addition to the carbohydrates described above, the
nutraceutical can contain natural or artificial (preferably low
calorie) sweeteners, e.g., saccharides, cyclamates, aspartamine,
aspartame, acesulfame K, and/or sorbitol. Such artificial
sweeteners can be desirable if the nutritional supplement is
intended to be consumed by an overweight or obese individual, or an
individual with type II diabetes who is prone to hyperglycemia.
[0069] Moreover, a multi-vitamin and mineral supplement may be
added to the nutraceuticals of the present invention to obtain an
adequate amount of an essential nutrient, which is missing in some
diets. The multi-vitamin and mineral supplement may also be useful
for disease prevention and protection against nutritional losses
and deficiencies due to lifestyle patterns.
[0070] The dosage and ratios of the at least one tricyclic
diterpene of formulae I and/or II with the definitions of R.sup.1
to R.sup.13 and preferences as given above administered via a
nutraceutical will, of course, vary depending upon known factors,
such as the physiological characteristics of the particular
composition and its mode and route of administration; the age,
health and weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of
treatment; and the effect desired which can be determined by the
expert in the field with normal trials, or with the usual
considerations regarding the formulation of a nutraceutical.
[0071] A nutraceutical according to the invention may comprise at
least one tricyclic diterpene of formulae I and/or II with the
definitions of R.sup.1 to R.sup.13 and the preferences as given
above in an amount of about 0.001 mg to 1 g, preferably in an
amount from 0.01 mg to 1 g, most preferably in the range of 2.0 mg
to 300 mg per serving.
[0072] In dietary compositions, especially in food and beverages
for humans, the at least one tricyclic diterpene of formulae I
and/or II, with the definitions of R.sup.1 to R.sup.13 and the
preferences as given above, is suitably present in an amount in the
range of from about 0.0001 (1 mg/kg) to about 5 weight-% (50 g/kg),
preferably from about 0.001% (10 mg/kg) to about 1 weight-%, (10
g/kg) more preferably from about 0.01 (100 mg/kg) to about 0.5
weight-% (5 g/kg), based upon the total weight of the food or
beverage.
[0073] In food and drinks in a preferred embodiment of the
invention the amount of the tricyclic diterpene of formulae I
and/or II, with the definitions of R.sup.1 to R.sup.13 and the
preferences as given above is in the range of from 10 to 30 mg per
serving, i.e. 120 mg per kg food or drink.
[0074] For animals excluding humans a suitable daily dosage of a
tricyclic diterpene of formulae I and/or II, with the definitions
of R.sup.1 to R.sup.13 and the preferences as given above, for the
purposes of the present invention may be within the range of from
0.001 mg per kg body weight to about 1000 mg per kg body weight per
day. More preferred is a daily dosage in the range of from about
0.1 mg to about 500 mg per kg body weight, and especially preferred
is a daily dosage in the range of from about 1 mg to 100 mg per kg
body weight.
[0075] If instead of the pure compounds a plant material or plant
extract comprising at least one tricyclic diterpene of formulae I
and II with the definitions of R.sup.1 to R.sup.13 and the
preferences as given above the dosages to be applied can be
calculated accordingly.
[0076] In another aspect, the invention relates to a pharmaceutical
comprising the at least one tricyclic diterpene of formulae I and
II with the definitions of R.sup.1 to R.sup.13 and preferences as
given above and a pharmaceutically acceptable. In particular
invention relates to a pharmaceutical comprising the at least one
tricyclic diterpene of formulae I and II with the definitions of
R.sup.1 to R.sup.13 and preferences as given above and a
pharmaceutically acceptable the carrier for the treatment,
co-treatment or prevention of inflammatory disorders such as
arthritis, in particular of osteoarthritis and rheumatoid arthritis
and/or joint disorders.
[0077] A person skilled in the art knows which carriers can be used
as pharmaceutically acceptable carriers. Suitable pharmaceutical
carriers are e.g. described in Remington's Pharmaceutical Sciences,
supra, a standard reference text in this field. Examples of such
pharmaceutically acceptable carriers are both inorganic and organic
carrier materials, suitable for oral/parenteral/injectable
administration and include water, gelatin, gum arabic, lactose,
starch, magnesium stearate, talc, vegetable oils, and the like.
[0078] The pharmaceutical may further comprise conventional
pharmaceutical additives and adjuvants, excipients or diluents,
including, but not limited to, water, gelatin of any origin,
vegetable gums, ligninsulfonate, talc, sugars, starch, gum arabic,
vegetable oils, polyalkylene glycols, flavoring agents,
preservatives, stabilizers, emulsifying agents, buffers,
lubricants, colorants, wetting agents, fillers, and the like.
[0079] In a preferred embodiment the pharmaceutical is in the form
of a powder, tablet, capsule, gel, liquid or solid embodiment.
[0080] The dosages and ratios of the individual components in a
pharmaceutical can be determined by the expert in the field with
normal preclinical and clinical trials, or with the usual
considerations regarding the formulation of pharmaceutical
composition.
[0081] The pharmaceutical may comprise the at least one tricyclic
diterpene of formulae I and/or II with the definitions of R.sup.1
to R.sup.13 and preferences as given above in an amount from
preferably 1 mg to 2000 mg per dosage unit, e.g., per capsule or
tablet, or from 1 mg per daily dose to 3000 mg per daily dose of a
liquid formulation. In a preferred embodiment at least one
tricyclic diterpene of formulae I and/or II with the definitions of
R.sup.1 to R.sup.13 and preferences as given above, preferably in
the form an enriched plant extract encompassing the at least one
tricyclic diterpene of formulae I and/or II with the definitions of
R.sup.1 to R.sup.13 and preferences as given above in an amount of
at least 30 weight-% is administered via a pharmaceutical
composition either in the form of a single dose or by multiple
doses in an amount of at least 0.01 mg/kg bodyweight/day,
preferably in an amount of 0.1-50 mg/kg body weight/day, most
preferably in an amount of 0.3-15 mg/kg body weight/day. If instead
of the pure compounds a plant material or plant extract comprising
at least one tricyclic diterpene of formulae I and II with the
definitions of R.sup.1 to R.sup.13 and the preferences as given
above the dosages to be applied can be calculated accordingly.
