USEFUL AS AN ADJUVANT IN THE TREATMENT OF CHRONIC PAIN

DESCRIPTION

Field of the invention The present invention relates generally to the field of dietary supplements, and more precisely to a supplement in the form of a composition of plant extracts and natural substances described below, to the process for the preparation thereof and to the supplement itself for use as an adjuvant in the treatment of chronic pain.

Background of the Invention Chronic pain is defined as a pain that has been ongoing, afflicting a patient for at least six months or that has persisted for at least one month after healing that should have ended it. This is a condition that, unlike acute pain, can occur even in the absence of an obvious cause and does not appear to have a useful function; it can also persist for a long time, even for years, and is extremely difficult to recognise and diagnose, but also to treat once diagnosed.

An epidemiological study of the situation in Europe indicates that 95 million European adults in the 15-64 age group suffer from chronic pain, which is far more than the 60 million European citizens suffering from diabetes (see Brevik et al. “Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment” Eur. J. Pain 2006; 10:287-333).

This and other similar studies highlight how chronic pain can result from a disease or trauma from which one has now recovered, or it can develop for no apparent reason, also affecting any part of the body, arms, legs, hands or feet, with a prevalence however reported by European patients for back pain. The physical consequences and the emotional and social impact of this disease can be devastating, with a strong impact on the patient's daily life and work. Depending on the severity of the chronic pain and how well the patient can manage it, it can in fact reduce the patient's mobility to the point of making him or her non-self-sufficient, and also reduce his or her ability to cope with stress and anxiety, leading to social isolation and depression.

By its very nature, chronic pain, even when correctly diagnosed, can be very difficult to treat by doctors and have enormous costs on public health systems and society. The drugs available, particularly for severe chronic pain, are those based on opioids, which in the vast majority of cases cause severe side effects in patients, such as nausea, vomiting, migraine, etc., as well as addiction if used for a long time. It is clear from the above that there is a strong need to have effective products available to improve, if not eliminate, the conditions of chronic pain of the many subjects who are affected.

Summary of the invention

The Applicant has now found a dietary supplement based on natural substances and titrated plant extracts, thus in a controlled dosage of the active ingredients contain therein, which solves the problems described above in that it has proved to be an effective adjuvant in the therapeutic treatment of chronic pain, both alone and in combination with known products already used for these therapies.

In particular, the supplement in the form of composition of this invention has been shown to be effective as an adjuvant in patients suffering from chronic pain, under treatment with Cannabis Medica. As illustrated below, this supplement had a positive effect both on the intensity of chronic pain and on aspects related to patients' psychological well-being and improved quality of life.

At the same time, the supplement of the invention is also palatable to the patient, due to the convenience of taking the product in tablet form, and also due to the absence of major side effects.

The object of the invention is therefore a dietary supplement, the essential characteristics of which are defined in the first of the appended claims. Further important characteristics of the supplement according to the invention are defined in the dependent claims of the first one.

A further object of the invention is a process for the preparation of the aforesaid supplement, the essential features of which are defined by the respective independent claim appended hereto.

Still a further object of the invention is the aforesaid supplement for use as an adjuvant in the therapeutic treatment of chronic pain.

Other important features of the supplement, of the process for the preparation thereof and of the supplement for use according to the invention are given in the following detailed description, also with reference to the figures.

Brief description of the drawings

Figure 1: graph in the form of histograms showing the percentage of patients with decreased pain for the different diseases tested in the study described in the experimental part below;

Figure 2: graph showing the trend over time of the decrease in pain for the subjects subjected to the study described in the experimental part below, in the time interval between 10 and 30 days after the start of the study; DVAS1 indicates the average of the pain values declared by the subjects according to the visual analogue scale of pain after 10 days from the start of the study, DVAS2 indicates the average of the pain values declared after 20 days and DVAS3 indicates the average of the pain values declared after 30 days from the start of the study;

Figure 3: graph in the form of histograms showing the number of patients, among those recruited for the study, who dropped out before the end, with the relative reasons.

Detailed description of the invention

Definitions

Within the scope of the present invention, unless otherwise specified, when a % by weight of a single component of a composition or combination is indicated, it is to be understood as a % by weight with respect to the total weight of the composition or combination of components.

The term “dosage unit” herein means a single tablet, pill, capsule, or other available form that can be administered to a subject as a single unit. The term “phytosomal preparation” referring to an active substance means a preparation in which the active substance is in the form of a complex with phospholipids to reduce the polarity thereof and improve the bioavailability thereof, according to a technology known as Phytosome ^® patented by Indena SpA (see Petrangolini G. et al. “A new Food-grade Coenzyme Q10 Formulation Improves Bioavailability: Single and Repeated Pharmacokinetic Studies in Healthy Volunteers” in Current drug Delivery 2019, 16(8):759-767). The term “standardized” with reference in particular to natural substances or plant extracts means a titrated product, for which the exact quantity of active ingredient present in the substance or extract respectively is known.

