Note: Descriptions are shown in the official language in which they were submitted.
CA 02851947 2014-04-11
Doc. No.: 106-84 CA/PCT
Patent
USE OF EXTRACTS FROM FILIPENDULA FOR THE TREATMENT AND
PROPHYLAXIS OF CHRONIC PAIN CONDITIONS
The present invention relates to the use of extracts from Filipendula for the
treatment or prophylaxis of chronic pain without identifiable organic causes.
Chronic pain is more or less severe pain, which can affect one or more body
regions and which lasts more than three months. Different processes can result
in
chronic pain (e.g. trauma, nerve damages, previous diseases or psychological
factors),
for which reason the symptoms of chronic pain are allocated to different
indication areas
(e.g. ICD-10 F45 õSomatoform Disorders", G43 õMigraine", G44 õOther Headache
Syndromes", R51 õHeadache", R52 õPain, not elsewhere classified", M79.7
õFibromyalgia" R20.2 õParesthesia of the Skin", K58 õIrritable Bowel
Syndrome", N94.3
õPremenstrual Complaints"). Chronic pain that is affected by this patent is
only such in
which no acute organic reasons for pain can be detected.
Chronic pain is clearly different from acute pain, since acute pain has a
clear
physiological function, namely avoiding further harmful impact on the
corresponding
tissue or the complete organism. Acute pain is induced by an acute stimulus
(e.g.
temperature, pressure, injury, infection), is usually locally restricted to
the affected site,
is perceived as "sharp" and leads to a protection and avoidance reaction that
should
prevent further harmful impact. As soon as the impairment is over, also the
pain
disappears.
This physiological function is not present in chronic pain. The pain is not
connected with an acute danger of a physiological impairment. Often, chronic
pain is
also less locally directed and perceived as rather "vague" and located deeper
in the
tissue. Chronic pain does not disappear. Hyperalgesia is a typical symptom of
chronic
pain, where pain caused by a similar stimulus is perceived much stronger than
would
normally be the case. Another example is allodynia, wherein a stimulus is
perceived as
painful, which normally does not cause pain.
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Acute and chronic pain can also mechanically be distinguished well. Acute pain
is
caused by a stimulus of the nociceptive nerve endings (either directly or via
receptors)
and is processed as an action potential via the spinal cord and the brain.
This leads to
clear activation of nerves that afterwards go back to the initial state. When
the
peripheral stimulus triggering is prevented, also the pain can be prevented.
Additionally,
substances in the central nervous system can influence the pain processing and
thereby cause analgesic perceptions.
In chronic pain different stimuli of the nerve system occur. Presently it is
presumed
that dysregulation of the nerve system e.g. a loss of inhibition of the NMDA
receptor and
defective processing of pain processes in the brain are involved in chronic
pain (Villman
and Becker 2007; Neuroscientist; 13 (6); 594-615 / Woolf and Salter 2000,
Science;
288; 1765-1768). Additionally, learn and psychosocial processes are involved
in pain
perception. This leads as a complex and multifactorial system to a continuous
pain
perception, for which in many cases no physical cause is detected. Since not
only
"typical" processes of pain processing are involved, neither analgesic
substances that
prevent the peripheral conduction of the stimuli (e.g. lidocaine), nor several
centrally
active analgesics have a long-term therapeutic benefit (Mello and Dickenson
2008;
British Journal of Anaesthesia; 101 (1); 8-16 / Hucho and Levine 2007; Neuron;
55; 365-
376). Additionally, such substances (e.g. opioids) often have a problematic
spectrum of
side effects.
In contrast, in many chronic pain disorders, psychoactive medicaments such as
e.g. pregabalin, ketamine or milnaciprane are used in individual cases, of
which the
effects are however limited (Lawson 2008; Drug Discovery Today; 13 (7-8); 333-
340 /
Hauser et al 2009; JAMA; 301 (2); 198-209 / Sud et al. 2008; European Journal
of
Pharmacology; 588; 217-231). Therefore, there are no generally effective
standard
treatments available for chronic pain. Additionally, the discussed
psychoactive
substances are often contraindicated due to their neurological side effects.
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In many diseases with chronic pain without organic cause, stress is discussed
as
an important inducing or accompanying parameter. It is known that continuing
stress is
often accompanied by the symptoms of chronic pain and causes this also in
animal
experiments (Dina et al. 2009; Neuroscience; 160; 501-507 / Imbe et al 2006;
Frontiers
in Bioscience; 11; 2179-2192 / Vidal and Jacob 1986; Annals New York academy
of
sciences; 73-81).
The object of the present invention is therefore to provide a means, which can
effectively be used in the treatment of chronic pain without identifiably
organic cause
and which is substantially free of side effects.
