CA2141126A1 - Combinational drug for treating migraine and other illnesses - Google Patents
Combinational drug for treating migraine and other illnessesInfo
- Publication number
- CA2141126A1 CA2141126A1 CA002141126A CA2141126A CA2141126A1 CA 2141126 A1 CA2141126 A1 CA 2141126A1 CA 002141126 A CA002141126 A CA 002141126A CA 2141126 A CA2141126 A CA 2141126A CA 2141126 A1 CA2141126 A1 CA 2141126A1
- Authority
- CA
- Canada
- Prior art keywords
- composition
- sesquiterpene lactone
- complex vitamin
- riboflavin
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A preparation for pharmaceutical use, especially in the treatment of migraine, cluster headaches, arthritis and bronchial complaints, comprises a sesquiterpene lactone such as parthenolide and B-complex vitamins such as riboflavin (vitamin B2), as well as a method of treating and providing prophylaxis against such illnesses by use of such a combination.
Description
CO~B~q~ DR~
F0R q!~T~ ~.
PI OF ~B ~rI
Thisl invention relates to aompo~itions and metho~
u6eflll in 'chs treatment of migraine h~ches and re3~ated il1n~ 6.
1121D QF ~ r~TIo~
Ths ~ncidenc~ of migraine including clufft~r ~ ch~s, i~ 6aid to ~e ~y~LOXi~ately lo-ao~ of the male population an~ Z 0-3 OS of t~e femal~ population. Trsa~ment ~or ~any pati~nt~ havi~ the occaffional migrain~ involve~ 3imp~e analgesics ~ith or without s~dative~. approximately 10~ of ~igraine 6u~fer~r6 hav~ three or more attacks per month and warrant prophylactic treatment. ~wenty-five to ~i~t~
.
.
-`- 2141126 , percent o~ thl~ group benef~t ~r~m treatment w~th beta-adr~nor~cept~r ~locking agent~, cl~nidine or, in the femal~
s~f~erer, ge~tag~n hormonQs. In the re~aining population of migra~ne ~uff~rer~, and ~ n tho~e with intolerable s~de-s~fectg from availabl~ drug~, th~re i~ a laoX of con~elll ional pharmaceutiaal prep~rat~on~ that sxhibit therap~tic Qffsct, wit~out ~svere ~ide-Qff~ct6.
F~v~rf~w, rich in ~e~quitel~c.le lactone~, principally parthenolide, hag algo besn ~hown to hav~ a prophylactic effsct again~t-migraine. ~n one ~tu~y, mors than ~0~ of the fevsrfew Users cla~ed that the herb haa d~cr~a~e~ the frequency of.thelr att~ck~, cauesd th~m to be l~ pain~ul, or -~oth. In another 8tu~y, ~xt~-eight p~C~L of ~igrainQ
~Uf~t-~l~ d~played ~m~lO~Qment when tr~ated y~ ylac~;c~l~y wlth riboflavin.
Al~h th~ ~ ~ cau~ or ~ of ~igrain~
arthrl~is, an~ a~ r~a~n ~ , all three ~ ee - are a~c;~t4d wi~h a :postulatQ~ local or gy~temic relea8e of active ~uL c~ o ;~l--A~ n t~e ca~e Of mi~raine and/or it~ variant~: ..w~ ephrins (--vra~ n~l ;ne), ~-h~d~ L~y~mine (~erotonLn~, histam~ne, ~ p51~n~na and ~l~dy~;n~n; ~n the ca~e of arthr~is~ pro8tagt~ n~, higtam~ns, 5 ~L~L~ am$ne ana brady~1~;n; and in t~e ca~;e of a~thma; his~mine, 5 l~J~ yL~ ne~ brady~n;r~
25 acetylcboline, ~G~I,J~3~ n~ ~nd the leukotrien~s.
endo.~ ~-o~ t7 hav~ in- co..,. ,on t~ h; 1 Sty to cau~e ~mooth m~scle to cc ~ act ti.~. go into ~epa~m~, and ~a~y - are also pai~ n~ ~ubst~r~Ge~, e . g . S--hydroxytryptamine, braClykinin, histamlne and 30 pro~:taglAnA~ . Non--sQ3.eCt$ve an~:agoniC t drugs wil~, ther~for~, not only reduc:s t~ ~mooth muscular spasm (o~
. .int:rscranial blood ~e~;s~ls in t;h~ case o~ migra~n~, or bron~h~ moot:h muscle in the ca~e of asthma~ ~ut a}~o th~
pain (o~ ~igraine and arthr~ti~ a~ociat~d w~t~ their 35 r~lease.