The term “DVAS” in the present invention refers to pain according to the Visual Analogue Scale (VAS), which is one of the internationally recognised methods of algometry or pain measurement, which is extremely simple and understandable for patients of all ages, perfectly reproducible and has high correlation with other algometric methods (see Scott-Huskisson E.C. “Graphic Representation of Pain” in Pain 1976; 2:175-84). This scale ranges from 0 for no pain to 100 for severe or very severe pain, and is based on the subjective graphic response of the patient who must indicate a value on the scale to give a measure of the pain experienced.

The term “HADS” in the present invention means the Hospital Anxiety and Depression Scale. This is a self-assessment scale developed to detect states of depression, anxiety and distress in chronically ill patients; it consists of 14 points, 7 for anxiety and 7 for depression, and allows discrimination between psychopathological and somatic symptoms.

Detailed description

The dietary supplement according to the invention comprises a combination of plant extracts of Zingiber officinale and Acmella Oleracea, coenzyme Q10, and one or more vitamins of group B.

In one aspect of the invention, the above-mentioned combination of plant extracts comprises the two extracts, with a high degree of standardization. Preferably the plant extracts present in the supplement of the invention are obtained by extraction with supercritical carbon dioxide. In a preferred aspect of the invention, the combination of plant extracts of the present supplement is a combination of standardized botanical extracts of ginger and Acmella oleracea, originally in oil form, formulated in powder form by addition of lecithin, e.g. sunflower lecithin.

In a preferred aspect of the invention, the coenzyme Q10 is in the form of a phytosomal preparation, wherein the coenzyme Q10 is in the form of a complex with lecithin, for example sunflower lecithin, to form a solid dispersion of the active ingredient in a lecithin matrix.

In another aspect of the invention, the combination of plant extracts and/or the phytosomal preparation further comprise food grade excipients, selected for example from maltodextrin, silica dioxide, cellulose and derivatives thereof, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and microcrystalline cellulose, and mixtures thereof.

In this supplement, the above-mentioned combination of plant extracts may be present for example in amount comprised between 50 mg and 1000 mg per dosage unit; preferably in amount equal to about 350 mg. The amount of coenzyme Q10 in this supplement may for example be comprised between about 10 mg and about 200 mg per dosage unit, and between about 10 mg and about 1000 mg per dosage unit when the coenzyme Q10 is present in the supplement in the form of a phytosomal preparation. According to a preferred embodiment of this supplement, it comprises about 150 mg per dosage unit of a phytosomal preparation of coenzyme Q10.

The supplement of the invention may comprise, for example, as a combination of the plant extracts mentioned above, a product having the following composition shown in Table 1 for a 350 mg unit dosage form, like in the commercial product known as Mitidol®. Table 1

The supplement of the invention may comprise, for example, as a phytosomal preparation of coenzyme Q10 standardized to 18-22% for a 150 mg unit dosage form, a product having the following composition shown in Table 2 and obtainable using ethyl acetate as a solvent, like in the commercial product known as Ubiqsome®.

Table 2

“Vitamins of group B” according to the invention preferably means the vitamins selected from the group consisting of vitamin B1 or thiamine, vitamin B6 or pyridoxine, vitamin B12 or cyanocobalamin, and mixtures thereof. In one aspect of the invention, the supplement comprises more vitamins of group B, preferably a mixture of vitamin B1, vitamin B6 and vitamin B12. In the supplement of the present invention, vitamin B1 may be present for example in amount from about 0.50 to about 12.5 mg, vitamin B6 in amount from about 0.7 to about 5 mg and vitamin B12 in amount from about 1.25 mg to about 500 mg, independently of each other.

In a particularly preferred embodiment of this invention, the supplement comprises, per dosage unit, about 350 mg of the combination of plant extracts, about 150 mg of coenzyme Q10, about 0.55 mg of vitamin B1, about 0.7 mg of vitamin B6 and about 1.25 mg of vitamin B12.

The components of the supplement according to the invention may be formulated according to conventional methods, such as those described for example in “Remington’s Pharmaceutical Handbook”, Mack Publishing Co., N.Y., USA.” In particular, the present supplement may be formulated according to conventional formulation techniques for lipophilic ingredients suitable for oral administration, mainly in the form of tablets, hard or soft gelatine capsules, cellulose capsules, dragees, and similar. A process for the preparation of the supplement, comprising the steps of mixing the above-described combination of plant extracts with one or more vitamins of Group B and with the coenzyme Q10, and formation of the dosage units for oral administration, is part of the present invention. Optionally, this process comprises a preliminary step of formulating the combination of plant extracts and of the coenzyme Q10 in the form of a phytosomal preparation, prior to mixing.