[0082] The nutraceuticals and pharmaceuticals according to the
present invention may be in any galenic form that is suitable for
administering to the animal body including the human body, more in
particular in any form that is conventional for oral
administration, e.g. in solid form, for example as
(additives/supplements for) food or feed, food or feed premixes,
fortified food or feed, tablets, pills, granules, dragees,
capsules, and effervescent formulations such as powders and
tablets, or in liquid form, for instance in the form of solutions,
emulsions or suspensions, for example as beverages, pastes and oily
suspensions. The pastes may be filled into hard or soft shell
capsules. Examples for other application forms are forms for
transdermal, parenteral, topical or injectable administration. The
nutraceutical and pharmaceutical compositions may be in the form of
controlled (delayed) release formulations. Examples of
pharmaceutical compositions also include compositions suitable for
topical application and transdermal absorption of the phenolic
compound, such as cremes, gels, sprays, dry sticks, powders
etc.
[0083] Moreover, a multi-vitamin and mineral supplement may be
added to the nutraceuticals or pharmaceuticals of the present
invention to obtain an adequate amount of an essential nutrient,
which is missing in some diets. The multi-vitamin and mineral
supplement may also be useful for disease prevention and protection
against nutritional losses and deficiencies due to lifestyle
patterns.
[0084] A person skilled in the art knows which carriers can be used
as pharmaceutically acceptable carriers. Examples of such
pharmaceutically acceptable carriers are both inorganic and organic
carrier materials, suitable for oral/parenteral/injectable
administration and include water, gelatin, gum arabic, lactose,
starch, magnesium stearate, talc, vegetable oils, and the like.
[0085] Besides the at least one tricyclic diterpene of formulae I
and II and a pharmaceutically acceptable carrier, the
pharmaceutical composition according to the present invention, may
further comprise conventional pharmaceutical additives and
adjuvants, excipients or diluents, including, but not limited to,
water, gelatin of any origin, vegetable gums, ligninsulfonate,
talc, sugars, starch, gum Arabic, vegetable oils, polyalkylene
glycols, flavoring agents, preservatives, stabilizers, emulsifying
agents, buffers, lubricants, colorants, wetting agents, fillers,
and the like.
[0086] The at least one tricyclic diterpene of formulae I and/or II
with the definitions of R.sup.1 to R.sup.13 and preferences as
given above may be used in combination with other nutraceutical
compositions or therapeutic agents known to those skilled in the
art for treatment or prevention of inflammatory disorder and 7 or
joint disorders by administration prior to, simultaneously with or
following the administration of the at least one tricyclic
diterpene of formulae I and/or II with the definitions of R.sup.1
to R.sup.13 and preferences as given above.
[0087] According to the present invention not only the tricyclic
diterpenes of the formulae I and II themselves, with the
definitions of R.sup.1 to R.sup.13 and the preferences as given
above, but also plant materials and extracts containing them in an
amount of at least 30 weight-% (i.e. from 30 to 100 weight-%),
preferably in an amount of at least 50 weight-% (i.e. from 50 to
100 weight-%), more preferably in an amount of at least 70 weight-%
(i.e. from 70 to 100 weight-%), most preferably in an amount of at
least 90 weight-% (i.e. from 90 to 100 weight-%), based on the
total weight of the plant material or extract, as well as dietary
and pharmaceutical compositions containing them can be used as
medicament, especially for the treatment, co-treatment or
prevention of inflammatory disorders such as arthritis, in
particular of osteoarthritis and rheumatoid arthritis and/or for
the treatment, co-treatment or prevention of joint disorders
[0088] The tricyclic diterpenes or their derivatives of the
formulae I and/or II with the definitions of R.sup.1 to R.sup.13
and the preferences as given above as well as (mixtures of) plant
materials and plant extracts containing them (especially in an
amount of at least 30 weight-%, preferably in an amount of at least
50 weight-%, more preferably in an amount of from 70 to 90
weight-%, most preferably in an amount of at least 90 weight-%,
based on the total weight of the plant material or extract), and
dietary/pharmaceutical compositions containing them are thus
suitable for the treatment of animals including humans.
[0089] In yet another aspect the invention also relates to the use
of at least one tricyclic diterpenes of formulae I and/or II with
the definitions of R.sup.1 to R.sup.13 and the preferences as given
above for the treatment, co-treatment or prevention of inflammatory
disorders of the skin such as sunburn, impure skin such as acne or
the results of chronic skin inflammation such as photoageing. The
composition comprising the at least one tricyclic diterpenes of
formulae I and/or II with the definitions of R.sup.1 to R.sup.13
and the preferences as given above for the treatment, co-treatment
or prevention of inflammatory disorders of the skin such as
sunburn, impure skin such as acne or the results of chronic skin
inflammation such as photoageing may be designed for oral delivery
such as a nutraceutical or a medicament or may be for topical
application such as a cream or lotion without being limited
hereto.
[0090] In another aspect, the invention relates to a cosmetic or
dermatological preparation (the latter preparation are a specific
type of a pharmaceutical) comprising an effective amount of at
least one tricyclic diterpenes of formulae I and/or II with the
definitions of R.sup.1 to R.sup.13 and the preferences as given
above or compositions containing them (plant materials/extracts
containing them in an amount of at least 30 weight-%, preferably in
an amount of at least 50 weight-%, more preferably in an amount of
from 70 to 90 weight-%, most preferably in an amount of at least 90
weight-%, based on the total weight of the plant material or
extract; dietary/pharmaceutical compositions) and a cosmetically or
dermatologically acceptable carrier.
[0091] The cosmetic or dermatological composition may further
comprise conventional cosmetic respectively dermatological
adjuvants and/or additives and/or additional active
ingredients.
[0092] Preferably the cosmetic or dermatological preparations are
skin care formulations for the treatment, co-treatment or
prevention of inflammation of the skin, in particular of sunburn
caused by UV-radiation, of contact dermatitis (particularly diaper
area dermatitis), atopic dermatitis, xerosis, eczema, rosacea,
seborrhea, psoriasis, neurodermitis, thermal burns, photoageing or
for the treatment, co-treatment or prevention of impure skin such
as acne. Examples of impure skin include pimples, acne and other
skin impurities with an inflammatory aspect.
[0093] In yet another aspect the invention also relates to a
composition comprising at least one tricyclic diterpenes of
formulae I and/or II with the definitions of R.sup.1 to R.sup.13
and the preferences as given above for the treatment, co-treatment
or prevention of inflammatory skin conditions. The composition
comprising at least one tricyclic diterpenes of formulae I and/or
II with the definitions of R.sup.1 to R.sup.13 and the preferences
as given above for the treatment, co-treatment or prevention of
inflammatory skin conditions may be designed for oral
administration such as e.g. a nutraceutical or a pharmaceutical or
a medicament or may be designed for topical application such as a
cream or lotion without being limited hereto. If the composition
comprising at least one tricyclic diterpenes of formulae I and/or
II with the definitions of R.sup.1 to R.sup.13 and the preferences
as given above for the treatment, co-treatment or prevention of
inflammatory conditions of the skin is intended for oral
administration it may be in the form of a nutraceutical or a
pharmaceutical with all the definitions and preferences as given
above. Such products are also known as beauty foods and
supplements. If the composition comprising at least one tricyclic
diterpenes of formulae I and/or II with the definitions of R.sup.1
to R.sup.13 and the preferences as given above for the treatment,
co-treatment or prevention of inflammatory conditions of the skin
is intended for topical application it may be in the form of a
cosmetic or dermatological preparation as described herein.