8esquiterpene lac~on~s ar~ known to b~ pre~ent in many pl~nt~, for exampl~ ~n A5ter~c~a, Nagnol~ac~ae, and in particular in Tan~c~tum parthen~um (f~ver~ew~, an~ are thought to b~ re~pon5ible for ob~rved bioactivity of the leaf mater~ al .
su~A~Y OF TH~ I~V~IO~
It ha~ no~ been di&oo~c ~ that a mixt~Q o~ a ~esqu~t~rpen~ lactone and a B-vi~am$n, is esp~c~ally effeGtive in both the ~e~Lm~nt an~ prophylaxis of 10 migraine, arthrit:i~, and a2~ ~ a~
In aocordanqe with the y~. ~nt invent$on, a se-quiterp~ne lacton~a, or a 2~0~ ~ of se~
l~ctone~, s~lch as se~ait~.e, laa~ .a c~ n~n~ plant~
asld ~lant ex~r'aats, i~ u~ed in cc~ n~tion W~th a B-compl~x 16 ~ita~in, Bt~h as ribofla~rin. i ~a~ lo~ ~mpriging eeuGh a coD~bination are al~o pro~rided that: hav~ ~har~aceut1 cal u~e, par~ ly in the tr~atment oi~ ~gra~ne, inc~udin~
ClU8t~ hq~r~ an~ variou~ rit~ c and ~LO-~
condition~, OEUtih ag a~thma~
~ ~ D~8C~r:~l ~ ~S ~1~ ~3~1!1!~
q~e 8-complex vit~n t~at i~ u~eful in accorClanos with t~e ~ ~ t i~vent~on includ~6 riboflavin, r~boflavin -te, flavin ~ n~ ~n ~n1sotia~ niootin~c aciCl-, folic aaid, cy2~ ha l~in, para-amino benzoic acid~
25 thia~ns, pyr~ , panto'rh-n;~, aci~, ~iot1n, choline inos$tol, and carn~tine.
The ~e~qUitsrpQne lacton~ that i~ u~eful in aac~rdance with the ~~ ~t inv~ntion include~ ~ ~cranolid~, ~ A~lid~, and ~ ~lidQS, in particular tho~e se6qUiterpQne lac~one~ having an ~-m~thyl~ne &ub~tituent in the la~ton~ ring, ~uch a~ parthenolide. ParthQnolide and squiterpene lacton~-con~n~ plant material~, ~uch a~
~verf~w l~a* or extract~ fro~ such plant mat~rial~ are . prQferred . .
~1~1126 Although bath ~e~qUit~rp~nQ la~ones and 8-complex vitA ~ n~ have bee~ found, individUally, to be effect~ve for treatm~nt or prophylaxis of migraine, ~he combination ~f the two typ~ of active~, in accordance with the pre~ent ~nv~ntion, leads to eyn~rgist~c ef~cts. Thus, a combinat~on o~ f~ver~w or other ~ourc~ o parthenolids with a B-vitamin additiv~ lead~ to a further d~crease in the frQquency of ~h~ attacks an~ cau~e~ the attacks to b~
l~g painful. An inCreasQd perc~nta~Q o~ m~graine sufer~rs ~hould thQrefore d$splay an improvement in frQquency~ sQVerity~ or bo~h, wh~n treated prophylactically with th~ comb$national ~rug. ThQ co~b$national drug ~a~
low to~ty, ~ty~ i~ingly few ~id~-e$f~cta an~ may be ta~en for ~he ext~ fl p~riod~ required for effsct~ve 15 ~ o~h~l~xis, w~ thout ~ e re;~c~ion~ .
~OP~ ~-~ ANn Pua~t~ T~ ~p~D-~T~a~ N
The ~c -~o of ~ctivo ingredients w~ll, of couree, vary fra3l~ indlYid~lal to ind~vid~lal an~ will ~E!~n~ upon many ~a~or~, inal~ boa~ ~reight, nleta~1 i~m, and 1:he lilce.
In general, ho~rer~ t i6 believea that, in l~o'ch treat~ent and ~-~pl~laxi6, a giVen indlvi~ual ~ 1~ receive ~rom abo~t S0 to about lO,O00 mi~r~y~ms, preferably ~rom about 250 to a~out loOO ~ic~vy ~ms, and ~ost p~ferably a~out 250 ~i~r~.~ms o~ eesquiL~cne lactone, ~u~h a8 F~r~henolide, per d~y. ~n general, it ia a~o believed that a gi~en individua~ ehould rece~ve fro~ about 0.1 to about 5,000 gram~, preferably from about 100 to about 500 ~illlgram~, an~ modt preferably about 400 ;ll~gr~m~ of B-co~plQx vitamin, s ~ t~lly r~hnflAvin, per day. More, hc~ , may ~e need in the case of aCut~ attack~.
Th~lS, in accordanc~ with th~ prssent inv~ntion, phar~ac~utical do8sge ~orms ars prov~ l that conta~ n 50 to about lO,OoO mi~o.J~ , preferaPly ~rom abou~ 250 to about lO00 m~ -;r 0~L , an~ mo~ preferably a~o~lt 250 mi~ o~ se~iterpene lacton~, ~u~h as par~henol ~ de, in combinat~on with abaut 0.1 to about 5,000 milligram~, - pre~rably from about 100 to about 500 milligram~, ~nd mo~t pr~erably about 400 m~lligrams of B-compl~x ~ltamin, e~pec~ally r~boflav~n, p~r day.
