Patent Publication Number: US-2006020046-A1

Title: Compositions comprising lycopene for the treatment and prevention of angiogenesis associated pathologies

Description:
The present invention relates to the use of lycopene in the prevention and coadjuvant treatment of angiogenesis-associated pathologies. More specifically, the present invention relates to the use of lycopene in the primary prevention (i.e., the prophylactic supplementation of healthy subjects) of the onset of angiogenesis-associated pathologies, in the coadjuvant treatment (i.e. the supplementation accompanying a running therapy of angiogenesis-associated-pathologies) and in the secondary prevention (i.e., the supplementation after a successful therapy for the prevention of relapse) of angiogenesis-associated pathologies.  
      Angiogenesis, the process of new capillary formation from the preexisting vasculature, is required for successful tumor growth and metastasis. Furthermore, increased neovascularisation is part of the pathology of several non-cancerous diseases, e.g. in chronic inflammations and several eye diseases.  
      When a primary tumor first arises, proliferation of cancer cells may be balanced by apoptosis, and the tumor may remain undetectable for years until neovascularization appears. Though the relative sudden onset of neovascularization in primary tumors, described as angiogenic switch from avascular to vascular phenotypes, is a discrete event distinct from tumor initiation, unrestricted growth of solid tumors is limited by angiogenesis, as in the absence of access to an adequate vasculature, tumor cells become necrotic and/or apoptotic. For several carcinomas, an elevated serum VEGF level, the major inducer of angiogenesis, is reported, e.g. for epithelial ovarian neoplasms, esophageal squamous cell carcinoma, head and neck carcinoma, lung carcinoma, non-Hodgkin lymphoma, ovarian carcinoma, prostate carcinoma, renal cell carcinoma, and urothelial carcinoma. Furthermore, angiogenesis and the vascular density of tumors have been shown to be associated with tumor metastasis. Several studies reveal that the higher the microvessel count is in areas of highest vessel density, the lower is the rate of overall survival of the tumor patients, see Weidner N, Semple J P, Welch W R, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med (1991) 324:1-8.  
      Beside cancer, other diseases are also associated with increased neovascularization. In the first acute phase of inflammation, functional changes in the vasculature, such as dilatation, increase in permeability and endothelial activation occur. In the second subacute phase, capillaries and venules remodel with extensive endothelial mitotic activity. Upon chronic stimulation, both increases in capillary density and vascular dilatation can be observed, although these responses can differ significantly between strains of mice and possibly between species. In many chronic inflammatory diseases, e.g. in rheumatoid arthritis or in psoriasis, neovascularization can be identified in the inflamed lesions. These observed pathology accompanying neovascularizations are in line with reports of elevated serum VEGF levels, the major inducer of angiogenesis, in several inflammatory diseases, e.g. inflammatory bowel disease comprising ulcerative colitis and Crohn&#39;s disease, inflammatory arthritis (rheumatoid arthritis, self-limiting arthritis and psoriatic arthritis) and osteoarthritis.  
      Diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity belong to a group of ischemic retinal disorders which are associated with intraocular neovascularization. In neovascular retinopathies, such as proliferative diabetic retinopathy, there is initially extensive active proliferation of new vessels. It has been shown that increased angiogenesis is a central element in these eye pathologies.  
      Furthermore, neovascularization is a principal cause of visual loss also in the wet form of age-related macular degeneration (AMD), the overall leading cause of blindness.  
      According to the present invention, it has been found that angiogenesis can be suppressed or inhibited by the administration of lycopene.  
      The present invention, therefore, is concerned with the use of lycopene in the manufacture of a composition for the primary and secondary prevention of angiogenesis-associated pathologies and coadjuvant treatment thereof. Furthermore, the present invention is concerned with a method of preventing or treating angiogenesis-associated pathologies which comprises administering to a subject in need of such treatment for therapy or prophylaxis an effective amount of lycopene. The present invention is also concerned with certain novel solid galenical formulations comprising lycopene.  
