Patent Publication Number: US-2013236438-A1

Title: Composition for Treating Phonatory and Olfactory Apparatus Disorders

Description:
FIELD OF THE INVENTION 
     The present invention relates to a composition consisting of coenzyme Q10, vitamin A and suitable excipients for treating disorders of the phonatory and olfactory apparatus. 
     PRIOR ART 
     Abuse or misuse of the voice can cause pathological processes, for example temporary or chronic inflammatory processes, which may mainly affect the mucosa and the musculature of the larynx and, in particular, that of the vocal cords. They are situations caused by vocal stress that is particularly violent or protracted. 
     The early symptoms indicative of vocal problems to which attention is to be paid are dysphonia, phonasthenia (change in one&#39;s voice over the course of the day), sensation of lack of air, frequent need to clear one&#39;s throat, feeling of tension and/or tenderness of the neck, cough and hoarseness, episodes of loss of voice (aphonia) with some difficulty of recovery, sensation of inadequacy of one&#39;s own vocal volume, difficulty in reaching vocal extensions that were comfortable before (in the context of singing, including amateur), difficulty swallowing (dysphagia). In particular situations, characterized by abuse of the voice, the vocal cords can form polyps or nodules, usually always in the same position, exactly as occurs for the formation of calluses in areas of skin more exposed to external traumatic factors. 
     Specifically, there are conditions in which abuse or misuse of the voice can cause, through a mechanism of hyperaemia, a chronic inflammatory process, which leads to the formation of laryngeal nodules. It should also be considered likely that changes in muscular dynamics such as in the case of phonatory fatigue, following said abuse of the voice, results in a muscular change that also causes dysphonia. A vocal nodule represents the clinical result of altered muscular dynamics and of changes in elasticity and of the sliding of the vocal cords. It is often the point of contact of a phonatory posture in which the vocal cords are disposed on a plane with upper concavity, caused by muscular hypotonia. 
     A previous vocal nodule can evolve into a vocal polyp such as to affect the mucosal corium with variable representation of histological components (vascular and connective). 
     Medical treatment is known for these phonatory disorders only and exclusively of the logopaedic type, which envisages cycles of phoniatric therapy by avoiding phonatory abuse, making possible a gradual reduction of the nodular formation. In the area of olfactory disorders, with transient or permanent dysosmia, there is a change in the ability to perceive one or more odours. Dysosmia can involve complete loss of olfaction (anosmia) or partial loss (hyposmia). 
     The object of the present invention is to find a product that is effective for the aforementioned applications, but which at the same time makes it possible to improve the overall result following application of the known treatments. 
     SUMMARY OF THE INVENTION 
     The abovementioned object was achieved by a composition consisting of coenzyme Q10, Vitamin A and pharmaceutically acceptable excipients. 
     In another aspect, the present invention relates to the use of this composition for treating phonatory and olfactory apparatus disorders, for example anosmia and dysosmia. 