In gener~l, ~uch pha~aCeut~cal do~age ~o~ms ~ay compr~e from about 5 to 300 mg, e~pQcially 50 to 200 mg, of f~verfs~ lea~, contA;n~ng a~out 250 m~crogl~ of parthenolidQ, in com}~ination with from al~out 0.1 to 400 mg o~ riboflav~n per day. For treat~ent, mors than onQ dose ~ay be required, as in thQ casQ of the treatment of an acut~ ~ttacX of m~graine or a~liQd di~ord~r. Th~ fever$ew ~ ~ may ~e adjusted to ~ccommodat~ thQ nat~urally vari~le level~ of ~Qs~uiteL~-e lactone~, s~ch a~
parthen~lide. A par~ ~ly pr~f~rred c~p~ e contain~
16. abaut 125 mg o~ hiy~ pa.lh~nol;~e fsverf~ and 400 mg of r~boflavin. 'It ~S prQferrea that thQ c~mpo8ition o~ the nt inv~ntion be aomini~ersd as t~o tablst~ daily;
~a~h tablet cont~ ng 125 mg fs~erf~W (cont~in;~ 250 mq o~ ~sqult~ ~.~ - lactone) an~ 200 mg r~boflav~n or oth~r B-GomplsY vitamin.
For thQ L ~ment or p~ lax~s o~ m~graine the ~ a~$ona may be admini~t*red orally, or ~ erallyand ~ ~.i~ntly take t~e form of a tablet, ~r~ ~t, c~r~t~le~ 1~7-~, in~ectable solution, liguid ~uspensi~n or ~ ~. Circum~ r~ may ari~e wh~rein the dos~ i~ best a~in~stsr~ by ~ c-itory, in~7~tion, slow releas~
$~p1ant, ~l~w ~slea~e patch or oth~r topical ~hi ~1~.
~ he combination of active ~ngredients are usually ~e9t gi~en ~n an or~l form ma~e up as a tablet, caplet, capsule, or a6 a 1 ~ quid su~pen~i on or ~1~Y; r on~ or two timQS daily.
For oral adm~ni~trat~on, the pr8para~ion may bs adm~xe~
wi~h any ~onventio~al ta~l~t~ng or ~r~ ing carrier, ~r a&
a ~-=p4l~ion ~r ~olut~on ~n-any orally accspta~le non-toXic li~uid carrier. If ds6ired, the drug may be prov~de~
in ~noap~ula~s~ form ~or ~u~t~e~ rel~ase over a period of time. For paren~eral a~n~tra~lon th~ drug ~ay be 21~1126 provide~ as a ~u~pens ion or sol~ltion in any ~uitable, ~terile injeation medium, e.g. sterile aqueous ~3aline olution. Giv~n thQ de~3~red doage rates indicated above, ~ he appropriat~ method of formulat~ on of the drug in a f~orm 5 suitabl~ for oral or parenteral admini~;trat:ion will be obv~ou~ to psr~on~ ~killed in th8 art. Th~ ~amQ appl~ e~
for ~nh~l~t~ and rectal or ~low - rQlea~Q implant mod~s of administration, which ar~ aleo feasibl~.
~he p~arm~ceut~cal formulstlons may ad~iti~nally $n~1ude, in add~tion to the aforemention~d active agent~, OthOE known anti-migrain~ pr~parat$on , analge~ics and anti~meticg OEuch ae:
L tC~ 0101 h~ Q~iCle Ergo~am~ne tartrat~
~ethysergi~e ~alea~e Dil,yo~- t~amine ~Q4yiate 8 ~,y~O. h~id8 Iso~et~spten~ Mucate ~ in~ Dih~ok~ id~
Metoclopra~ds ~,dk~ e Pizot$fen h~d~o~en ~alat~
A6pirin an~ other non-steroldal anti-in~lam~o agent~
Wh4 ~e willow ~ark and its extrac~
Oth~r ~-v~ sro~dal anti-infla~matoxy agent~ of plant orig4n Paracstamol and other minor analq~c~
P~n~:azoc~ns ~ O-~hl ~rid8 ProchlG~ ~dzins CaffelnQ
Me~GL~. -te E~h~rta~ ~ ne Citrate Zomsp4rac Mepta~inol IIyJl~chlori DEH
sumatr~ptin 21~112~
Ging~r Brazilian Coc~a Excellent ~fficacy o~ a pr~paration in accordance w~th thi~ inv~ntion ~s lik~ly in ~11 form~ o~ migra~ne including the trcatment of cla~ical and common migra~n~, m~grainous n~uralgla (clust~r heA~-~h~), an~ premen~rual and m~n~trual migra~n~ and ot~er h~-che6~
m e ~ ro~tion~ o~ the ~r~ n~ inven~ion ~ay bs used in tbe ~evd~Lion ~f th~ a~orement;Qne~ ~y~- - of h~che by r~J--~ln~ the frequency, severity and duration of the at~adk~ and.by ,c~ n~ th~ ~sa and ~omitin~ ~ymptom~.
Th~ composition~ ~ay also be u~ed to trs~t acute attaok~ of the afor~mentio~ed types of ~ æ~ y reA~G~ng the~r dl-ation~ qeverity and ~h~ intensity of ~r-i~ted eymptom~.
For the trea~me~t of arthritic con~ition6, -eyd~aLion~ ln accoroance w~th the in~ention may be ad~nietered orally, or parenterally and ~.v~.iently tak~
the form of ~ tablet, cap~ule, in~e,~abl~, ligu~d 6ucF~e~on or ~1~Y~, circuL~ , may ar$ee ~her~ it i~
b~St adm$n~elel ~y ~a~ nb-l~t~on, slow r~
~rl~n~ 81q~ r~l~ patch, or oth~r top~cal vehicle.
-DoRage and admin;~tration ~ a~ ;~te~ a~o~e.
