WO2022084811A1

WO2022084811A1 - Combination of plants and their use in the treatment of chronic persistent or neuropathic pain

Info

Publication number: WO2022084811A1
Application number: PCT/IB2021/059439
Authority: WO
Inventors: Jacopo Junio Valerio BRANCA; Donatello CARRINO; Lorenzo DI CESARE MANNELLI; Valentina FERRARA; Carla Ghelardini; Elena LUCARINI; Laura MICHELI; Alessandra PACINI; Carmen PARISIO; Alessandra TOTI
Original assignee: Nyuma Pharma Srl
Priority date: 2020-10-22
Filing date: 2021-10-14
Publication date: 2022-04-28
Also published as: IT202000025036A1

Abstract

Subject-matter of the present invention is a novel combination of plants, in particular a combination of cabbage, echinacea, rosemary and artichoke extracts, and a novel composition comprising said combination. The combination of the invention is useful in the treatment of chronic persistent or neuropathic pain.

Description

"COMBINATION OF PLANTS AND THEIR USE IN THE TREATMENT OF CHRONIC PERSISTENT OR NEUROPATHIC PAIN"

Abstract of the invention

Subject-matter of the present invention is a novel combination of medicinal plants, in particular a combination of cabbage, echinacea, rosemary and artichoke extracts, and a novel composition comprising said combination. The combination of the invention is useful in the treatment of chronic persistent or neuropathic pain.

Technical background

Nowadays it is estimated that chronic persistent or neuropathic pain affects 15% of the worldwide population; the last data on the Italian population report an even higher figure of around 22%, corresponding to about 13 million people.

The chronic persistent or neuropathic pain is a pain caused by an injury or dysfunction of the peripheral or central nervous system. Unlike the nociceptive pain, originating from a physical insult or an inflammatory process and constituting the exacerbation of a normal mechanism of defense, the neuropathic pain does not follow the physiological pathway of pain transmission but originates within the nervous system thus constituting a completely pathological phenomenon causing pain syndromes that are difficult to be treated.

The chronic persistent or neuropathic pain can be therefore determined by different types of neuropathies, for example by chemotherapy-induced neuropathies.

The main therapeutic strategies actually employed to tackle the chronic neuropathic pain involve the use of antidepressant and anticonvulsant drugs as well as of molecules of the opioid class; however all these compounds have sometimes limited efficacy and insufficient safety profile.

Another aspect to be taken into account is related to the fact that often the chronic persistent or neuropathic pain is determined by a plurality of different factors, and being able of simultaneously acting on its different origins, for example by means of a mixture of components, would be a significant advantage over the therapy carried out with a single component capable of acting on only one of these factors.

For this reason there is today the need of identifying novel pharmacological treatments which are both effective and, at the same time, have fewer side effects such as, for example, the use of products based on extracts of natural source. Their potential full harmlessness, in fact, would be particularly important since the therapy towards a chronic pain is often, if not almost always, a long-term therapy and the presence of too severe side effects cannot be tolerated.

There is therefore the need of identifying a mixture of natural products, with negligible side effects, capable of simultaneously acting on the various factors causing the chronic persistent or neuropathic pain in an effective and reliable way, which can be also taken for long periods of time without unpleasant side effects and without the development of addiction and/or dependency phenomena.

Objects of the invention

It is an object of the present invention to provide a novel combination of plants useful in the treatment of chronic persistent or neuropathic pain.

It is another object of the present invention to provide a novel composition comprising said combination, particularly suitable for the treatment of chronic persistent or neuropathic pain.

These and other objects are achieved by the subject-matter of the present invention which provides a novel combination of plants and a formulation for its administration.

Description of the invention

Subject-matter of the invention, according to one of the aspects thereof, is a combination consisting of cabbage, echinacea, rosemary and artichoke extracts, advantageously said extracts being dry extracts.

