Nutraceutical composition for use in the treatment of subjects over 50 with chronic fatigue

Abstract

The present invention relates to a composition, preferably a nutraceutical composition, for use in a method of treatment of subjects over 50 suffering from chronic fatigue, particularly due to: arthritis / chronic arthritis; heart disease; post-operative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory failure; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long-Covid / fatigue post Covid-19 syndrome.

Description

[0001] NUTRACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OF SUBJECTS OVER 50 WITH CHRONIC FATIGUE

[0002] ***

[0003] Field of the Invention

[0004] The present invention relates to a composition, preferably a nutraceutical composition, for use in a method of treatment of subjects over 50 with chronic fatigue, particularly due to: arthritis / chronic arthritis; heart disease; postoperative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long-Covid / fatigue post Covid-19 syndrome.

[0005] Background of the invention

[0006] The term "chronic tiredness” or "chronic fatigue” or “fatigue" is defined as the feeling of extreme physical, emotional and cognitive fatigue, out of proportion to the activity performed, so exhausting that it interferes with the performance of everyday life.

[0007] "Chronic tiredness” or ‘chronic fatigue' or ‘fatigue’ can be described as a persistent phenomenon involving the whole body with physical and psychological manifestations that are not relieved by the usual methods of recovery. The most frequent causes that can lead to this condition are acute events, such as stroke, cerebral ischemia and hospitalizing interventions, or chronic conditions such as chronic rheumatic diseases, heart disease, chronic arthritis / arthritis, overweight / obesity etc.

[0008] Chronic fatigue has been studied in a range of conditions (e.g., cardiomyopathy, cancer, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis), and has typically been associated with reduced quality of life. Unlike daily fatigue, chronic fatigue does not go away, is not relieved by sleep or rest, and is accompanied by the feeling that, every day, it somehow gets worse.

[0009] Chronic fatigue results in decreased ability to concentrate and memorize, decreased resistance to psychophysical stress, decreased desire and interpersonal and social skills, increased psychophysical discomfort and emotional weakness, and tends to have a major negative impact on patients' quality of life, limiting their daily life.

[0010] Precisely because of its consequences on the daily life and quality of life of patients and also their family members, countering chronic fatigue is one of the priorities to be addressed in order to improve the living conditions of patients suffering from it.

[0011] There is good evidence that fatigue induced by causes such as cancer treatments, postoperative course, chronic or autoimmune diseases can be managed with dietary supplements of minerals, vitamins and phytoextracts to improve the quality of life of those affected. However, the results obtained are not yet fully satisfactory.

[0012] There remains a high need to provide new and effective methods to counter chronic fatigue that have no side effects, are well tolerated by the treated subjects, and are also easy to administer, particularly for a category of subjects, such as patients over 50, still with full capacity and ability to work.

[0013] The Applicant, against the backdrop of intensive research, has developed oral compositions comprising selected blends of vitamins, minerals, amino acids and plant extracts that are effective, free of side effects and with high tolerability, for use in a method of treatment of subjects over 50 suffering from chronic fatigue, particularly due to osteoarthritis / chronic arthritis; heart disease; post-surgery convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; and drug use, wherein said subjects are not suffering from Long-Covid / faf / gue post Covid-19 syndrome.

[0014] The compositions of the invention, formulated for oral use, are preferably in solid form and may be formulated, by the addition of specific excipients and additives, as solid compositions in granular form dispersible in water, or in tablet form. Said solid-form compositions are effective in the treatment of subjects over 50 suffering from chronic fatigue, particularly due to arthritis / chronic arthritis; heart disease; post-operative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; and drug use, wherein said subjects are not suffering from Long-Covid / fef / gue post Covid-19 syndrome.

[0015] The compositions of the invention, have no major side effects, are easy to prepare and cost-effective.

[0016] These aims and others, which will be apparent from the detailed description that follows, are achieved by the compositions and mixtures of the present invention by the technical features claimed in the accompanying claims. Brief description of the Figures

[0017] Figure 1. Incidence rates of the causes of fatigue among subjects over 50 enrolled in the clinical study.

