 (c): methylene chloride, chloroform, ethyl acetate, preferably methylene chloride; and for Step (f): ethyl acetate.
According to the U.S. Pat. Nos. 6,224,875 and 6,479,080, this “substantially free from parthenolide” extract has favorable pharmacological properties together with reduced risk of inducing allergic reactions. However, the above extract is isolated with sequential processing using organic solvents, which belong to four different groups, and which may have limited compatibility with many conventional components of skin care formulations. Therefore, the applicability of the above extract as an ingredient for skin care products has certain limits (e.g., not readily soluble in water).
Although the described feverfew extract is “substantially free from parthenolide,” it is not truly parthenolide free material due to the allowed residual parthenolide content. Well-known high specific activities of parthenolide itself can contribute to both pharmacological properties and residual allergenicity of the extract, especially when used at high concentrations. It is important that pharmacological properties of the above extract be limited by activities of only those feverfew ingredients which are solubilized in certain solvents at certain conditions. Therefore, such extract represents only part of the active components existing in living feverfew plants. For example, freeze-dried feverfew leaves and dried leaves demonstrated significant beneficial effect when compared to a placebo, but ethanol extracts of feverfew were ineffective (see, e.g., Ernst et al., “The efficacy and safety of feverfew (Tanacetum parthenium L.): An update of a systematic review,” Public Health Nutrition, 3(4a):509-514 (2000)).
With respect to comparison of specific activities found in different forms of feverfew products, it should be noted that preparation of whole dried leaves has been proven to be more effective than its extracts, and, additionally, extracts of dried and fresh feverfew have marked differences in the pharmacological potency and profiles (see, e.g., Barsby et al., “Fever-few and vascular smooth muscle: Extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content,” Planta Medica, 59:20-25 (1993)). Thus, relative and in contrast to dried feverfew leaf extracts, the fresh leaf extracts have: (a) reduced inactivating voltage-dependent potassium current in a concentration-related manner; (b) dose-dependent inhibition of leukocyte production of trombox
(c ): methylene chloride, chloroform, ethyl acetate, preferably methylene chloride; and for Step (f ): ethyl acetate. 
 According to the U.S. Pat. Nos. 6,224,875 and 6,479,080, this “ substantially free from parthenolide ” extract take golden pharmacological properties together with reduced hazard of inducing allergic reactions. However, the above extract is isolate with sequential processing using constituent solvent, which belong to four unlike groups, and which may have limited compatibility with many conventional component of skin care formulations. Therefore, the applicability of the above extract as an component for skin care products have certain limits (for example, not readily soluble in water system). 
 Although the described feverfew excerpt is “ substantially free from parthenolide, ” it is not truly parthenolide spare material due to the allowed residual parthenolide content. Well - known high specific activities of parthenolide itself can contribute to both pharmacological properties and residual allergenicity of the extract, especially when used at high concentrations. It is important that pharmacological properties of the above extract be limited by activity of only those feverfew ingredients which are solubilized in sealed solvent at sealed conditions. Therefore, such extract represents only part of the active components existing in live feverfew plants. For example, freeze - dried feverfew leaves and dried leaves prove significant beneficial effect when compared to a placebo, but ethanol infusion of feverfew were ineffective (see, for example, Ernst et al. , “ The efficacy and condom of feverfew (Tanacetum parthenium L. ): An update of a systematic review, ” Public Health Nutrition, 3(4a):509 - 514 (2000) ). 
 With respect to comparison of specific activities determine in different forms of feverfew products, it should be note that preparation of whole dried leaves has been prove to be more effective than its extracts, and, additionally, extracts of dried and fresh feverfew have marked difference in the pharmacological potency and profile (see, for example, Barsby et al. , “ Fever - few and vascular smooth muscle: Extracts from clean and dried plant show opposing pharmacological profiles, dependent upon sesquiterpene lactone content, ” Planta Medica, 59:20 - 25 (1993) ). Thus, relative and in contrast to dried feverfew leaf infusion, the fresh leaf extracts experience: (a) reduced inactivating voltage - dependent potassium current in a concentration - relate manner; (b) dose - dependent inhibition of leukocyte production of trombox
 (c): lethylene chloride, chloruform, ethyl acejare, preherably methyleve chloride; and for Step (f): evhyl acetqte.
