Abstract:
The present invention relates to compositions containing, as their only active ingredients, an extract of  Curcuma  spp, optionally as curcumin in the form of a complex with phospholipids, and an extract selected from  Echinacea  spp extract or lipophilic extract of  Zanthoxylum  spp, which are useful in the topical and systemic treatment of peripheral pain and of superficial and deep inflammatory and painful conditions. The compositions according to the invention are particularly effective in the treatment of osteoarthritis and rheumatoid arthritis in patients unable to tolerate long-term treatment with NSAIDs or steroids.

Description:
SUMMARY OF THE INVENTION 
       [0001]    The present invention relates to compositions containing, as their only active ingredients, an extract of  Curcuma  spp, optionally as curcumin in the form of a complex with phospholipids, and an extract selected from  Echinacea  spp extract or a lipophilic extract of  Zanthoxylum  spp, which are useful in the topical and systemic treatment of peripheral pain and of superficial and deep inflammatory and painful conditions. The compositions according to the invention are particularly effective in the treatment of osteoarthritis and rheumatoid arthritis in patients unable to tolerate long-term treatment with NSAIDs or steroids. 
       STATE OF THE ART 
       [0002]    Osteoarthritis is one of the major causes of physical disability in elderly people. As well as reducing the quality of life of millions of individuals all over the world, it also causes financial loss to both families and the community, because the costs of the care involved are very high. 
         [0003]    Conventional treatments for osteoarthritis involve symptomatic treatment with analgesics and therapeutic treatment with non-steroidal anti-inflammatory drugs, which are known to induce serious side effects that often lead to discontinuance of the treatment. Similar considerations also apply to rheumatoid arthritis. For these reasons, research has also focused on phytotherapy medicaments and natural plant remedies in general. 
         [0004]    Lipophilic extracts and alcoholic extracts of  Echinacea  spp. possess both topical and systemic anti-inflammatory activity attributable to their isobutylamide content, isobutylamides being ligands of the CB1 and CB2 cannabinoid receptors and vanilloid receptor TRPV1. The lipophilic extracts of  Echinacea angustifolia  described in EP 0464298 are particularly effective in this respect, due to their high isobutylamide content. 
         [0005]    The roots and rhizomes of turmeric ( Curcuma ) have been used as spices in India since time immemorial, and are also used in many industrialised countries today. Its active constituent is curcumin, the yellow compound that constitutes the main ingredient of curry and other traditional Indian dishes. The uses described in traditional medicine include the treatment of indigestion, flatulence and diarrhoea, and especially of inflammatory conditions and joint pain after long-term treatment. Many of these traditional uses have been confirmed by in vitro biochemical tests or pharmacology. 
         [0006]    Curcumin is now one of the molecules most frequently investigated from the biochemical standpoint, and in recent years, as well as numerous publications of doubtful scientific value, controlled double-blind clinical trials have also been conducted according to the protocols of modern clinical pharmacology. Preliminary clinical trials have demonstrated the low bioavailability of the molecule, which is unstable at intestinal pH (half-life at pH 7&lt;10 min), and its low oral absorption, which limit many of the applications indicated by the in vitro tests. Plasma concentrations of 50 ng are reported after administration of 12 g of compound, the secondary metabolites, glucuronides and sulphates also being measured. 
         [0007]    Like many polyphenols, curcumin is poorly soluble in water and fats. The Applicant has therefore devised a patent WO2007101551 that describes its complexing with phospholipids to improve its bioavailability. Curcumin in phospholipid-complexed form provides improved systemic and topical absorption, which allows it to be administered to humans. 
         [0008]    Clinical trials conducted on patients with osteoarthritis have demonstrated that long-term treatment with phospholipid-complexed curcumin (Belcaro et al, Alternative Medicine Review, 4, 338, 2010) gives favourable but still insufficient results due to the low level of pain reduction, which obliges patients to take NSAIDs. 
         [0009]    However, significant improvements were only obtained after 8 months&#39; treatment, and many patients had to use NSAIDs or other analgesics to alleviate the pain. 
     