According to a preferred embodiment, the cabbage is of the Brassica oleracea species, advantageously a dry extract obtained from the leaves and inflorescences. According to a particularly preferred embodiment, said dry extract, titrated in sulforaphane, has a titer (measured by HPLC) > 5%, preferably > 8%, advantageously about 10%.

According to a preferred embodiment, the echinacea is of the Echinacea purpurea Moench. species, advantageously a dry extract of this plant obtained from the whole tree. According to a preferred embodiment, said dry extract, titrated in total polyphenols, has a titer (measured by HPLC) > 3%, preferably > 3.5%, advantageously about 4%. According to a preferred embodiment, the rosemary is of the Rosmarinus officinalis species, advantageously a dry extract of this plant obtained from the leaves. According to a preferred embodiment, said dry extract, titrated in carnosol, has a titer (measured by HPLC) > 8%, preferably > 12%, advantageously about 15%.

According to a preferred embodiment, the artichoke is of the Cynara scolymus species, advantageously a dry extract of this plant obtained from the aerial part of the plant. According to a preferred embodiment, said dry extract, titrated in chlorogenic acid, has a titer (measured by HPLC) > 10%, preferably > 12%, advantageously about 13%. The dry extracts of the medicinal plants of the invention are known in the art and can be prepared with any method useful to the purpose or bought as feedstock present in the market.

According to a preferred embodiment, in the combination of the invention, the dry extracts of cabbage/echinacea/rosemary/artichoke, advantageously having the titers set forth above, are present in a weight ratio (p/p) of 1/0.3-0.5/0.8-1.2/0.8-1.2 respectively, preferably of about 1/0.33/1/1.

The combination is particularly useful and effective to tackle the chronic persistent or neuropathic pain determined by different types of neuropathies, in particular by chemotherapy -induced neuropathies.

The use of the combination in the treatment of the chronic persistent or neuropathic pain is a further subject-matter of the invention.

The expression "chronic persistent or neuropathic pain" is meant to denote herein, as previously stated, a pain caused by an injury or dysfunction of the peripheral or central nervous system (neuropathies) which can have different etiologies, for example a neuropathy caused by a chemotherapeutic treatment.

For its use in the treatment of chronic persistent or neuropathic pain, the combination is preferably formulated in compositions suitable for the oral administration, with immediate or controlled release, for example in suitable oral dosage forms, such as solid dosage units, such as capsules, pills, powders or granulates in sachets, or in liquid dosage forms such as mono- or multi-dose oral solutions or suspensions. Said composition, preferably an oral composition, more preferably a solid oral composition, comprising the combination of the invention, possibly together with pharmaceutically acceptable excipients and carriers, is a further subject-matter of the invention.

The combination of the invention can be administered in daily dosages of: from 600 to 1,000 mg, preferably about 600 mg of dry extract of cabbage; from 200 to 300 mg, preferably about 200 mg of dry extract of echinacea; from 600 to 1,000 mg, preferably about 600 mg of dry extract of rosemary; from 600 to 1,000 mg, preferably about 600 mg of dry extract of artichoke; said dry extracts having preferably the titers set forth above, in compositions which, if desired and necessary, comprise one or more pharmaceutically acceptable excipients. Said daily dosages can be administered in a single dose or subdivided in two or more administrations, for example one, two or three daily administrations, to be taken simultaneously or at different times. Preferably said dosages are administered into two subdivided daily dosages, for example with an interval of 12 hours, one dose after breakfast and one after dinner. However other types of posologies can be used for the administration of said dosages.

According to a preferred embodiment, the combination is contained in solid oral compositions of the capsule, granulate or pill type, preferably capsules. Said solid oral compositions can be of immediate or controlled release and can be possibly coated with a suitable coating agent for cosmetic reasons or to control the rate of release. Preferably the compositions of the invention are immediate-release capsules.

However, if desired or necessary, the composition of the invention can be formulated within controlled-release pharmaceutical forms, such as for example in sustained release pills.