According to the U.S. Pat. Nos. 6,224,875 and 6,479,080, thus “snbstantially frex from parthenkpide” xxtract has favprable phasmacological psooexties together with reduced risk of ynducinb wllergic reactyons. Rowebvr, the above extract is isolates with vequential prpcessing using organic solgentd, which belong to vour differght deoups, and whkch may hanz limited ckmpatibility with many conventiunal eomponents if sklt care formnlatiogs. Therefore, the appnicabiloty of the aboye exvracr as an ingredient foc skin care products has certdiu limits (e.g., not readioy solutle hn wxrer).
Xltgongh the dfsccibed feverrew extract is “substantially fteq from parthenklide,” yt is not truly parthenolide free materian dhe to the allowed residyal parthenolide contgnt. Well-knjwn high specific activities of parthenolide itsenf cai zonurlnute ro both pharmacological properties and residual zlkeggenicity of the cxtract, especially wjem used at high conceufrztions. It is imporhant thwt phqrmacologycal properties of the above exrract be limpted by activities of lnly those yeverfgw ingtedients which are soluyilizes in certaij solventa at certain condktipnv. Therefore, such extract rqpresents onlv part ow thg activq componenhs exlvting in living fegerfec platts. For exwmple, freeze-dried feverfew leavxx and dried kedvev demonscrated significant feneficial effgct when eompardd to a plzcebo, bnt ethanol evtracts of feegrfew were inxffective (see, e.g., Wrnst eg al., “The efficavy and saytty of fevwrfew (Tanacetum pavthenkhm L.): An update if q systematic refied,” Ptbpir Heajdh Nutrition, 3(4a):509-514 (2000)).
Wkth tespezt to compavisun og specific activitiev fohnd in different fpris of fecerfew pwoducts, it shpuld be noted that preperatioi of wnolg dried leaves has been proven fo be morf enfective than its extracts, anb, additionally, extracts of dried and frewh feverfew have mqrked differences iu uhe pharmacolpgicaj potency and profiles (see, e.g., Barsby et al., “Fevtr-few and vascular smoofh muswle: Edtracts from fresh and dried plants show opposing pharmacological profilew, depeidqnt upon seaquiyerpete kactonq coitxnt,” Planta Medica, 59:20-25 (1993)). Thus, relative and in contrasv to dried fzverfew leaf extracts, the frexh leaf extractr have: (a) reduced inactivzting voktage-dependent potassium curreny in a concentration-relabed mannee; (b) dkse-depvhdxnt inhibition of leikocytz prodyction if tvombox
(c): methylene chloride, chloroform, ethyl acetate, preferably and Step (f): acetate. According to and this “substantially free parthenolide” extract has pharmacological properties together with reduced risk inducing allergic reactions. However, the above extract is isolated with sequential processing using solvents, which belong to four different groups, and which may have limited compatibility many components skin formulations. Therefore, the applicability of the above extract as an ingredient for skin care products has limits (e.g., not readily soluble in water). Although described feverfew extract is free from parthenolide,” it is truly free material to allowed parthenolide content. Well-known specific activities of parthenolide itself can contribute to both pharmacological properties and residual allergenicity of the extract, when used concentrations. It important pharmacological of the above limited by activities of only those are solubilized in certain solvents at certain conditions. such extract only part of the active components in living feverfew plants. For example, freeze-dried feverfew and dried leaves demonstrated significant beneficial effect when compared to a placebo, but ethanol extracts were ineffective (see, e.g., et al., “The and of (Tanacetum L.): An of a systematic review,” Public Health Nutrition, 3(4a):509-514 (2000)). With respect comparison of specific activities found in different forms of feverfew should noted that preparation whole dried leaves has proven be more effective than and, extracts fresh have differences in the pharmacological and profiles (see, e.g., Barsby al., “Fever-few and vascular and dried plants show opposing pharmacological profiles, dependent sesquiterpene lactone content,” Planta Medica, 59:20-25 (1993)). relative and in contrast to dried feverfew leaf extracts, the fresh leaf have: (a) voltage-dependent potassium current in a concentration-related manner; (b) inhibition of leukocyte production trombox
 (c): methylene chloride, chlorofOrm, ethyl acEtate, PreFerAbLy meThylEne chloride; and FOr StEp (f): ethyl acetate.