    
     DESCRIPTION OF THE INVENTION 
       [0010]    It has now surprisingly been found that compositions containing as the only active ingredients  Curcuma  spp extract and an extract selected from  Echinacea  spp extract or lipophilic extract of  Zanthoxylum  spp possess potent analgesic and anti-inflammatory activity, which is greater than that found when the extracts are used separately. 
         [0011]    Particularly favourable results have been observed with compositions containing phospholipid-complexed curcumin and lipophilic extracts of  Echinacea angustifolia.    
         [0012]    Good results have also been obtained by replacing the  Echinacea  extracts with extracts of other plants having a high isobutylamide content, especially lipophilic extract of  Zanthoxylum  spp. 
         [0013]    The object of the invention is therefore compositions substantially consisting of an extract of  Curcuma  spp or curcumin, and an extract selected from  Echinacea angustifolia  extract or lipophilic extract of  Zanthoxylum bungeanum , mixed with acceptable excipients. 
         [0014]    The invention relates in particular to compositions substantially consisting of an extract of  Curcuma  spp or curcumin, and an extract selected from  Echinacea angustifolia  extract or lipophilic extract of  Zanthoxylum bungeanum , mixed with acceptable excipients. 
         [0015]    The compositions according to the invention may be administered orally or topically. 
         [0016]    According to a preferred aspect, the compositions for oral administration will contain phospholipid-complexed curcumin in amounts ranging from 100 to 1000 mg, and  Echinacea  extract in amounts ranging from 1 to 200 mg, or alternatively lipophilic extract of  Zanthoxylum  spp. in amounts ranging from 5 to 25 mg per oral dose unit. According to a particularly preferred aspect, the compositions for oral administration will contain 500 mg of phospholipid-complexed curcumin and 5 mg of  Echinacea  extract, or alternatively 10 mg of lipophilic extract of  Zanthoxylum  spp., per oral dose unit. 
         [0017]    According to a preferred aspect, the compositions for topical administration will contain phospholipid-complexed curcumin in amounts ranging from 0.1 to 0.5% by weight, and  Echinacea  extract in amounts ranging from 0.05 to 0.5% by weight, or alternatively lipophilic extract of  Zanthoxylum  spp in amounts ranging from 0.1 to 1% by weight. According to a particularly preferred aspect, the compositions for topical administration will contain 0.2% by weight of phospholipid-complexed curcumin, and 0.2% by weight of  Echinacea  extract, or alternatively 0.5% by weight of lipophilic extract of  Zanthoxylum  spp. 
         [0018]    The compositions according to the invention can be used to treat peripheral pain of all kinds, ranging from diabetic neuropathy to joint and muscle pain of various origins. It is particularly important that the compositions according to the invention do not cause side effects in the gastrointestinal tract, to allow its use by patients with gastric problems who are unable to tolerate NSAIDs. 
         [0019]    Lipophilic extracts of  Echinacea  spp can be obtained by extraction from the roots or rhizomes with alcohols, ketones or aliphatic ethers, or preferably with carbon dioxide under supercritical conditions in accordance with EP464298. 
         [0020]    Alcoholic extracts of  Echinacea  spp still containing a pharmacologically active amount of isobutylamides have proved effective provided that at least a minimal dose of 1 mg of isobutylamine complex is administered to the patient. The active clinical doses range from 0.5 mg to 10 mg, preferably 5 mg for a mean body weight of 70 Kg. 
         [0021]    The lipophilic extract of  Zanthoxylum  spp can be prepared in accordance with WO 00/02570. 
         [0022]    However, the compositions according to the invention provide almost immediate relief of patients&#39; symptoms, with no need to use other medicaments. Patients with gastro-oesophageal reflux and at the pre-ulcerative stage are also able to take the compositions according to the invention. 
         [0023]    Pharmacological Tests 
         [0024]    1. Tail-Flick Test in the Rat 
         [0025]    The analgesic activity of the compositions according to the invention (combination of phospholipid-complexed curcumin and  Echinacea  extract) was compared with that of the individual ingredients administered separately to rats. The results demonstrated a clear synergy between the two ingredients of the compositions according to the invention, as shown in Table 1 below. 
         [0026]    The analgesic activity was evaluated with the tail-flick test in the rat. Before treatment, 3 basic measurements were conducted on the animals to ensure that they were suitable for the handling and apparatus involved. The parameters used were 15V of radiant heat and a 15-second cut-off (to prevent irreversible harm to the animals), with evaluation of the tail-flick. The animals were treated with 0.1 ml of ointment of the composition described in example 4, 5 cm from the base of the tail. The analgesic effect was measured 15 and 30 min. after administration. 
         [0027]    The two individual ingredients of the composition were evaluated with the same experimental model, in two separate formulations which contained the same amount of one of the active ingredients as the composition described in example 4. The control animals were treated with 0.1 ml of the oil used to dissolve the two ingredients (carrier). 
         [0000]    
       
         
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                   
                 Latency time 
               
             
          
           
               
                   
                   
                   
                   
                 % 
               
               
                 Treatment 
                 after 15 min 
                 % increase 
                 after 30 min 
                 increase 
               
               
                   