[0018] Figure 2: Percentage of improvement in the physical component (Figure 2A) and mental component (Figure 2B) of chronic fatigue.

[0019] Figure 3: Percentage of improvement in the worst fatigue perceived in the last 24 hours (Figure 3A) and in the impact of fatigue on daily activities in the last week (Figure 3B).

[0020] Figure 4: Fatigue trend in the last week at TO (at recruitment), T 1 (after 7 days from the start of treatment) and T2 (after 35 days from the start of treatment).

[0021] Detailed description of the invention

[0022] It is an object of the present invention to form a mixture for use in a method treatment of subjects over 50 suffering from chronic fatigue, particularly due to osteoarthritis / chronic arthritis; heart disease; postoperative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic disease; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long-Covid / faf / gue post Covid-19 syndrome (in short, mixture M of the invention) comprising or, alternatively, consisting of:

[0023] (i) a vitamin selected from the group comprising or, alternatively, consisting of: vitamin C, vitamin D, vitamin E, B group vitamins and mixtures thereof,

[0024] (ii) a compound comprising a mineral selected from the group comprising or, alternatively, consisting of zinc, iron, magnesium, and mixtures thereof,

[0025] (iii) an amino acid selected from the group comprising or, alternately, consisting of carnitine, arginine and mixtures thereof, preferably selected from the group comprising or, alternately, consisting of L-carnitine, L-arginine and mixtures thereof,

[0026] (iv) a plant extract selected from the group comprising or, alternatively, consisting of, ginseng extract, eleutherococcus extract and mixtures thereof.

[0027] It is also an object of the present invention to provide a composition comprising the mixture (M) and at least one technological additive of pharmaceutical and / or food grade, wherein said composition is for use in a method treatment of subjects over 50 suffering from chronic fatigue, particularly due to arthritis / chronic arthritis; heart disease; post-operative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long-Covid / fat / gue post Covid-19 syndrome.

[0028] It is also an object of the present invention a composition comprising the mixture (M) and at least one technological additive of pharmaceutical and / or food grade, wherein said composition is for use in a method treatment of symptoms or disorders such as: persistent physical and / or mental fatigue, decreased ability to concentrate and memorize, decreased resistance to psychophysical stress, decreased desire and interpersonal and social skills, increased psychophysical discomfort and emotional weakness, in subjects over 50 suffering from chronic fatigue, particularly due to arthritis / chronic arthritis; heart disease; post-operative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long- Covid / fat / gue post Covid-19 syndrome.

[0029] The mixture (M) of actives according to the present invention, comprises (I) a vitamin selected from the group comprising or, alternatively, consisting of vitamin C (or ascorbic acid or L-ascorbic acid, terms synonymous with vitamin C), vitamin D, vitamin E, B group vitamins, and mixtures thereof.

[0030] The vitamins used in this context are vitamins having a pharmaceutically acceptable degree of purity. These vitamins may be selected from vitamins having a pharmaceutically acceptable degree of purity that are commercially available.

[0031] Vitamin E is a group of eight fat-soluble compounds that includes four tocopherols and four tocotrienols. Both tocopherols and tocotrienols exist in the a (alpha), |3 (beta), y (gamma), and 5 (delta) forms, as determined by the number and position of methyl groups on the chromanol ring. Preferably, the vitamin E used in the present context is DL-a-tocopherol acetate.

[0032] The B group vitamin used in the present context preferably is a B1 vitamin and / or a B3 vitamin. When both are present, these may be in a vitamin B1 :vitamin B3 weight ratio of from 30:1 to 20:1 , for example, in a weight ratio of 18: 1.

[0033] The vitamin D used in the present context preferably is a vitamin D3 and / or a vitamin D2, more preferably a vitamin D3.

[0034] Preferably, said vitamin (I) comprised in the mixture (M) is in an amount by weight from 1 % to 5%, preferably from 2% to 4%, e.g., 1 %, 2%, 3%, 4%, 5%, relative to the total weight of the mixture.