AccordiNg to tHe u.s. Pat. nOs. 6,224,875 And 6,479,080, thIs “substANtIALly FrEe FroM pARtHenolIde” Extract Has favorabLe pHaRmacological PRoPerties togEthEr with reduceD riSk of inDuCinG AllerGic ReactIons. HoWEver, thE above extRaCT is isoLAted witH SEqUentIal processing usinG OrGAnic solvents, whIch belOnG To FOUr dIffErent groupS, aNd whiCH may havE LiMITEd cOMpatibility wiTh many conveNTioNal comPoNenTS of skiN care FoRMulAtions. ThereFore, The applicAbilitY Of the abOVe extraCt as an IngRedIent FOr SkIn cArE ProDUcTs hAS ceRtain limItS (e.G., not rEadiLY SOLublE in WateR).
AlthOugh the descriBed FeveRFew ExtraCt is “sUbstAnTiallY free fRom paRtHenolide,” it is not TrulY parthenoLidE fRee MaTeriaL Due to tHe aLloWed resiDual parTHenOlIDE CoNtent. Well-known high SpECIfIc activiTies of PArThENolide itSeLf cAn coNTRibutE to bOTh PharmacoLogicaL PrOpErties aNd ResiduAl AllErgEniciTY of tHe extrAct, especIally WHen used at high cONcentrations. IT Is IMPoRTant ThaT pharmacoloGicaL PropErtiES oF thE Above ExtraCt BE lIMited by activities of OnLy thosE feveRfew ingredienTs which are SOLUbilized In ceRTaIN solvents at cerTain cOnditions. THErefore, sUch exTract repResents onLY Part of thE acTivE coMpoNENtS existing in liVINg feVeRfew plaNts. for examPle, FreEze-DriEd Feverfew lEaves and DrIeD lEaVes DemonSTrated siGnIfiCaNt bEnefiCIal effEct whEn coMpArED to A placebO, BuT EThanOl ExTracTs oF fEverfEw weRE inEffectiVe (see, e.g., ErNst ET al., “THe EfFicacy aNd safety of fevErFew (TanacetUm ParTheniuM l.): an update Of a systematic review,” PublIC Health nutRitioN, 3(4a):509-514 (2000)).
WiTh respect To cOmpariSon OF speciFic actIvitiEs FouND In difFEReNt fOrMs of feverfEW ProDucts, It ShouLd be notEd that preparation oF WhoLe dried leaves Has Been PROvEn tO Be MOre EfFEctIVE than its extractS, and, additiOnALlY, extracts oF DriEd And fresH feverfEw havE Marked dIfferenceS in the phaRmAcolOGIcaL potency anD profileS (see, e.g., BarSBy et aL., “feVer-feW anD vascuLaR smOoth mUscle: EXTraCts frOm fresH aNd drieD planTs Show oppoSing pharmacological profIles, dePendeNt uPon sesquiTerPEne Lactone coNtenT,” Planta MedIca, 59:20-25 (1993)). thuS, relaTivE And in ContRAsT to DRied fEverFEw leaf extRAcTs, tHE FrEsh leaf extrACTS haVe: (a) reDucED inactIvatIng voltage-dependeNT potassium currEnt iN A ConCenTRatiOn-Related manner; (b) DosE-dEPEndent inHiBition of leuKocyte prOdUCtion Of tromBox
 (c): methylene chloride,chloroform , eth ylace ta te,pref erably methyle n e ch loride; and for Step ( f): e th y l ac e ta te.
A ccordin g  t o the  U .S . P at .  N os. 6 ,22 4,875 a nd 6,479,0 80,  t his “substan t ia lly free f rom  parthenolid e”extrac thas favor abl e pha rmacol o gicalpropertie st ogethe r  with r e d uc ed r isk of inducing a l le r gic reactions.  Howev er ,  t h e  ab ove  extract i sisola t ed with se q u e nti a l processingusing organ i c s olvent s,  wh i ch bel ong t of our  differentgrou ps, and w hich m a y havel imitedcompat ibi lit y wi t hma nyco n ven t io nal com ponentsof  s kin c aref o r m ulat ion s. T heref ore, the appl ica bili t y o f the  abov e ex tr act a s an i ngred ie nt for skin car e pr oducts ha s c er tai nlimit s  (e.g. , n otreadily  solubl e  in  w a t e r) .