[0094] The term `inflammatory skin conditions` encompasses
inflammatory diseases of the skin such as e.g. contact dermatitis
[particularly diaper area dermatitis], atopic dermatitis, xerosis,
eczema, rosacea, seborrhea, psoriasis, neurodermitis, acne, thermal
and radiation burns such as sunburn as well as any other types of
skin inflammation such as e.g. photoageing which is a result of
chronic skin inflammation. The term `inflammatory skin conditions`
also encompasses the term `Impure skin`. "Impure skin` can be
caused by various factors: skin irritation through various
exogenous and endogenous stimuli (e.g. sun, wind, cold, dryness,
incompatibility or sensitivity to cremes, or other skin care
products, overproduction of sebum consequently leading to pimples,
black spots and acne). It is generally accepted that inflammatory
processes in the epidermis are involved in the processes leading to
skin irritation, sensitive skin and impure skin. It is furthermore
well established, that in these mechanisms cytokines play an
important role. Pro-inflammatory cytokines are released from
keratinocytes in the epidermis upon inflammatory stimuli (Boniface
K, Lecron J C, Bernard F X, Dagregorio G, Guillet G, Nau F, Morel
F. Keratinocytes as targets for interleukin-10-related cytokines: a
putative role in the pathogenesis of psoriasis, Eur. Cytokine Netw.
2005 December; 16(4):309-19).
[0095] Accordingly, reduction of the response of skin cells to
inflammatory stimuli can lead to an improvement of an impure or
sensitive skin condition and may help to produce a pure skin with
healthy and natural radiance and glow.
[0096] Thus, the invention also relates to the use of at least one
tricyclic diterpenes of formulae I and/or II with the definitions
of R.sup.1 to R.sup.13 and the preferences as given above for
promoting an optimal health, natural radiance and glow and/or a
beautiful look of the skin. Furthermore, the invention encompasses
the use of at least one tricyclic diterpenes of formulae I and/or
II with the definitions of R.sup.1 to R.sup.13 and the preferences
as given above for supporting a clear, pure appearance of the
skin.
[0097] The term "effective amount" means preferably at least 0.001%
of each active agents based on the total weight of the cosmetic or
dermatological composition. Preferably, the cosmetic or
dermatological preparations comprise the active agents selected
from the list above in an amount between 0.01 wt.-% and 20 wt.-%,
more preferably between 0.05 and 10 wt.-%, still more preferably
between 0.1 and 5 wt.-%.
[0098] The amount of the cosmetic or dermatological preparation
which is to be applied to the skin depends on the concentration of
the active ingredients in the preparation and the desired cosmetic
or pharmaceutical effect. For example, the application can be such
that a creme is applied to the skin. A creme is usually applied in
an amount of about 1 to 2 mg creme/cm.sup.2 skin. The amount of the
composition which is applied to the skin is, however, not critical,
and if with a certain amount of applied composition the desired
effect cannot be achieved, a higher concentration of the active
preparations which contain more active ingredient might be
employed.
[0099] The invention also relates to the use of the cosmetic
preparation for the cosmetic treatment, co-treatment or prevention
of inflammation of the skin, in particular for the cosmetic
treatment, co-treatment or prevention of sunburn, contact
dermatitis (particularly diaper area dermatitis), atopic
dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis,
neurodermitis, thermal burns or photoageing as well as of sensitive
skin towards environmental stressors (such as wind, soaps, dry
climate).
[0100] Also, the invention relates to a method for the treatment,
co-treatment or prevention of inflammation of the skin, in
particular of sunburn in humans, of impure skin such as for example
acne or of photoageing which is associated with chronic skin
inflammation, said method comprising the step of administering an
effective amount of the dermatological composition according to the
invention to humans, which are in need thereof. Also, the invention
relates to a method for cosmetic treatment, co-treatment or
prevention of inflammation of the skin, in particular of sunburn or
of impure skin such as acne by a cosmetic preparation according to
the invention. Sunburn prevention is preferably achieved with
topical application comprising the composition of the invention
preferably in combination with suitable light screening agents.
[0101] The cosmetic or dermatological preparations according to the
invention may be in the form of a suspension or dispersion in
solvents or fatty substances, or alternatively in the form of an
emulsion or micro emulsion (in particular of O/W or W/O type, O/W/O
or W/O/W-type, wherein O stands for oil phase and wherein W stands
for water phase), such as a cream, a paste, a lotion, a thickened
lotion or a milk, a vesicular dispersion in the form of an
ointment, a gel, a solid tube stick or an aerosol mousse, and may
be provided in the form of a mousse, foam or a spray foams, sprays,
sticks or aerosols or wipes. Examples of cosmetic or dermatological
preparations are skin care preparations, in particular, body oils,
body lotions, body gels, treatment creams, skin protection
ointments, moisturizing gels, moisturizing sprays, revitalizing
body sprays, after sun preparations or sunscreen formulations.
[0102] The cosmetic or dermatological composition for the
treatment, co-treatment or prevention of inflammation of the skin,
such as for example sunburn, photoageing or impure skin may be in a
form that is conventional for oral administration, examples of
which are described above and also include beauty foods and
supplements.
[0103] The cosmetic or dermatological preparations of the invention
for instance as sunscreen formulations or after sun preparations
may further comprise the usual cosmetic respectively dermatological
adjuvants and/or additives such as preservatives/antioxidants,
fatty substances/oils, water, organic solvents, silicones,
thickeners, softeners, emulsifiers, additional light screening
agents, antifoaming agents, moisturizers, fragrances, surfactants,
fillers, sequestering agents, anionic, cationic, nonionic or
amphoteric polymers or mixtures thereof, propellants, acidifying or
basifying agents, dyes, colorants, pigments or nanopigments, light
stabilizers, insect repellants, skin tanning agents, skin whitening
agents, antibacterial agents, preservatives active ingredients or
any other ingredients usually formulated into cosmetics.