[0035] In a preferred embodiment, (I) may be a mixture consisting of vitamin C, vitamin D3, vitamin E, vitamin B1 , and vitamin B3, preferably comprised in an amount by weight of from 1 % to 5%, preferably from 2% to 4%, e.g., 1 %, 2%, 3%, 4%, 5%, relative to the total weight of the mixture.

[0036] In a preferred embodiment, said vitamin (I) comprised in the mixture (M) is in a solid form comprising or, alternatively, consisting of (a) at least one vitamin selected from the group comprising or, alternatively, consisting of vitamin C, vitamin D, vitamin E, B group vitamins, and mixtures thereof (each taken individually or as a mixture of vitamins), (b) a phospholipid, preferably a lecithin, (c) a sucrester, and optionally (d) pregelatinized rice starch. In the present context, it will be referred to as a sucrosomial vitamin for short. Examples of sucrosomial vitamins, and their methods of preparation, are as given in patent document WO 2021 / 111407.

[0037] For example, vitamin (I) may be a solid form comprising or alternatively consisting of.

[0038] (a) a vitamin C;

[0039] (b) at least one phospholipid;

[0040] (c) a sucrester or sucrose esters, and optionally (d) pregelatinized rice starch (sucrosomial vitamin C for short).

[0041] Vitamin (I) may be a solid form comprising or alternatively consisting of

[0042] (a) a vitamin D, preferably a vitamin D3 and / or D2, even more preferably a vitamin D3;

[0043] (b) at least one phospholipid;

[0044] (c) a sucrester or sucrose esters; and optionally (d) pregelatinized rice starch (sucrosomial vitamin D or sucrosomial vitamin D3 or sucrosomial vitamin D2 for short).

[0045] Vitamin (I) may be a solid form comprising or alternatively consisting of

[0046] (a) a vitamin E;

[0047] (b) at least one phospholipid;

[0048] (c) a sucrester or sucrose esters, and optionally (d) pregelatinized rice starch (sucrosomial vitamin E for short).

[0049] Vitamin (I) may be a solid form comprising or alternatively consisting of

[0050] (a) a B vitamin, preferably a B1 and / or B3 vitamin;

[0051] (b) at least one phospholipid;

[0052] (c) a sucrester or sucrose esters; and optionally (d) pregelatinized rice starch (sucrosomial vitamin B or sucrosomial vitamin B1 or sucrosomial vitamin B3 for short).

[0053] Vitamin (I) may be a solid form comprising or alternatively consisting of

[0054] (a) at least two vitamins selected from the group consisting of vitamin C); a vitamin D, preferably vitamin D3 and / or vitamin D2 and / or mixtures thereof; vitamin E; B group vitamins, preferably vitamin B1 and / or vitamin B3 and / or mixtures thereof;

[0055] (b) at least one phospholipid;

[0056] (c) a sucrester or sucrose esters; and optionally (d) pregelatinized rice starch (sucrosomial vitamin for short).

[0057] In a preferred embodiment, vitamin (I) is a mixture comprising or, alternatively, consisting of a sucrosomial vitamin C and / or a sucrosomial vitamin D3 and / or a sucrosomial vitamin E and / or a sucrosomial vitamin B1 and a sucrosomial vitamin B3, and / or mixtures thereof.

[0058] Mixture (M) also comprises (ii) a compound comprising a mineral selected from the group comprising or, alternately, consisting of zinc, iron, magnesium, and mixtures thereof.

[0059] Preferably said compound (ii) comprising a mineral is a salt or complex or oxide of said mineral (iron, magnesium, or zinc), or a mixture of a salt or complex or oxide of said mineral.

[0060] Thus, compound (ii) may comprise a salt of a mineral, and / or an oxide of the same or different mineral, and / or a complex of the same or different mineral.

[0061] Preferably, said (ii) is present in an amount by weight of from 7% to 15%, preferably from 8% to 10%, relative to the total weight of the mixture.