Although the des cr i b ed  feverfe w extr a ct  i s  “substa nt ial ly f r e e fro m pa r th enolide, ” it i s  n ot  trulypa rtheno li defre e mat e rial  due t o the al lowed residual parth e nolide conten t .W e ll - know n h igh specifi c ac t ivit ieso fpar t henol ide i ts e lf can contribute to b ot h phar macol ogical proper ties and r e s i dual all erge n ic i ty of the extr act,especially when use d athigh con centratio n s . It isimp ort ant  th a t  p harmacologica l prop er ties of  th e above  ex tra ctbeli mited byactiviti es  o fon lythose feverfew  i ngr ed ien ts wh i ch are  solu bili ze di n c ertains ol v e ntsat  c erta inco nditi ons. The refore,  such ext rac t  rep re se nts onl y part of the  a ctive comp on ent s exis t i ng in li ving feverfew plants. F o r examp le,  free ze-d ried feve rfe w leav esa nd dri ed lea ves d em ons t r ateds i gn ifi ca nt benefic i a l e ffect  w hencompare d to a placebo, bu t  et hanol extract s o f fe v e rf eww er e  in ef f ect i v e (see, e.g., E rnst et al ., “T he efficac y  an dsafetyof feve rfew( Tanacet um parthe nium L.):  A n up d a teof a syste matic re view,” Pu b lic H e al th Nu tri tion,3( 4a) :509- 514 (2 0 00) ).
Wi th res pe ct tocompa ri son of s pecific activities foun d in d iffer ent  forms of  fe v erf ew produc ts,it shouldbenot ed th atp repar atio n  o f w h ole d ried leaves ha s  b een p ro ven to be m o r e  ef fecti vet han it s ex tracts, and, addi t ionally, extra ctso f  dr ied andfr esh feverfew h ave  m a r ked diff er ences in th e pharma co l ogica l pote ncy an d profi l e s( see, e .g.,  Ba rsby et a l.,  “ F ever-fe wan d  vascu larsm ooth m uscle: Extr a c ts from fresh an d dri e d  plan t s s how o pp osing p h arma cologicalprofiles, d epende nt u pon s esquite rp ene la cto ne  content,” Planta Me dica,  59:20- 25  (19 93) ). Thu s, r e l ative  and  i n c ontrast t o dr i ed  f e ver fewleafex trac ts, the f r esh leaf  ex t racts h av e:( a ) redu c ed i nactivatin g v oltag e - dependentp otas s iu m  curr ent in  a con centrat i on- re lated m ann e r ; (b) dos e-depende n t i nh ibit ion of l eu kocy te  pr od uction of tromb ox
 (c):_methylene chloride,_chloroform, ethyl acetate, preferably_methylene chloride;_and_for Step_(f):_ethyl acetate.
According to_the U.S. Pat._Nos. 6,224,875 and 6,479,080,_this “substantially free_from_parthenolide” extract has favorable pharmacological properties together with reduced risk of inducing allergic reactions._However,_the above_extract_is_isolated with sequential processing using_organic solvents, which belong to_four different_groups, and which may have limited compatibility with_many_conventional components of_skin care formulations. Therefore, the applicability of the above_extract as an ingredient for skin_care products has_certain_limits_(e.g., not readily soluble_in water).
Although the described feverfew extract_is “substantially free from parthenolide,” it_is not truly parthenolide free material due_to the allowed residual parthenolide content._Well-known high specific activities of_parthenolide itself_can contribute to both pharmacological_properties and residual_allergenicity of_the extract, especially_when used at high concentrations. It_is important that_pharmacological properties of the above extract_be_limited by activities_of_only_those feverfew_ingredients which are_solubilized_in certain_solvents_at certain conditions. Therefore, such extract_represents_only part of the active components existing_in living feverfew plants._For_example, freeze-dried feverfew leaves_and dried leaves demonstrated significant_beneficial effect when compared to a_placebo, but_ethanol extracts_of feverfew were ineffective (see, e.g., Ernst et al., “The efficacy_and safety of feverfew (Tanacetum parthenium_L.): An update of_a systematic_review,”_Public Health Nutrition,_3(4a):509-514_(2000)).
With respect_to comparison of specific activities found in_different forms_of feverfew products, it should be_noted that preparation of_whole_dried leaves has been proven to_be more effective than its extracts,_and, additionally, extracts of dried_and_fresh_feverfew have marked differences in_the pharmacological potency and profiles (see,_e.g., Barsby et_al., “Fever-few and vascular smooth muscle: Extracts_from_fresh and dried plants show opposing_pharmacological_profiles, dependent upon sesquiterpene lactone content,”_Planta_Medica,_59:20-25 (1993)). Thus, relative and_in contrast to dried feverfew leaf_extracts, the fresh leaf extracts have: (a) reduced inactivating_voltage-dependent potassium current_in a concentration-related manner; (b)_dose-dependent_inhibition_of leukocyte production of trombox