      In a further and preferred embodiment of the invention, lycopene is used together with vitamin E and/or vitamin C. Most preferred is a combination of lycopene, vitamin E and vitamin C. The term vitamin E as used herein includes racemic vitamin E (D,L-α-tocopherol) or natural vitamin E, as well as derivatives thereof which have biological vitamin E activity, e.g. carboxylic acid esters, such as vitamin E acetate, propionate, butyrate or succinate. The term vitamin C as used herein includes derivatives thereof which have biological vitamin C activity, e.g. esters and salts, such as sodium ascorbate, sodium ascorbyl phosphate, and ascorbyl palmitate. In a further embodiment of the invention, one or more of the following components can be used together with these active ingredients: 
          (a) Astaxanthin ((3S,3′S)-3,3′-dihydroxy-β,β-carotene-4,4′-dione) and/or one or more isomers and/or monoesters and/or diesters, preferably esters of saturated alkanoic acids, such as acetic, propionic, palmitic, stearic, and succinic acid, mono-unsaturated fatty acids, such as oleic acid, and poly-unsaturated fatty acids, such as linolic, linoleic, docosahexaenoic, and arachidonic acid;     (b) β-Carotene and/or one or more isomers thereof;     (c) β-Cryptoxanthin ((3R)-β,β-carotene-3-ol) and/or one or more isomers or esters thereof, preferably esters of saturated alkanoic acids, such as acetic, propionic, palmitic, stearic, and succinic acid, mono-unsaturated fatty acids, such as oleic acid, and poly-unsaturated fatty acids, such as linolic, linoleic, docosahexaenoic, and arachidonic acid;     (d) (−)-Epigallocatechin gallate (EGCG) and/or (−)-epicatechin gallate (ECG) and/or one or more derivatives thereof;     (e) Genistein aglycone (4′,5,7-trihydroxyisoflavone) and/or one or more derivatives thereof (genistein glucosides, genistein sulfates, genistein glucuronides);     (f) Lutein ((3R, 3′R, 6′R)-β, ε, carotene-3,3′-diol) and/or one or more isomers and/or monoesters and/or diesters, preferably esters of saturated alkanoic acids, such as acetic, propionic, palmitic, stearic, and succinic acid, mono-unsaturated fatty acids, such as oleic acid, and poly-unsaturated fatty acids, such as linolic, linoleic, docosahexaenoic, and arachidonic acid, thereof;     (g) Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyrano-4-one) and/or dihydroquercetin and/or one or more derivatives thereof (quercetine glucosides, quercetin glucuronides, quercetine sulphates, methylquercetins (isohamnetin (3′-O-methylquercetin), tamarixetin(4′-O-methylquercetin));     (h) Myricetin and/or one or more derivatives thereof;     (i) Resveratrol (cis-3,4′,5-trihydroxystilbene and/or trans-3,4′,5-trihydroxystilbene) and/or one or more derivatives thereof (resveratrol glucosides, resveratrol sulfates, resveratrol glucuronides);     (j) Rhizoxin and/or one or more derivatives thereof (palmitoyl rhizoxin);     (k) Silymarin (extract from  Silybum marianum ) and/or one or more derivatives thereof (silymarin dihemisuccinate sodium salt) and/or one or more of its four main components (silybin [synonymous with silibinin, and sometimes incorrectly called silybinin] and/or isosilybin and/or silydianin and/or silychristin) and/or one or more derivatives thereof (silybin-dihemisuccinate, disilybin, silybin-phosphatidylcholine complex, silybin-phosphate);     (l) Vitamin A and/or one or more derivatives thereof (all-trans retinol or all-trans retinyl acetate or all-trans retinyl palmitate);     (m) Vitamin D2 or vitamin D3 or 1α,25-dihydroxyvitamin D3 or 25-hydroxyvitamin D3 or 1α,24R, 