[0062] Iron, as used in the present context, in the form of a salt or complex or iron oxide, may be a salt or complex comprising an iron (III) or iron (II) cation (iron salt or complex for short). The term "iron salt or complex” as used in the context of the present invention, refers to any iron salt, such as iron pyrophosphate or ferric diphosphate ferrous sulfate, ferrous gluconate, ferrous lactate and ferric ammonium citrate, as well as any iron salt that is slowly soluble in water but readily soluble in dilute acids, such as ferrous fumarate, ferrous succinate and ferric saccharate. Preferably, the iron used in the present context is iron pyrophosphate.

[0063] Zinc used in the present context, in the form of a salt or complex or zinc oxide, is preferably zinc oxide.

[0064] Magnesium used in the present context, in the form of a salt or complex or magnesium oxide, is preferably magnesium oxide.

[0065] In a preferred embodiment said (ii) is a mixture of pyrophosphate iron, zinc oxide, and magnesium oxide, comprised in an amount of from 7% to 15%, preferably from 8% to 10%, relative to the total weight of the mixture.

[0066] In a preferred embodiment, said compound comprising a mineral (ii) is a compound comprising (a) a salt or complex or oxide of said mineral (iron, zinc, or magnesium, each taken individually), (b) a phospholipid, preferably a lecithin, (c) a sucrester and, optionally, (d) pregelatinized rice starch. In this context, it will be referred to briefly as a sucrosomial mineral. Examples of sucrosomial minerals, and their methods of preparation, are as disclosed in patent documents WO 2014 / 009806, WO 2015 / 033216, and WO 2019 / 239372. Commercial formulations of minerals such as Sideral®, Sucrosomial Iron®, UltraMag®, UltraZin®, and Sucrosomial Zinc®, which are registered trademarks of patented products of Pharmanutra S.p.A., may also be used.

[0067] For example, (ii) may be a compound comprising (a) an iron in the form of an iron salt or iron complex or iron oxide, preferably a pyrophosphate iron;

[0068] (b) at least one phospholipid;

[0069] (c) a sucrester or sucrose esters; and optionally (d) pregelatinized rice starch (sucrosomial iron for short). Compound (ii) can also be a compound comprising (a) zinc oxide;

[0070] (b) at least one phospholipid;

[0071] (c) a sucrester or sucrose esters; and, optionally, (d) pregelatinized rice starch (sucrosomial zinc for short); Compound (ii) may be a compound comprising (a) magnesium oxide;

[0072] (b) at least one phospholipid;

[0073] (c) a sucrester or sucrose esters; and optionally (d) pregelatinized rice starch (sucrosomial magnesium for short). In a preferred embodiment, compound (ii) is a mixture comprising or, alternatively, consisting of a sucrosomial iron, a sucrosomial zinc, and a sucrosomial magnesium, preferably in an amount by weight of from 7% to 15%, preferably from 8% to 10%, relative to the total weight of the mixture.

[0074] The mixture (M) further comprises (ill) an amino acid selected from the group comprising or, alternatively, consisting of arginine, carnitine, and mixtures thereof.

[0075] Preferably, (ill) is present in an amount by weight of from 20% to 80%, preferably from 40% to 75%, relative to the total weight of the mixture.

[0076] Carnitine is a short-chain non-protein amino acid, a zwitterion, found in animal tissues, and in modest amounts, in plants. Preferably, the carnitine used in the present context is an L-carnitine.

[0077] Arginine is a basic polar (with a hydrophilic side chain) amino acid. The basicity of the amino acid is due to the guanidine group in its side chain, which is strongly basic. The L enantiomer is one of the 20 ordinary amino acids. Carnitine and arginine used in this context have pharmaceutical and / or food grade purity and can be selected from commercially available products, preferably L-Carnitine-L-Tartrate is used.

[0078] Preferably, said amino acid (ill) is selected from the group consisting or alternatively comprising L-carnitine, L- arginine and mixtures thereof.

[0079] Preferably, (ill) is a mixture of L-carnitine and L-arginine in a weight ratio of from 1 :5 to 1 :1 , e.g., 1 :2.