[0104] Light screening agents which may be incorporated into
cosmetic or dermatological preparations of the invention for
instance sunscreen formulations are advantageously selected from
IR, UV-A, UV-B, UV-C and/or broadband filters. Examples of UV-B or
broad spectrum screening agents, i.e. substances having absorption
maxima between about 290 and 340 nm may be organic or inorganic
compounds. Organic UV-B or broadband screening agents are e.g.
acrylates such as 2-ethylhexyl 2-cyano-3,3-diphenylacrylate
(octocrylene, PARSOL.RTM. 340), ethyl 2-cyano-3,3-diphenylacrylate
and the like; camphor derivatives such as 4-methyl benzylidene
camphor (PARSOL.RTM. 5000), 3-benzylidene camphor, camphor
benzalkonium methosulfate, polyacrylamidomethyl benzylidene
camphor, sulfo benzylidene camphor, sulphomethyl benzylidene
camphor, therephthalidene dicamphor sulfonic acid and the like;
Cinnamate derivatives such as ethylhexyl methoxycinnamate
(PARSOL.RTM. MCX), ethoxyethyl methoxycinnamate, diethanolamine
methoxycinnamate (PARSOL.RTM. Hydro), isoamyl methoxycinnamate and
the like as well as cinnamic acid derivatives bond to siloxanes;
p-aminobenzoic acid derivatives, such as p-aminobenzoic acid,
2-ethylhexyl p-dimethylaminobenzoate, N-oxypropylenated ethyl
p-aminobenzoate, glyceryl p-aminobenzoate; benzophenones such as
benzophenone-3, benzophenone-4,2,2',4,4'-tetrahydroxy-benzophenone,
2,2'-dihydroxy-4,4'-dimethoxybenzophenone and the like; esters of
benzalmalonic acid such as di-(2-ethylhexyl)
4-methoxybenzalmalonate; esters of
2-(4-ethoxy-anilinomethylene)propandioic acid such as 2-(4-ethoxy
anilinomethylene)propandioic acid diethyl ester as described in the
European Patent Publication EP 0895 776; organosiloxane compounds
containing benzmalonate groups as described in the European Patent
Publications EP 0358584 B1, EP 0538431 B1 and EP 0709080 A1 such as
polysilicone-15 (PARSOL.RTM. SLX); drometrizole trisiloxane
(Mexoryl XL); imidazole derivatives such as e.g. 2-phenyl
benzimidazole sulfonic acid and its salts (PARSOL.RTM.HS). Salts of
2-phenyl benzimidazole sulfonic acid are e.g. alkali salts such as
sodium- or potassium salts, ammonium salts, morpholine salts, salts
of primary, sec. and tert. amines like monoethanol amine salts,
diethanol amine salts and the like; salicylate derivatives such as
isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate,
ethylhexyl salicylate (PARSOL.RTM. EHS, NEO Heliopan OS), isooctyl
salicylate or homomethyl salicylate (homosalate, PARSOL.RTM. HMS,
NEO Heliopan OS) and the like; triazine derivatives such as
ethylhexyl triazone (Uvinul T-150), diethylhexyl butamido triazone
(Uvasorb HEB). Encapsulated UV-filters such as encapsulated
ethylhexyl methoxycinnamate (Eusolex UV-pearls) or microcapsules
loaded with UV-filters as e.g. disclosed in EP 1471995 and the
like. Inorganic compounds are pigments such as microparticulated
TiO.sub.2, ZnO and the like. The term "microparticulated" refers to
a particle size from about 5 nm to about 200 nm, particularly from
about 15 nm to about 100 nm. The TiO.sub.2 particles may also be
coated by metal oxides such as e.g. aluminum or zirconium oxides or
by organic coatings such as e.g. polyols, methicone, aluminum
stearate, alkyl silane. Such coatings are well known in the
art.
[0105] Examples of broad spectrum or UV A screening agents i.e.
substances having absorption maxima between about 320 and 400 nm
may be organic or inorganic compounds e.g. dibenzoylmethane
derivatives such as 4-tert. butyl-4'-methoxydibenzoyl-methane
(PARSOL.RTM. 1789), dimethoxydibenzoylmethane,
isopropyldibenzoylmethane and the like; benzotriazole derivatives
such as
2,2'-methylene-bis-(6-(2H-benzotriazole-2-yl)-4-(1,1,3,3,-tetramethylbuty-
l)-phenol (TINOSORB M) and the like; bis-ethylhexyloxyphenol
methoxyphenyl triazine (Tinosorb S) and the like;
phenylene-1,4-bis-benzimidazolsulfonic acids or salts such as
2,2-(1,4-phenylene)bis-(1H-benzimidazol-4,6-disulfonic acid)
(Neoheliopan AP); amino substituted hydroxybenzophenones such as
2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester
(Uvinul A plus) as described in the European Patent Publication EP
1046391; Ionic UV-A filters as described in the International
Patent Publication WO2005080341 A1. Pigments such as
microparticulated ZnO or TiO2 and the like. The term
"microparticulated" refers to a particle size from about 5 nm to
about 200 nm, particularly from about 15 nm to about 100 nm. The
particles may also be coated by other metal oxides such as e.g.
aluminum or zirconium oxides or by organic coatings such as e.g.
polyols, methicone, aluminum stearate, alkyl silane. Such coatings
are well known in the art.
[0106] As dibenzoylmethane derivatives have limited photostability,
it may be desirable to photostabilize these UV-A screening agents.
Thus, the term "conventional UV-A screening agent" also refers to
dibenzoylmethane derivatives such as e.g. PARSOL.RTM. 1789
stabilized by, e.g. 3,3-Diphenylacrylate derivatives as described
in the European Patent Publications EP 0 514 491 B1 and EP 0 780
119 A1; Benzylidene camphor derivatives as described in the U.S.
Pat. No. 5,605,680; Organosiloxanes containing benzmalonate groups
as described in the European Patent Publications EP 0358584 B1, EP
0538431 B1 and EP 0709080 A1.
[0107] Active ingredients which may be included in the cosmetic or
dermatological preparations of the invention are for example
vitamins and derivatives thereof, for example tocopherol,
tocopherol acetate, ascorbic acid, ascorbyl phosphate, vitamin Q,
D, and K, retinol, retinal, retinoic acid, retinol acetate, retinol
palmitate, biotin, carotenoid derivatives such as beta-carotene,
lycopene, astaxanthin, vegetable extracts, antibacterial
ingredients, instable amino acids comprising dipeptides,
oligopeptides and polypeptides such as methionine, cysteine,
cystine, tryptophan, phenylalanine, tyrosine, phenols, polyphenols
or flavanoids, bisabolol, allantoin, phytantriol, panthenol, AHA
acids, ubiquinones such as coenzyme Q 10, ceramides,
pseudoceramides, essential oils, plant extracts deoxyribonucleic
acid, phytanic acid.