A ~ a~ on in accordance with th~ inven~ion may addi~n~11y ~n~~ e other an~ Lh.iti6 agQnt~ $ncluding-I.C - ~ t~o$~al anti-inlammatory drugs, ~n~l~J~ icg, skeletal mu~cle re~ ~ts, steroids, gol~ an~ pen~c~llam~n~.
Exa~pl~ of ~uch agents ar~;
a~p~rin, indomethacin, p~roxic~m, bQnorylat~, ~b~profen, parac~tamol, 21~1~26 -~_ 8 ~alicylam~ne, di~lunlzal, ethoh~ptazine, fenoprof~n ~calci~m ~enoprofate~
~luf~namic acid, mefenamic acid, naprox~n ~od~um, k~toprofen, phenylbut~zone, ~ulindac, p~ni~ f ~
sallcylate, fenclofenaa~
flurbipro~n, 1 5 fenb/u~en, fQp~a~one~ -~odium aurothiomalate, nay 0~
~O~ Oren, AlO~lr~ia, l~d~o~y~Lloroq~ine st~l~h~te, - az~ ~7qn~, ~ol~mtin~
cho}ine m~ ltF ~ l~m tr~ d~ l i aylate, diclofQnac~
adrenal steroi~ ~UCh as pre~ r~n~ or ~ qA~ one~
white willo~ax~ and itS extract~, other ~on ~LQro~ dal anti-in~lammatory ag~nt~ of plant origin ~vening primrOse oil gamma linole~a aci~
bor~ge oil ~l~x seed 21~1126 ~_ g Th~ compo~it~on~ of the present invention may be used in the treatm~nt of rheumato~d ar~hrit~s, ost~oarthriti~, arthriti~ a~sociated with Felty'~ syndrome, 5till~s di~Qase, ~ystemia lupu5 erythemato~u~, polyarter~tis nodosa, sclero~erma, gout, achalasia of ~he cardia, Crohn~
disQa~e, chronlc ~ruc~llo~is, ankylo~ng spondyliti~, ~arcoidosi~, psoria~is an~ gonorrhoea.
The preparatione are ~el~eved to be useful ~n the ~v~J,Lion o~ ths above arthr~tids~, betng effective in reducing ths freq~ncy, 6ever~ty and durstion of the ~X ~oms The preparations can ~lgo be u~ to treat the acut~ attack~ of th~ above arthritides r~At~a~ n~ th~r ~uration, ~ ity ana a~ t~d ~ymptom8.
It is alao bellevsd that th~ e~f icacy Of She 1~ compositiong o~ the y~ t in~ntion c~n be ~nh~n~QA by the ~ of gamma ~ c aa~. Thu~, the compasitions way compr~6e, in add~tion to a se~g~t~
lactons and a B-co~plsx ~itamin, gamma linol~c acid or a ~ur~ th~a~L. The l~n~ts;~ ac~ -~u~e m~y b~, for exa~p~e, evening pri~ross oll or Lor~y~ oil.
For th~ tr~atm~nt o4 ast~ma~ ~l ~L~L~ an~ in accordan~e wi~ th~ in~ntion ~ay be aaministersd orally, -or ~a~ erally and ~A~,~.i~ntly take-the form o~ a ~abl~t, ~p~tl~, in~ A~l~, liquid ~~ -a~on or ~irc~m~ -c~-- may ari8a where $t is ~e~t a~ni~tsred by Y~ 'o~;tory~ ~nh~l~tion~ 810w rel~ass implan~, ~low r~leass patch or other ~opical ~hicl~. Do6age and administrat$on-are a~ ind$catsd above.
A preparation in accor~anc~ ~ith ths invent$on may bs 30 co - a~ ter~d ~ith o~ addi~A 1 1 y lnclu~e oth~r ingr~i~nts ~uch as ~o--~hod~lator, antihistamine an~ anti-~nf~ctivs agent~, ~xample~ o~ which ag~nt~ are:
i~opr~ n~ sulphate, orcipr~n~l~ne, adr~n~l~r~, ter~u~aline ~-11rh~
- -- 2~112~
theophyllin~, brazil~an cocoa choline th~Qphyllina~Q, aminophyll~ne, ~rhQ~rin~ hydrochloride, papaverin~ hydr~chloride, ipratropium ~L~
atropinQ methonitratQ, b~cl ~ ~n~On~ dipropionate, fenot~rol ~r~L ~m~d~, be~ t~, ieoetharine me~ylate or hy~v~.lorid~, phenyl~phrin~ ~dhG~ de or bitartrate, thenyidia~ne hy~ ~id~, -~p~o~ol ~k ~hlQ~i~e, de ~ opin~ citrate, bu~etha~ate cl~rate, pify~ n~
diphenylpyraline L~3r~hlQr~e, ~ ~ cromoglycate, -etaE$phylllne camsylat~, in~ ~ r~ ~la~ine, etaredrine h~d~l.lorid~, bufylline, g~ el ~.,.. ; n, ~d~ a~amlnQ h~ de and o~her hi~
Hl~ ~. anta~oni~t6, dly~l.~ll5.ne, mcU.~X~ na~in~ 1,~l~o~l-loride, rimitQr~l hydrobro~ide, - hyo~n~ hydrobromid~, ~albut~ol ~ulphate, ketotifen hy~L~I fumarate, ~S~ ~rh9~rine hy~Lo~lloride, 3~ ne hy~rochlorid~, and antifungal, ant~bacterial and antiviral agents -Th~ comp~sition in accordana~3 with th~ pre~ent invention i~; ~elieved to be useful in the ~r~atmen~ of bronchial a~thma, 3~ronchocon~ ction a~sociate~l with chronic bronchiti~, and ~ymptom~; asso~iated ~ th hist~rl nQ
5 release in all~rgic hyper~snsiti~rity ph~nomena such a6 hay fever and anaphylaxis.