[0080] The mixture (M) also comprises (iv) a plant extract selected from the group consisting of or, alternatively, comprising ginseng extract, eleutherococcus extract, and mixtures thereof.

[0081] Preferably, said extract (iv) is present in an amount by weight of from 2% to 8%, preferably from 4% to 7%, relative to the total weight of the mixture.

[0082] In this context, the term "ginseng extract” or “Panax extract” describes the extract obtained from the root of at least one of eleven different plant species belonging to the genus Panax, each typical of a different region of the world. The most common ginseng is derived from the root of Panax ginseng (C. Meyer). Ginseng root extract (or Panax root extract) or Panax ginseng comprises triterpene or pentacyclic, oleanoic acid-related saponins (e.g., ginsenosides, panaxosides, chikusetsusaponins), polysaccharides (e.g., panaxans), sterols, and vitamin D. Preferably, an extract derived from ginseng root, having a ginsenoside titer of from 5% to 45% by weight relative to the total weight of the extract, is used in the present context, e.g. titrated at (5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%).

[0083] Eleutherococcus {Eleutherococcus senticosus) is also known as Siberian ginseng; the plant extract has a rich composition comprising saponosides (such as eleutherosides A, B, E), phenylpropane compounds, caffeic acid derivatives, lignans, and coumarins. The preferred extract used in the present context is titrated from 0.2%-1 % in eleutherosides B+E and is obtained from the root / leaves.

[0084] In a preferred embodiment (iv) is a mixture of ginseng root extract and eleutherococcus root extract, preferably in a weight ratio of from 1 :5 to 1 : 1 .

[0085] The mixture (M) may also comprise at least one trace element, at least one antioxidant compound, at least one vitamin selected from the group consisting of vitamin E, H and mixtures thereof. Preferably said trace element is a compound of iodine and / or selenium and said antioxidant compound is Coenzyme Q10 and / or a lycopene.

[0086] Preferably, said at least one trace element, said at least one antioxidant compound, and said at least one vitamin are each independently comprised in amounts sufficient to meet at least or more than 100% of the Nutrient Reference Value (NRV).

[0087] Example 1 : An example of a mixture according to the present invention is shown in Table 1.a

[0088] Table 1.a: *lron, zinc, and magnesium formulated as sucrosomial minerals. Quantity is intended as the amount by weight of mineral supplied.

[0089] Example 2: A second example of a mixture according to the present invention is shown in Table 1 ,b (e.g., product with trade name Apportal®).

[0090] Table 1.b: *lron, zinc, and magnesium formulated as sucrosomial minerals. Quantity is intended as the amount by weight of mineral supplied.

[0091] Advantageously the mixture or composition comprising the mixture (M) are for use in a method treatment of subjects over 50 suffering from chronic fatigue, particularly due to arthritis / chronic arthritis; heart disease; postoperative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long-Covid / faf / gue post Covid-19 syndrome.

[0092] The mixture (M) or the composition comprising the mixture (M) for use in the above method is preferably administered orally, 2 times daily for at least 7 days, and then 1 time daily for at least 28 days.

[0093] Preferably, said mixture is administered in a daily amount ranging from 600 mg to 2500 mg, preferably ranging from 1000 mg to 2100 mg, e.g., 2070 mg.

[0094] Advantageously, the authors of the present invention have found that the mixture (M), described in the present context, or the composition, comprising the mixture (M), is capable of treating / relieving symptoms or disorders, such as persistent physical and / or mental fatigue and / or decreased ability to concentrate and memorize and / or decreased resistance to psychophysical stress and / or decreased desire and interpersonal and social skills and / or increased psychophysical distress and emotional weakness, in subjects over 50 suffering from chronic fatigue, particularly due to arthritis / chronic arthritis; heart disease; postoperative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory insufficiency; chronic respiratory disease; allergic diseases; overweight / obesity; and drug use, wherein said subjects are not suffering from Long- Co idlfatigue post Covid-19 syndrome. In particular, it offers benefit in reducing persistent physical and mental fatigue.