     For the purposes of the present invention, by the term “vitamin A” it is meant both the free form vitamin A, i.e. retinol, and derivatives thereof, such as retinaldehyde, retinoic acid, retinyl retinoate, a salt thereof, such as sodium retinoate, an ester thereof, such as retinyl acetate, retinyl propionate, retinyl palmitate, retinyl stearate, retinyl oleate, methyl retinoate, ethyl retinoate, or a mixture thereof. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The characteristics and advantages of the present invention will be clear from the detailed description given below, from the illustrative, non-limiting examples, and from the appended drawings, wherein: 
         FIG. 1  shows the percentage Jitter pre-treatment and post-treatment with the composition of the present invention as per Example 9; and 
         FIG. 2  shows the percentage Shimmer before and after treatment with the composition of the present invention as from Example 9. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention therefore relates to a composition consisting of coenzyme Q10, vitamin A and pharmaceutically acceptable excipients. 
     In fact, it has been surprisingly found that this composition is particularly effective in treating disorders of both the phonatory and olfactory apparatus, such as anosmia and dysosmia, as will be demonstrated in the examples presented below. Coenzyme Q10, also called ubiquinone (or vitamin Q) is an organic molecule, and more precisely a benzoquinone having a side chain with 10 isoprene units. Structurally, it is similar to vitamin K and vitamin E. 
     Preferably, said vitamin A is retinol, retinaldehyde, retinoic acid, retinyl retinoate, sodium retinoate, retinyl acetate, retinyl propionate, retinyl palmitate, retinyl stearate, retinyl oleate, methyl retinoate, ethyl retinoate, or a mixture thereof. Preferably, in the composition of the invention, coenzyme Q10 is in an amount up to 30 wt. %, and vitamin A is in an amount up to 12 wt. %, on the composition weight. 
     More preferably, in the composition of the invention, coenzyme Q10 is in an amount of 1-25 wt. %, and vitamin A 0.3-10 wt. %, based on the weight of said composition. 
     Even more preferably, in the composition of the invention, coenzyme Q10 is in an amount of 2-20 wt. %, and vitamin A 0.5-8 wt. %, on the composition weight. According to a particularly preferred embodiment, in the composition of the invention, coenzyme Q10 is in an amount of 3-15 wt %, and vitamin A 1-6 wt. %, on the composition weight. 
     A composition wherein coenzyme Q10 is in an amount of 5-10 wt. %, and vitamin A 1.5-5 wt. %, on the composition weight, is further preferred. Alternatively, a composition is preferred wherein coenzyme Q10 is in an amount of 5-10 wt. %, and vitamin A 0.3-2.5 wt. %, based on the weight of the composition. According to a preferred embodiment of the composition of the invention, the amount of coenzyme Q10 is higher than the amount of vitamin A. 
     As far as the pharmaceutically acceptable excipients are concerned, these are diluents, disintegrants, glidants, binders, lubricants, stabilizers, adsorbents, preservatives, controlled release agents and mixtures thereof. Preferably, said excipients are chosen from colloidal silica, dibasic calcium phosphate, maltodextrins, sugar esters, microcrystalline cellulose, lactose, talc, magnesium stearate, calcium stearate, aluminium silicate or magnesium silicate, and mixtures thereof. More preferably, said excipients are chosen from colloidal silica, dibasic calcium phosphate, maltodextrins, sugar esters, and mixtures thereof. The term “sugar esters” means sucrose monopalmitate, sucrose monostearate, sucrose dipalmitate, sucrose distearate, sucrose alkylate and mixtures thereof. According to a preferred embodiment, the composition of the invention consists of:
         6 wt. % of coenzyme Q10,   2.1 wt. % of vitamin A, and   91.9 wt. % of a mixture of colloidal silica, dibasic calcium phosphate, maltodextrins, and sugar esters.       