[0108] The necessary amounts of the cosmetic and dermatological
adjuvants, additives and/or additional active ingredients can,
based on the desired product, easily be chosen by a person skilled
in the art and will be illustrated in the examples, without being
limited hereto.
[0109] The invention will now be elucidated by way of the following
examples, without however being limited thereto.
EXAMPLES
[0110] The Sageone (VII) and 8,11,13-Abietatriene-11,12,20-triol
(in the following referred to Abietatrienetriol) (VIII) were
obtained from Analyticon, carnosic acid 12-methylether (XI) was
isolated from a lipophilic extract of rosemary needles by
chromatography in a purity >95%.
Example 1
Anti-Inflammatory Effects
[0111] The anti-inflammatory effects of carnosic acid-12-methyl
ether, sageone and abietatrientriol were evaluated in activated
macrophages by determining the inhibition of the synthesis of
nitric oxide and/or proinflammatory prostaglandins (PG). PGE.sub.2
plays a critical role in the inflammation process, while nitric
oxide (NO) is a hallmark of inflammation in various chronic
inflammatory diseases including various forms of arthritis,
gastro-intestinal diseases and metabolic syndrome.
[0112] The compounds were dissolved in DMSO in concentrated form
and did not contain byproducts that interfered with the assays.
Final vehicle (DMSO) concentration did not exceed 0.2% v/v in the
assays.
[0113] The anti-inflammatory effects of compounds was tested in
cellular assays using a murine macrophage indicator cell line,
RAW267.7, which was purchased from American Type Culture
Collection, (ATCC) and cultured in DMEM according to the protocol
provided by ATCC. Cells (.about.50'000/well) were seeded into
flat-bottomed microtiter plates and cultured for one day. Cells
were then starved in complete medium containing 0.25% fetal calf
serum (FCS) (D-025). After overnight culture, medium was removed
and replaced by 100 .mu.L of D-025 containing the test compounds at
twice the final concentration. Subsequently, 100 .mu.L of D-025
containing 2 .mu.g/ml lipopolysaccharide (LPS) was added (i.e.
final LPS concentration of 1 .mu.g/ml) and the cells were cultured
for 24 hours. Substances were usually tested in a concentration
range from 0.2 to 50 .mu.M in two-fold dilution steps.
Concentrations of nitrite which was generated from nitric oxide
released by cells were determined by the Griess reaction (see e.g
Imai et al. Biochem Biophys Res Comm, 197, 105 [1993]) using sodium
nitrite as standard. Briefly, 50 .mu.l of supernatant was mixed
with Griess reagent 1 (25 .mu.L) and Griess reagent 2 (25 .mu.L),
centrifuged and the optical density at 540 nm determined. PGE.sub.2
secreted into the cell culture medium was determined by EIA
obtained from Cayman Chemicals (Ann Harbor, Wis., USA) and used
according to the manufacturer's instructions. IC.sub.50 values were
calculated using a two-parametric least-square fitting equation
[y=A+((B-A)/(1+((C-x) D))] for best-fit curves (Excel fit software
program).
[0114] In Table 2 it is shown that all substances idiosyncratically
inhibited the production of inflammatory mediators. This is
indicated by IC.sub.50 values, which vary between substances
reflecting substance-specific biological potencies.
TABLE-US-00002 TABLE 2 IC.sub.50 values for single substances
Substance IC.sub.50 PGE.sub.2 IC.sub.50 Nitric Oxide Sageone (VII)
16.9 .+-. 0.8 .mu.mol/L 7.3 .+-. 2.1 .mu.mol/L Abietatriene triol
(IX) 7.8 .+-. 4.6 .mu.mol/L 12.5 .+-. 4.8 .mu.mol/L Carnosic
acid-12-methyl 44.4 .+-. 6.1 .mu.mol/L 3.8 .+-. 0.6 .mu.mol/L ether
(XII)
Example 2
Influence of Substances on the Expression of Genes Involved in the
Build-Up and Break-Down of Cartilage
[0115] In articular cartilage, a delicate balance between anabolic
(build-up) and catabolic (break down) events needs to be maintained
in order to prevent hypertrophy and excessive degradation of
extracellular matrix (ECM), respectively. The ECM is built up of
collagen and proteoglycans that are the products of collagen genes,
for example human collagen I or aggrecan genes, which are activated
and expressed during anabolic processes.
[0116] Catabolic events are controlled by the expression of genes,
for example those genes that encode matrix metalloproteinases
(MMPs) that eventually break down collagen or proteoglycans. Of the
MMPs, MMP-1, MMP-3 and MMP-13 have a major role in decomposing the
ECM in cartilage degradation.
[0117] The cells were treated with IL-1.beta., which is one of the
natural mediators that induce cartilage breakdown and is detected
in substantial amounts in osteoarthritic cartilage tissues and
cells derived thereof. Treatment of cells with IL-1.beta. triggers
the expression of genes that are involved in catabolic events, such
as MMPs. Also, treatment of the cells with IL-1.beta. reduces the
collagen expression levels (compared to untreated cells)
[0118] Chondrocytes (SW1353; purchased from the American Tissue
Culture Collection [ATCC]) were grown in cell culture medium
according to the instructions from ATCC. For experimental
treatments, cells were seeded into 6-well plates and cultured for
two days until they reached confluence. Total cellular RNA was
extracted from cultured cells and reverse-transcribed as described
by Richard et al. Mol. Nutr. Food Res. 49, 431-442, 2005.
Expression levels of distinct genes were determined by quantitative
real-time PCR as described in Richard et al. Mol. Nutr. Food Res.
49, 431-442, 2005. Results of this experiment are shown in Table 2
below:
TABLE-US-00003 TABLE 3 Effect of compounds on gene expression in
human chondrocyte cells. Percentages indicate gene expressionlevels
relative to cells that were treated without the compound. 12.5
.mu.M Carnosic 0 .mu.M 12.5 .mu.M acid 12-methyl 12.5 .mu.M Gene
compound Abietatrienetriol ether Sageone Human 100% 30% 94% 3%
MMP-1 Human 100% Not done 69% 112% MMP-3 Human 100% 49% 60% 36%
MMP-13 Human 100% 257% Not done 120% collagen I Human 100% 295%
139% -- collagen II Aggrecan 100% 264% 123% 152%
[0119] Compounds drastically reduced the expression of genes
involved in the degradation of cartilage (MMP-1, MMP-3 and MMP-13),
whereas they stimulated the expression of some genes associated
with the build-up of cartilage (human collagen I, human collagen
II, aggrecan). These results suggest that the indicated compounds
not only prevent degradation of cartilage, but also help to
regenerate cartilage tissue.
