WO2014115140A1 - Compositions comprising heat-treated clear tomato concentrate - Google Patents

Compositions comprising heat-treated clear tomato concentrate Download PDF

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Publication number
WO2014115140A1
WO2014115140A1 PCT/IL2014/050075 IL2014050075W WO2014115140A1 WO 2014115140 A1 WO2014115140 A1 WO 2014115140A1 IL 2014050075 W IL2014050075 W IL 2014050075W WO 2014115140 A1 WO2014115140 A1 WO 2014115140A1
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Prior art keywords
ctc
com
ion
therapeutic
inhibition
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PCT/IL2014/050075
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French (fr)
Inventor
Tatyana ATLASMAN
Yoav Blatt
Rachel Levy
Yoav Sharoni
Joseph Levy
Morris Zelkha
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Lycored Ltd
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Lycored Ltd
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Priority to BR112015017355A priority Critical patent/BR112015017355A2/en
Priority to KR1020157022879A priority patent/KR20150109471A/en
Priority to JP2015553229A priority patent/JP6641180B2/en
Priority to RU2015135595A priority patent/RU2015135595A/en
Priority to MX2015009385A priority patent/MX2015009385A/en
Priority to CA2898284A priority patent/CA2898284C/en
Priority to EP14742819.7A priority patent/EP2948005B1/en
Priority to US14/762,343 priority patent/US10993982B2/en
Application filed by Lycored Ltd filed Critical Lycored Ltd
Priority to ES14742819T priority patent/ES2824204T3/en
Priority to CN201480017192.5A priority patent/CN105228467A/en
Publication of WO2014115140A1 publication Critical patent/WO2014115140A1/en
Priority to ZA2015/05259A priority patent/ZA201505259B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine

Definitions

  • e re &at invention is also dirss ⁇ to 3 ⁇ 4 sjR rgis ic da foii3 ⁇ 4a ioB of a heat- reat d tomato-derived s .ae®atrafc itn o&ro n ids .
  • Th ⁇ s inflammato y pr cess which farms aa im r nt part of the non-spec fic iraumei sys m., is eharaet3 ⁇ 4ri.-s# b .
  • oQsspl «3 ⁇ 4x g t of chsieal a d c llular c anges t at are e &ential for host defense in the f&e ⁇ s of ic obi l agents a d othe potential y harmful enviroiuste& al factors , How&vsr, its.
  • t e may be a need to inhibit or rewn t e de lo isent of o»e r mote &: ⁇ peet ⁇ of the inf l vat r process, in particular, in •c s®s of non-i f-e tio g infiaTOatory di&e&sos «
  • T e i ivO production of MO is sses iafcod by a family of nitric oxide synt ase (mS) x m f Including induei lo- nitrie sddo syn hase ⁇ - ⁇ ), which is activated by m&ay d fferent I «o&olo-gie&X stimuli including li ⁇ lysaco & ide
  • TOF-nlpha occupies a key position in tho early stage of inflammatory prooass is s3 ⁇ 43 ⁇ 4 cmsible for stiai3 ⁇ 4ii3 ⁇ 4 i8 the r u io of o her factors suc m mielear factor- *sB 3 ⁇ 4? ic:h ii3 ⁇ 4 tu ca ses 3 ⁇ 4sti : y&tiot of. a wide range of r -inlX3 ⁇ 4»atory g&tn3 ⁇ 4s * h3 ⁇ 4s , in WL®M of iti ke -in lava ory role, NF-al ha. is clearly im ortant te ti l the a eutic; t rget for ant -in lam ⁇ ato agen s *
  • the t rm ⁇ CfC refers to concen ed toma garaen that is tained by t &m- of gepmratlsg t5Mt& ma ial ⁇ oh as c us ed «to «8 or tossa o juice ⁇ 1st pul a.ad ssros, discarding tliss pulp and m. oorsc&iy r ing said serum to a :erlx vaX 3 ⁇ 4 e e n bo 40 a d 80, refera ly ' abo e S** ex.
  • h nc n ra d s rum is refer e to as TTC*".
  • &%il ⁇ se e al differen eating egimes may foe used, to epar the »foreroentioned ' ⁇ 3 ⁇ 4t-tres.t@d Cfc, in anst refe red scs o iment , the CTC (at a.
  • c sn.c®i*t,rafc.t & corres onding to a roxim tely tSSBx is e3 ⁇ 4te3 ⁇ 4d ⁇ fO q& ⁇ sg C for a iod of ' te wM 1 and 3 m3 ⁇ 4rsi » IK a particularly re err d x3feodi35 ⁇ n h ⁇ t ⁇ risa3 ⁇ 4ed CTC is pre a ed by fesg& i&g CTC for 1 smr at tO def ees c* i 3 ⁇ 43 ⁇ 4* &fa rsid emb diassR f tl1 ⁇ 2 erape ic eamposlti a o t e esent in en ion consists essentially of ⁇ a trea d CTC.
  • ⁇ ⁇ initios com ises ®m m oarotepoids selected from t e group consisting; of lysopene* pls tosn «* b t.afiu@ ⁇ F ⁇ ta-car tene nd Imtain f ⁇ ndi o lsslr deri a ives, Howev r * it is t b ec nised that many other car inolds- may als bo us d to repare t.3 ⁇ 4® s nerg stic cois -o ⁇ itiaas- of the present ipv ptlpr
  • e herapeu ic composition consists essentially of a synergistic e std & i n of k at t s.3 ⁇ 4;tgd C C & oi3 ⁇ 4 or » ⁇ * ca o-tenoids Mlas s frorsi t.h& g a consisting of lyeo esn ⁇ , p ytoane f p yt.Qfl ene, teta-caro ens and lu ein * In ne ar icula ly eferred eihodimeot f fc ' t ombi atio om osi iom c m ises ycope ⁇ . os preferably f t ooss osi iors comsis-ts €sss
  • h «r@ia t3 ⁇ 4# am fiKoi s include ly ⁇ p «B» the coaeeatrati s of said ly o eas is at, leeit 0 * 1% ( /w) * h& resent i&y fc ioa als- ⁇ rela es to combin tions of ⁇ or it3 ⁇ 4or@ camttnoids
  • ano her ⁇ mb d msht* n& application is directed to a therapeutic casi osition c mp isi g a s Mrg s ie coiabx a i of at l as ne caroteaoid og her with C C having a fr@® • glts amisse tsc&iitraticm of l ss than 0 * 1% w/ «
  • the re nt invention proides a method for Inhibiting or educi g the roduction of one or more aivti ⁇ nf.1 e tory me iatory la a.
  • a fyrtii#r asp@et t t resen in en ioa is directed to t e 3 ⁇ 4 ⁇ of h a - r a ed CK in the mrufaetura of a ⁇ dicasR@R . for -th ea m nt of condi ions res onsive to i hi i ion f iaf la3 ⁇ 43 ⁇ 4tory medi t r »- pa tieul sly NO, SF- al ha and./ or iPtexIeukin 1 *
  • Irs a s3 ⁇ 4till fu th as ect f e resent iwM ion is dir cted to he us of any of th c m osi i n d sclosed @ ift l3o e
  • iwM ion is dir cted to he us of any of th c m osi i n d sclosed @ ift l3o e
  • the present in.wtstion also provides e od of tr a m nt of t olog c l eop&itions 1 which m, ⁇ $ ⁇ ®lp & and/or interieukin i ac aa a modalatoxs or Media o s f s id condition in a s jec in j3 ⁇ 43 ⁇ 4 d of su r&ai ⁇ R , erein said me hod oD;3 ⁇ 4p iss&& to said s3 ⁇ 4bjg « a t e a eutic composition according to any oae of e ⁇ 3S!bi ila5@K .s disclosed e eina ove * in ne eferred embo iment of tills th condition, to -r& - ed is s lected; from the ⁇ o ⁇ cassis l
  • a therapeutic com os ti a as disclosed n ⁇ r ⁇ iii bovi* * i ona pz®f.® t®d foodi bik of this s ect, th im rov men in oTi® eal h dim r ⁇ t t inhibition of hone r- s0r ti ⁇ m, 3 ⁇ 43 ⁇ 4 « b ® ba&ith y e us d i s bject having any condition or disease that will res ond • theret , is.
  • t sa subject ii a mamm li si subject nd sio e eferably a. tain sobjec .
  • Fig . 3 gra hically illustrates tb® effect of di fer n beating times -- lit)- imtes) on the ability of heat- treated CfC o inhibit 0 roduction by peritoneal macrop ges ⁇ ,.