     According to another preferred embodiment, the composition of the invention consists of:
         9 wt. % of coenzyme Q10,   2.1 wt. % of vitamin A, and   89.9 wt. % of a mixture of colloidal silica, dibasic calcium phosphate, maltodextrins, and sugar esters.       

     According to a further preferred embodiment, the composition of the invention consists of:
         9 wt. % of coenzyme Q10,   0.3 wt. % of vitamin A, and   90.7 wt. % of a mixture of colloidal silica, dibasic calcium phosphate, maltodextrins, and sugar esters.       

     The composition of the invention can be in the form of capsule, tablet, mini-tablet, micro-tablet, granule, micro-granule, pellet, multiparticulate, or micronized particulate. Preferably, it is in the form of capsule. 
     In another aspect, the present invention relates to the therapeutic application of the composition described above. 
     In particular, the composition of the invention is used in the treatment of phonatory and olfactory apparatus disorders, for example anosmia and dysosmia. “Phonatory apparatus disorders” means dysphonia, cordal hypotonia, phonatory fatigue, inflammatory states, nodules and polyps. As will in fact be seen from the examples given below, the composition of the invention has displayed a surprising synergistic effect ascribable to the suitable combination of the various components, which when used separately did not show suitable efficacy for the purposes of the present invention. 
     It has been, in fact, observed that coenzyme Q10 exerts a substantial action in the cells of the body, in that it permits production of energy and in particular synthesis of ATP (adenosine triphosphate) mainly in the muscles; a deficiency of coenzyme Q10 has the effect that the muscle fibres become more easily exhausted with clinical manifestations of hypotonia and muscular weakness. Moreover, coenzyme Q10 also exerts antioxidant and protective action against the production of free radicals, which represent one of the major causes of damage to cellular structures. For its part, vitamin A is an essential element in the formation and protection of the epithelial tissues in general (tissues with the function of internal and external coating of the surfaces of the body) and in maintaining conditions of well-being of the mucous membranes (organs coating surfaces communicating with the exterior). It is, moreover, necessary for protein synthesis at cellular level. 
     The composition of the present invention, moreover, can be used advantageously as adjuvant in treatments for logopaedic rehabilitation. 
     In this case, in fact, a suitable combination of coenzyme Q10 and vitamin A has been found to contribute to the prevention and reduction of muscular damage and restoration of the concentration of intracellular energy substances (ATP) necessary for proper functional capacity of the muscles of the vocal cords. Through its action on the epithelium of the vocal cords (in particular on the stellate cells), the composition was moreover found to contribute to the restoration and maintenance of the viscoelastic properties (elasticity and lubrication) of the whole vocal cord. The neuroprotective activity exerted by coenzyme Q10 contributes, together with vitamin A, to promoting functional recovery of the neurosensory network assigned to olfactory functionality. 
     Preferably, said composition is to be administered by the oral route. Alternatively, it can be administered parenterally after dilution in a suitable diluent. Moreover, other routes of administration are also possible, such as inhalation, aerosol, spray, transdermic, intravenous, intramuscular, transdermal, subcutaneous, intraperitoneal, intranasal, intrarectal, sublingual or topical. 
     Preferably, the composition of the invention is in the form of a unit dose comprising 3.3-83 mg of coenzyme Q10 and 1-26.6 mg of vitamin A. 
     More preferably, the composition of the invention is in the form of a unit dose comprising 15-35 mg of coenzyme Q10 and 5-15 mg of vitamin A. 
     Alternatively, the composition is preferred in the form of a unit dose comprising 15-35 mg of Coenzyme Q10 and 1-6.7 mg of vitamin A. 
     According to a preferred embodiment, said unit dose consists of:
         20 mg of coenzyme Q10,   7 mg of vitamin A, and   305 mg of a mixture of colloidal silica, dibasic calcium phosphate, maltodextrins, and sugar esters.       

     According to another preferred embodiment, said unit dose consists of:
         30 mg of coenzyme Q10,   7 mg of vitamin A, and   295 mg of a mixture of colloidal silica, dibasic calcium phosphate, maltodextrins, and sugar esters.       

     According to a further preferred embodiment, said unit dose consists of:
         30 mg of coenzyme Q10,   1 mg of vitamin A, and   301 mg of a mixture of colloidal silica, dibasic calcium phosphate, maltodextrins, and sugar esters.       

     The composition and the unit dose of the present invention are prepared by mixing the compounds in the proportions by weight defined above. 
     According to a preferred embodiment, said unit doses are administered in an amount of 1-2 doses per day, more preferably for a period of time between 10 consecutive days and several consecutive months. In the case of chronic pathologies, said dose could be taken in cycles of 15-25 consecutive days every 1-2 months. 
     Illustrative, non-limiting examples of carrying out the present invention are presented below. 
     EXAMPLES 
     Example 1 
     According to the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Quantity (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzime Q10 
                 20 
               
               
                   
                 Vitamin A (1)   
                 7 
               
               
                   
                 Colloidal silica 
                 5 
               
               
                   
                 Dibasic calcium phosphate 
                 120 
               
               
                   
                 Maltodextrins 
                 160 
               
               
                   
                 Sugar esters 
                 20 
               
               
                   
                   
               
               
                   
                   (1) retinyl acetate 
               
            
           
         
       
     
     Example 2 
     According to the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Quantity (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzime Q10 
                 30 
               
               
                   
                 Vitamin A (1)   
                 7 
               
               
                   
                 Colloidal silica 
                 5 
               
               
                   