Example 3
Soft Gelatin Capsule
[0120] Soft gelatin capsules are prepared by conventional
procedures providing a dose of Tricyclic diterpene of formulae I
and/or II such as carnosic acid 12-methylether (XI) of 10 mg. A
suitable daily dose is 1 to 5 capsules.
Other ingredients: glycerol. Water, gelatine, vegetable oil
Example 4
Hard Gelatin Capsule
[0121] Hard gelatin capsules are prepared by conventional
procedures providing a dose of Tricyclic diterpene of formulae I
and/or II such as carnosic acid 12-methylether (XI) of 20 mg. A
suitable daily dose is 1 to 5 capsules.
Other ingredients: Fillers: lactose or cellulose or cellulose
derivatives q.s. Lubricant: magnesium stearate if necessary
(0.5%)
Example 5
Tablet
[0122] Tablets are prepared by conventional procedures providing as
active ingredient 20 mg of Tricyclic diterpene of formulae I and/or
II such as carnosic acid 12-methylether (XI) per tablet, and as
excipients microcrystalline cellulose, silicone dioxide
(SiO.sub.2), magnesium stearate, crospovidone NF (which is a
disintegration agent) ad 500 mg.
Example 6
Soft Drink
[0123] A soft drink containing a Tricyclic diterpene of formulae I
and/or II such as carnosic acid 12-methylether (XI) may be prepared
as follows:
[0124] A soft drink is prepared from the following ingredients:
TABLE-US-00004 ingredient [g] A. juice concentrates and water
soluble flavours 60.3.degree.Brix, 5.15% acidity 657.99
43.5.degree. Brix, 32.7% acidity 95.96 Orange flavour, water
soluble 3.43 Apricot flavour, water soluble 6.71 water 26.46 B.
color .beta.-carotene 10% CWS 0.89 water 67.65 C. Acid and
antioxidant Ascorbic acid 4.11 Citric acid anhydrous 0.69 water
43.18 D. stabilizers pectin 0.20 Sodium benzoate 2.74 water 65.60
E. oil soluble flavours Orange flavour, oil soluble 0.34 Orange oil
distilled 0.34 F. active ingredient Tricyclic diterpene of formulae
I and/or II Amount providing 500 mg such as carnosic acid
12-methylether (XI)
[0125] Fruit juice concentrates and water soluble flavours are
mixed without incorporation of air. The color is dissolved in
deionized water. Ascorbic acid and citric acid are dissolved in
water. Sodium benzoate is dissolved in water. The pectin is added
under stirring and dissolved while boiling. The solution is cooled
down. Orange oil and oil soluble flavours are premixed. The active
ingredient as mentioned under F is stirred into the fruit juice
concentrate mixture of A.
[0126] In order to prepare the soft drinks all components A-F are
mixed together before homogenizing using a Turrax and then a
high-pressure homogenizer (p.sub.1=200 bar, p.sub.2=50 bar).
Example 7
Dry Dog Feed Comprising Carnosic Acid 12-Methylether (XI)
[0127] Commercial dry dog food (Hill's Science diet "Canine
Maintenance dry" for dogs as supplied by Hill's Pet Nutrition GmbH,
Liebigstrasse 2-20, D-22113) is sprayed with an aqueous ROPUFA (as
supplied by DSM Nutritional Products) in an amount sufficient to
administer to a subject a daily dose of 4 mg to 120 mg ROPUFA per
kg body weight. Further L-ascorbic acid-monophosphate (ROVIMIX.RTM.
STAY-C.RTM. 35 from DSM Nutritional Products AG, Vitamin E and
beta-carotene and carnosic acid-12-methylether are incorporated in
an amount sufficient to provide 30 mg ROVIMIX.RTM. STAY-C.RTM.
35/kg, and 300 IU vitamin E/kg and 280 mg beta-carotene/kg and 100
mg of carnosic acid-12-methylether in the final food composition
before extruding the entire blend. The food composition is dried to
contain dry matter of about 90% by weight.
Example 8
Wet Cat Food Comprising Sageone (VII)
[0128] Commercial wet cat food (Hill's Science diet "Feline
Maintenance wet" for cats as supplied by Hill's Pet Nutrition GmbH,
Liebigstrasse 2-20, D-22113) is mixed with an aqueous dispersion of
ROPUFA (as supplied by DSM Nutritional Products) in an amount
sufficient to administer to a subject a daily dose of 4 mg to 120
mg ROPUFA. Further L-ascorbic acid-monophosphate (ROVIMIX.RTM.
STAY-C.RTM. 35 from DSM Nutritional Products AG, Vitamin E and
beta-carotene and sageone are incorporated in an amount sufficient
to provide 30 mg ROVIMIX.RTM. STAY-C.RTM. 35 kg, and 300 IU vitamin
E/kg and 280 mg beta-carotene/kg and 200 mg/kg of sageone in the
final food composition before cooking the entire blend. The food
composition is dried to contain a dry matter of about 90% by
weight.
Example 9
Preparation of a Dermatological Composition Comprising a Tricyclic
Diterpene of Formulae I and/or II Such as Carnosic Acid
12-Methylether (XI) (Treatment Cream) which May be Used for
(Cosmetic) Treatment of Inflammation of the Skin Caused by
Sunburn
[0129] A treatment cream may be prepared with the following
ingredients, in the following amounts:
TABLE-US-00005 Ingredients INCI Nomenclature % w/w A Glyceryl
Myristate Glyceryl Myristate 2.00 Tricyclic diterpene of formulae
e.g. carnosic acid 0.05-25 I and/or II 12-methylether (XI) Cetyl
Alcohol Cetyl Alcohol 0.50 Myritol 318 Caprylic/Capric 5.00
Triglyceride Crodamol DA Diisopropyl Adipate 5.00 Vitamin E acetate
Tocopheryl Acetate 2.00 Butylated Hydroxytoluene BHT 0.05 Phenonip
Phenoxyethanol & 0.60 Methylparaben & Ethyl-paraben &
Propylparaben & Butylparaben Edeta BD Disodium EDTA 0.10
AMPHISOL K Potassium Cetyl 2.00 Phosphate B Water deionized Aqua ad
100 1,2-Propylene Glycol Propylene Glycol 2.00 D-PANTHENOL 75 L
Panthenol 2.00 Ethanol Ethanol 5.00 Allantoin Allantoin 0.20
Carbopol ETD 2001 Carbomer 0.30 C KOH 10% sol. Potassium Hydroxide
1.50 D Perfume Perfume q.s. Procedure: Heat part A) and B) to
85.degree. C. while stirring. When homogeneous, add part B) to A)
under agitation. Cool to about 45.degree. C. while stirring. Add
part C). Homogenize at 11000 rpm to achieve a small particle size.