As described in the experimental part below, the supplement of this invention has shown remarkable efficacy in reducing chronic pain in particular in certain diseases. It can be used alone, or administered to patients already receiving traditional medications for treating chronic pain such as opioids or even Cannabis medica. Particularly in patients already undergoing treatment with Cannabis medica, the supplement of this invention has made it possible to significantly reduce pain, allowing in some cases a reduction in the daily dose of cannabis and thus also the relative side effects.

The efficacy in reducing chronic pain shown by the present supplement has exceeded all expectations of the inventor starting from the knowledge of the individual components, whose anti-inflammatory activity has also been described and the use in pain management has been proposed.

The combination of the plants Zingiber and Acmella, known for their anti inflammatory and analgesic activity, was studied by the inventor in relation to their activity on the endocannabinoid system, testing it on patients responding to Cannabis Medica therapies, and combining it with the bioavailable Coenzyme Q10, known to reduce oxidative stress and inflammatory cytokines, and vitamins of Group B. Patients treated with Cannabis Medica in pain therapy had chronic diseases with a major neurodegenerative component. The combination of natural active ingredients with cannabis has proven to be more effective than traditional treatments. Without wishing to be bound by a theory, this could be linked to the completeness of the action of the painkiller with the supplement of this invention: anti-inflammatory, modulatory of the endocannabinoid system and neuroprotective.

The dietary supplement described above for use as an adjuvant in the therapeutic treatment of chronic pain, alone or in combination with one or more conventional pain-relieving drugs, in particular therapeutic cannabis, is also an object of the present invention, as is a method for therapeutic treatment of chronic pain comprising administering an effective dose of the aforesaid supplement, alone or in combination with one or more conventional pain-relieving drugs, to a subject in need thereof. Such a supplement for use or method of treatment preferably comprises oral administration of the supplement, possibly combined with the administration of one or more of the above drugs.

As mentioned above, this supplement has no significant side effects (there were only a few cases of nausea in those taking Cannabis at high THC concentrations, at the time when the dosage of this conventional therapy had not yet been reduced, contrary to the recommendation given in the study described below, demonstrating the mechanism of action on the receptors of the endocannabinoid system of this supplement and the efficacy thereof). The present supplement therefore also helps in this sense to improve the conditions of the patient and increase his or her compliance with the therapy; it also reduces the administration of any conventional drugs which on the contrary have important side effects.

In addition, this supplement has also been shown to induce muscle relaxation, increased activation and greater energy in daily activities.

Another advantage of this supplement is its formulation based on natural products and plant extracts, which are, however, standardized and titrated for an exact and constant dosage in the final product.

The following experimental part is given by way of illustration and not limitation of the present invention.

Experimental part A pilot study was carried out in order to evaluate the efficacy of the supplement subject-matter of this invention as an adjuvant in the treatment of chronic pain, in subjects already being treated with conventional drugs for such therapy. In particular, the Study was aimed at assessing the influence of this supplement on the reduction of chronic pain and the improvement in quality of life, compared to therapy with the conventional painkiller alone.

The Study also aimed to demonstrate that taking the supplement of this invention can enable the dosage of conventional medication to be reduced even in subjects who have been treated for some time with this drug therapy.

Study design, data management and ethical considerations This open-ended pilot Study lasted four weeks. The variables investigated were measured at baseline, and during periodic follow-up meetings held once a week during the 4 weeks of the Study, to highlight correlations and possible changes over time.

All subjects joined the Study on a voluntary basis after having given their free and informed written consent to join the Study and after having received the necessary and due explanations as well as a detailed and comprehensive description of the Study. Each subject was free to withdraw their consent to participate in the Study at any time.

All data collected has been handled with the utmost attention to the protection of privacy, in accordance with current legal provisions, and has been stored with the help of Excel platforms. Patients' names were anonymised through the automatic generation of a code on the basis of the origin and sequence number. The Study was carried out in compliance with and according to the basic principles, guiding principles and supplementary guidelines of the 6th and final 2008 version of the Declaration of Helsinki of 1975. The opinion of the relevant Ethics Committee has also been sought.

Enrolment and inclusion/exclusion criteria The procedures for enrolling the volunteers in the Study took place at the

POLIPAIN CLINIC Pain Therapy Clinic in Cascina, Pisa, Italy.