[0095] Experimental Part

[0096] Prospective observational study regarding the benefit of taking the composition according to the present invention on subjects over 50 with chronic fatigue.

[0097] Study Objectives

[0098] This prospective observational study evaluated the effect of supplementation with a composition according to the present invention in subjects over 50 who reported chronic fatigue with the aim of achieving a reduction in fatigue of at least 30% from baseline. The secondary objective was to improve the quality of life of the subjects involved, and to evaluate tolerability and compliance with supplementation.

[0099] Study design

[0100] Recruited subjects were advised to take two sachets per day of the composition of the invention of Example 2 (Apportal®) for the first 7 days and then one sachet per day for the remaining 28 days. At recruitment (TO) the subject was asked to complete 2 questionnaires to objectively assess fatigue (Brief Fatigue Inventory) and quality of life (SF-12). The same questionnaires were repeated 7 days after initiation (T1) and 35 days after initiation (T2). The SF12 questionnaire consists of 12 questions in which the subject is asked about how he / she feels and how well he / she manages to perform daily activities, evaluating the day in which he / she fills out the questionnaire. According to the questionnaire interpretation algorithm, two measures related to two different aspects of health (physical health and mental health) are derived: physical QoL (Physical Component Score - PCS) and mental QoL (Mental Component Score -MCS).

[0101] Both values are expressed on a continuous numerical scale with increasing values, indicating better mental and physical health. The average for the healthy population has a score around 50.

[0102] The Brief Fatigue Inventory (BFI) is a questionnaire consisting of nine questions scored from 0 to 10 points. The BFI is divided into two parts: the first three questions assess current, usual and worst fatigue levels over the past 24 hours, while the remaining six questions assess the impact of fatigue on activity, mood, walking, work, relationships and quality of life (IBS). The last question asks subjects to indicate whether they had experienced the same fatigue condition (LWF) in the past week.

[0103] For each question, a score of 0 to 3 indicates low fatigue, a score of 4 to 6 moderate fatigue, and a score of 7 to 10 severe fatigue. Inclusion / exclusion criteria

[0104] Subjects enrolled had to manifest chronic tiredness {fatigue) and be aged 50 years or older. All cancer patients on active treatment, subjects infected with Covid-19 in the 30 days prior to recruitment or who contracted Covid-19 during the study, and subjects who manifested chronic fatigue related to Covid-19 infection (Long-Covid, even if the infection had occurred more than 30 days before the start of the study) were excluded.

[0105] Results

[0106] A total of 458 subjects were recruited, 167 men (36.46%) and 291 women (63.54%), with a mean age of 68.68 ±10.53 years. Twelve percent of subjects reported that their tiredness was due to an acute event, while the remaining 88% reported fatigue resulting from a chronic condition. The main causes of tiredness reported by subjects were arthritis / chronic arthritis (19.32%), heart disease (11 .78%), advanced age (10.64%), and overweight / obesity (10.23%). Each subject could indicate one or more causes of tiredness. The incidence rates of the various causes of tiredness and the characteristics of the sample analyzed are shown in Table 2. The causes of tiredness are shown in Figure 1.

[0107] Table 2

[0108] 1. Quality of Life (SF-12)

[0109] The results of the SF-12 questionnaire demonstrated a statistically significant improvement over time in both the physical and mental components (Fig.2 A-B). Different subgroups within the entire sample were analyzed, and the only statistically significant differences are found on physical QoL by recording a greater improvement in this parameter for subjects under 70 and for subjects with post-acute fatigue at T2. However, as shown in Table 3, there is no significant interaction between the subgroups with respect to time trend, in practice the baseline conditions are different but the improvement over time is comparable. No differences were found between the two genders.

[0110] Table 3 Considering the whole sample, the physical component (Physical QoL) improves by 10.12 points between the beginning and the end of the study (29.0% from the initial value), while the mental component (Mental QoL) improves by 21.43 points (77.4% from the initial value). The initial increase after the first week of intake is 15.4% for physical QoL and 63.7% for mental QoL. On average, adding initial and end points results in an overall improvement in quality of life of 50.5%. Figure 2 shows the trends of the of improvement in the physical component (Figure 2A) and the mental component (Figure 2B) of chronic fatigue.