Cool to ambient temperature while stirring. Then add part D).
Example 10
O/W Sun Milk
TABLE-US-00006 [0130] Ingredients INCI Nomenclature % w/w A) PARSOL
SLX Polysilicone-15 6.00 Neo Heliopan AP 3.00 Tinosorb S
Hydrogenated Cocoglycerides 3.00 Lanette O Cetearyl Alcohol 2.00
Myritol 318 Caprylic/capric Triglyceride 6.00 Mineral oil Mineral
oil 2.00 Vitamin E acetate Tocopheryl Acetate 1.00 Prisorine 3515
Isostearyl Alcohol 4.00 B) Edeta BD Disodium EDTA 0.10 Phenonip
Phenoxyethanol & 0.60 Methylparaben & Ethylparaben &
Propylparaben & Butylparaben Amphisol K Potassium Cetyl
Phosphate 2.00 Water deionized Aqua ad100 1,2-Propylene Glycol
Propylene Glycol 5.00 Carbopol 981 Carbomer 0.30 Tinosorb M
Methylene Bis-Benzotriazolyl 6.00 Tetramethylbutylphenol KOH 10%
solution Potassium Hydroxyde 2.10 C) Tricyclic diterpene of e.g.
sageone (VII)) 0.05-2 formulae I and/or II Procedure: Heat part A)
and B) to 85.degree. C. while stirring. When homogeneous, add part
B) to A) under agitation. Cool to ambient temperature while
stirring and add part C). Homogenize to achieve a small particle
size.
Example 11
Sun Milk Waterproofed
TABLE-US-00007 [0131] Ingredients INCI Nomenclature % w/w A) PARSOL
SLX Polysilicone-15 6.00 PARSOL 1789 Butyl 2.00
Methoxydibenzoylmethane PARSOL 5000 4-Methylbenzylidene Camphor
4.00 Uvinul T 150 Ethylhexyltriazone 2.00 Silicone DC 200/350 cs
Dimethicone 1.00 Lanette O Cetearyl Alcohol 2.00 Softisan 100
Hydrogenated Coco-Glycerides 3.00 Tegosoft TN C12-15 Alkyl Benzoate
6.00 Cetiol B Dibutyl Adipate 7.00 Vitamin E acetate Tocopheryl
Acetate 2.00 BHT BHT 0.05 Edeta BD Disodium EDTA 0.10 Phenonip
Phenoxyethanol & 0.60 Methylparaben & Ethylparaben &
Propylparaben & Butylparaben Amphisol Cetyl Phosphate DEA 2.00
B) Water deionized Aqua ad 100 Propylene Glycol Propylene Glycol
5.00 Carbopol 980 Carbomer 0.30 KOH (10% sol.) Potassium Hydroxide
1.50 C) Tricyclic diterpene of e.g. carnosic acid 0.05-25 formulae
I and/or II 12-methylether (XI) Procedure: Heat part A) and B) to
85.degree. C. while stirring. When homogeneous, add part B) to A)
under agitation. Cool to ambient temperature while stirring and add
part C). Homogenize to achieve a small particle size.
Example 12
Sun Milk for Babies and Children
TABLE-US-00008 [0132] Ingredients INCI Nomenclature % w/w A)
Tegosoft TN C12-15 Alkyl Benzoate 5.00 Silicone 2503 Cosmetic
Stearyl Dimethicone 2.00 Wax Cetyl Alcohol Cetyl Alcohol 1.00
Butylated BHT 0.05 Hydroxytoluene Estol GMM 3650 Glyceryl Myristate
4.00 Edeta BD Disodium EDTA 0.10 Phenonip Phenoxyethanol & 0.60
Methylparaben & Ethylparaben & Propylparaben &
Butylparaben Amphisol A Cetyl Phosphate 2.00 B) Water deionized
Aqua ad 100 Carbopol 980 Carbomer 0.6 Glycerine Glycerine 3.00 KOH
sol. 10% Potassium Hydroxide 2.4 C) Tricyclic diterpene of e.g.
carnosic acid 0.05-25 formulae I and/or II 12-methylether (XI)
Procedure: Heat part A) and B) to 85.degree. C. while stirring.
When homogeneous, add part B) to A) under agitation. Cool to
ambient temperature while stirring and add part C). Homogenize to
achieve a small particle size.
Example 13
High Protective Sun Milk
TABLE-US-00009 [0133] Ingredients INCI Nomenclature % w/w A) PARSOL
SLX Polysilicone-15 6.00 PARSOL 1789 Butyl 2.00
Methoxydibenzoylmethane PARSOL 5000 4-Methylbenzylidene Camphor
4.00 Uvinul T 150 2.00 Silicone DC 200/350 cs Dimethicone 1.00
Lanette O Cetearyl Alcohol 2.00 Softisan 100 Hydrogenated
Coco-Glycerides 3.00 Tegosoft TN C12-15 Alkyl Benzoate 6.00 Cetiol
B Dibutyl Adipate 7.00 Vitamin E acetate Tocopheryl Acetate 2.00
BHT BHT 0.05 Edeta BD Disodium EDTA 0.10 Phenonip Phenoxyethanol
& 0.60 Methylparaben & Ethylparaben & Propylparaben
& Butylparaben Amphisol K Potassium Cetyl Phosphate 2.00 B)
Water deionized Aqua ad 100 Propylene Glycol Propylene Glycol 5.00
Carbopol 980 Carbomer 0.30 KOH (10% sol.) Potassium Hydroxide 1.50
C) Tricyclic diterpene of e.g. sageone (VII)) 0.05-5 formulae I
and/or II D) Perfume Perfume q.s. Procedure: Heat part A) and B) to
85.degree. C. while stirring. When homogeneous, add part B) to A)
under agitation. Cool to ambient temperature while stirring and add
part C) and D). Homogenize to achieve a small particle size.
Example 14
Water-Free Sun Gel
TABLE-US-00010 [0134] Ingredients INCI Nomenclature % w/w A) PARSOL
MCX Ethylhexyl Methoxycinnamate 6.00 PARSOL 1789 Butyl
Methoxydibenzoylmethane 4.00 PARSOL 5000 4-Methylbenzylidene
Camphor 4.00 Uvasorb HEB Diethylhexyl Butamido Triazone 1.50 Uvinul
A plus 2.00 Vitamin E acetate Tocopheryl Acetate 1.50 Tegosoft TN
C12-15 Alkyl Benzoate 9.00 Elefac I-205 Ethylhexyldodecyl
Neopentanoate 2.00 Alcohol Alcohol ad 100 Isopropyl Alcohol
Isopropyl Alcohol 20.00 B) Klucel MF Hydroxypropylcellulose 2.00 C)
Tricyclic diterpene of For example carnosic acid 0.05-25 formulae I
and/or II 12-methylether (XI) D) perfume q.s. Procedure: Mix part
A) and B) while stirring. When homogeneous, add part C) and D)
under agitation.