~ __ ition~3 in accordance with th~ invention will now bQ illus'crat~ in more d~tail with refeL~-~:e to the ~ollo~ing Exan~ple:
~XP~E 1 on o~ r~ 5 F~w~e ~ feverfew ~ and riboflavin are mixed in ths ~ollowing ~, ~.po~ Lions:
~ æt~nd~~ Qverfew lea~ rd~r tcon~ ; n~ at leaet ~.29~ LLcnol~de) 125 mg ribofla~in 400 mg ~he mixturs 1~ ~.c~ l atea into a ~o~t shell ca,~ e or ha~d ~hell ¢~p~-l~ or two pie¢e hard shell gelatin c~r~ . The c~ may be treat~d to r~tard ~ie~ntegratlon ar ab~orption by th~ u~e of ga~LLo r~_istant caatlnge, ~uch a~ dLo~m~thyl propy} c~ll~lo-^, or th~
- contsnt may ~ mixsd w~th polymer~c matr~x materials a~
those known to the pharmaeeutical indus~ry, to r~l~e~ the ac~ivQ ingr~ient6 ~t a ~l~r~lled rate. The soft shell or t~o piece har~ ~hell gelatin ~ -18 may be us8~ via the oral or re~t~l r~ute.
I~:~a2U?~;E Z
~?r~paration ~ tabl~ts:
~ f~ollowing ingre~ ent~ ar~ mixe.d in the ~iven r~lativ~ ,~r V~.J.L Lions:
st.;~nA~rdized f~verf~w leaf~ powd~r (r~ ch in ~squiterpen~ lactone~) 60 mg ribof~lavin 200 mg , !
milk ~ug~r (p~wder) 150 mg starch 4 4 m~
talc 40 mg stearic acid 1. 4 mg tartar~c acid as reguired All ingr~dient~ ar~ m~xed tho~ y. SUf f ici~nt tart3ric acid sho~ld ~e ussd in th~ mixtur~ to adju~t ths pH to L~_~n 2 and 6 5, prefer~bly to ~ 4.5. The mixture i~
compressQd ~nto ~lug~, which are ~ro~,d and Fcreened to 14-16 me6h gr~n~ , which ar~ then rscom~r~s~ed into tablsts.
The tabl~ts may bs ~nteric coated, sugar coatea, filmcoatsd or ~o~ as a laminatQd tablQt. Two tabl~te ars rQcommsn~ed for daily ing~tion.
~a~PLæ 3 :' 15 Preparat~on of in~ectable:
The ~ollowing ar~ mixed;
part~ 2500 ~g ribofla~in 2 g ~8P wat~r for in~ection lO ml The p~ ie ad~uste~ to ~ _an 2 and 6.s, u~ng HCl.
~he in~ ~tA~l ~ may be administered by intram~
~Pcu~o~d, or iuL~ n~ct$on. The ~.~.~Lion ~o~ be ~tored in ti~ht, light-resistant con~.~in~r~
-preferably L~ ~n 15-25 C.
E~ANPL~ ~
Preparation o~ capl~t~:
ThQ following ingr~ient~ ars ~Ye~ in the g~Ven rslative ~.~ion~
~t~n~-rdized feverfew lsaf pow~er (rich ~n ssSquit~rpen~ la~tone~) 60 g r~bo~lavin 750 g ~tarch gs g ~141126 lactose 4 2 g zein 4 5 g magne~ium ~tearate 8 g ThQ mixture of riboflavin, starch and lacto~e is granulated with z~in (10~ in ethyl alcohol, adding additi~nal alcohol if necessary to obtain good w~t granule~)~ The granulatsd mixture i~ wet ~creen~ through 8 ~tainle~s 6~el ~creen and ~ry at 110-120 F, and i~ then dry screened thr~u~l~ a ~0 ~tainle~6 eteel ~cre~n. F~V~rew lQaf pow~er i~ then added, which ha~ been 8~r~ ~ ~ ' u~ing a ~8 e~nl~ ~tee~
~creen. The ~ompoeition i~ then mixed thoroughly, lubricated and compL---~d into caplets. ~ach caplet should w~igh S00 mg.
Caplets may ~e enteric coated, ~ugar coa~ed, film coated or ~a~l a8 a lamin~tsd tabl~t.
~2~NP~ 5 ,eration of D~srQn~on:
ThQ ~ollowing are ~Y9~
~ethyl c~llulo~ 0.5 g ~ ~d fs~Qrfe~ leaf ~
~rich in ~esquit~L~- e lactone~ 2.0 g riboflavln 4,0 g purifi~ wat~r 100 ml bsnzoic acid (pre6ervative~ 0.1 g ~la~oring aqent (e.g.; v~ n) 0.1 ml ~he dry solids are tritur~te~ an~ ~he purifis~ ~ater i8 810wly a~ed wi~h ~rituration. The pH i8 a~u~ted to between 3 and 6.5 u8ing ~Cl as req~ired.