The existence of the following criteria for inclusion in the Study were ascertained for each subject recruited:

-presence of chronic pain; -use of pain-relieving drugs of the conventional pharmacopoeia, for at least 3 months, without achieving full efficacy;

-ability to fully and consciously understand the research process and sufficient ability to provide informed consent; and the absence of the following exclusion criteria: -presence of organic or psychiatric disorders that might interfere with the ability to judge and understand; -presence of pain for less than 3 months;

-patients with an allergy to the ingredients of the dietary supplement of the invention;

-pregnant or breast-feeding patients;

-patients with arrhythmia or ischaemic heart disease.

Materials and Methods Population in the Study

The Study population consisted of 48 subjects (mean age = 58.56 years), of which 10 males (22.91% of the total population) and 38 females (79.16% of the total population), all under treatment with Cannabis medica for chronic pain of different types: 4 subjects (8.3%) were suffering from headaches and migraines, 9 subjects (18.7%) were suffering from Central Nervous System disorders, 26 subjects (54.1%) were suffering from fibromyalgia, and 9 subjects (18.7%) from neuropathic pain.

Study outcome Physiological variables

The main physiological variables measured within the Study were:

-the intensity of the pain;

-the presence/absence of a range of benefits (reduction/disappearance of pain, muscle relaxation, mental relaxation, increased activation, improved quality of sleep, overall improvement in quality of life); and

-the presence/absence of a range of side effects (lack of concentration, mental blankness/disorientation; tachycardia, dry mouth, drowsiness, multiple side effects, increased appetite, hyperactivity/agitation).

Psychological variables

The main psychological variables measured within the Study were:

-clinical characteristics of pain (Italian Pain Questionnaire, QUID);

-psychological variables comprise symptoms of anxiety and depressive psychopathology as measured by the Hospital Anxiety and Depression Scale (HADS);

- pain intensity is measured with the Visual Analogue Scale (VAS).

Discussion of the results of the Study

At the end of the 4 weeks of data collection, the evaluation was carried out: Primary Endpoints:

-Pain intensity (VAS scale); and

-Type and quality of pain (Italian Pain Questionnaire, QUID); and

Secondary Endpoints:

-Anxiety and depression (HADS scale).

25 subjects reported a decrease in pain with an average of 0.46 Dvasl in the first 10 days; an average of 0.66 Dvas2 after 20 days and 0.96 Dvas3 after 30 days showing a decrease in pain after about 30 days of treatment.

Of these 25 subjects, 13 perceived a decrease in pain at the level of the sensory component, which supports the hypothesis of a real effect of the supplement of this invention on pain. 9 subjects perceived an improvement in the affective component of pain; and 10 subjects in the evaluative component. The latter two values indicate the level of perceived tolerability, which is also related to the mood.

Of the 25 subjects who reported a decrease in pain, only 7 made changes in the Cannabis dosage; 2 subjects decreased the THC dosages and increased the CBD dosages, whereas 5 subjects decreased the CBD dosages and increased the THC dosages.

The decrease in pain referred to the diseases they were suffering from was as follows:

-2 subjects with migraine reported a decrease in pain intensity by 50%;

-5 subjects with Central Nervous System diseases (myelitis, multiple sclerosis, SLA) perceived a 55.5% decrease in pain;

-13 subjects suffering from rheumatological and autoimmune diseases experienced a 50% decrease in pain;

-5 subjects with neuropathic pain perceived a decrease in pain of 55.5%.

23 subjects reported no change in pain perception. Of them, 3 patients dropped out of the Study in the first 20 days due to poor adherence to therapy; 3 patients dropped out of the Study due to nausea; and 1 patient dropped out of the Study due to worsening of underlying symptoms. Figure 3 shows the schematic representation of these drop-outs and their reasons. There was no correlation between psychological factors related to anxiety and depression and drop-out from treatment. None of the patients who decided to drop out of the Study had anxiety and/or depressive symptoms.

Of the 16 subjects who did not perceive a decrease in pain, but continued till the end of the 30-day treatment period, 4 subjects still perceived other benefits, such as muscle relaxation, increased activation, and greater energy in daily activities. Conclusions

The index of 0.96 Dvas3 after only 30 days of treatment is suggestive of the validity of using this supplement in patients suffering from chronic pain.

Of the 41 subjects who completed the Study, 60.97% showed an improvement in their pain symptoms. The verified synergy among the components of this supplement is supported by the percentage data obtained which lead the inventor to believe that the combination of active ingredients in this supplement may lead to further benefits in relieving chronic pain in the medium/long term.

In addition, interactions between Cannabis medica and the supplement of this invention are demonstrated by a variation, in some of the subjects of the Study, in the dosage of the active ingredients of the Cannabis, while using the supplement.

The present invention has been described herein with reference to a preferred embodiment. It is to be understood that there may be other embodiments that relate to the same inventive nucleus, all falling within the scope of protection of the claims provided below.