  • Fi * 3 graphically illustrates & eonceRt a on of gluc ses is each of £iw se a ate ba c es of C C., both efore ami after heating,,
  • Fig * 5 shows the inhibitory ffect of ho&t-treated C C on TOP production by LFS- timalst d mac o h ges * he fi s ®£ eac group three a s re es nts the inhibition obtained wit fresh heat-treated CTC* hil® the is3 ⁇ 4oon.d ard third- ba s e es n ths res lts ob ain d -wit.lt he t- rissttisd CTC that 3 ⁇ 4ras s o ed for si . months a room t tsp &ture or at 4DC, reepee iv ly »
  • Fig, -6 graphically cois sr ⁇ s he inhibition of N oduc ion y peritouei&l macro hages caused y toet&to oleoxesin ⁇ Lyc ⁇ - -ato ⁇ slow, and hss-atea; C C alone f wi 3 ⁇ 4 c m in ion, of tomato ⁇ l&o esin and heated CTC.
  • Fig, 8 graphically r resents t inhibition of W> oduc i n by peritoneal macrop ages oass by be - carotene &lone % ⁇ . e ed CTC &lo f with a om i a i , of beta-carotene and heated CTC *
  • Fig. 9 graphically Illustrates tte i hibit ry effect of a combination of L c-O- ato and 3 ⁇ 43 ⁇ 4at d CTC on the production, of interieukin i-B in mo l of carragmen-is3 ⁇ 4d ⁇ d rat paw i fl ⁇ &tioo * fig * 10 graphically com ares- t ability o heated C C and nan-ho3 ⁇ 4ted CTC to inhibit ft3 ⁇ 43 ⁇ 4»i.-Ir.da3 ⁇ 4 «d s e clast differeniiation , s measured by a tra e Resista t Acid Phosphatase ⁇ RAP) activity * t e res l s indiesa e that tested CTC is s gnifi antly mor ⁇ o en than non-heated CTC,
  • Fiffraction 11 graphically com sxss the influen.ee of i,y ⁇ n drawne with C € alone and wit ⁇ eo e e and CTC addition, on tte inhibition of R IKL ind ced osteoclast differertt &tia , as me su ed fay IMP,
  • Fi ⁇ note 12 graphically c-csmpa ⁇ the ⁇ &® de nden activation of thfe antioxidant espons eie:»ftt (A B by heated CTC in. MC3 3 osteobla i cells with t ⁇ lack f sueh ac ivati n that is see with non-heated CTC «
  • Step 12 i Sa urn is st red fcempor&riiy i:n & large container .
  • h-@ s ⁇ rum is. o & nt.rated, der vacuum i3 ⁇ 4 an evapo a or to th desi ed Bx -v lue.
  • h ⁇ 3 ⁇ 4 a ov sc3 ⁇ 43 ⁇ 4 ⁇ e is nly ne example of a. r cess- for producing C C, and va i us, other prsce&s&s »;y lso be d ed, with ut deviating itsm t e #? ⁇ 3 ⁇ 4 of the presefst i dent on..
  • s r d c which c iieists of Clear TOsiatO Concen rate ⁇ is coenof-ly mi t d to as CTC ⁇ Fu her nfo ma ion concura n the prepa i n and p ope ies of Cf € may be f und in co-a ⁇ tmd wo ⁇ 9 60868, w!ti is inco or ted h «»ai.s.
  • h CTC of the present inv ntion is su je ed to hea t estsjett * ifs several different Se t ng r3 ⁇ 4g»3 ⁇ 4 ® t3 ⁇ 4 us@d to re are the afo mentioned hsa ⁇ tr at,@d C C, in one preferred embod ment * th® CT ⁇ at a « ⁇ : ⁇ 3 ⁇ 4 ⁇ 3 ⁇ 4* ⁇ , ⁇ e rr s o-miing to a roxima ely € %) ii heated at 90 degrees C for a period of tween 1 nd 3 hours, in a particularly preferred em odiment, t- tr t d CTC is prepared by he ting C C £ ⁇ r 1 hour at 0 referred daily «o>$i s of the heated CTC presen- in ss com osi ons that are
  • concentration of at least e com osition of th « pr&s&n inven ion may fom3 ⁇ 4.lated for ei h r syst mic r topical ase *
  • th® h@at ⁇ re ted CTC may be i co porate in o oral dosage forms such as le s f C&ple s, a &ul s syrups* elixirs, lipids eiss. in o er ⁇ £ r d ⁇ mbodi3 ⁇ 4 T?
  • the composition of he rss&at i ⁇ vemtior * may b admi is ered o ically, for ex mple on b skin ⁇ auoous mssas r&si ⁇ s as cre3 ⁇ 4ti r lotions, oi&ftwemts etc,)-.
  • e present wrniti iss, h eve bombard Is not limited to tile & ic3 ⁇ 4I&r m odi.mn.ts disclosed its.
  • ⁇ is 3 ⁇ 4yi3 ⁇ 4®r ⁇ ist c inhibition of NO rod c on by LPS re ts toy coa inati s of ea ed C C in the r ge of 1 ⁇ 0 to mODO dilutions i h 0,2 3 tyc-O-m&o» he first bar in ⁇ act.
  • 3 ⁇ 4is dmcxmm® was simila in magnitude to that caused bf the iclofenac; ositive co l * oth piStecM-ast and osteoclasts a e involved ia feo ⁇ remodelin * fh® resent, investors h3 ⁇ 4w fesrod that heated- C C i ⁇ prow foo&g healt by at Xe»»t tm &m®l m?i.&ry

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Abstract

The present invention provides a therapeutic composition comprising heat-treated clear tomato concentrate (CTC), which has been found to possess both anti-inflammatory and bone-health promoting effects. The present invention is also directed to a composition comprising heat-treated CTC in combination with one or more carotenoids.

Description

CONCENTRA E
T' @ prois¾st in ention elat s to a c©sipositi r¾ ccmprisi g a beat- r ated ate-dsri ^d so ea t &te hich ' g esm found to poss ss a 3i UR x ®cfeediy hig - level of a^ti- inflam ory Mtiwi y. e re &at invention is also dirss ^ to ¾ sjR rgis ic da foii¾a ioB of a heat- reat d tomato-derived s .ae®atrafc itn o&ro n ids .