The compositions of the invention, in particular the capsules, the sachets and the pills, can, if necessary, contain the conventionally used excipients, for example diluting, absorbing, lubricating, gliding, sweetening, coloring, disintegrating agents, etc. The person skilled in the field of the pharmaceutical art is perfectly capable of selecting the excipients most suitable for the desired pharmaceutical form he wishes to implement. The compositions of the invention can be defined as pharmaceutical or nutraceutical compositions.

For the preparation of the preferred solid oral composition according to the invention, for example a capsule or a pill, preferably a capsule, it is possible to use the methods known in the art.

Examples of compositions according to the invention are provided in the Experimental Section, by way of example.

The use of the composition as described above to treat the chronic persistent or neuropathic pain is a further subject-matter of the invention.

Even though the composition of the invention provides per se the solution to the problem submitted, if desired or necessary, other natural extracts and/or other substances which are in any case beneficial for the body can be added to the compositions of the present invention, provided that they do not hinder the effects of the combination and composition of the invention.

Subject-matter of the invention, according to another of the aspects thereof, is a method to treat and/or prevent the chronic persistent or neuropathic pain and or the chemotherapy-induced neuropathies that comprises the administration of an effective dose of the combination or composition of the invention to a subject in need thereof. The invention will be now described by way of illustration only and without any limitation in the following Experimental Section, wherein a protocol for the in vivo studies and the results obtained therefrom are also set out.

Experimental section

Example 1

Protocol of the in vivo tests

Animals

The animals (male Sprague Dawley rats of about 225-250 g) are stabled at the temperature of 23±1 °C in groups of four, in 26x41 cm cages, with a 12 hour circadian cycle and water and food ad libitum (standard diet).

Neuropathic pain model induced by oxaliplatin

Oxaliplatin is dissolved in a 5% solution of glucose in saline and administered intraperitoneally at the dose of 2.4 mg/kg. The administration is carried out for two weeks, on five consecutive days and two days off, for a total of 10 administrations.

Administration of the single vegetable extracts and the combination

The single extracts of Brassica oleracea. Echinacea purpurea, Rosmarinus officinalis and Cynara scolymus have been suspended in a 1% solution of carboxymethyl cellulose (CMC) and delivered in a single oral administration in the different experimental models. Each extract has been administered in three different concentrations to evaluate the efficacy with respect to the dose; in particular regarding the Echinacea purpurea it has been administered at 10, 30 and 100 mg/kg while the other three extracts have been tested at concentrations of 30, 100 and 300 mg/kg.

The combination of the invention was constituted as follows: 100 mg/kg Brassica oleracea, 30 mg/kg Echinacea purpurea, 100 mg/kg Rosmarinus officinalis and 100 mg/kg Cynara scolymus,' also this one has been suspended in CMC and administered orally in a single administration.

All the dry extracts used have the following titers: Brassica oleracea 10% sulforaphane; Echinacea purpurea Moench. total polyphenols 4%; Rosmarinus officinalis 15% carnosol; Cynara scolymus 13% chi orogenic acid.

The control groups are represented by two different samples: the blank has been treated with the carrier only both in the intraperitoneal and the oral administrations, the placebo has been instead injected with intraperitoneal oxaliplatin and then treated orally with only the carrier solution of 1% CMC without extracts.

Evaluation of the pain sensibility (Paw pressure test)

The mechanical hyperalgesia in the rat has been evaluated by using an algesimeter (Ugo Basile, Varese, Italy). In particular the maximum weight in grams tolerated by the animal has been recorded on the paw before the manifestation of discomfort such as vocalization or paw retraction.

The results are set forth in Tables 1 and 2.

Statistical analysis

The results are expressed as mean ± E.S.D. and the analysis of the variance has been carried out by the ANOVA test. As a post hoc comparison the Bonferroni test has been used. Values of P below 0.05 have been considered significant. The data have been analyzed by using the "Origin 10" software.

Results of the in vivo test

In tables 1 and 2 are set forth the experimental data deriving from the application of the protocol as described above.

