Patent Publication Number: US-2017368115-A1

Title: Compositions containing curcumin having improved bioavailability

Description:
TECHNICAL FIELD 
     The present invention relates generally to compositions comprising curcumin, whose bioavailability is considerably improved with respect to known compositions. 
     BACKGROUND 
     Curcumin is a natural phenol and has long been used not only in the nutritional field (mainly as a colorant), but also for its health benefits. In fact, curcumin is a highly active antioxidant, an efficient antiseptic and antibacterial, as well as a powerful anti-inflammatory. Other beneficial effects are cited in the literature, in particular for diverse human and animal diseases, especially cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn&#39;s disease inter alia. 
     Unfortunately, it has been found that when used alone, curcumin is very rapidly eliminated by the body. Different studies on humans and especially the rat have shown that orally administrated curcumin exhibits a limited bioavailability, both because of the low intestinal absorption and because of high renal and biliary excretion. Other studies have demonstrated that intravenous administration of curcumin in rats leads to a biliary excretion of curcumin of more than 50% in 5 hours. 
     In pharmacy (but also in nutrition), the term bioavailability is used to describe a pharmacokinetic property of a compound, namely the fraction of a dose which, in its unchanged form, enters the bloodstream. This is an essential concept in pharmacokinetics because the bioavailability must be taken into account when calculating doses for routes of administration other than intravenous routes. 
     Above certain concentrations in the blood, curcumin is also known to produce a laxative effect in many animal species, particularly also in humans. 
     Consequently, any proposed solution should improve the bioavailability but without increasing the levels of curcumin beyond troublesome concentrations. 
     Numerous attempts have in fact been made to address the problem of the reduced bioavailability of curcumin. By way of example, reference is made to the use of piperine (present in black pepper) that is purported to inhibit the elimination paths of curcumin, thereby multiplying its bioavailability by a factor of 20 (Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas P S. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998 May; 64(4): 353-6.). However, even though the bioavailability was improved, the blood level values were not optimal and the piperine produced an irritating effect in the intestine. 
     Other approaches to overcome the low bioavailability include, for example, the use of liposomal curcumin; the preparation of curcumin nanoparticles; the use of curcumin-phospholipid complexes; and the use of structural analogues of curcumin. 
     BRIEF SUMMARY 
     A subject matter of the present invention is therefore to propose compositions comprising curcumin which enable an improved bioavailability of curcumin in comparison to curcumin taken alone, wherein these compositions may serve, if need be, as alternatives to or to complement existing solutions. 
     To solve the abovementioned problem, the present invention proposes, in a first aspect, the pharmaceutical and non-pharmaceutical use of an effective quantity of  spirulina  and/or of  spirulina  extract(s) for improving the bioavailability of administered or orally administered curcumin in animals, in particular domestic animals or pets, such as the horse, the pig, the dog and the cat; or in humans. 
     The invention also proposes the use of an effective quantity of  spirulina  and/or of  spirulina  extract(s) and of curcumin for manufacturing oral pharmaceutical and non-pharmaceutical preparations of curcumin with improved bioavailability. 
     In a further aspect, the invention also relates to oral pharmaceutical and non-pharmaceutical preparations (particularly food supplements) comprising curcumin and an effective quantity of  spirulina  or of  spirulina  extract(s). 
     In fact, surprisingly for a person skilled in the art, the inventors have found that by combining curcumin with  spirulina  the bioavailability of curcumin is significantly increased when it is taken orally. Moreover, it was shown that the invention not only increases this bioavailability but also controls the maximum concentration in the blood and maintains it at a sufficient level for a longer period, i.e. increases the fraction of curcumin that is absorbed at the level of the intestine, and at the same time prolongs the presence of the curcumin at useful concentrations. 
     Although  spirulina  and  spirulina  extracts, due to their high nutritional value, have long been known as a food or food supplement, their beneficial effect on the bioavailability of curcumin taken orally remained unknown up to now. 
     In fact, generally speaking, the term  spirulina  is used to indicate a certain number of different cyanobacteria of the genus  Arthrospira , notably  Arthrospira platensis  (sometimes called  Spirulina platensis ), but also  Arthrospira maxima, Arthrospira pacifica , etc. This term also designates preparations based on these cyanobacteria, here as a food, but most frequently as food supplements, for example when dried and compressed. In the context of the present invention, the term  spirulina  may designate cyanobacteria or preparations containing them according to the context, wherein quantitative indications that refer to  spirulina  relate to the effective dry weight of the cyanobacteria of the genus  Arthrospira . The terms  spirulina  extract or  spirulina  extracts in the context of the invention designate one or more extracts obtained from  spirulina  as defined above, i.e. one or more extracts of cyanobacteria of the genus  Arthrospira , wherein the extract was obtained by a known extraction process, preferably the extract is an ethanol extract. The quantitative indications concerning the  spirulina  extracts refer, unless otherwise explicitly stated, to the dry weight of the extract. 