Figure imgf000002_0001
Th<s inflammato y pr cess,, which farms aa im r nt part of the non-spec fic iraumei sys m., is eharaet¾ri.-s# b . oQsspl«¾x g t of chsieal a d c llular c anges t at are e &ential for host defense in the f&e<s of ic obi l agents a d othe potential y harmful enviroiuste& al factors , How&vsr, its. many eai§sr infl w ti n may toe triggerad ί ina o ria e t and r stay e ist to a d^gr^® wfcicsh b^c-omeg amfttl to tho host* In suc as s-, t e may be a need to inhibit or rewn t e de lo isent of o»e r mote &:§peet§ of the inf l vat r process, in particular, in •c s®s of non-i f-e tio g infiaTOatory di&e&sos «
A vet? large n ber of different chemical m dia ors have Me & .<$m. to b involved In. e development and control of the inflamma ory roe&ss. R osmt ¾t¾di©g by a n¾¾bis of different l o atories ave Impli ted nitric ®x±d® i O} &s an im o an ^oetal&t r of & varie y of a ute d ch onic in lamma ory disorders„ i no ladi g various yp@s of r eritis , gastro*~intestinal diseases, I l&rm&tory conditions o t <& cent al rs#JfWM- gystem a d certain forms of
Figure imgf000003_0001
r it has boon oposed t at inhibiti n of H prodnct£o¾ could prwide a useful torapeutic TO0ha»is» for the treatment and/or maaagement of h se inftaMs o y disorders* Fur he m re f inhibition, of syn esis also to¾®i¾ ¾ o¾m to be o&eful in sossa oonditions ta es t¾at ar tm primarily inflammatory in na ure* tms, for exam le, in i ti n of uo synthesi has b an found to educe glucose u ake into limb tissue in &divid &ls with ype 2 d a etes during exe cise*
T e i ivO production of MO is sses iafcod by a family of nitric oxide synt ase (mS) x m f Including induei lo- nitrie sddo syn hase {ϊ-Νθβ), which is activated by m&ay d fferent I«o&olo-gie&X stimuli including li^ lysaco & ide |LPS|f I te eron gamma. &jxd in rleukin: 1 (It-I ) +
Inhibition of s¾3 &y achieved both in vitro and. i vivo by the u. of L- -.m » »%e byi &rginine oitrmt I addition, several o her ε;αΜρο¾¾ϊ$8 including a numbe o£ natu al od c s * h¾ve also be sho n to inhibi t MO production.. Th- latter g ou ' includes es« ¾md such ais lutein ( fl M-.M. at ®l. fol mt Food R®s. 200? Mmri51 (3}t 333~40f Choi? J.S* Nutrition. 200® Jim;22(6) t€§8- 72] and iyc ne [SAti≠ M*H< et aI* J Food Eei* 200? Jan; 72 { ϊ μΒ0§9-74 j «, Efwwa ,- the effic cy d otency of many of t is na ral duct NO inhibitors h w rayers o fee not ticul I ig * rs-e&d t f re xigst§ or i oved: 0 prados- ian-ift ibiiisig com osi ions of n tu al igiis * ot er ifhl importan infla ma ory mediato is t®m® necr sis c -al h iY_3F~al h&> , fci t* is ¾ cyt kine* oduced by a va iety f eeXI types including macrophages F ne rop ils and lymphocy es . TOF-nlpha occupies a key position in tho early stage of inflammatory prooass is s¾¾ cmsible for stiai¾ii¾ i8 the r u io of o her factors suc m mielear factor- *sB ¾? ic:h ii¾ tu ca ses ¾sti:y&tiot of. a wide range of r -inlX¾»atory g&tn¾s * h¾s , in WL®M of iti ke -in lava ory role, NF-al ha. is clearly im ortant te ti l the a eutic; t rget for ant -in lam^ato agen s*
Tur ing so to s o h aspect, in rder to peserve ¾¾al.thy t normal oos st ootor , totm is continually su jected to r«odel og , whe oi^ bono in r kon dovm by steoclasts and re-bolit by osteo lasts * e diffe ntistioa of osteoclasts is influence inte *2i* by AS L (recoptor activa or of MW li.g*TK3>, a cytokine* prodoeed. by ost oblasts , which . inds to osteoclas pr gsai r ceils. InhihitioR f this- r cess would load to reda tion in steoclastic acti ity, and the e y inhibit teme resorption,
¾ alternative strateg f lteri g the b lanc ise ^een o.# reso ti n a d t o product of b®m-. in h# b®m xe zdmlln gr®&®m would b® to o oso iTs e ^d ©stso i¾&£ activity* Whil® his resul My potentially b chieved la several ays, one ossibl rotte is via ac ivation of an i xidan r&s oss element ( T£,/®x£.2) signaling in osteo las s <· n iahalaaes b we n >on¾ formation and ¾>on-@ resorption can lead to the toraiojs©n of path i&gieal onditions; s esi s steo orosis, arth itic, &riod ss &I disease, multipl
and m-@tastat.ie cancers. Fo Individu ls ¾?i h osteo o osis f bone fractures- re resen life-threatening even s and today h®r® in && m of 70 million eo le world ide at. ri.sk»
In cas s of & #¾si e bq¾ resorption { ®msh as occu s in ostto pii aisj ?■ it ¾¾ald @ advantageous to- e &bl¾ to alt r the al e hst a res ion aad the laying d wn of new one., Ideally, this would be chie ed by t e uae of a natural ? oA-toxic s bst nce that is substantially fr@« o ad ers ®££@ots. One of th® ϋ » of the p es n imrentioa
Figure imgf000005_0001
ine purpose of tha resent inventio to rovide a natural product op ositio that nsay e nsacl to inhibit the prodac ion of one o motes k&f i lmm& tY mediators ¥ mti.
W3 Β,ηά 'MF-al fca, as roeans for tre ting or ssa agiag paiholo-gie&I tat&s and ro esses in whic s id .mediators &r ist licat<sd *
It Is- a er purpose of e r s nt invention to provide a tom o-derivgid Qd?t Q itioh haviag imp oved aati™ i flfflm& oty properties* A still fart er xsr os© o tha p @s**nt isi¾a i i¾ Is to r id a na r l product com sition for improving on heal h. otter aims ami pur ses will bee ¾s a pa nt as he description proee cis-.
It has now h srn found by e resen . inventors that t s¾ apti-iftfIsOTimtory ro e t ess of a PSj o-derivgd rodtate kpo n as clea oma o oarso rs r te CTCj e en anced y subjecting said CTC to heat r a m nt prior to se. the t rm ^CfC refers to concen ed toma garaen that is tained by t &m- of gepmratlsg t5Mt& ma ial { oh as c us ed «to«8 or tossa o juice} 1st pul a.ad ssros, discarding tliss pulp and m. oorsc&iy r ing said serum to a :erlx vaX ¾ e e n bo 40 a d 80, refera ly' abo e S** ex. h nc n ra d s rum is refer e to as TTC*". Fart er details of e e atiop of C will ovided li P Ls below* ¾ res nt invention is t erefo e p iti iij directed to a t eu ic coipoi.ition com risin nsat-trsated CTC.
&%il© se e al differen eating egimes may foe used, to epar the »foreroentioned ' ©¾t-tres.t@d Cfc, in anst refe red scs o iment , the CTC (at a. c sn.c®i*t,rafc.t & corres onding to a roxim tely tSSBx) is e¾te¾d ± fO q& ^sg C for a iod of 'te wM 1 and 3 m¾rsi » IK a particularly re err d x3feodi35©n h© t~ risa¾ed CTC is pre a ed by fesg& i&g CTC for 1 smr at tO def ees c* i ¾¾* &fa rsid emb diassR f tl½ erape ic eamposlti a o t e esent in en ion consists essentially of ©a trea d CTC.
It is to be mo ^d that the term " ona s s ^s^ tially o£ as ased •fc.r Efhost. is; discl s re and a nded, claims- refers to tte si ua ion w ere n the compaiitioa of the r sen iavMtioa may ccsnpri&e* in addi ion to the p imary ac ive aubst iwe cheated CTC 5 ,< t a com o ds, su s a c s and agen s ich do not mterdaily a fec the basis » ao?8l ¾d lt «¾ti -¾ ch cter s ics; of he p sen .is ntion .
In e preferred Qnsbodimea * e abov ~d.i&dl-oted QQ o itio se^p isi&g heat™treatad CTC has a total £r«e amino acid ccmcwtration that. Is l ss th&a 2% w w» s * th® free glsiaminis concentration of the eosag sifcioii oo¾¾ rising h#at-trstated CTC is refer bly less an
/ .
Fur h«r«sr®». it as no® b@sm ne ecte ly foand tha ea d CTC interacts synsrgisti lly with c& ot noid# »· thereby producing an eiihasic d asti-infl s^ sry offset.. ί» pr@s@ t. i yeati a is e efore ur h directed to therapeutic compos.ition cosaprising a synergistic mbin ion £ b@a ~- reated. CTC and i® or ^ore a&ro enoidis ÷ In ©n® r«s£^r sd e sodi sst of is eoMbiaation c m osi i n* he -total free mino acid concen ration is less than 21 f/s. Bl larly, the free glu mine oj¾sen.tratios is pre e ably less than 0,1% ¾r/w-. liil® any different &rat^oids may be incorporated ists? the composi ion f the resen inventicm, in a preferred omfeodijnsn j said ο ^ αinitios com ises ®m m oarotepoids selected from t e group consisting; of lysopene* pls tosn«* b t.afiu@ ©F ^ta-car tene nd Imtainf ^ndi o lsslr deri a ives, Howev r* it is t b ec nised that many other car inolds- may als bo us d to repare t.¾® s nerg stic cois -o^itiaas- of the present ipv ptlpr
In a partietila if efer ed emb dis n i the cosi^o lti s of t resent in ention c m ises hs&ted CTC nd toma o, oltortiis, erein s id oi oresln comprise tii c^ro noids lyco^n®, phyto 3®p p ytofXueiie a d ^ta- a otSB^. & ec«#reislly-availa,blg exam le of s¾ch a tom t ©leoresin is L «-0-Ha O«» manui&e u &d. and supplied, by the a plica »· LycoBsd Ltd.. of ¾e* ®x S ^ a, Isr l, in one r erred eiisbo lmo t the t erapeutie c m sillon of the esen ind ntion co sis s essen ially of a synergistic scs a& on of heat tt«¾ted CTC and on m seo caro-teno ds . in a ar icula l refsnr ^d @mbodimaat, e herapeu ic composition consists essentially of a synergistic e std & i n of k at t s.¾;tgd C C & oi¾ or »α* ca o-tenoids Mlas s frorsi t.h& g a consisting of lyeo esn©, p ytoane f p yt.Qfl ene, teta-caro ens and lu ein* In ne ar icula ly eferred eihodimeot f fc' t ombi atio om osi iom c m ises ycope^ . os preferably f t ooss osi iors comsis-ts €sss »tiall f hea t ^at d esc a d tpma cj
Figure imgf000009_0001
Preferably j, he total concentration of he c ro ers ids in th com ination c m sition Is at least QUI! s In anothgr referres embodim n ,, h«r@ia t¾# am fiKoi s include ly∞p«B», the coaeeatrati s of said ly o eas is at, leeit 0*1% ( /w) * h& resent i&y fc ioa als-ο· rela es to combin tions of οκ§ or it¾or@ camttnoids |a¾ i¾elo¾ed oreina e) together with a modified CTC ts img a ©tesa cal and or biochemical opposition simil r to that of ® h -treated C d^fiss d hereinab e or to said m di ied CK alone* Tims*, in ooe as ec t ® presen iiwetttlon i& dirootod to a ttttr&peutio c mposi on comprising a synergistic com i ation of asm or »or© oarotehoids together with CfC havi&g a total fre amino acid c &cesi atIon of i®s_s than It w/w. ano her ^mb d msht* n& application is directed to a therapeutic casi osition c mp isi g a s Mrg s ie coiabx a i of at l as ne caroteaoid og her with C C having a fr@® •glts amisse tsc&iitraticm of l ss than 0*1% w/ «
Ih n t aspect * the re nt invention pro ides a method for Inhibiting or educi g the roduction of one or more aivti~ nf.1 e tory me iatory la a. sybjee , as a isi& ns fa rea ing or ma gi g pathological, states and rocesses is hi« ^ai media o Is implic ted., feo sin s d me hod cojs isss adndnistari g o said s^bja t a t era eu ic- com os?it.iee according to any of he e bodi nts disclosed her i above* While said m t od may e ixsssd inhibit -e produc iem of sasy diffe ent ia£I«i»te£¥ «di .to sf in ®t preferred ^ s imest.^ - h@ aa l-iaf lamssat ry media or is ssleci^d f o t # g o p coniisting of no, HF- lpba d interl ukin I. «
In a fyrtii#r asp@et t t resen in en ioa is directed to t e ¾ © of h a - r a ed CK in the mrufaetura of a ∞dicasR@R . for -th ea m nt of condi ions res onsive to i hi i ion f iaf la¾¾tory medi t r »- pa tieul sly NO, SF- al ha and./ or iPtexIeukin 1*
In ® £¾ or s c * the ogsent ijs¥«r¾ oi¾ ii direet&di t t-he sis® of eat- tre ed CTC &r.d -®Ά® or §¾oro c ary enoids in the &ftttf®€ ¾r® of a edicamen or t e t a ment of oo:¾ditio¾s esp nsi e to inhibition of m, TW-alpto and/or iriterleukin 1.