                 Dibasic calcium phosphate 
                 20 
               
               
                   
                 Maltodextrins 
                 240 
               
               
                   
                 Sugar esters 
                 30 
               
               
                   
                   
               
               
                   
                   (1) retinyl acetate 
               
            
           
         
       
     
     Example 3 
     According to the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Quantity (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzime Q10 
                 50 
               
               
                   
                 Vitamin A (1)   
                 15.5 
               
               
                   
                 Colloidal silica 
                 100 
               
               
                   
                 Dibasic calcium phosphate 
                 166.5 
               
               
                   
                   
               
               
                   
                   (1) retinyl acetate 
               
            
           
         
       
     
     Example 4 
     According to the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Quantity (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzime Q10 
                 10 
               
               
                   
                 Vitamin A (2)   
                 1.5 
               
               
                   
                 Microcrystalline cellulose 
                 115 
               
               
                   
                 Magnesium stearate 
                 125 
               
               
                   
                 Talc 
                 80.5 
               
               
                   
                   
               
               
                   
                   (2) retinol 
               
            
           
         
       
     
     Example 5 
     In accordance with the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Amount (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzyme Q10 
                 30 
               
               
                   
                 Vitamin A (2)   
                 1 
               
               
                   
                 Colloidal silica 
                 5 
               
               
                   
                 Dibasic calcium phosphate 
                 23 
               
               
                   
                 Maltodextrins 
                 240 
               
               
                   
                 Sugar esters 
                 33 
               
               
                   
                   
               
               
                   
                   (2) retinol 
               
            
           
         
       
     
     Example 6 
     In accordance with the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Amount (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzyme Q10 
                 70 
               
               
                   
                 Vitamin A (3)   
                 12 
               
               
                   
                 Colloidal silica 
                 10 
               
               
                   
                 Dibasic calcium phosphate 
                 3 
               
               
                   
                 Maltodextrins 
                 224 
               
               
                   
                 Sugar esters 
                 13 
               
               
                   
                   
               
               
                   
                   (3) sodium retinoate 
               
            
           
         
       
     
     Example 7 
     In accordance with the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Amount (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzyme Q10 
                 40 
               
               
                   
                 Vitamin A (4)   
                 10 
               
               
                   
                 Colloidal silica 
                 32 
               
               
                   
                 Dibasic calcium phosphate 
                 30 
               
               
                   
                 Maltodextrins 
                 200 
               
               
                   
                 Sugar esters 
                 20 
               
               
                   
                   
               
               
                   
                   (4) retinyl oleate 
               
            
           
         
       
     
     Example 8 
     In accordance with the present invention, 332 g of a composition was prepared consisting of: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Amount (mg) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Coenzyme Q10 
                 10 
               
               
                   
                 Vitamin A (5)   
                 5 
               
               
                   
                 Colloidal silica 
                 50 
               
               
                   
                 Dibasic calcium phosphate 
                 7 
               
               
                   
                 Maltodextrins 
                 250 
               
               
                   
                 Sugar esters 
                 10 
               
               
                   
                   
               
               
                   
                   (5) ethyl retinoate 
               
            
           
         
       
     
     Example 9 
     Evaluation of efficacy of the composition of the invention Gelatin capsules were prepared, each containing the composition obtained according to Example 2. 
     These capsules were then administered at a dose of two a day for a period of 12 consecutive days to 10 individuals, suitably selected. 
     The evaluation is presented below, divided into two phases:
         Phase I: pre-treatment with the composition of the invention; and   Phase II: post-treatment with the composition of the invention.       

     Phase I 
     1) Logopaedic evaluation, comprising the phases of:
         a) taking a brief anamnesis of the 10 individuals, with particular attention to the presence of gastro-oesophageal reflux, allergic pathology and cigarette smoking;   b) evaluation of tone of the respiratory muscles;   c) evaluation of respiratory dynamics;   d) evaluation of the duration of vocalization of “ah”;   e) perceptive evaluation of the quality of the voice; and   f) compilation of the GIRBAS scale(*).
 