This object is, according to the invention, solved by using extracts from
Filipendula
species, preferably of Filipendula ulmaria, for therapy and prophylaxis of
chronic pain
without identifiable organic causes, especially of chronic pain, which is
caused by
somatoform disorders, and of vulvodynia as well as of abdomen, jaw joint,
other joint,
extremities, neck, shoulder, back, lumber, pelvic or spinal pain which is not
of rheumatic
origin, as well as of chronic pain which is induced by irritable bowel
syndrome or by
premenstrual complaints, by fibromyalgia or by paresthesia of the skin or
migraine,
cluster headache, chronic paroxysmal hemicrania, vasomotoric headache, tension
headache or chronic posttraumatic headache. Preferably, the above-ground parts
of
plants (foliage) are used.
Filipendula is classified in the family of the Rosaceae and includes according
to
the invention the following species: F. ulmaria, F. angustiloba, F. digitata,
F. formosa,
F. glaberrima, F. kamtschatica, F. kiraishiensis, F. multijuga, F.
occidentalis, F. palmata,
F. purpurea, F. rufinervis, F. rubra, F. vestita und F. vulgaris (syn. F.
hexapetala). A
preferred Filipendula species is Filipendula ulmaria. A further preferred
Filipendula
species is Filipendula vulgaris. A further preferred Filipendula species is
Filipendula
purpurea. The distribution region of the preferred plant Filipendula a ulmaria
includes
the northern regions of Europe, America and Asia. The traditional medicinal
uses can
be found in the area of colds and rheumatoid diseases (as diseases which
involve
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inflammatory processes), wherein as medicinal substance both the flowers, as
well as
the dried above-ground parts of the flowering plant are used (foliage).
Filipendula
ulmaria contains salicylic acid derivatives and is brought in connection with
the
development of aspirin. Aspirin belongs as a salicylic acid derivative in the
group of non-
steroidal anti-rheumatics (NSAIDs), of which the common working principle is
the
inhibition of Cyclooxygenase 1 and 2 (COX 1 and 2). By the inhibition of the
COX
enzymes, the inflammatory cascade is inhibited, since the cyclooxygenases
produced
the inflammatory mediating prostaglandins from arachidonic acid.
Prostaglandins are
next to the actual inflammation also involved in the mediation of pain caused
by
inflammation, for which reason NSAIDs are also used in acute, inflammation-
mediated
pain (Brune 2004; Rheumatology; 43 (Supp1.1; i16-i20) / Wallace 2007; British
Journal
of Pharmacology; 152; 421-428).
It was now surprisingly found that extracts from Filipendula are effective in
animal
models for non-inflammatory chronic pain, which suggests their therapeutic
usefulness
in chronic pain without identifiable organic causes. Such an effect has not
yet been
described for Filipendula extracts and was not to be expected on the
pharmacological
and clinical effects which were until now known for Filipendula.
To prepare the extracts from Filipendula which are used according to the
present
invention, the dried and ground plant material is extracted with an organic
solvent or
water or a mixture of one or more organic solvents and/or water at a
temperature
between 10 C and 100 C. The extracted plant material is separated from the
extract
solution, e.g. by filtration, and optionally again extracted with a solvent
according to the
first step and again separated from the extract solution. The thereby obtained
extract
solutions are combined, evaporated and dried.
Preferred organic solvents for the extraction are alcohols or ketones,
preferably
ethanol or acetone and mixtures thereof with water. Especially preferred are
mixtures of
ethanol and water in a weight ratio of 20/80 to 80/20 (20 wt.% to 80 wt.%),
preferably
50/50 to 70/30 (50 wt.% to 70 wt.%), as well as water. Useful extraction
methods are
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Doc. No. 106-84 CA/PCT Patent
e.g. maceration or percolation (see European Pharmacopeia, Edition 6.0).
Drying
is possible by methods known per se, such as e.g. freeze drying or drying in
vacuum at
room temperature or elevated temperature. To increase the concentration of
selected
ingredients, further concentration steps can be performed, such as e.g. liquid-
liquid
distribution with e.g. 1-butanol/water or ethyl acetate/water, adsorption-
desorption on
ion exchangers, Sephadex LH20, Diaion HP20 and other resins, or
chromatographic
separations over RP 18, silica gel, etc.
In a preferred embodiment, a kind of the grinded foliage (above-ground parts)
of
the desired Filipendula species is stirred with five to ten parts 50 wt.% to
70 wt.%
ethanol during 1/2 hour to 3 hours at 50 C to 60 C. The extracted plant
material is
separated from the extract solution by filtration and again stirred with five
to ten parts
50 wt.% to 70 wt.% ethanol during 1/2 hour to 3 hours at 50 C to 60 C and
filtered. The
combined filtrates from both extraction steps are freed from the ethanol in a
vacuum at
40 C to 60 C and freeze dried and/or dried in vacuum at 40 C to 60 C in a
drying
cabinet.