Irs a s¾till fu th as ect f e resent iwM ion is dir cted to he us of any of th c m osi i n d sclosed @ ift l3o e In the m nufacture of a m dieamarfe M&fui for ixa ro¥"ing bone h al h. In one preferred 0¾ di¾enti sa d :m&d ea«Rt is a& & ls of inhi iting horse or tio s and m y be use^ i the reven ion, tre tmen o ssan gse en of con-ditiorss s ch s | b¾ n t limi ed to) o& e oxOiis* arthritis,, erio ontal di»e«ee» multiple m ^l usa &®d
Furthermo e, the present in.wtstion also provides e od of tr a m nt of t olog c l eop&itions 1 which m, Τϊ$Έ~ ®lp & and/or interieukin i ac aa a modalatoxs or Media o s f s id condition in a s jec in j¾¾ d of su r&ai^R , erein said me hod oD;¾p iss&&
Figure imgf000011_0001
to said s¾bjg« a t e a eutic composition according to any oae of e ©3S!bi ila5@K .s disclosed e eina ove* in ne eferred embo iment of tills
Figure imgf000011_0002
th condition, to -r& - ed is s lected; from the ^ o ^ cassis l g of e¾t« nilama ory coBditi RSi- ehr nic infiammatory conditions f rh@umat.oid arthritis, adxslt esp ator dist ess syndrome {AR0S i asthma ., hinitis, idiop thic p im a rf f os s, peritonitis * cardi &scs l#.r ittf la¾.¾tiQ f Myocardial ischemia* r p rfusio iaj^ry, a^heros ie a s,, se sis f rauma f diahe sss type n.f . eti a- &hy» pso i sis, gastro n es inal in£l:&s¾is.tio f cirrhosis, peritonitis and i¾£l&rnmaia y bo el diss s®, and i¾au 4f ¾ii^ at ¾ diseases, s ch as fo osample &.i¾h#i¾ex* s disease , in ¾¾ e er ed m odi∞ntf t-h® coi-sdifci rs to be treated is n inflatatnatory condition.
in anothe aa e » t e p esent iiw^- ion i_¾ &ix®ct«ad to a ethod for isfs r ying bone tee&lth i a subject, com rising admin stering to sss.i sa&j ct. a therapeutic com os ti a as disclosed n^r^iii bovi** i ona pz®f.® t®d foodi bik of this s ect, th im rov men in oTi® eal h dim r ^t t inhibition of hone r- s0r ti<m, ¾¾«
Figure imgf000011_0003
b ® ba&ith y e us d i s bject having any condition or disease that will res ond •theret , is. .i g, u not limited to osteo orosis, arthritis ί periodontal dises&s , -mil-tl la myelom nd etastatic e ftcsrs, la prefer ed sish^diments of the matbods dis orib d hereinabove, t sa subject ii a mamm li si subject nd sio e eferably a. tain sobjec .
While in th® a o¥@-discl.©s@d me ods? theratpest-ie
Figure imgf000012_0001
be dministe ed by any c n eni nt ®a¾sf ifi on® pref rred m odimaRt said os^sDsi i n. is aefei i^ arssd ±n a h rm ce ti al do-gag fe>«* In a& tber p e e bodimen t ho eve * ® therapeutic com osi ion is iac^r ar&teo: into a oods u f or: beverage*
AAiill t a@ aabbtdsww mmdd ootthher cchha&rraaccttearriisstiicess aa«add aadd^mannttaagg-ass ooff tthhee pprreesseenntt- iiOTOTeeaattiioonn wwiillll,, bbee ffuurrtthheerr nndd rrssttooodd ffrromm tthhee ffoolllloowwiingg iilllluusttratiivvee aanndd nnoonn--lliimmiittaattllTOTO aammppllssaa ooff pprrseff rrr dd --emmbbooddiimmeenntss thhae eeooff..
Figure imgf000012_0002
Fif I g a hically co -a ess the inhibition of MO oduction p itoneal mac paiif s bf tr atm^rt egula , tson-bsated C C { ig. IA) with ha cause by t ^ tment. with hssat- reated CTC *F.ig. I },
Fig . 3: gra hically illustrates tb® effect of di fer n beating times -- lit)- imtes) on the ability of heat- treated CfC o inhibit 0 roduction by peritoneal macrop ges·,.
Fi * 3 graphically illustrates & eonceRt a on of gluc ses is each of £iw se a ate ba c es of C C., both efore ami after heating,,
Fi . graphically illust ates the concen r tion f fructose In e& of ive se a a e b& eheis of CTC, both befo e and after ea ng*
Fig* 5 shows the inhibitory ffect of ho&t-treated C C on TOP production by LFS- timalst d mac o h ges* he fi s ®£ eac group three a s re es nts the inhibition obtained wit fresh heat-treated CTC* hil® the is¾oon.d ard third- ba s e es n ths res lts ob ain d -wit.lt he t- rissttisd CTC that ¾ras s o ed for si . months a room t tsp &ture or at 4DC, reepee iv ly »
Fig, -6 graphically cois sr^s he inhibition of N oduc ion y peritouei&l macro hages caused y toet&to oleoxesin {Lyc~ - -ato} slow, and hss-atea; C C alone f wi ¾ c m in ion, of tomato ©l&o esin and heated CTC.
Fi , 7 graphically r resents the inhibition of m produc icm by ritoneal ta¾.c o a-ges c¾os«3d: y lutein, ne and CTC alone, ith a ormbination of lutein and he t d CTC.