(*) GIRBAS scale (acronym for Grade, stability, Roughness, Breathiness, Asthenia, Strain):
   0=normal   1=slight deterioration   2=moderate deterioration   3=severe deterioration       

     Referring to Table 1 below, analysis of the data obtained identified that 5 individuals presented inadequate parameters (individuals B, C, F, G, I), while the remaining 5 individuals were adequate (individuals A, D, E, H, L). 
                     TABLE 1                  Logopaedic evaluation before treatment                                                             Perception of               Muscular   Respiration   Duration “ah”       voice quality                                                                                 Sex   tone   dynamics   vocalization   VHI-10   FO   I   Timbre   G   I   R   B   A   S   Anamnesis                                                                                         A   M   +   ad.   20″   0   +   +   +   0   0   0   0   0   0   R       B   M   +   n.ad.   20″   0   +   +   +   0   2   2   0   0   1   R + F       C   F   +   n.ad.   20″   0   +   +   +   0   1   0   0   0   0       D   F   +   n.ad.    9″   0   +   +   +   0   0   0   0   0   0   A       E   F   +   ad.   12″   0   +   +   +   0   0   0   0   0   0   A       F   F   +   ad.   13″   2/40   +   +   +   0   1   0   0   0   0   R + A       G   M   +   n.ad.   20″   0   +   +   +   0   1   0   0   0   0       H   M   +   ad.   10″   0   +   +   +   0   0   0   0   0   0       I   M   +   ad.   14″   4/40   +   +   +   2   2   1   0   1   1   R + A       L   F   +   ad.   20″   0   +   +   +   0   0   0   0   0   0               ad. = adequate;       n.ad. = not adequate       FO = fundamental frequency;       I = Intensity       VHI-10 = Voice handicap Index       R = gastro-oesophageal reflux;       F = cigarette smoking;       A = allergies            
2) Evaluation of vocal quality using the Multi-Dimensional Voice Program (MDVP) Referring to the drawings,  FIG. 1  represents the percentage Jitter, i.e. the average relative period-to-period short-term variability of the fundamental period. It is an indicator of irregularity of glottic vibration: the higher its percentage value, the hoarser the individual&#39;s voice.
 
     In its turn,  FIG. 2  shows the percentage Shimmer, i.e. the average relative period-to-period short-term variability of the peak-to-peak amplitude. Also this parameter is an indicator of irregularity of glottic vibration: the higher its percentage value, the more the individual&#39;s voice is husky and hoarse. 
     Finally, the Soft Phonation Index (SPI) was measured. This parameter is inversely proportional to the force of adduction of the vocal cords. In fact, the higher the force of adduction, the lower the value of SPI, because there is greater richness of high-frequency harmonics. 
     From the results obtained, it was observed that:
         in 5 individuals with inadequate vocal parameters, the Jitter values were altered in 2 individuals/5 (“B” and “I”), at the upper limits of the normal range in 2 individuals/5 (“C” and “G”)  2  normal in 1 individual/5 (“F”); the Shimmer values were altered in 4 individuals/5 (“B”, “C”, “G”, “I”), at the upper limits of the normal range in 1 individual/5 (“F”) and normal in 0 individuals. The values of SPI were found to be normal in 5 individuals/5 (“B”, “C”, “F”, “G”, “I”).   in 5 individuals for whom adequate vocal parameters were observed, the Jitter values were altered in 0 individuals, at the upper limits of the normal range in 1 individual/5 (“D”) and normal in 4 individuals/5 (“A”, “E”, “H”, “I”); the Shimmer values were altered in 0 individuals, at the upper limits of the normal range in 3 individuals/5 (“D”, “E”, “H”) and normal in 2 individuals/5 (“A”, “I”). The values of SPI were at the upper limits of the normal range in 1 individual/5 (“H”) and 4 individuals normal (“A”, “D”, “E”, “L”).       