The s~l~rsn~on may be adminlstQred by ing~tion. ~he preparation ~houl~ be ~or~d i~ tight~ light-resletan~
conta~ner~, pr~rably b~tw~n lS-Z5 C
,
F0R q!~T~ ~.
PI OF ~B ~rI
Thisl invention relates to aompo~itions and metho~
u6eflll in 'chs treatment of migraine h~ches and re3~ated il1n~ 6.
1121D QF ~ r~TIo~
Ths ~ncidenc~ of migraine including clufft~r ~ ch~s, i~ 6aid to ~e ~y~LOXi~ately lo-ao~ of the male population an~ Z 0-3 OS of t~e femal~ population. Trsa~ment ~or ~any pati~nt~ havi~ the occaffional migrain~ involve~ 3imp~e analgesics ~ith or without s~dative~. approximately 10~ of ~igraine 6u~fer~r6 hav~ three or more attacks per month and warrant prophylactic treatment. ~wenty-five to ~i~t~
.
.
-`- 2141126 , percent o~ thl~ group benef~t ~r~m treatment w~th beta-adr~nor~cept~r ~locking agent~, cl~nidine or, in the femal~
s~f~erer, ge~tag~n hormonQs. In the re~aining population of migra~ne ~uff~rer~, and ~ n tho~e with intolerable s~de-s~fectg from availabl~ drug~, th~re i~ a laoX of con~elll ional pharmaceutiaal prep~rat~on~ that sxhibit therap~tic Qffsct, wit~out ~svere ~ide-Qff~ct6.
F~v~rf~w, rich in ~e~quitel~c.le lactone~, principally parthenolide, hag algo besn ~hown to hav~ a prophylactic effsct again~t-migraine. ~n one ~tu~y, mors than ~0~ of the fevsrfew Users cla~ed that the herb haa d~cr~a~e~ the frequency of.thelr att~ck~, cauesd th~m to be l~ pain~ul, or -~oth. In another 8tu~y, ~xt~-eight p~C~L of ~igrainQ
~Uf~t-~l~ d~played ~m~lO~Qment when tr~ated y~ ylac~;c~l~y wlth riboflavin.
Al~h th~ ~ ~ cau~ or ~ of ~igrain~
arthrl~is, an~ a~ r~a~n ~ , all three ~ ee - are a~c;~t4d wi~h a :postulatQ~ local or gy~temic relea8e of active ~uL c~ o ;~l--A~ n t~e ca~e Of mi~raine and/or it~ variant~: ..w~ ephrins (--vra~ n~l ;ne), ~-h~d~ L~y~mine (~erotonLn~, histam~ne, ~ p51~n~na and ~l~dy~;n~n; ~n the ca~e of arthr~is~ pro8tagt~ n~, higtam~ns, 5 ~L~L~ am$ne ana brady~1~;n; and in t~e ca~;e of a~thma; his~mine, 5 l~J~ yL~ ne~ brady~n;r~
25 acetylcboline, ~G~I,J~3~ n~ ~nd the leukotrien~s.
endo.~ ~-o~ t7 hav~ in- co..,. ,on t~ h; 1 Sty to cau~e ~mooth m~scle to cc ~ act ti.~. go into ~epa~m~, and ~a~y - are also pai~ n~ ~ubst~r~Ge~, e . g . S--hydroxytryptamine, braClykinin, histamlne and 30 pro~:taglAnA~ . Non--sQ3.eCt$ve an~:agoniC t drugs wil~, ther~for~, not only reduc:s t~ ~mooth muscular spasm (o~
. .int:rscranial blood ~e~;s~ls in t;h~ case o~ migra~n~, or bron~h~ moot:h muscle in the ca~e of asthma~ ~ut a}~o th~
pain (o~ ~igraine and arthr~ti~ a~ociat~d w~t~ their 35 r~lease.
8esquiterpene lac~on~s ar~ known to b~ pre~ent in many pl~nt~, for exampl~ ~n A5ter~c~a, Nagnol~ac~ae, and in particular in Tan~c~tum parthen~um (f~ver~ew~, an~ are thought to b~ re~pon5ible for ob~rved bioactivity of the leaf mater~ al .
su~A~Y OF TH~ I~V~IO~
It ha~ no~ been di&oo~c ~ that a mixt~Q o~ a ~esqu~t~rpen~ lactone and a B-vi~am$n, is esp~c~ally effeGtive in both the ~e~Lm~nt an~ prophylaxis of 10 migraine, arthrit:i~, and a2~ ~ a~
In aocordanqe with the y~. ~nt invent$on, a se-quiterp~ne lacton~a, or a 2~0~ ~ of se~
l~ctone~, s~lch as se~ait~.e, laa~ .a c~ n~n~ plant~
asld ~lant ex~r'aats, i~ u~ed in cc~ n~tion W~th a B-compl~x 16 ~ita~in, Bt~h as ribofla~rin. i ~a~ lo~ ~mpriging eeuGh a coD~bination are al~o pro~rided that: hav~ ~har~aceut1 cal u~e, par~ ly in the tr~atment oi~ ~gra~ne, inc~udin~
ClU8t~ hq~r~ an~ variou~ rit~ c and ~LO-~
condition~, OEUtih ag a~thma~
~ ~ D~8C~r:~l ~ ~S ~1~ ~3~1!1!~
q~e 8-complex vit~n t~at i~ u~eful in accorClanos with t~e ~ ~ t i~vent~on includ~6 riboflavin, r~boflavin -te, flavin ~ n~ ~n ~n1sotia~ niootin~c aciCl-, folic aaid, cy2~ ha l~in, para-amino benzoic acid~
25 thia~ns, pyr~ , panto'rh-n;~, aci~, ~iot1n, choline inos$tol, and carn~tine.