Fig, 8 graphically r resents t inhibition of W> oduc i n by peritoneal macrop ages oass by be - carotene &lone %ηά . e ed CTC &lo f with a om i a i , of beta-carotene and heated CTC*
Fig. 9 graphically Illustrates tte i hibit ry effect of a combination of L c-O- ato and ¾¾at d CTC on the production, of interieukin i-B in mo l of carragmen-is¾d∞ d rat paw i fl ^&tioo* fig* 10 graphically com ares- t ability o heated C C and nan-ho¾ted CTC to inhibit ft¾¾»i.-Ir.da¾«d s e clast differeniiation , s measured by a tra e Resista t Acid Phosphatase { RAP) activity* t e res l s indiesa e that tested CTC is s gnifi antly mor© o en than non-heated CTC,
Fif„ 11 graphically com sxss the influen.ee of i,y ^n alorse with C € alone and wit ^ eo e e and CTC addition, on tte inhibition of R IKL ind ced osteoclast differertt &tia , as me su ed fay IMP,
Fi§„ 12 graphically c-csmpa ^ the ύο&® de nden activation of thfe antioxidant espons eie:»ftt (A B by heated CTC in. MC3 3 osteobla i cells with t © lack f sueh ac ivati n that is see with non-heated CTC«
Figure imgf000014_0001
M discl ad !- ein& ve, t present liw ntiosi pr-wid&s compositions comprising heat-treated CfC alo-n®
with one or mar® e&ro esioidi-,- he fraction known as CTC maj typical if tat m cl } be prepa ed fey means of he £oi.!s¾?iR rocess ί
B It Mat&ss a e w sh d d sorted &eeo dii¾g to their color ahd q ality* CX atJ tomatoee are c ushed; at s poisst t e raw e u^!sed tomatoes are § amplest for ljc®pm® content and s^gar conten *
¾ _ i law s ss!sed tomatoes are sc eened th ough -6
Mddlti& X $te 3.1 ¾ water is added to the- e in d solids a ¾ £¾r r screened on 0. S and 0*8!ts«s tt4»t% in or tar t ;rM ¥& el pa io s*
S p 4t slu y obtained f om st¾ 3 is farther screen d or; 1*5 to- 4M nets . l fiLJI* S lor ies om stsp 4 ed 3.1 are o led toge her and s ored In a con ainer j at this point h slu ries a e sa l d aad
Figure imgf000015_0001
St®p €t. Slurry is trans er ed to la ge s orag tanks . slu is te¾£#d to SG-H5*€ md $ l*d,
| _|3 ¾e∑# emp r re has ea hed
Figure imgf000015_0002
tte a & os h se: is s ar d from t e solids in horizontal -e&R ifsi^ s (discaa s s) g ©» ί The solid ma erial pul j is cked is. laminate gs placed in m tal dr ^s whi h a e tfta¾ s m led and la eled. The pulp containing draaas e then fro n and. s ed ir¾. r san conditions
Ste 10i hqn o ases (se ^im from d c¾rs er) is sam led* te I.I ; S ¾ is filtered and de- erated ¾maar cnujK in order t& elmin e e cess foam
Step 12 i Sa urn is st red fcempor&riiy i:n & large container .
£ _Jj5: he s^ iiiK is. c rs rifug d a¾d the sludge is sssn back to St 5*
,£¾ .... S ,h-@ s^rum is. o & nt.rated, der vacuum i¾ an evapo a or to th desi ed Bx -v lue. h<¾ a ov sc¾¾∞e is nly ne example of a. r cess- for producing C C, and va i us, other prsce&s&s »;y lso be d ed, with ut deviating itsm t e #?© ¾ of the presefst i dent on.. towwr , e kof st ges of is r cess «y b& s¾sraari ed as follo s ? Crus ed tomatoes are se rated into ■Km* fractio s ·- m and pulp -s h t nto s rum is eonCiBt stsd -to rix v ise b twe n 40 and. 80.† re e ably ig er fcfcajj 55!>¾, s r d c , which c iieists of Clear TOsiatO Concen rate^ is coenof-ly mi t d to as CTC÷ Fu her nfo ma ion concura n the prepa i n and p ope ies of Cf€ may be f und in co-a^tmd wo §9 60868, w!ti is inco or ted h«»ai.s.
A ex l i ed hers*isi above, h CTC of the present inv ntion is su je ed to hea t estsjett* ifs several different Se t ng r¾g»¾ ® t¾ us@d to re are the afo mentioned hsa ~tr at,@d C C, in one preferred embod ment* th® CT {at a «ό:ο¾ηΐ ¾*Ι,οο e rr s o-miing to a roxima ely € %) ii heated at 90 degrees C for a period of tween 1 nd 3 hours, in a particularly preferred em odiment, t- tr t d CTC is prepared by he ting C C £©r 1 hour at 0 referred daily «o>$i s of the heated CTC presen- in ss com osi ons that are dmiitisstisred to »i. j#c .s 1B n d of sne treatmen are in © rang© of 100 to 5& .ttg«,
Preferred daily amounts of total earo-tenolds in t e ct o&i iem containing both heat-treated CTC a d caroiSKOids, which are
Figure imgf000017_0001
to fmfoj&a s in need: of r atMii , te is t ® ra ge of 2 to 2S mq*
Preferably* irs the oom sitio s -containing .both at- ated CTC nd «ar t«noids, th carotenoids are present at a concentration of at least I« one: preferred ^ odiMen of the invention f ss combin io com osi ions (t*e» boss c m si ions containing both heated-C C and c& o rs ids) comprise lyeo-p ne at a. concentration of at least e com osition of th« pr&s&n inven ion may fom¾.lated for ei h r syst mic r topical ase* In the cas of sys emic ad nifttxa ion, th® h@at~ re ted CTC may be i co porate in o oral dosage forms such as le s f C&ple s, a &ul s syrups* elixirs, lipids eiss. in o er ©£ r d ^mbodi¾ T? s , the composition of he rss&at i^vemtior* may b admi is ered o ically, for ex mple on b skin κ auoous mssas r&si^s as cre¾tir lotions, oi&ftwemts etc,)-. Further d ails of sui a le m#thot1¾- of incorporating t e heat, treated. d C-cont- iain^ c i¾ ¾si. ion§ of the resen i ventioft iftto the Y&rio¾i di ereint dos ge or s my b® b &iws& from, any s andard ref ence work kno n to the skilled rtisan in£ludi¾gf for
Figure imgf000018_0001
Rsmiagion * s F a mmc tic l Scien es* ack Publishing Cof Ea tPfi, a, ΌΒ& ^ 1 80 J .
In other preferred modim s,, th-s oompoidtioia of the resent inv n io is pre ared ¾s a food additive that is ^uitetole for diroot i½«orp=oratio into a foods ff or e r&ge, he follo ing examples a e provided or illustrative ur oses and in o der to m r© .particularif
Figure imgf000018_0002
and deseri&e the res«¾ in ention. e present wrniti iss, h eve „ Is not limited to tile & ic¾I&r m odi.mn.ts disclosed its. t es exass lss*
M&c & h&g® isolation snd cell ultur - peritoneal macrophages ere ooliedtsd f o¾¾ t'te eri on al cavity £ 6~ 8 eek old mal ICR mice f Marian Isr elJ tha had ^eeft givan as* intr¾peri.taseal injeotion of 1.5 srsl of thio-g yooll&te roth { 1 4 days before .& e&t* Peritoneal, macrophages re washed tfer«e imes wittfc PBS if ee-ded^ a fc otcmic lysis of o yth ocy es sas perrormod, yieldiag 90-95! pu i y · he a roph ges we e iden ified by F&C8 nalysis using FIT€~co»jug&tod rat an i-m^se F4/80 | tm 9?Fi Berot c:f Oxford, Sngls^ by flow mier fIu ri∞ ry o PICS (Bect ft D.iekiascmf Mountain Vi.-**?, €¾.j For each sample, 10 > 00 light scat «r~g fced viable cells wre analysed. Feri.ton.esl m¾c ^h& ®s -we cul u ed; in RP&I 1.640 medium 3 n a.iai. 10% FCS, 2 X^ltttaaine? 100 (/at psaicillirii iOS etreptemycitt. (Beit-i m M:,,
Israel) in 96-*»ll la es 1. * ιθ' cells well) at :37*c in 5% €¾ a mos re?. Cells- wfeSa s iiMiia isd with LPS (I ug ml) in tile resettee or bs nee of bes ed C'iC «
A rop iate volraiaa of SO {0 l»<3 *2 ) o e add@d to e controls a d th« ercen inhibition in eac test tube was c lcul ed in relation to its control -
Cl a tomato Concentrate (C7C) prepared as described ^ia&ba ® ,adf since It ptar sol le., s ddled directly to sm cul u e ∞dii„m at the desdred dilations* Unless oth wis stated,, he* tea .- rs t«d CI'C ussad in -this s ¾dy efers to C C that s h a ed to Q d^qn s C for a period, of one bout. > production assay ~ O itx s^ ©rn¾ta s of cell cul u es w re ^terssis&d by assaying nitrite levels using & i@ss- reag n ¾n sodismt saltrite s a standard :ss desc bed in g eem,, L* C. * ¾8 »r, D,. A* f Gl,o¾ iki, Jt, Sk er, p, L, * ¾?is¾n©k# J- S. f &&d -nan aum* S» E. {1932) Mml BXO&h^m* 126; 131-138.