25-trihydroxyvitamin D3;     (n) Zeaxanthin ((3R,3′R)-β,β-carotene-3,3′-diol) and/or one or more isomers and stereo-isomers (preferably mesozeaxanthin, 3R,3′S-zeaxanthin) and/or monoesters and/or diesters, preferably esters of saturated alkanoic acids, such as acetic, propionic, palmitic, stearic, and succinic acid, mono-unsaturated fatty acids, such as oleic acid, and poly-unsaturated fatty acids, such as linolic, linoleic, docosahexaenoic, and arachidonic acid, thereof;     (o) Apigenin and/or one or more derivatives thereof;     (p) Carnosic acid and/or one or more derivatives thereof;     (q) Carnosol and/or one or more derivatives thereof;     (r) Depudecin and/or one or more derivatives thereof;     (s) Eponemycin and/or one or more derivatives thereof;     (t) Dihydroeponemycin and/or one or more derivatives thereof;     (u) Epoxomicin and/or one or more derivatives thereof;     (v) Ergosterol and/or one or more derivatives thereof;     (w) Fisetin and/or one or more derivatives thereof;     (x) Fumagillin and/or one or more derivatives thereof;     (y) Lactacystin and/or one or more derivatives thereof;     (z) Luteolin and/or one or more derivatives thereof;     (aa) Motuporamine C and/or one or more derivatives thereof;     (bb) Ovalicin and/or one or more derivatives thereof;     (cc) Radicicol and/or one or more derivatives thereof;     (dd) Curcumin and/or one or more derivatives (demethoxy-curcumin, bis-demethoxycurcumin, sodium curcumionate, bis-demethylcurcumin, tetrahydrocurcumin, diacteylcurcumin, triethylcurcumin) thereof;     (ee) Squalamine and/or one or more derivatives thereof;     (ff) Isoliquiritin, isoliquiritigenin, liquiritigenin and/or one or more derivatives thereof;     (gg) Very-long-chain omega-3 fatty acides (eicosapentaenoic acid [C20: 5, omega-3], decosahexaenoic acid [C22: 6, omega-3], polyunsaturated ω-3 fatty acids);     (hh) Shark cartilage extract.     (ii) Glucosinolate derivatives (Methylsulfinylalkyl glucosinolates [1-methylsulfinylmethyl glucosinolate, 2-methylsulfinylethyl glucosinolate, 3-methylsulfinylpropyl glucosinolate (glucoiberin), 4-methylsulfinylbutyl glucosinolate (glucoraphanin), 5-methylsulfinylpentyl glucosinolate (glucoalysin), 6-methylsulfinylhexyl glucosinolate, 7-methylsulfinylheptyl glucosinolate, 8-methylsulfinyloctyl glucosinolate, 9-methylsulfinylnonyl glucosinolate, 10-methylsulfinyldodecyl glucosinolate] or allyl glucosinolate (sinigrin) or phenylethyl glucosinolate (gluconasturtiin) or 3-butenyl glucosinolate (gluconapin) or indol-3-ylmethyl glucosinolate (glucobrassicin) or derivatives thereof [N-methoxyindol-3-ylmethyl glucosinolate (neoglucobrassicin), 4-hydroxyindol-3-ylmethyl glucosinolate (4-OH glucobrassicin), 4-methoxyindol-3-ylmethyl glucosinolate (4-CH 3 O glucobrassicin)]).     (jj) Isothiocyanate derivatives (Methylsulfinylalkyl isothiocyanate [1-methylsulfinylmethyl isothiocyanate, 2-methylsulfinylethyl isothiocyanate, 3-methylsulfinylpropyl isothiocyanate, 4-methylsulfinylbutyl isothiocyanate (sulforaphane), 5-methylsulfinylpentyl isothiocyanate, 6-methylsulfinylhexyl isothiocyanate (6-HITC), 7-methylsulfinylheptyl isothiocyanate, 8-methylsulfinyloctyl isothiocyanate, 9-methylsulfinylnonyl isothiocyanate, 10-methylsulfinyldodecyl isothiocyanate] or allyl isothiocyanate or phenylethyl isothiocyanate (PEITC) or 3-butenyl isothiocyanate or indol-3-ylmethylisothiocyanate or derivatives thereof (N-methoxy indol-3-ylmethylisothiocyanate, 4-hydroxy indol-3-ylmethylisothiocyanate, 4-methoxy indol-3-ylmethylisothiocyanate) or 3-indolmethanol (indol-3-carbinol, I3C).        