[0111] 2. Fatigue severity questionnaire (BFI).

[0112] The score given to the worst fatigue perceived in the last 24 hours decreased, so there was an improvement, statistically significantly between TO and T1 and between T1 and T2 (Fig.3-A). The percentage reduction is 46% between start and end of treatment, 27.3% after the first 7 days. The average of the 6 scores attributed to the impact of fatigue on daily activities in the last week (IBS) (Fig.3-B) was also significantly improved over time. The percentage improvement was 47.5%, with an initial (T1) improvement of 25.4%. Different subgroups within the whole sample were analyzed, and differences were found between the two genders, between different age groups (over 70 and under 70), and between those reporting fatigue from acute or chronic condition. However, there is no significant interaction between the subgroups with respect to time, in practice the baseline conditions are different but the improvement over time is comparable, as can be seen from the results shown in Table 4.

[0113] Table 4

[0114] The fatigue rating charged in the last week (LWF) showed a statistically significant reduction of 60.16%, as shown in Table 5 and Figure 4. Tab e 5

[0115] Adverse effects

[0116] Subjects were asked to indicate any adverse effects that, in their opinion, had occurred as a result of taking the dietary supplement. A survey was not conducted to determine the actual correlation with supplementation; the effects indicated were grouped into macro-categories and are described Table 6.

[0117] Table 6

[0118] Conclusions

[0119] The subjects aged 50 years and older who participated, reported their joint problems as the main cause of fatigue, secondarily heart disease, along with advanced age and overweight / obesity.

[0120] The data collected showed that taking a composition of the invention (Example 2, ApportAL®) led to a progressive improvement in the subjects' quality of life, both in mental and physical terms, with improvement especially in the mental component, which also started from a worse condition. Looking at the improvement trend of the parameters obtained from the SF-12 questionnaire, it is observed that mental QoL increased surprisingly by 63.4% in the first week alone. This finding indicates that the initial well-being of the subjects is tangible and is the first appreciated benefit; the physical component improves progressively although less quickly than the mental component. It is possible to speculate that the physical improvement may be attributable both to the tonic-energizing substances present (Magnesium, Arginine, Carnitine, Taurine, Iron), but also to the parallel improvement in mental fatigue achieved by the supplement as a whole.

[0121] Overall, the fatigue experienced in the last week was significantly reduced (-60.16%) from the initial 94.07% to the final 33.99%. The worst fatigue experienced and the impact fatigue had on daily activities, such as ability to walk, work, relationships with other people, and enjoyment of life, were also reduced.

[0122] Adverse effects reported as a result of taking the composition of the invention were minor and, in some cases, hardly related to the supplement; furthermore, by switching from the intake of 2 sachets per day to only 1 sachet per day, they were reduced from 10.3% to 8.5%.

[0123] In conclusion, the composition of the invention can be considered as a valuable support in cases of chronic fatigue of the adul t / elderly subject (over 50) suffering from chronic fatigue, particularly due to arthritis / chronic arthritis; heart disease; post-operative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory failure; chronic respiratory disease; allergic diseases; overweight / obesity; drug use (wherein said subject does not suffer from Long-Covid / fef / gue post Covid-19 syndrome), improving the quality of life and the impact of chronic fatigue on everyday life, enabling the subject to carry out his or her activities, cultivate his or her social relationships, and thus live better both physically and mentally.