S tisti l m&lysim - Data, a resen ed § the ^&ift t SE . Statistical signi icance fo comparisons bet¾ree¾ groups was d¾ ¾r irs¾ei using student's p ired two-t iled te t.
808Φ d&pen&& Inhibition &0 pr&S & i& bf CTC &
As s o ii in Figure I , addition of C C or he -tr a ed CTC in iffe e t *!ilotions to the mac ophages 1 h efore addition of laag nsl L S for ¾4 f ¾. s®d a diose de s&ds-st inh biti n, wlled as ¾ignifican-t y much mo e efficient in the ca e of t-tre ed C C*
As seen, in Fig. IA, ths inhibition by (un eate ) C C w s first bserved at dilution and c used !6* t inhibition w¾ile Baxitt&l inhibition of 100% was c ieved by ltZ5 dil tio of C* T e inhibition by the ti@&t~ r©at«d CTC {Fig. IB} m h mo ® ma kad than, t at ea s d. y aon~&eafc<sd C C at the ®am®. ooneeatratior*,. va at a dilu io o£ ls|0§0 idata not .sho ii) a slig t ia ibitiof? of 3.5+1,5% was d ec ed. At. & 1:; 200(1 diluion the inhibition o s r ed a grea er than 29%, a dos@-d¾ @nd&« i crease in efficacy being S S I u until dilu ion of i$20O, at which g*ds¾i Mxiamm {1601) inhibiti & of M pro so on w¾§ o gi ed*
Figure imgf000021_0001
in order to in s igate tfe leng of heati g~tiit¾ n ed d to produce a m :si?m5K increase In anti-inf1asmatory efficacy, CTC eated to § *C for diff ent time du at ons efore b ing adde to e Js&e pha<¾s» ¾¾ sho a in Fi re 2f 1 h incubation is sufficie to achieve ns x ma Inhibition o HO production for all of he different CfC dilutions tested,
Charact ristics of . i ^fcr ...glg
The c c ntrat o s of certain key constituen s of ne - tre ed C C »sre d«¾temit,ed d es¾ a ed with the im&Xs of said ons i ue s in regi l&r CTC that as not bssea subj c d to beat tre tmen -2:1-
fbs concent a ions of varioas f e® amino eids .in CTC ΜΜ Ι^ {he ted a d rsheated } were d& ersaia^d a$i» a T®v®r - ®. 8PLC method. a s rb&si E«Iips¾ MDi~€8 column w¾s us©d for the s ra ion; of ftaoc derivatisatsd amia soidsr In which an aceta e buf e /aei?tonitriles gradient -w s -eed as the stabile hasss, at a flow rate of 1.5 ml/mi.n. ha fluted c¾ro on®n s w e d«¾et&d asd u ntifi d ¾gi g a
The C C sam les £ ea <¾d and unheat dj »re pre ared s f l lovs s On®, gram of CTC as diluted In a 0.2 molar soluti n [ re ed by digsolving i§*8 g of sodium carbon te in one liter of wa ar* 0 si of the diluted; C C «a.¾ th n transferred to a clean vial* to w ich a 0,5 l of a stand rd amino sol i s added (pre ared toy di solving 2·δ to 0 of each amino acid standard in the afor«fcatl &*¾d .bas® solution, to a tirsal v®l¾ fc of 100 ml}* nfc ml of an s>c s lu i n ^ r ar d by dissol i g 40 of FPOC- RSO in 100 ml. o a ?5¾ sce ose / 251 wa er ix re) was dded to h vial, ic w s th&ti agitated •gently for 30 minute at rooii. tempers r©. ϊ» ord^r to pr^vopt rae misati n and dipeotide f .a¾at.i. R» the sapples prepared as d so fed above wre analysed within w h urs following tit® c m le io of tfo« Wt c reaction*
Ά calibration curve ¾ra.ss s blished ys n a a d j-o' s iutiosis of fr©# amino eid r a ed in th s ^e ma ner as t. i¾ C C sampler, a d u¾sd to deri t.h§ eo^ ^at a ioss of said amino ael ss in he C C s ples . ,T>. s r smelts obtained from a y issi BJ¾C rue ar« s
Figure imgf000023_0001
ffe«se res l s indicate- that ttm s is a. rednctloti in the total, amou t of tlm ussasur^d fr ¾ aasino cids in CTC heati¾g ( 1.07% i hm& md CfC as p osed o 1.88% in nh®at«d dTC'Si , ¥® *,h&rt mf »8t of this, £ d¾etio¾ is dus to t.h® marked dee e is in the concen r ion of free giu asKin from a level of B9I in ui.li@st.ed CTC to 0,Q5¾ in hea d CTC .
) Sugars ··· gl c&BW id fru &s®
The concentra ion a of globose and fructose la CTC sam l s- «at d and aftbeated) e measu ed xasinq n FLG te hni ue ·„ he rsssilts btained for t glucose d ruc ose assays in five ss & a © a ches of C before and after beat ing J a e Show 1» Figs* 3 and 4, r spec i ely. Tne s t of ars, a fch® front of <&m .figure epreis#nt& the esul s obtained for a ed CTC, while the rea et ra reise tiis results obtained R©&™fee t d CTC:. It can be ss n f∑osa these figures, that teatlrsg a CTC wplo esul s i& a de ease o£ ateou 3S& in fct» gln-coss conc@:si .rs. l ss oi assa a jri -Iais ,· id a ®cx® ® of a out 1 % In tbe fruc ose concentration* I ¾i? &
J¾ fa ther study smd@rt.atea in o de to •detemin® the dose dependent inhibi ion o alpha production by heated
CTC*
Bes ed cl a toma o Concent at fCfC was r ared s d teri-bed. ein bove > aero hagea ¾?ero stimu ate wi h £FS ia s p es nce of h toata CTC, d the l els of SF~ alpha, production me s d desc i d below) folXm^ing treatment i h the heated CT€. P-alph& tod etion ass y « Concentrations of HF~¾lpha e e quantified sing kit® { Bieiofend mc, , S xs Diego, Gft) ,· fMFGf odu i®n in ibi ion as o s d with he concentra ions of lie&ted-CTC indicated, bot w en ¾¾i.d heated~CTC as fr^^ ly-pr^ a ed and after storage for six moiTfchs at either t?os& tem era ure 1 degre s Cj csr at an accelerated stor ge
Figure imgf000024_0001
of 0 degrees C» re lts of t is study ar® euina&riKed in Fig» 5* sh n in hi figure;, addition of eat- re te CTC at dlff re& dilutions to t ma ro hages caws a d se de e d®at inhi i ion* slight inhibition by the atad CTC as first absesrrv at !;:208Cf dilution and wa much ¾3o:t¾ ma ked a a Is 1000 dilution... A tsBe-depen n incr as in e ficacy eing see up until a dilution £ 1:200, ¾i¾.ip¾ p in maximim {801} i∑shlMti∞ of T fo: r duc ion as observed*
Fur her,- it may @ s«s@ . f o® the bar g shown in t is figure {first bar ia eatSi groap of three te s tr¾at at all dilutions of h ¾t©d~C C th$t re ested, n IOS of Ί Έ' prodiaeti .* inhibiti as o served af er s orage for six m n hs s ssittar MS« tem e ature (2¾ d grees C? eco d bar i i¾aeh groap| o at an accelera ed s orage t« ^rat\srs of 0 degrees C ξ third bar in each grou ) ..