     Phase II 
     1) Logopaedic evaluation 
     Referring to Table 2 below, analysis of the individuals shows that for the 5 individuals whose voice parameters proved to be inadequate, individual “I” did not have improvements, remaining stable, individual “B” had an improvement of the vocal parameters, but without normalization thereof, individuals “C”, “F” and “G” saw normalization of their vocal parameters. 
     In conclusion, after administration of the composition of the invention, 8 individuals/10 had adequate vocal parameters, 1 individual/10 had improved but inadequate vocal parameters, and only one individual/10 did not show significant improvements. 
                     TABLE 2                  Logopaedic evaluation after treatment                                                             Perception of               Muscular   Respiration   Duration “ah”       voice quality                                                                                 Sex   tone   dynamics   vocalization   VHI-10   FO   I   Timbre   G   I   R   B   A   S   Anamnesis                                                                                         A   M   +   ad.   20″   0   +   +   +   0   0   0   0   0   0   R       B   M   +   n.ad.   20″   0   +   +   +   0   1   0   0   0   1   R + F       C   F   +   n.ad.   20″   0   +   +   +   0   0   0   0   0   0       D   F   +   n.ad.    9″   0   +   +   +   0   0   0   0   0   0   A       E   F   +   ad.   12″   0   +   +   +   0   0   0   0   0   0   A       F   F   +   ad.   13″   2/40   +   +   +   0   0   0   0   0   0   R + A       G   M   +   n.ad.   20″   0   +   +   +   0   0   0   0   0   0       H   M   +   ad.   10″   0   +   +   +   0   0   0   0   0   0       I   M   +   ad.   14″   4/40   +   +   +   2   2   1   0   1   1   R + A       L   F   +   ad.   20″   0   +   +   +   0   0   0   0   0   0               ad. = adequate;       n.ad. = not adequate       FO = fundamental frequency;       I = Intensity       VHI-10 = Voice handicap Index       R = gastro-oesophageal reflux;       F = cigarette smoking;       A = allergies            
2) Evaluation of vocal quality using the Multi-Dimensional Voice Program (MDVP) Referring to the appended drawings, analysis of results obtained showed that of the 5 individuals whose vocal parameters were inadequate, individual “I” showed an improvement of the Jitter and Shimmer values, but they remained altered, whereas individual “B” showed a more marked improvement, although still with altered values, while individuals “C”, “F” and “G” all presented a clear improvement both of Jitter and of Shimmer.
 
     Therefore, after administration of the composition of the invention, 8 individuals/10 showed normal values of Jitter and Shimmer, whereas in 2 individuals/10 these parameters, although improved, remained altered. 
     In the 5 individuals with adequate vocal parameters, the values of Jitter and Shimmer were improved in 5 individuals/5. 
     Conversely, the values of SPI decreased in all 10 individuals. 
     Thus, based on the tests that were carried out, it was observed that after taking the composition of the invention, all the parameters taken into consideration with FMDVP were improved. Moreover, these results were in agreement with the perceptive evaluation of the voice. 
     Based on spectrographic analysis of the voice, a clear improvement of vocal stability was observed both with respect to the fundamental frequency (FO) and the regularity of the formants. The harmonic spectrum appeared improved in 10 individuals out of 10. This result can probably be attributed to better cordal tonicity with better vocal performance. However, vocal attack appeared unchanged as none of the individuals had undergone logopaedic sessions for improving vocal emission. Moreover, some improvement was also observed in individuals with gastro-oesophageal reflux. This pathology definitely alters vocal quality, obliging the individual to exert intense vocal effort with overloading of the musculature to the detriment of the tension of the vocal ligament. In this connection, it is important to note that the use of the composition of the invention also provided a partial improvement in these individuals. So, it can be asserted that the composition of the invention potentiates vocal performance, allowing partial recovery of the capacity of vocal tension compromised by the underlying pathology. The composition of the invention therefore proved to be a surprisingly valid support both for subjects submitted to intense vocal loading, and for patients undergoing surgery, and for patients with acute and chronic inflammatory pathologies, advantageously speeding up the process of endemic healing to reintegrate the compartment of the fundamental nutrients for proper cordal function. 
     Example 10 
     Evaluation of Efficacy 
     Comparative Tests 
     Four groups of gelatin capsules were prepared, containing respectively: 
     i) the composition obtained according to Example 5,
 
ii) a composition of coenzyme Q10 (30 mg) and excipients,
 
iii) a composition of vitamin A (1 mg) and excipients, and
 
iv) a placebo composition of excipients only.
 