Claims

CLAIMS1 . A mixture for use in a method of treatment of subject over 50 suffering from chronic fatigue, particularly due to: osteoarthritis / chronic arthritis; heart disease; postoperative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic disease; stroke; cerebral ischemia; respiratory failure; chronic respiratory disease; allergic disease; overweight / obesity; drug use, wherein said subjects are not suffering from Long- Covid / fatigue post Covid-19 syndrome, comprising or, alternatively, consisting of:(I) a vitamin selected from the group comprising or, alternatively, consisting of: vitamin C, vitamin D, vitamin E, B group vitamins, and mixtures thereof,(ii) a compound comprising a mineral selected from the group comprising or, alternatively, consisting of zinc, iron, magnesium, and mixtures thereof,(ill) an amino acid selected from the group comprising or, alternatively, consisting of carnitine, arginine and mixture thereof, preferably selected from the group consisting of L-carnitine, L-arginine and mixture thereof,(iv) a plant extract selected from the group comprising or, alternatively, consisting of ginseng extract, eleutherococcus extract and mixtures thereof.

2. The mixture for use according to claim 1 , wherein said (I) is present in an amount by weight from 1 % to 5%, preferably from 2% to 4%, relative to the total weight of the mixture.

3. The mixture for use according to any one of the preceding claims, wherein said B group vitamin is selected from the group comprising or, alternatively, consisting of vitamin B1 , vitamin B3, and mixtures thereof.

4. The mixture for use according to any one of the preceding claims, wherein said vitamin D is selected from the group comprising or, alternatively, consisting of vitamin D3, vitamin D2, and mixtures thereof.

5. The mixture for use according to any one of the preceding claims, wherein said (ii) is present in an amount by weight from 7% to 15%, preferably from 8% to 10%, relative to the total weight of the mixture, preferably wherein said (ii) is a mineral in the form of a salt or complex or oxide of said mineral.

6. The mixture for use according to any one of the preceding claims, wherein said (ill) is present in an amount by weight from 20% to 80%, preferably from 40% to 75%, relative to the total weight of the mixture.

7. The mixture for use according to any one of the preceding claims, wherein said (iv) is present in an amount by weight from 2% to 8%, preferably from 4% to 7%, relative to the total weight of the mixture, preferably wherein said ginseng extract is a ginseng root extract titrated in ginsenosides from 5% to 45% by weight relative to the total weight of the extract, and wherein said eleutherococcus extract is titrated in eleutherosides B+E from 0.2% to 1 %, by weight relativeto the total weight of the extract.

8. The mixture for use according to any one of the preceding claims, wherein said mixture further comprises atleast one trace element, at least one antioxidant compound, at least one vitamin selected from the group consisting of vitamin E, vitamin H and mixtures thereof, preferably wherein said trace element is a compound of iodine and / or selenium, and wherein said antioxidant compound is Coenzyme Q10 and / or a lycopene, preferably wherein said at least one trace element, said at least one antioxidant compound, and said at least one vitamin are each independently included in amounts sufficient to meet at least or more than 100% of the Nutrient Reference Value (NRV).

9. The mixture for use according to any one of the preceding claims wherein said mixture is administered orally, 2 times a day for at least 7 days, and thereafter 1 time a day for at least 28 days, preferably, wherein said mixture is administered in a daily amount ranging from 600 mg to 2500 mg, preferably ranging from 1000 mg to 2100 mg.

10. A composition comprising the mixture according to any one of the preceding claims and at least one pharmaceutical and / or food grade technological additive, wherein said composition is for use in a method of treatment of subjects over 50 suffering from chronic fatigue, particularly due to: osteoarthritis / chronic arthritis; heart disease; post-operative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory failure; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long-Covid / fatigue post Covid-19 syndrome.

11. A composition comprising the mixture according to any one of the preceding claims and at least one pharmaceutical and / or food grade technological additive, wherein said composition is for use in a method of treatment of persistent physical and / or mental fatigue and / or decreased ability to concentrate and memorize and / or decreased resistance to psychophysical stress and / or decreased interpersonal and social desire and ability and / or increased psychophysical distress and emotional weakness, in subjects over 50 suffering from chronic fatigue, particularly due to: osteoarthritis / chronic arthritis; heart disease; postoperative convalescence; depression; diabetes; fibromyalgia; chronic rheumatic diseases; stroke; cerebral ischemia; respiratory failure; chronic respiratory disease; allergic diseases; overweight / obesity; drug use, wherein said subjects are not suffering from Long-Covid / fatigue post Covid-19 syndrome.

Images