Mmaroph&g® I l ti n md :«.I « © - Per t neal macr ag s re collec ed from, fch® e ito e l, c vi y of 6- 8 ek old iile ICB mice {Harlan, IsraelJ t.tat had bgs n giv n int a er toneal injection of 1*5 ral of tM.©gIycGll.ai© o 4t) 4 days fore it* Peritaaeal
Figure imgf000025_0001
er ashed tnr e issss wit.¾ PBS and, if ad d,, a y oto i lysis of erythroeytes as form d, yielding 90-95% purity. ts® macr hages ware identified b FACS ai¾ l isi ng FlTOeonj ¾ated rat an siOTs®
MCA4S7F] (S rot#c, xfords England) by flow microfl orims rY o F.&CS { ar on piakinsoa ( Mmmtftia ¥ a¾?f £A.}* For -e c:. sample.t 10,0 0 light sc t er- ated viable cells w_¾r«s analysed * P&rt ontal mac ph ges w¾ a alt¾rad; i mm. M ^in coRtainiag 10% 2 wM L-glatamne
1-00 q/j¾l penicillin; 100- ysg/ml s re o ycin. ( eit- &enek, 4S-
lsira@l) in ist s {1 « 106 c®lls ¾«¾LI) at 3?¾ in 5% ec¾ amos e e, Cslla ¾®r<& s imu a d with W§ il » nu) in the rese ce asenc of Lycoraafco or CTC and t ei combinat ons*
In some x e ime s , Lye-o- git© s d ssol ed in ΐΜΒϋ o a final eoncen.tra i H of 5mm) » The ^i:^tu e vorte&ed and incu a ed, in a wate bath at 37¾ {with s aki g fo 10 min and then sonicated In soaie&hor a h three times for IS s conds sash time* Using this s ock solu t'h© desi ed cooc nt ationss ¾re e re ared b t e addition of a ro riate v l m s thereof to arm c lture medium*
The co& eft ration f lyeopene in he solution was de«mi»ed. after extraction as follows% 0.5 ml is a oi + h x&si die i o^ ne 1:5 v V) cwn aiftiftg
BH e e dded to 1 ml of lyco «ii® s-o atlois f es ly rs rs^ at con ent at on of ¾Ch.¾M in preheated msdiuss* The solution was vor«K.@d a d the ases ¾?e e s a t d centri itigatioa 3 ¾¾ m for 10 mln... s trum analysis is con ucte to measur the content of l eopen® ( absorption peak at 471 ius )
I® other expe.t eats, purified te a-carotene or lutein we us d in cos¾bin±i»ii i , the heated CTC. Stock solutions and dilu i ns of ©aci of th ® c^xo & id^ ere a ed escribed h&re rmbove in relation, to Lyc-O- s o. Ap rop ia vol¾»®s of DMSO {6-1-0*5*) were added to the c nt ols; and & erc n iftiiibitior. in a cii tes u s was •csl-csslat^d in r l tion to its esmtsfol. *
Cl r tomato Concentrate (C Q) s re red ,$ descr ed eiaafeo e aa i sine® it is watgf s luble , was directi to w&xm <mltun m dium at tbe esired dilations* tRlssis ther ise st ed, th@- heat-treated C € us d in this refe to C C that ¾as heated to 9 d g ees € far a period of m our,
Si pzoduetimt aBsay - BQ l wis n su rnatan s of cell cul ures ww@ dgs e ^i^ d by assaying nitrite levels using Gri@ss r#&ger¾t and s dium nitrite as a standa d as des i ed in Grws, L. C*, ner, D* &„f G ogo ski, 3»f Skip er, * L. » ishaok* Ji 8* » and t^nrabaiM 8, |1982 Anal Bi&Chem* 116; 13.1-138*
Statistical analysis --- Oatm are pr sen ed, s h an ± Βΐϋ* Statistical si^aificance for c m aris ns e ween gto¾ s Sfias d^t& ^ined using Stude t's ired two-tailed t est.
S mmrgig&i® ia&I tiim f MO pr&&uGti&a &γ e&tibinm imts of
&<f€&ma ® with k®M&&d € €* shown i Fig, 6, hes ^ is ¾yi¾®r§ist c inhibition of NO rod c on by LPS re ts
Figure imgf000027_0001
toy coa inati s of ea ed C C in the r ge of 1^ 0 to mODO dilutions i h 0,2 3 tyc-O-m&o» he first bar in ©act. pair of fears in h i u e i¾p es@Bts t & rssu.lt btaissd with heated-CfC: alone„ whil® th s cond ar in each pair re resen s the esul obtaiied i h a c m ina ion f t e indica ed dilu i n of te&fc d-TC and. 0,2 $m LyeoM&t , The resul s sho n at¾ thg eas alues for rs® ss ar&t® x erimen s* ssao performed in triplicate;*
'¾¾ greateit syae -gls ie etfas was ain d by & ooiinhin tion of CT dilution of ii4CHH? ¾sd.t.& 0,2 μ LycoSsa e* a caus d. 28.1+6% in ibi ion. Hesed-CSC {Ιί4009 aXoi¾ e u - »¾3*.!% inhibition &nd 0*2 Ijc&mto e&us@d ¾agI gl .¾ tahl tipr itmss the effect ®£ t is combinaion s 5,7 ld higher than the additive effect of each of thss
Ass s own ii Fi , 7,f
Figure imgf000028_0001
of asted CTC in th range of iiiGOe to I; 7)0 dilution with bo 1 μ end 2 M lute n, c us-a syj« gistic inhibition, of HO duc ion by LPS rs& sd ss sr hagss , ss results shows* ¾ e the y&lsie-s for three s arate ^x e imnta♦
It will b© n ted t at -t. © greatest synergistic: effect as ob ined by a combinat on of latelxi (¾t th cra-e®.ntr«tίosas st l togth« wi h eated C C ilu ions in th r&aige of Iϊ 000 to 1*5000. i s^ear&t&^ with &t&d € €~
Ά s¾o¾ra in Fig* 8, calcinations of heated CTC In the r&ag® of liie O fc Is 7000 dilu ions with 9*5 μ and 1 μ l^ -ear¾t¾¾e synergis ic inhibition of » production, by LPS trea d isacro hagess„ Tim res l s shown a e t *s »aa alues fo r e se a ate eri ents*
It will not d that ia the cas l 0*5 pm b a-carpt ae(- h grea es y^ gi^ti effect as ob ain by & dombiaa-ticm it!s heated CT dilutions i». th© range oi 1:2®Θ0 o 1*7000.. ss« results cX-a&rly iadioafce that fctece is a. syne gistic i& nac ion &* t¾? -®n heaed. CfC a.nd caro snoids i h egard o thgir ability to iahibit imf asim t an*
Figure imgf000029_0001
A s&rr&geen&n-'indu d a: irsf'I&Msia ioii mael i as used in ©rd@r to in estigate ®f ©« o ¾ c si ii¾ t oa of @a reat d CTC sad -tomato aleoresin
Figure imgf000029_0002
Ltd,, Is aeli on the roduction of e pr -iftflanm&torf cytokine, ILi~bet&,
Metho
Lyc^O-M ta* and h -t e ed C C { re ar d ass described! harslnahwe} w© # adnsinistamd | se ratal and tog ther) by t oral route to labo atory ra s o ce daily , for 1 days* ' icl fe a (a mi ist red i.p. tvo hours prior to c¾alleiif i was asad as & ositi e e atroi*
At day Si a e mge&isaa solution as in ected into the left, w o£ rats. Follo ing is Irs.jmo i n, inflamm tion* mediated hj the influ of n ro hils c gea r ia ROS and ro~in.i'i&Msatory cy okines,- develo ed in t & treated p * Sae isti a of the pro-iafl »4to y cy okine, in.torieukio.~4 beta iato the inflamed issm© was measur d «s g a s a dad kit*
It m y ba &®&® f m Fig. 9: that a combination of 3 m§/kg Lys-O-Ha- o (tomato ol# esin oget e wit 5 mg/kg oatad- CfC caused a marked and statistically si.9ni.fi0a.nt decre se in th¾ ie ra loii of li-lbe a. Into the inflmssd tissue, ¾is dmcxmm® was simila in magnitude to that caused bf the iclofenac; ositive co l*
Figure imgf000031_0001
oth piStecM-ast and osteoclasts a e involved ia feo © remodelin * fh® resent, investors h¾w fesrod that heated- C C i^prow foo&g healt by at Xe»»t tm &m®l m?i.&ry
I * Seduction of osteoclast di ferestiatior
2.» Stimulation of anti xidan - s¾s erns© Eleven! sigmliftg (»¾ »Ι2) in steo lasts* h¾ inhibit ry ffec of C C QS¾ l¾ l:L"i!ediat.ss-d stfcoelas •di£f®r ti iation a d aet vation was t di d in wltro* t ads t
2* O& &o let&t diff enti tian
C&lls f m ssoist »ii0cy ™sti¾c © age cell lim MS 2§4*7t an osfce ciast- r©¾? rs rs lin& s, ere in-o'uoated for 3 days with K&M&L 2:0 t&g/ial wit.ii or wit o CTC { non- ahe-d or h- a -sd a tte iactic&t&d dilutions md stalrse-d for AP activity a ssa k& for te cl sts differe ia ion! he ercent iR.Mb.ition was calculated £r«M the activity & taise4: i¾ the pt& % of waf s.l®m* L c&sa- o •C©qui¾¾i@i¾.±. to 1 ί iyeo sne} was &«*<®d as- indicatoei in Fig* t.. Da are from a repr sen sti oat of 3 x i,siset¾t¾f each performed in tri licates* 2. M&sss em t ®ί Antioxidant M p m- El mnt (ARE/mrfS} sig ali g in Q®i®obl&$
Culture* ®i C3T1-11 t lagtte cells ¾i e sed fo this ♦ CTC (hea ed and. n n- eated) alans, or tog t er
¾it the lyeo ea^ i 6,1 * xid ti n product was dd d to the arid M reporter q® r nscri ional ac ivi y was :ie&s¾reel i : aecor aace with t e et ods d iEjribed I« ee-o ii d WO 2067/643046. he 3fe&¾dt of this study a ® sOTMrig d ifi Figs. 10-12♦
,¾s s o its Fig. is:f bert heated and mm~ e&t d CTC ca s s dosss -rela ed imbibition of R ¾L- ed & ad asteoel st differentiation, as m asured, by R ? Howver, hea ing the CTC sa pQ.® remi s in a sii ni les&'& . increase In t e potency of C C in inhibiti fi osteoclas differentiation. fig* II r sette the results s ewing the inhibition of osteocl s dlf emnti&tiem cruised by eom na oos f ea - reat d CTC with lyco e , Comp risen of the revisi s of t e ¥atioiss reatments sh wn in the graph indicates s ft flsf be ween lycc ene and h¾ai- eated C C.