The extracts can preferably orally be administered in form of drops, powders,
granules, tablets, coated tablets or capsules. However, also a parenteral
administration
in the form of an injection solution or a topical application in form of
creams, ointments,
suppositories, patches or similar formulations is possible.
For the preparation of tablets, the extract is mixed with excipients that are
pharmaceutically acceptable and acceptable according to food law such as e.g.
lactose,
cellulose, silicon dioxide, croscarmellose and magnesium stearate and pressed
into
tablets, that can optionally be provided with a suitable coating, e.g. of
hydroxymethylpropyl cellulose, polyethylene glycol, dyes (e.g. titanium
dioxide, iron
oxide) and talcum.
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The extracts can also, optionally by adding excipients that are
pharmaceutically
acceptable and acceptable according to food law such as e.g. stabilizers,
fillers etc., be
filled in capsules.
The dosing is such that 5 to 2000 mg per day, preferably 10 to 1000 mg,
especially
preferred 60 to 600 mg extract are administered.
The extracts as well as the products made from them can be used both as drug
products and as food products. Food products are here to be understood as
especially
dietetic food products, food supplements such as "medical food" and "dietary
supplements".
The effectiveness of the extracts from Filipendula is demonstrated by the
experiments described below.
Pharmacological studies
Swimming stress induced hyperalgesia:
The pain sensitivity of rats is tested on a hot plate. The licking of the food
or
jumping is considered as a pain reaction. The time until this reaction occurs
is
measured and used as a measure for the pain sensation. Swimming stress during
three
consecutive days (30 min each) results in a clear reduction of the pain
threshold
(hyperalgesia). This effect can be reversed by the treatment with extract from
Filipendula ulmaria according to Example 1 or ketamine 5 mg/kg (reference
substance).
Figure 1 shows the influence of extract from Filipendula ulmaria according to
Example 1 on hyperalgesia induced by swimming stress. The base values of the
reaction times on the hot plate at different days (1 and 4), as well as the
times 30 and
60 minutes after the p.o. administration of solvent control, extract or
reference
substance at day 4 (arrow) are indicated.
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Glucocorticoid induced hyperalgesia:
Stress reactions are physiologically largely mediated by the release of
glucocorticoids (Kolber et al. 2008; Stress; 11(5); 321-338). By administering
corticosterone via drinking water during a time period of 14 days, a chronic
stress
situation is simulated in rats, which causes a hyperalgesia. This hyperalgesia
is
measured by an apparatus which determines the pain threshold when exercising
an
increasing pressure on a back paw. Here, the time until the paw is drawn away
as a
pain reaction is measured. At day 15, 6 measurements are performed over a time
period of 8 hours (0, 1/2, 1, 2, 4, 8 hours) and the "Area under the Curve"
(AUC) is
calculated on the basis thereof. As can be derived from Figure 2, the extract
from
Filipendula ulmaria according to Example 1 inhibits in all evaluated dosages
the
hyperalgesia induced by corticosterone.
Figure 2 shows the influence of extract from Filipendula ulmaria on
hyperalgesia
induced by corticosterone. Indicated is the "Area under the Curve" of the time
course
measurement curves. *: error probability p 5_ 0.05
Example 1: Extract from Filipendula ulmaria
600 g of finely ground foliage (above-ground parts) of Filipendula ulmaria are
stirred twice with 4200 g 60 wt.% ethanol during 1 hour at 60 C, the
suspension is
subsequently drawn via a Fritte P4, the combined filtrates are freed from
ethanol in
vacuum at 60 C, the remaining aqueous residue frozen and lyophilized. The
obtained
solid is dried in vacuum at 40 C over P205 and KOH: 146.2 g (24.4%) dry
extract.
Example 2: Tablets
A dry extract from Filipendula ulmaria (extract according to Example 1) is
mixed
with excipients and pressed to tablets (tablet core = position 1 ¨ 6). The
tablets are
coated with a coating of hydroxypropyl methyl cellulose (position 7 ¨ 10).
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Component mg/tablet
1 Dry extract from Filipendula ulmaria 100.0
according to Example 1
2 Microcrystalline cellulose 117.0
3 Lactose monohydrate 58.0
4 Croscarmellose 15.0
Highly dispersed silicon dioxide 3.0
6 Magnesium stearate 6.0
7 Hydroxypropyl methyl cellulose 15.0
8 Polyethylene glycol 3.0
9 Talcum 1.0
Titanium dioxide 2.0
8