     For the capsules of each type, a group of 9 individuals with cord hypotonia, suitably selected, was enrolled. Each individual was administered the capsules of the assigned type at a dose of two a day for a period of 10 consecutive days. 
     Each individual underwent the following evaluations both pre-treatment and post- the treatment:
         logopaedic balance, completing the hetero-evaluation scale GIRBAS (Grade, Instability, Roughness, Breathiness, Asthenicity, Strain) and the Voice Handicap Index-10 self-assessment questionnaire   Quantitative analysis of the vocal acoustic spectrum by Multi-Dimensional Voice Program with measurement of: Jitter (v.n.&lt;1.04%), Shimmer (v.n.&lt;3.81), Soft Phoniation Index (v.n.&lt;14.12), harmonics/noise ratio, mean fundamental frequency and relative coefficients of variation. The study was conducted on vocal emissions between 55 and 65 dB and with sufficient spectrum stability. Background noise was monitored continuously and was kept below 30 dB.       

     Results 
     The mean values post-treatment on the GIRBAS scale for each group are given in Table 3 below. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Logopaedic evaluation on the GIRBAS scale expressed as number 
               
               
                 and percentage of individuals improved post-treatment 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 composition 
                 G 
                 I 
                 R 
                 B 
                 A 
                 S 
               
               
                   
               
            
           
           
               
            
               
                 Number of individuals 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 comp. i) 
                 7 
                 6 
                 4 
                 2 
                 2 
                 0 
               
               
                 (Example 5) 
               
               
                 comp. ii) 
                 3 
                 2 
                 1 
                 1 
                 1 
                 0 
               
               
                 (coenzyme Q10) 
               
               
                 comp. iii) 
                 2 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                 (vitamin A) 
               
               
                 comp. iv) 
                 1 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 (placebo) 
               
            
           
           
               
            
               
                 % individuals 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 comp. i) 
                 77.8% 
                 66.7% 
                 44.4% 
                 22.2% 
                 22.2% 
                 0% 
               
               
                 (Example 5) 
               
               
                 comp. ii) 
                 33.3% 
                 22.2% 
                 11.1% 
                 11.1% 
                 11.1% 
                 0% 
               
               
                 (coenzyme Q10) 
               
               
                 comp. iii) 
                 22.2% 
                 11.1% 
                   0% 
                   0% 
                   0% 
                 0% 
               
               
                 (vitamin A) 
               
               
                 comp. iv) 
                 11.1% 
                   0% 
                   0% 
                   0% 
                   0% 
                 0% 
               
               
                 (placebo) 
               
               
                   
               
            
           
         
       
     
     From the results obtained using the GIRBAS scale and presented above, an extremely significant improvement was observed for all the parameters considered in the case of composition i) of the invention, i.e. comprising the combination coenzyme Q10+vitamin A. In contrast, composition ii) with only coenzyme Q10 achieved a modest improvement, limited to the parameters G and I, whereas for the other 4 parameters, the result was unsatisfactory. With respect to composition iii) comprising only vitamin A, the result was substantially comparable to that of the placebo, and therefore completely unsatisfactory. 
     Moreover, the following Table 4 presents the pre- and post-treatment values of VHI-10 (i.e. Voice Handicap Index-10), as well as the difference between the resultant values. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Logopaedic evaluation Voice Handicap Index-10 expressed 
               
               
                 as difference between pre- and post-treatment 
               
               
                 VHI-10 
               
            
           
           
               
               
               
               
               
            
               
                 composition 
                 Pre- 
                 Post- 
                 Difference 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 comp. i) 
                 Mean 
                 22.00 
                 12.44 
                 9.56 
                 (−43.45%) 
               
               
                 (Example 5) 
                 S.D. 
                 8.87 
                 9.72 
               
               
                 comp. ii) 
                 Mean 
                 19.44 
                 16.00 
                 3.44 
                 (−17.69%) 
               