     The term effective quantity in the present invention means a quantity of  spirulina  and/or  spirulina  extract(s), which afford a major and significant positive effect on the bioavailability of curcumin taken orally. Although the actual value of this effective quantity may vary, particularly as a function of the animal in question or of other possible ingredients of the preparation, it is easy for the person skilled in the art to verify the effective quantity needed to obtain the desired effect in a given situation. This effective quantity is preferably expressed as a weight ratio of  spirulina  or  spirulina  extract to the quantity of curcumin whose bioavailability is improved. This weight ratio  spirulina :curcumin (respectively  spirulina  extract(s):curcumin) is preferably comprised between 20:1 and 1:3, more preferably between 10:2 and 1:2, in particular between 8:3 and 3:4. 
     The quantity of curcumin comprised in the preparations according to the invention is, of course, dependent on a number of factors, including the desired effect, respectively the required indication, the animal considered, its size/weight, the presence of other ingredients or active principles, etc. 
     In practice, the quantities of curcumin to be used frequently range between 0.1 and 20 mg/kg, preferably between 0.5 and 15 mg/kg, more preferably between 1 and 10 mg/kg body weight, most preferably between 3.5 and 7.5 mg/kg. 
     Clearly, depending on the utility of the preparation and the animal to be treated, the preparation will comprise other active ingredients or not and therefore the concentration of curcumin in the preparation may vary widely. 
     The present invention envisages ready for use oral preparations, but also concentrated preparations to be mixed with common foods, as liquid or solid preparations, as powders, in the form of tablets or capsules. It should be noted that the invention explicitly foresees that the  spirulina  or its extracts are not necessarily taken at the same time or in a mixture with the curcumin in order to have the desired effect. It is also possible or conceivable to sequentially administer the  spirulina  and the curcumin (in any order, but preferably beginning with the  spirulina ), while ensuring, however, that the two administrations are preferably made within 1 hour, in particular within half an hour. 
     The disease to be treated or the reasons to administer the curcumin are numerous and the following examples do not limit the scope of the invention in any way, but rather serve to illustrate it. 
     Another aspect of the present invention relates to pharmaceutical and non-pharmaceutical preparations that additionally comprise other pharmaceutically active or health-beneficial ingredients. These ingredients may be selected from anti-inflammatory agents, analgesics, anti-cancer agents, vitamins, essential fatty acids, etc. These ingredients are preferably of natural origin, in particular the extracts of white willow ( Salix alba ), of  boswellia  ( Boswellia serrata ), of  yucca  ( Yucca schidigera ) and of Harpagophytum. 
     The preparations of the present invention can also comprise other ingredients that serve particularly to improve the composition in regard to the formulation, the taste, the consistency, the presentation, especially the colour, etc. These ingredients may be selected from among those generally known in the field according to the type of preparation and the desired outcome. 
     It should be noted that the preparations according to the invention may also comprise other components that could improve the bioavailability of the curcumin, for example piperine. It is also conceivable that the curcumin (or part of it) could be in the form of liposomal curcumin; of nanoparticles of curcumin; of phospholipid-curcumin complexes; and/or of structural analogues of curcumin. 
     Another aspect of the present invention relates to pharmaceutical and non-pharmaceutical preparations that comprise only curcumin and  spirulina  as the active ingredients, possibly with excipients and supports (pharmaceutically or nutritionally acceptable substances). Such preparations preferably consist of a combination of curcumin with  spirulina  and/or one or more  spirulina  extract(s). 
     In other words, the invention also envisages compositions comprising solely curcumin and an effective quantity of  spirulina  (or its extracts). 
     Finally, a further aspect of the invention relates to a manufacturing process for a preparation such as is described in this document, wherein the process comprises a step of mixing an effective quantity of  spirulina  and/or one or more  spirulina  extracts with curcumin, possibly with other active ingredients, excipients or supports, which are acceptable in the field of pharmacy or nutrition. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Other distinguishing features and characteristics of the invention will emerge from the detailed description of several advantageous illustrative embodiments presented below, by referring to the appended figures. They show: 
         FIG. 1 : is a graph representing the bioavailability (or the kinetics) of the curcumin preparation S1 according to the invention, administered orally to a horse; 
         FIG. 2 : is a graph representing the comparative bioavailability (or the kinetics) of a curcumin preparation, administered intravenously to a pig. 
     