The ~e~qUitsrpQne lacton~ that i~ u~eful in aac~rdance with the ~~ ~t inv~ntion include~ ~ ~cranolid~, ~ A~lid~, and ~ ~lidQS, in particular tho~e se6qUiterpQne lac~one~ having an ~-m~thyl~ne &ub~tituent in the la~ton~ ring, ~uch a~ parthenolide. ParthQnolide and squiterpene lacton~-con~n~ plant material~, ~uch a~
~verf~w l~a* or extract~ fro~ such plant mat~rial~ are . prQferred . .
~1~1126 Although bath ~e~qUit~rp~nQ la~ones and 8-complex vitA ~ n~ have bee~ found, individUally, to be effect~ve for treatm~nt or prophylaxis of migraine, ~he combination ~f the two typ~ of active~, in accordance with the pre~ent ~nv~ntion, leads to eyn~rgist~c ef~cts. Thus, a combinat~on o~ f~ver~w or other ~ourc~ o parthenolids with a B-vitamin additiv~ lead~ to a further d~crease in the frQquency of ~h~ attacks an~ cau~e~ the attacks to b~
l~g painful. An inCreasQd perc~nta~Q o~ m~graine sufer~rs ~hould thQrefore d$splay an improvement in frQquency~ sQVerity~ or bo~h, wh~n treated prophylactically with th~ comb$national ~rug. ThQ co~b$national drug ~a~
low to~ty, ~ty~ i~ingly few ~id~-e$f~cta an~ may be ta~en for ~he ext~ fl p~riod~ required for effsct~ve 15 ~ o~h~l~xis, w~ thout ~ e re;~c~ion~ .
~OP~ ~-~ ANn Pua~t~ T~ ~p~D-~T~a~ N
The ~c -~o of ~ctivo ingredients w~ll, of couree, vary fra3l~ indlYid~lal to ind~vid~lal an~ will ~E!~n~ upon many ~a~or~, inal~ boa~ ~reight, nleta~1 i~m, and 1:he lilce.
In general, ho~rer~ t i6 believea that, in l~o'ch treat~ent and ~-~pl~laxi6, a giVen indlvi~ual ~ 1~ receive ~rom abo~t S0 to about lO,O00 mi~r~y~ms, preferably ~rom about 250 to a~out loOO ~ic~vy ~ms, and ~ost p~ferably a~out 250 ~i~r~.~ms o~ eesquiL~cne lactone, ~u~h a8 F~r~henolide, per d~y. ~n general, it ia a~o believed that a gi~en individua~ ehould rece~ve fro~ about 0.1 to about 5,000 gram~, preferably from about 100 to about 500 ~illlgram~, an~ modt preferably about 400 ;ll~gr~m~ of B-co~plQx vitamin, s ~ t~lly r~hnflAvin, per day. More, hc~ , may ~e need in the case of aCut~ attack~.
Th~lS, in accordanc~ with th~ prssent inv~ntion, phar~ac~utical do8sge ~orms ars prov~ l that conta~ n 50 to about lO,OoO mi~o.J~ , preferaPly ~rom abou~ 250 to about lO00 m~ -;r 0~L , an~ mo~ preferably a~o~lt 250 mi~ o~ se~iterpene lacton~, ~u~h as par~henol ~ de, in combinat~on with abaut 0.1 to about 5,000 milligram~, - pre~rably from about 100 to about 500 milligram~, ~nd mo~t pr~erably about 400 m~lligrams of B-compl~x ~ltamin, e~pec~ally r~boflav~n, p~r day.
In gener~l, ~uch pha~aCeut~cal do~age ~o~ms ~ay compr~e from about 5 to 300 mg, e~pQcially 50 to 200 mg, of f~verfs~ lea~, contA;n~ng a~out 250 m~crogl~ of parthenolidQ, in com}~ination with from al~out 0.1 to 400 mg o~ riboflav~n per day. For treat~ent, mors than onQ dose ~ay be required, as in thQ casQ of the treatment of an acut~ ~ttacX of m~graine or a~liQd di~ord~r. Th~ fever$ew ~ ~ may ~e adjusted to ~ccommodat~ thQ nat~urally vari~le level~ of ~Qs~uiteL~-e lactone~, s~ch a~
parthen~lide. A par~ ~ly pr~f~rred c~p~ e contain~
16. abaut 125 mg o~ hiy~ pa.lh~nol;~e fsverf~ and 400 mg of r~boflavin. 'It ~S prQferrea that thQ c~mpo8ition o~ the nt inv~ntion be aomini~ersd as t~o tablst~ daily;
~a~h tablet cont~ ng 125 mg fs~erf~W (cont~in;~ 250 mq o~ ~sqult~ ~.~ - lactone) an~ 200 mg r~boflav~n or oth~r B-GomplsY vitamin.