               
               
                 Carrier 
                 4.5 ± 0.33 
                 — 
                 4.6 ± 0.45 
                 — 
               
               
                 Composition described 
                 12.6 ± 0.61  
                 180 
                 8.5 ± 0.43 
                 84.8 
               
               
                 in example 4 
                   
                   
                   
                   
               
               
                 
                   Echinacea angustifolia 
                 
                 6.1 ± 0.44 
                 35.5 
                 4.8 ± 0.63 
                 4.4 
               
               
                 lipophilic extract 
                   
                   
                   
                   
               
               
                 Phospholipid- 
                 4.2 ± 0.63 
                 — 
                 4.6 ± 0.48 
                 — 
               
               
                 complexed curcumin 
               
               
                   
               
             
          
         
       
     
         [0028]    2. Analgesic Activity in Humans 
         [0029]    40 patients suffering from bone disease of the knee with constant pain were randomised and treated with two tablets a day according to Example 1, one in the morning and one in the evening, or with a placebo (consisting of the carrier only), or with the individual ingredients added to the placebo formulation at the same concentrations as in the formulation described in example 1. 
         [0030]    Efficacy was scored on an international analogue pain scale with scores from 0 to 10, 10 points indicating maximum pain and 0 the disappearance of pain. The effect was evaluated on the second day after administration of the tablet, in the mornings 60 and 120 minutes after treatment. 
         [0031]    The results are set out in Table 2 below. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                   
                 Pain scores at time 
               
             
          
           
               
                   
                 Treatment 
                 0 
                 60 min 
                 120 min 
               
               
                   
               
               
                   
                 Placebo 
                 8.3 ± 1.7 
                 9.1 ± 2.2 
                 8.2 ± 1.9 
               
               
                   
                 Composition described 
                 9.4 ± 2.6 
                 4.3 ± 0.9 
                 2.5 ± 1.4 
               
               
                   
                 in example 1 
                   
                   
                   
               
               
                   
                 
                   Echinacea angustifolia 
                 
                 8.7 ± 1.4 
                 7.4 ± 1.2 
                 7.1 ± 2.6 
               
               
                   
                 lipophilic extract 
                   
                   
                   
               
               
                   
                 Phospholipid- 
                 8.2 ± 1.6 
                 7.9 ± 0.6 
                 8.6 ± 1.8 
               
               
                   
                 complexed curcumin 
               
               
                   
               
             
          
         
       
     
         [0032]    3. Effect on Osteoarthritis 
         [0033]    Table 3 shows the results obtained, after treatment for up to three months with the composition according to the invention, on the global effect of osteoarthritis on the patients recruited, following the Karnofsky Scale for both selection and evaluation of efficacy (J.Clin.Oncology 1984; 2:187-193). 
         [0034]    The evaluation was conducted by measuring the distance traveled without pain, and with different degrees of pain, on a treadmill set to 3 Km/h and an inclination of 10%. 80 patients suffering from osteoarthritis of the knee were divided into two groups. After randomisation, one group was treated with the placebo and the other with the composition described in example 1. Pain was evaluated weekly during the treatment with the WOMAC index, and the humoral parameters, which constitute indexes of inflammatory parameters, were evaluated every month. (Table 4). 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Results of distance travelled on treadmill 
               
             
          
           
               
                   
                 Distance travelled at time 
               
             
          
           
               
                 Treatment 
                 0 
                 1 month 
                 3 months 
               
               
                   
               
               
                 Placebo 
                 84.6 metres 
                  90.1 metres 
                 xx 
               
               
                 Composition described 
                 78.4 metres 
                 186.4 metres 
                 370 metres 
               
               
                 in example 1 
               
               
                   
               
             
          
         
       
     
         [0035]    xx patients who left the trial for ethical reasons or were treated with other medicaments 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Evaluation of some inflammation markers 
               
             
          
           
               
                   
                 Placebo Composition 
               
               
                   
                 of example 1 
               
             
          
           
               
                 Inflammation indexes 
                 T. 0 
                 3 months 
                 3 months 
                 reduction 
               
               
                   
               
             
          
           
               
                 IL-1β (pg/ml) 
                 0.91 
                 0.89 
                 0.36* 
                 60.4% 
               
               
                 IL-6 (pg/ml) 
                 1.37 
                 1.36 
                 1.02* 
                   26% 
               
               
                 sCD4OL 
                 2.47 
                 2.46 
                 1.39* 
                 43.9% 
               
               
                 ESR (mm/h) 
                 35.64 
                 37.59 
                 26.3* 
                 26.2% 
               
               
                   
               
             
          
         