Example 15
Sun Gel
TABLE-US-00011 [0135] Ingredients INCI Nomenclature % w/w A)
Pemulen TR-2 Acrylates/C10-30 Alky 0.60 Acrylate Crosspolymer
Phenonip Phenoxyethanol & 0.60 Methylparaben & Ethylparaben
& Propylparaben & Butylparaben Edeta BD Disodium EDTA 0.1
Aqua Aqua ad 100 B) PARSOL 1789 Butyl 4.00 Methoxydibenzoylmethane
PARSOL 340 Octocrylene 3.00 Tegosoft TN C12-15 Alkyl Benzoate 15.00
Antaron V-216 PVP/Hexadecene Copolymer 1.00 Vitamin E acetate
Tocopheryl Acetate 0.50 Butylated Hydroxytoluene BHT 0.05 Cremophor
RH 410 PEG-40 Hydrogenated Castor 0.50 Oil Tris Amino Tromethamine
0.50 C) Tricyclic diterpene of For example carnosic acid 0.05-25
formulae I and/or II 12-methylether (XI) D) Perfume Perfume q.s.
Procedure: Heat part A) and B) to 85.degree. C. while stirring.
When homogeneous, add part B) to A) under agitation. Cool to
ambient temperature while stirring and add part C) and D).
Homogenize to achieve a small particle size.
Example 16
High Protection WO Sun Milk
TABLE-US-00012 [0136] Ingredients INCI Nomenclature % w/w A) PARSOL
1789 Butyl 2.00 Methoxydibenzoylmethane PARSOL 5000
4-Methylbenzylidene 4.00 Camphor Uvinul T 150 Ethylhexyl Triazone
2.00 Uvinul TiO2 Titanium Dioxide and 5.00 Trimethoxycaprylylsilane
Arlacel P 135 PEG-30 2.00 Dipolyhydroxystearate Tegosoft TN C12-15
Alkyl Benzoate 5.00 Cosmacol EMI Di-C12-13 Alkyl Malate 6.00
Miglyol 840 Propylene Glycol Dicaprylate/ 6.00 Dicaprate Butylated
Hydroxytoluene BHT 0.05 Phenonip Phenoxyethanol & 0.60
Methylparaben & Ethylparaben & Propylparaben &
Butylparaben B) Deionized water Aqua ad 100 Glycerin Glycerin 5.00
Edeta Disodium EDTA 0.1 NaCl Sodium Chloride 0.30 C) PARSOL HS
Phenylbenzyimidazole 4.00 Sulphonic Acid Water Aqua 20.00
Triethanolamine 99%. Triethanolamine 2.50 D) Tricyclic diterpene of
For example carnosic acid 0.05-25 formulae I and/or II
12-methylether (XI) E) Perfume q.s. Procedure: Heat part A), B) and
C) to 85.degree. C. while stirring. When homogeneous, add part B)
and C) to A) under agitation. Cool to ambient temperature while
stirring and add part D) and E). Homogenize to achieve a small
particle size.
Example 17
W/O Milk with Pigments
TABLE-US-00013 [0137] Ingredients INCI Nomenclature % w/w A)
Cremophor WO 7 PEG-7 Hydrogenated Castor Oil 6.00 Elfacos ST 9
PEG-45/Dodecyl Glycol 2.00 Copolymer PARSOL 1789 Butyl 3.00
Methoxydibenzoylmethane Tinosorb S 5.00 PARSOL 5000
4-Methylbenzylidene Camphor 4.00 microfine ZnO Zinc Oxide 2.00
Microcrystalline wax Microcrystalline Wax 2.00 Miglyol 812
Caprylic/capric Triglyceride 5.00 Vitamin E acetate Tocopheryl
Acetate 1.00 Jojoba oil Simmondsia Chinensis Seed Oil 5.00 Edeta BD
Disodium EDTA 0.10 Butylated BHT 0.05 Hydroxytoluene Phenonip
Phenoxyethanol & 0.60 Methylparaben & Ethylparaben &
Propylparaben & Butylparaben B) Water deionized Aqua ad 100
Glycerin Glycerin 5.00 C) Neo Heliopan AP 2.00 Water deionized Aqua
20.00 KOH 10% solution Potassium Hydroxide 4.00 D) Tricyclic
diterpene of For example carnosic acid 0.05-25 formulae I and/or II
12-methylether (XI) E) Perfume Perfume q.s. Procedure: Heat part
A), B) and C) to 85.degree. C. while stirring. When homogeneous,
add part B) and C) to A) under agitation. Cool to ambient
temperature while stirring and add part D) and E). Homogenize to
achieve a small particle size.
Example 18
Protective Day Cream with Vitamin C
TABLE-US-00014 [0138] Ingredients INCI Nomenclature % w/w A) PARSOL
SLX Polysilicone-15 4.00 PARSOL 1789 Butyl 1.50
Methoxydibenzoylmethane Glyceryl Myristate Glyceryl Myristate 2.00
Cetyl Alcohol Cetyl Alcohol 0.50 Myritol 318 Caprylic/Capric
Triglyceride 5.00 Crodamol DA Diisopropyl Adipate 5.00 Vitamin E
acetate Tocopheryl Acetate 2.00 Butylated BHT 0.05 Hydroxytoluene
Phenonip Phenoxyethanol & 0.60 Methylparaben & Ethylparaben
& Propylparaben & Butylparaben Edeta BD Disodium EDTA 0.10
Amphisol K Potassium Cetyl Phosphate 2.00 B) Water deionized Aqua
ad 100 1,2-Propylene Glycol Propylene Glycol 2.00 D-Panthenol 75 L
Panthenol 2.00 Ethanol Ethanol 5.00 Allantoin Allantoin 0.20
Carbopol ETD 2001 Carbomer 0.30 KOH 10% sol. Potassium Hydroxide
1.50 C) Water Aqua 10.00 Stay-C 50 Sodium Ascorbyl Phosphate 0.50
D) Tricyclic diterpene of For example carnosic acid 0.05-25
formulae I and/or II 12-methylether (XI) E) Perfume Perfume
q.s.
* * * * *