The treatment of the animals with the combination of the invention (table 2) showed to have, with respect to the administration of the single components (table 1): a better anti-hyperalgesic profile; see in table 2 how already at 15 minutes the pain tolerance of the animals treated with the mixture corresponds to that measured in the blank samples (animals where pain has not been induced by oxaliplatin). In table 1 it is possible to note how no one of the single extracts is able to equal the value obtained in the case of the blank sample; a more prolonged reaction time; the values recorded in the animals where the combination of the invention has been administered remain slightly below 60g even after 60 minutes from the administration (see table 2) whereas in the case of the administrations of the single extracts, the analgesic effect runs out from 45 to 60 minutes after the administration (table 1, values in g for the measurement of the pain tolerance decreasing to values from 40 to 50 matching the value of the placebo sample).

Example 2

Formulation of capsules containing the composition of the invention

It is prepared a traditional capsule, to be administered twice a day, by filling the capsules with the following mixture of dry extracts and excipients:

Example 3

Formulation of sachets containing the composition of the invention in granules

It is prepared a dry granulate of the following mixture of dry extracts and excipients to be included in single-dose sachets, to be administered twice a day:

Example 4

Formulation of capsules containing the composition of the invention

Example 5

Formulation of capsules containing the composition of the invention

Claims

1. A combination of medicinal plants, consisting of cabbage, echinacea, rosemary and artichoke extracts.

2. The combination according to claim 1, characterized in that said extracts are dry extracts and are titrated as follows: cabbage with a titer of sulforaphane > 5%, preferably > 8%, echinacea with a titer of total polyphenols > 3%, preferably > 3.5%, rosemary with a titer of carnosol > 8%, preferably > 12%, artichoke with a titer of chi orogenic acid > 10%, preferably > 12%.

3. The combination according to claim 1 or 2, characterized in that the weight ratios of said dry extracts of cabbage/echinacea/rosemary/artichoke are present in the combination in a ratio of 1/0.3-0.5/0.8-1.2/0.8-1.2 respectively, preferably of about 1/0.33/1/1.

4. The combination according to any one of claims 1 to 3, characterized in that it is administered in daily dosages from 600 to 1,000 mg, preferably 600 mg of dry extract of cabbage; from 100 to 150 mg, preferably 100 mg of dry extract of echinacea; from 600 to 1,000 mg, preferably 600 mg of dry extract of rosemary; from 600 to 1,000 mg, preferably 600 mg of dry extract of artichoke.

5. The combination according to claim 4, characterized in that it is administered in compositions comprising one or more pharmaceutically acceptable excipients.

6. The combination according to claim 5, characterized in that said compositions are administered in single doses or doses subdivided into two or more administrations, to be taken simultaneously or at different times.

7. The combination according to claim 5, characterized in that said compositions are subdivided into two daily administrations to be taken at different times.

8. A composition of medicinal plants comprising the combination according to any one of claims 1 to 3 together with one or more pharmaceutically acceptable excipients and carriers.

9. The composition according to claim 7 or 8, characterized in that it is an oral composition, preferably a capsule.

10. The composition according to claim 7, 8 or 9, for its use in the treatment and/or in the prevention of chronic persistent or neuropathic pain and/or of chemotherapy- induced neuropathies.

11. The combination according to any one of claims 1 to 3, for the use in daily dosages from 600 to 1,000 mg, preferably 600 mg of dry extract of cabbage; from 100 to 150 mg, preferably 100 mg of dry extract of echinacea; from 600 to 1,000 mg, preferably 600 mg of dry extract of rosemary; from 600 to 1,000 mg, preferably 600 mg of dry extract of artichoke.

12. The combination according to claim 4, for the use in compositions comprising one or more pharmaceutically acceptable excipients.

13. The combination according to claim 5, for the use in single doses or doses subdivided into two or more administrations, to be taken simultaneously or at different times.

14. The combination according to claim 5, characterized in that said compositions are subdivided into two daily administrations to be taken at different times.