Fig* 12 r s n s r sults e^o iiig s i»ia i ¾ of d se™ relat d «I &.ig¾&ling in cultu ed C3¾?3 o edbXastie by mea s of treat»nt with e ted CTC. it may also observed that o - iatjsd € C h s no effect in thi mod^l* 42
While* speci i es-bodimsnti of t e inven ion h ve bee stess ltngd for the ur ose f illust ation* it will b¾ ands» s od that t -e i en i n may e carried ut I . ractice te skilled rs ns with is&fty ra«xli ica ioas? variations and adaptations-»· w fcisciu de a t ng ro^ its s irit or ^eisdi¾g tfee s-e © of tfe claims.

Claims

i h thar& esit e com ositio cosa risi&g h£& -t ©&tedi cle r to o concen ra e (CT€ ,
2. ra -e^ ic com os i n according to clais? li ¾h r#irs the* total fr@@ ssalno acid concentration is less than 2% w/¾\
3» he t erapeu ic composition ac ording to claim 1# ere tftss free gl¾staMi¾e concentration is loss than 0.1 . A era eu ic composi ion gom risirsf a synergistic csst isatipn of !iest-tre tecl clear tomato c ncentrate CTC) and on or mor® carotenoids s
5. he t erapeutic opposition cco ding to claiis * wherein t ® t tal frees mi a id concentratio i£ less
(„ T ® r ut c ssp!S tiof¾ acc rding to l irfi * ¾rt½ eirs fret? latmi e concentration is- le than w,
7 * '!k t!½ra 8Utio composi ion according to atvv on«s of claims -i(r tersi t e one or Bore arotraaids is selec ed frcaa th& group consisting of iyco &n®„ tiy osns, p'bytofiuene,, bet&-c&rofc$?i@ md lot¾in,- and/o de i a ives tiiereox ,
8* era o c com osition according to elai_8 ?<■
*hersi& th aro onoid is lycop ne o -s derivative t ere f. 5* T h rape tic com ositi n according to any one of claims 4- , the -on® or more ca ot noids & g prwid®& by a ma oleoresie* i0* e t er eu ic composi ion according to ay one of cl ims -t# wl¾e el¾ he total eons@Rtrat.iaii of the carotsnoisis in id com etition is at least S*-l¾ | w) .
11. e tara ©Btia com o i ion ^ec rdisg to claim 1.0 # •¾ter¾i& e e aee¾tr¾tioa of l^eo me is at le s
12* & ethod for is ii¾g o reducing t ¾ duc ion of m m^i-lMlmmmt& mediator in a su jec f comprising administering to said s ject a therapeutic com ositio aocordiftg t f one of cl ims 1 to 11.,
13* lie fisetho accordin to «1 alias 12, a tas* anti-
Figure imgf000035_0001
consis ing of ϋ TSF- alpha and inter Issrtk in 1*
14 * & SKStfe d o£ tr&s * t of pathological conditions in whicb W ~.alp.ls» antS or ifttttrleukift Ι-be · ^ets ss a m dula or or mediator of said, condition in a ms»al.i«*i¾ su jec in sm®d of s ch fcreatawnfc, w ic mid e od com rises ad inis erin o mid su ject a fch#r&psu ie eos ositioxi sei co in , to &ay of claims 1 t II*
15* e metlio of atmen according to claim 14, w er in he conditior* to bt tres i ar¾ inf laamat ry condition* -i>3-
16, Tfee rct©t.hqd tre tiTs nt ac ording to elaim 14, ¾* ©r©In t e condition to . e re ted is selected r the grou c nsis i g; of rheumatoid: arthritis, adult, respi atory d stress syn4 (J¾H S) , asthma, ini i , di a h nl:£¾ na.ry fi osis* eri oni ist cardiov scul r iaflaimafei E, myocardial
Figure imgf000036_0001
epe faei injury* atherosclerosis, se sis, rauma, diabe es; y © II f .re i o a y, soriasis gas ointes nal Infla^mati n, ci osis, peritonitis and I il im o y b wl dise se, and n ¾rodi g n! ii:w diseases^ inoioding s eime * s disease,
11* A te isod for im rovi g one health in s§abjec * c m risi g dmimsieri:ft to said su jec a thera eutic com ositi n according to any o of el&iass i to 11*
18* T e m od according to eXaiss 1 , w ereia the im rovem nt in bo¾e health c mrises the inhibition of bone reso i
19. he method according to claim i? * wherein s id meth d is use to treat a conditio selected itom the grou oonsietlng of osteoporosis, arthritis, pe i dontal dis^as^, mul i le
Figure imgf000036_0002
c n rs*
SO, The method according to any on® of. claims .2 to 19, wherein the t era utic com osition is adminis red in a pharmaceutical do& f m*
21. h® me ho according to a y ne of claims 12 to 19.f wherein the therapeutic com si io s incor or te into- a foodstuff or b v rage,
22. A therapeutic com osi ion c m ising C C laying a total free amino acid concentrat ion. of IBB tx 2% w/w*
23. A therapeutic composition comprising CfC h ving a free glut&asimsi concentration oi l thm 0.1% ¾f/w,
24. A therapeutic composition eac!v ififif & synergis ic c«h±na aR of ons or m s ea o #i$oiSs toge h r with € C* ¾xerein th total free mino acid eou¾€^¾- a. ion in said CfC s l ss a 21 / *
25* A t er u ic cosmositi©s c m ris ng a synergistic ea¾ i¾at oi of ¾e <s &m earot tioids tsgot ar with CTC* ersin tta frse gi^tamia c ncentratioft in said CTC is less thafi 0*1% /w.
26. A thera outi omposi i n comp i^iftg a syne gist c com ati m of c or j¾o:e carotenoids oge her with CTC, h@rsin h COTC«a ra ioB o s id «i½tgno s i& at least.
27. fce therapeutic expos tion acco ding to claim 26, QSi r sisg lyaopane at a. co»centxation of at Issas 0.1%
PCT/IL2014/050075 2013-01-22 2014-01-22 Compositions comprising heat-treated clear tomato concentrate Ceased WO2014115140A1 (en)

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EP14742819.7A EP2948005B1 (en) 2013-01-22 2014-01-22 Compositions comprising heat-treated clear tomato concentrate
JP2015553229A JP6641180B2 (en) 2013-01-22 2014-01-22 Composition comprising heat-treated transparent tomato concentrate
RU2015135595A RU2015135595A (en) 2013-01-22 2014-01-22 COMPOSITIONS CONTAINING THERMAL PROCESSED TRANSPARENT TOMATO CONCENTRATE
MX2015009385A MX2015009385A (en) 2013-01-22 2014-01-22 COMPOSITIONS THAT INCLUDE CONCENTRATE OF CLEAR TOMATO TREATED WITH HEAT.
CA2898284A CA2898284C (en) 2013-01-22 2014-01-22 Compositions comprising heat-treated clear tomato concentrate
BR112015017355A BR112015017355A2 (en) 2013-01-22 2014-01-22 therapeutic composition, method for inhibiting or reducing the production of an antiinflammatory mediator in an individual, method of treating pathological conditions and method for improving bone health in an individual
CN201480017192.5A CN105228467A (en) 2013-01-22 2014-01-22 Comprise the composition through heat treated clear tomato concentrate
US14/762,343 US10993982B2 (en) 2013-01-22 2014-01-22 Compositions comprising heat-treated clear tomato concentrate
ES14742819T ES2824204T3 (en) 2013-01-22 2014-01-22 Compositions comprising a heat-treated clear tomato concentrate
KR1020157022879A KR20150109471A (en) 2013-01-22 2014-01-22 Compositions comprising heat-treated clear tomato concentrate
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