      Examples of angiogenesis associated pathologies comprise Hodgkin lymphoma, non-Hodgkin lymphoma, lymphosarcoma, lymphoblastoid leukemia, acute lymphatic leukemia, acute myeloic leukemia, chronic myeloic leukemia, chronic lymphatic leukemia, hemangioma, hemangioendothelioma, hemangiopericytoma, hemangiosarcoma, Kaposi sarcoma, osteosarcoma, fibrosarcoma, oesophageal squamous cell carcinoma, pancreatic carcinoma, gastrointestinal tumors, colon carcinoma, rectum carcinoma, stomach carcinoma, lymphangiosarcoma, brain tumors, neuroblastoma, schwannoma, pheochromocytoma, lung carcinoma, head and neck squamous cell carcinoma, melanoma, non-melanoma skin carcinoma, leiomyomas, leiomyosarcomas, mammary carcinoma, ovarian cancer, endometrial carcinoma, bladder carcinoma, cervix carcinoma, renal carcinoma, prostate carcinoma, metastasis formation, asthma, rheumatoid arthritis, synovitis, degenerative or inflammatory bone and cartilage destruction, non-rheumatoid arthritis, tendosynovitis, inflammatory pseudotumor, diabetic retinopathy, retinal vein occlusion, age-related macular degeneration, retinopathy of prematurity, choroidal and other intraocular diseases, keratoconjunctivitis, gingivitis, periodontal disease, epulis, gastritis, hepatitis, liver regeneration, chronic pancreatitis, tonsillitis, obesity, leukomalacia, rhinitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, interstitial pulmonary fibrosis, neurodermitis, psoriasis, thyroiditis, thyroid enlargement, endometriosis, and glomerulonephritis. Of primary interest for treatment in accordance with the present invention are prostate carcinoma, mammary carcinoma, bladder carcinoma, lung carcinoma, pancreatic carcinoma, melanoma, non-Hodgkin lymphoma, colon/rectum carcinomas, endometrial carcinoma, age-related macular degeneration, prostatitis, diabetic retinopathy, psoriasis, rheumatoid arthritis, non-rheumatoid arthritis and gastritis.  
      For the primary and secondary prevention and coadjuvant treatment of angiogenesis-associated pathologies in accordance with the present invention lycopene is administered to the subject in need of such treatment, i.e. humans, pets or farm animals in an amount of from about 0.0005 mg/kg body weight to about 5 mg/kg body weight per day. When vitamin E or derivatives thereof is co-administered the daily dosage is from about 0.1 mg/kg body weight to about 15 mg/kg body weight, based on tocopherol. When vitamin C or derivative thereof is co-administered the daily dosage is from about 0.2 mg/kg body weight to about 30 mg/kg body weight, based on ascorbic acid. Other components may be co-administered within dosage ranges set forth below:  
                                                      Astaxanthin   0.001   mg/kg   to   5   mg/kg       β-Carotene   0.001   mg/kg   to   5   mg/kg       β-Cryptoxanthin   0.001   mg/kg   to   5   mg/kg       (−)-epigallocatechin gallate   0.5   mg/kg   to   15   mg/kg       (EGCG) or (−)-epicatechin gallate       (ECG) or equimolar amounts of       derivatives       Genistein aglycone   0.015   mg/kg   to   6   mg/kg       Lutein   0.001   mg/kg   to   5   mg/kg       Quercetin   0.001   mg/kg   to   300   mg/kg       Myricetin   0.001   mg/kg   to   300   mg/kg       Resveratrol   0.01   mg/kg   to   1.5   mg/kg       or equimolar amounts of       derivatives       Rhizoxin   0.001   mg/kg   to   20   mg/kg       Palmitoyl Rhizoxin   0.001   mg/kg   to   20   mg/kg       Silymarin   0.01   mg/kg   to   100   mg/kg       Silybin   0.01   mg/kg   to   100   mg/kg       or equimolar amounts of       derivatives       Isosilybin   0.01   mg/kg   to   100   mg/kg       or equimolar amounts of       derivatives       Silydianin   0.01   mg/kg   to   100   mg/kg       or equimolar amounts of       derivatives       