               
                 (coenzyme Q10) 
                 S.D. 
                 8.47 
                 8.14 
               
               
                 comp. iii) 
                 Mean 
                 19.56 
                 18.22 
                 1.33 
                 (−6.79) 
               
               
                 (vitamin A) 
                 S.D. 
                 7.78 
                 7.05 
               
               
                 comp. iv) 
                 Mean 
                 22.44 
                 21.33 
                 1.11 
                 (−4.94) 
               
               
                 (placebo) 
                 S.D. 
                 9.94 
                 11.43 
               
               
                   
               
            
           
         
       
     
     From the results obtained by VHI-10 evaluation, presented above, an extremely significant reduction (i.e. −43.45%) was observed in vocal handicap in the case of composition i) of the invention, i.e. comprising the combination coenzyme Q10+vitamin A. In contrast, composition ii) with only coenzyme Q10 achieved a modest reduction, well below the preceding composition i). With respect to composition iii), comprising only vitamin A, the result was substantially comparable to that of the placebo, and therefore completely unsatisfactory. 
     The following Table 5 gives the post-treatment values obtained by Multi-Dimensional Voice Program (MDVP), expressed as the number and percentage of individuals improved. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Evaluation of vocal quality by Multi-Dimensional 
               
               
                 Voice Program (MDVP) expressed as number and percentage 
               
               
                 of individuals improved post-treatment 
               
            
           
           
               
               
               
               
               
            
               
                   
                 composition 
                 JITTER 
                 SHIMMER 
                 SPI 
               
               
                   
                   
               
            
           
           
               
            
               
                 Number of individuals 
               
            
           
           
               
               
               
               
               
            
               
                   
                 comp. i) 
                 6 
                 9 
                 2 
               
               
                   
                 (Example 5) 
               
               
                   
                 comp. ii) 
                 2 
                 4 
                 2 
               
               
                   
                 (coenzyme Q10) 
               
               
                   
                 comp. iii) 
                 1 
                 1 
                 1 
               
               
                   
                 (vitamin A) 
               
               
                   
                 comp. iv) 
                 0 
                 1 
                 1 
               
               
                   
                 (placebo) 
               
            
           
           
               
            
               
                 % individuals 
               
            
           
           
               
               
               
               
               
            
               
                   
                 comp. i) 
                 67% 
                 100%  
                 22% 
               
               
                   
                 (Example 5) 
               
               
                   
                 comp. ii) 
                 22% 
                 44% 
                 22% 
               
               
                   
                 (coenzyme Q10) 
               
               
                   
                 comp. iii) 
                 11% 
                 11% 
                 11% 
               
               
                   
                 (vitamin A) 
               
               
                   
                 comp. iv) 
                  0% 
                 11% 
                 11% 
               
               
                   
                 (placebo) 
               
               
                   
                   
               
            
           
         
       
     
     From the results obtained by MDVP, presented above, an extremely significant improvement was observed for all parameters considered in the case of composition i) of the invention, i.e. comprising the combination coenzyme Q10+vitamin A. In contrast, composition ii) with only coenzyme Q10 achieved a modest improvement, limited to the parameter Shimmer, whereas for the other 2 parameters, the result was unsatisfactory. With respect to composition iii) comprising only vitamin A, the result was substantially comparable to that of the placebo, and therefore completely unsatisfactory. 
     The results presented above clearly show the contribution demonstrated by the composition of the invention, for which unexpectedly significant and quantitative improvements were found. Moreover, it is shown that the combination of coenzyme Q10 and vitamin of the invention proved to be decidedly more effective than the individual components, as well as also more effective than the sum of the contributions of the two individual components, and it is therefore clear that the combination of the invention has a completely surprising synergistic effect. Therefore the composition of the present invention is particularly advantageous in the phonatory area (processes of production of language), in all cases of deterioration of the voice (dysphonia), including the professional and artistic voice and, in general, in states of fatigue of the laryngeal musculature due to a great variety of causes (functional and organic). Moreover, it proves particularly suitable as adjuvant in olfactory apparatus disorders characterized by anosmia and dysosmia.