    
    
     EXAMPLES 
     Materials and Method 
     A first composition comprising curcumin and  spirulina  was prepared by combining in the following order, with constant stirring and homogenisation, purified water, potassium sorbate, citric acid, sucrose, curcumin 95% (curcuminoid content: 95.7%, determined by HPLC),  spirulina  extract and Xanthan gum. The  spirulina  extract was obtained by dissolving 1 g of standard raw material in 20 ml water under reflux for 60 minutes. The aqueous extract was filtered then made into a dry concentrate in a desiccator under vacuum. The dry residue was then dissolved in 5 ml methanol so as to obtain the  spirulina  extract. This preparation is designated hereinafter as curcumin S1. 
     A first experiment to determine the bioavailability (pharmacokinetic study) of curcumin in the horse was carried out by determining the quantity of curcumin in the blood (plasma concentration). 
     The 3 selected horses were between 7 and 10 years old, each estimated to weigh 500 kg. The curcumin S1 was administered orally (2.6 grams of curcumin S1 for 500 kg of live weight, i.e. 5.6 mg/kg) in a single dose. 
     Plasma samples were taken prior to the administration (time TO) of the curcumin S1 preparation and 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 36 hours and 50 hours after administration of the preparation. 
     The samples were frozen at −18° C. until the analytical determination. 
     The technique used for the determination of the curcumin concentration in the plasma was HPLC (high performance liquid chromatography). 
     Results 
     The results of the mean curcumin concentrations in the plasma as a function of time are presented in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Curcumin concentration in the plasma after oral administration 
               
               
                 of a preparation curcumin S1 in the horse 
               
            
           
           
               
               
               
            
               
                   
                 Time (hours) 
                 Nanograms/millilitre 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 0 
                 0 
               
               
                   
                 3 
                 230 
               
               
                   
                 6 
                 260 
               
               
                   
                 9 
                 280 
               
               
                   
                 12 
                 410 
               
               
                   
                 24 
                 350 
               
               
                   
                 36 
                 150 
               
               
                   
                 50 
                 0 
               
               
                   
                   
               
            
           
         
       
     
     DISCUSSION 
     As can be seen, the curcumin concentrations in the plasma obtained with the preparation curcumin S1 are relatively high in relation to the orally administered single dose (2.6 grams of curcumin S1 for 500 kg of live weight, i.e. 5.6 mg/kg) with a plasma concentration peak at 12 hours and remaining almost constant for 12 hours (T12=410 ng/ml and T24=350 ng/ml). 
     Indeed, the comparison with a study in the pig after intravenous administration of 0.60 grams of curcumin for 23 kg of live weight, wherein the plasma concentration peaks at 24 hours and remains at a constant level during 10 hours (Table 2,  FIG. 2 ), shows that the curcumin S1 level, thanks to the presence of  spirulina  or  spirulina  extracts, exhibits a very good bioavailability after oral administration with reduced effects of excretion and consequently a more rapid plasma concentration peak (12 hours) that remains for at least 12 hours. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Curcumin concentration in the plasma after intravenous 
               
               
                 administration in the pig (for comparison) 
               
            
           
           
               
               
               
            
               
                   
                 Time (hours) 
                 Nanograms/millilitre 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 0 
                 0 
               
               
                   
                 3 
                 537 
               
               
                   
                 6 
                 557 
               
               
                   
                 9 
                 713 
               
               
                   
                 24 
                 724 
               
               
                   
                 48 
                 537 
               
               
                   
                 72 
                 385 
               
               
                   
                   
               
            
           
         
       
     
     CONCLUSIONS 
     The obtained results allow the following conclusions: 
     1) Curcumin S1 (preparation according to the invention) exhibits a very good bioavailability of the curcumin with a plasmatic half-life of at least 24 hours, after a single oral administration. 
     2) The pharmacokinetics of the orally administered curcumin S1 are similar to the kinetics of a curcumin used intravenously (in the pig).