       
     
         [0036]    Pharmaceutical compositions in the form of gels, creams and ointments have proved particularly useful in the topical treatment of peripheral pain and of superficial and deep inflammatory and painful conditions. The combination can be applied directly to the skin in the oil in which it is solubilised, or incorporated in creams or ointments suitable for administration. The treatment can be performed one to three times a day, applying a dose of 0.5-5 g of the topical formulation to the part of the body affected by the painful disorder. 
         [0037]    According to a further aspect, the compositions according to the invention may be administered together with other substances having a useful or complementary activity. 
         [0038]    The compositions according to the invention will be formulated according to conventional techniques, such as those described in “Remington&#39;s Pharmaceutical Handbook”, Mack Publishing Co., N.Y., USA. 
         [0039]    The examples below further illustrate the invention. 
       Example 1 
     Tablets Containing Phospholipid-Complexed Curcumin and Lipophilic Extract of  Echinacea   
       [0040]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 Phospholipid-complexed curcumin 
                 600.00 
                 mg 
               
               
                   
                   Echinacea ang.  extracted with CO2 
                 5.00 
                 mg 
               
               
                   
                 standardised to 25% isobutylamides 
                   
                   
               
               
                   
                 Mannitol 
                 345.25 
                 mg 
               
               
                   
                 Sodium bicarbonate 
                 120.00 
                 mg 
               
               
                   
                 Magnesium carbonate 
                 66.75 
                 mg 
               
               
                   
                 Croscarmellose sodium 
                 39.00 
                 mg 
               
               
                   
                 Silicon dioxide 
                 39.00 
                 mg 
               
               
                   
                 Talc 
                 20.00 
                 mg 
               
               
                   
                 Hydroxypropylcellulose 
                 10.00 
                 mg 
               
               
                   
                 Magnesium stearate 
                 5.00 
                 mg 
               
               
                   
                 Opadry White 
                 35.00 
                 mg 
               
               
                   
                 Opadry Yellow 
                 15.00 
                 mg 
               
               
                   
               
             
          
         
       
     
       Example 2 
     Soft Gelatin Capules 
       [0041]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Phospholipid-complexed curcumin 
                 300.00  
                 mg 
               
               
                   
                   Echinacea   ang . extracted with CO2 
                 5.00  
                 mg 
               
               
                   
                 standardised to 25% isobutylamides 
                   
                   
               
               
                   
                 Linseed oil 
                 to 700  
                 mg 
               
               
                   
                   
               
             
          
         
       
     
       Example 3 
     Tablets Containing Phospholipid-Complexed Curcumin and Alcoholic Extract of  Echinacea   
       [0042]      
         [0000]    
       
         
               
               
               
             
           
               
                   
               
             
             
               
                   
                 Phospholipid-complexed curcumin 
                 400.00 mg  
               
               
                   
                   Echinacea ang.  alcoholic extract 
                 100.00 mg  
               
               
                   
                 standardised to 1% isobutylamides 
                   
               
               
                   
                 Mannitol 
                 345.25 mg  
               
               
                   
                 Sodium bicarbonate 
                 120.00 mg  
               
               
                   
                 Magnesium carbonate 
                 66.75 mg 
               
               
                   
                 Croscarmellose sodium 
                 39.00 mg 
               
               
                   
                 Silicon dioxide 
                 39.00 mg 
               
               
                   
                 Talc 
                 20.00 mg 
               
               
                   
                 Hydroxypropylcellulose 
                 10.00 mg 
               
               
                   
                 Magnesium stearate 
                  5.00 mg 
               
               
                   
                 Opadry White 
                 35.00 mg 
               
               
                   
               
             
          
         
       
     
       Example 4 
     Ointment Containing Phospholipid-Complexed Curcumin and Lipophilic Extract of  Echinacea angusafolia   
       [0043]      
         [0000]    
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 Phospholipid-complexed curcumin 
                 200.00 
                 mg 
               
               
                   
                   Echinacea ang.  extracted with CO2 
                 200.00 
                 mg 
               
               
                   
                 standardised to 25% isobutylamides 
                   
                   
               
               
                   
                 Linseed oil 
                 4 
                 g 
               
               
                   
                 Stearic acid 
                 12 
                 g 
               
               
                   
                 Glycerin 
                 10 
                 g 
               
               
                   
                 Cetostearyl alcohol 
                 2 
                 g 
               
               
                   
                 Potassium hydroxide 
                 0.9 
                 g 
               
               
                   
                 Paraben 
                 0.2 
                 g 
               
               
                   
                 Demineralised water 
                 q.s. for 100 
                 g