Silychristin   0.01   mg/kg   to   100   mg/kg       or equimolar amounts of       derivatives       All-trans Retinol   3   μg/kg   to   100   μg/kg       All-trans Retinyl acetate   3.5   μg/kg   to   115   μg/kg       All-trans Retinol palmitate   5.5   μg/kg   to   180   μg/kg       Vitamin D2 (Ergocalciferol)   0.1   ng/kg   to   10   μg/kg       Vitamin D3 (Cholecalciferol)   0.1   ng/kg   to   10   μg/kg       1α, 25-Dihydroxyvitamin D3   0.1   ng/kg   to   0.5   μg/kg       25-Hydroxyvitamin D3   0.1   ng/kg   to   10   μg/kg       1α, 24R, 25-Trihydroxyvitamin D3   0.1   ng/kg   to   0.5   μg/kg       Zeaxanthin   0.001   mg/kg   to   5   mg/kg       Apigenin   0.01   mg/kg   to   500   mg/kg       Carnosic acid   0.01   mg/kg   to   250   mg/kg       Carnosol   0.01   mg/kg   to   250   mg/kg       Depudecin   0.01   mg/kg   to   500   mg/kg       Eponemycin   0.01   mg/kg   to   500   mg/kg       Dihydroeponemycin   0.01   mg/kg   to   500   mg/kg       Epoxomicin   0.01   mg/kg   to   500   mg/kg       Ergosterol   0.1   mg/kg   to   2000   mg/kg       Fisetin   0.01   mg/kg   to   500   mg/kg       Fumagillin   0.1   mg/kg   to   300   mg/kg       Lactacystin   0.01   mg/kg   to   250   mg/kg       Luteolin   0.01   mg/kg   to   100   mg/kg       Motuporamine C   0.1   mg/kg   to   500   mg/kg       Ovalicin   0.1   mg/kg   to   250   mg/kg       Radicicol   0.1   mg/kg   to   1000   mg/kg       Curcumin   0.1   mg/kg   to   200   mg/kg       or equimolar amounts of       derivatives       Squalamine   0.001       to   200   mg/kg       Isoliquiritin   1   ng/kg   to   1   mg/kg       Isoliquiritigenin   1   ng/kg   to   1   mg/kg       Very-long-chain omega-3 fatty   0.001   g/kg   to   0.05   g/kg       acides       Shark cartilage extract   0.001   g/kg   to   0.1   g/kg       Glucosinolate derivatives   0.01   mg/kg   to   200   mg/kg       e.g. 4-methylsulfinylbutyl gluco-       sinolate (glucoraphanin)       Isothiocyanate derivatives or I3C   0.001   mg/kg   to   200   mg/kg       e.g. 4-methylsulfinylbutyl       isothiocyanate (sulforaphane)                  
 
      Lycopene, optionally together with the vitamins E and C as well as compounds (a) to (jj) can find use in accordance with the present invention for the completion of human nutrition, nutrition of pets and farm animals.  
      Said compounds may be provided as the active ingredient in compositions, preferably for enteral application, which may be solid or liquid galenical formulations, dietary compositions or animal feed compositions. Examples of solid galenical formulations are tablets, capsules (e.g. hard or soft shell gelatin capsules), pills, sachets, powders, granules and the like which contain the active ingredient together with conventional galenical carriers. Any conventional carrier material can be utilized. The carrier material can be organic or inorganic inert carrier material suitable for oral administration. Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, and the like. Additionally, additives such as flavouring agents, preservatives, stabilizers, emulsifying agents, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding. They may also be used in dietary compositions which may be a food, a food premix or a fortified food or a beverage. While the individual active ingredients are suitably administered in a single composition they may also be administered in individual dosage units.  
      Preferably lycopene is used in accordance with the present invention together with vitamin E or vitamin E and vitamin C. Preferred additional components are the active ingredients (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), and/or (n); more preferably the active ingredients (b), (d), (e), (f), (g), (h), (i), (j), (k), and/or (n).  
      Particularly preferred is the administration of the following active ingredients:  
      Lycopene, in a concentration so that the daily consumption by a human adult is in the range of from 0.25 mg/day to 50 mg/day, preferably from 1 mg/day to 30 mg/day; and/or  
      Vitamin E or its derivative, in a concentration so that the daily consumption by a human adult is in the range of from 15 mg/day to 600 mg/day; and/or  
      Vitamin C or its derivative, in a concentration so that the daily consumption by a human adult is in the range of from 50 mg/day to 1000 mg/day; and/or  
      β-Carotene, in a concentration so that the daily consumption by a human adult is in the range of from 0.1 mg/day to 20 mg/day, preferably from 2 mg/day to 10 mg/day; and/or  
      (−)-Epigallocatechin gallate (EGCG), in a concentration so that the daily consumption by a human adult is in the range of from 50 mg/day to 500 mg/day; and/or  
      Genistein, in a concentration so that the daily consumption by a human adult is in the range of from 20 mg/day to 200 mg/day; and/or  
      Lutein, in a concentration so that the daily consumption by a human adult is in the range of from 0.1 mg/day to 50 mg/day, preferably from 0.25 mg/day to 30 mg/day; and/or  
      Quercetin, in a concentration so that the daily consumption by a human adult is in the range of from 1 mg/day to 500 mg/day; and/or  
      Myricetin, in a concentration so that the daily consumption by a human adult is in the range of from 1 mg/day to 500 mg/day; and/or  
      Resveratrol, in a concentration so that the daily consumption by a human adult is in the range of from 5 mg/day to 50 mg/day; and/or  
      Silymarin (extract from  Silybum marianum ) or its four main components (silybin and/or isosilybin and/or silydianin and/or silychristin), in a concentration so that the daily consumption by a human adult of Silymarin or its four main components (silybin, isosilybin, silydianin, silychristin), respectively, is in the range of from 1 mg/day to 1000 mg/day, preferably from 50 mg/day to 800 mg/day; and/or  
      Zeaxanthin, in a concentration so that the daily consumption by a human adult is in the range of from 0.1 mg/day to 50 mg/day, preferably from 0.25 mg/day to 30 mg/day.  
      Typical examples of galenical formulations for use in accordance with the present invention are given below. The Examples are for the purpose of illustrating the invention and are not intended to limit the scope of the invention in any way. 
    
    
     EXAMPLE 1  
      A tablet for the coadjuvant treatment of prostate carcinoma is formulated to contain 5 mg of lycopene, 200 mg of vitamin E, 250 mg of vitamin C, 37.5 mg of resveratrol, and 50 mg of quercetin. The daily dose corresponds to two such tablets.  
     EXAMPLE 2  
      A tablet for the primary prevention of gastritis is formulated to contain 3.5 mg of lycopene, 150 mg of vitamin E, 100 mg of vitamin C, 25 mg of resveratrol, 2.5 mg of lutein and 3.5 mg of β-carotene. The daily dose corresponds to two such tablets.  
     EXAMPLE 3  
      A tablet for the primary prevention of age-related macular degeneration is formulated to contain 3.5 mg of lycopene, 50 mg of vitamin E, 50 mg of vitamin C, 5 mg of lutein, 5 mg of zeaxanthin and 5 mg of β-carotene. The daily dose corresponds to two such tablets.  
     EXAMPLE 4  
      A patient weighing 70 kg and receiving conventional prostate carcinoma therapy is administered, for the duration of carcinoma therapy, 10 mg of lycopene, 200 mg of vitamin E, 250 mg of vitamin C, 37.5 mg of resveratrol, and 50 mg of quercetin per day in a single dosage unit, e.g. by administration of 2 tablets of Example 1, or in individual dosage units of the components.  
     EXAMPLE 5  
      A patient weighing 70 kg with a history of episodes of gastritis is administered, prophylactically, 7 mg of lycopene, 300 mg of vitamin E, 200 mg of vitamin C, 50 mg of resveratrol, 5 mg of lutein and 7 mg of β-carotene per day in a single dosage unit, e.g. by administration of 1 tablet of Example 1, or in individual dosage units of the components.  
     EXAMPLE 6  
      A patient weighing 70 kg who is prone to age-related macular degeneration is administered 7 mg of lycopene, 100 mg of vitamin E, 100 mg of vitamin C, 10 mg of lutein, 10 mg of zeaxanthin and 10 mg of β-carotene per day in a single dosage unit, e.g. by administration of 1 tablet of Example 1, or in individual dosage units of the components.