For thQ L ~ment or p~ lax~s o~ m~graine the ~ a~$ona may be admini~t*red orally, or ~ erallyand ~ ~.i~ntly take t~e form of a tablet, ~r~ ~t, c~r~t~le~ 1~7-~, in~ectable solution, liguid ~uspensi~n or ~ ~. Circum~ r~ may ari~e wh~rein the dos~ i~ best a~in~stsr~ by ~ c-itory, in~7~tion, slow releas~
$~p1ant, ~l~w ~slea~e patch or oth~r topical ~hi ~1~.
~ he combination of active ~ngredients are usually ~e9t gi~en ~n an or~l form ma~e up as a tablet, caplet, capsule, or a6 a 1 ~ quid su~pen~i on or ~1~Y; r on~ or two timQS daily.
For oral adm~ni~trat~on, the pr8para~ion may bs adm~xe~
wi~h any ~onventio~al ta~l~t~ng or ~r~ ing carrier, ~r a&
a ~-=p4l~ion ~r ~olut~on ~n-any orally accspta~le non-toXic li~uid carrier. If ds6ired, the drug may be prov~de~
in ~noap~ula~s~ form ~or ~u~t~e~ rel~ase over a period of time. For paren~eral a~n~tra~lon th~ drug ~ay be 21~1126 provide~ as a ~u~pens ion or sol~ltion in any ~uitable, ~terile injeation medium, e.g. sterile aqueous ~3aline olution. Giv~n thQ de~3~red doage rates indicated above, ~ he appropriat~ method of formulat~ on of the drug in a f~orm 5 suitabl~ for oral or parenteral admini~;trat:ion will be obv~ou~ to psr~on~ ~killed in th8 art. Th~ ~amQ appl~ e~
for ~nh~l~t~ and rectal or ~low - rQlea~Q implant mod~s of administration, which ar~ aleo feasibl~.
~he p~arm~ceut~cal formulstlons may ad~iti~nally $n~1ude, in add~tion to the aforemention~d active agent~, OthOE known anti-migrain~ pr~parat$on , analge~ics and anti~meticg OEuch ae:
L tC~ 0101 h~ Q~iCle Ergo~am~ne tartrat~
~ethysergi~e ~alea~e Dil,yo~- t~amine ~Q4yiate 8 ~,y~O. h~id8 Iso~et~spten~ Mucate ~ in~ Dih~ok~ id~
Metoclopra~ds ~,dk~ e Pizot$fen h~d~o~en ~alat~
A6pirin an~ other non-steroldal anti-in~lam~o agent~
Wh4 ~e willow ~ark and its extrac~
Oth~r ~-v~ sro~dal anti-infla~matoxy agent~ of plant orig4n Paracstamol and other minor analq~c~
P~n~:azoc~ns ~ O-~hl ~rid8 ProchlG~ ~dzins CaffelnQ
Me~GL~. -te E~h~rta~ ~ ne Citrate Zomsp4rac Mepta~inol IIyJl~chlori DEH
sumatr~ptin 21~112~
Ging~r Brazilian Coc~a Excellent ~fficacy o~ a pr~paration in accordance w~th thi~ inv~ntion ~s lik~ly in ~11 form~ o~ migra~ne including the trcatment of cla~ical and common migra~n~, m~grainous n~uralgla (clust~r heA~-~h~), an~ premen~rual and m~n~trual migra~n~ and ot~er h~-che6~
m e ~ ro~tion~ o~ the ~r~ n~ inven~ion ~ay bs used in tbe ~evd~Lion ~f th~ a~orement;Qne~ ~y~- - of h~che by r~J--~ln~ the frequency, severity and duration of the at~adk~ and.by ,c~ n~ th~ ~sa and ~omitin~ ~ymptom~.
Th~ composition~ ~ay also be u~ed to trs~t acute attaok~ of the afor~mentio~ed types of ~ æ~ y reA~G~ng the~r dl-ation~ qeverity and ~h~ intensity of ~r-i~ted eymptom~.
For the trea~me~t of arthritic con~ition6, -eyd~aLion~ ln accoroance w~th the in~ention may be ad~nietered orally, or parenterally and ~.v~.iently tak~
the form of ~ tablet, cap~ule, in~e,~abl~, ligu~d 6ucF~e~on or ~1~Y~, circuL~ , may ar$ee ~her~ it i~
b~St adm$n~elel ~y ~a~ nb-l~t~on, slow r~
~rl~n~ 81q~ r~l~ patch, or oth~r top~cal vehicle.
-DoRage and admin;~tration ~ a~ ;~te~ a~o~e.
A ~ a~ on in accordance with th~ inven~ion may addi~n~11y ~n~~ e other an~ Lh.iti6 agQnt~ $ncluding-I.C - ~ t~o$~al anti-inlammatory drugs, ~n~l~J~ icg, skeletal mu~cle re~ ~ts, steroids, gol~ an~ pen~c~llam~n~.
Exa~pl~ of ~uch agents ar~;
a~p~rin, indomethacin, p~roxic~m, bQnorylat~, ~b~profen, parac~tamol, 21~1~26 -~_ 8 ~alicylam~ne, di~lunlzal, ethoh~ptazine, fenoprof~n ~calci~m ~enoprofate~
~luf~namic acid, mefenamic acid, naprox~n ~od~um, k~toprofen, phenylbut~zone, ~ulindac, p~ni~ f ~
sallcylate, fenclofenaa~
flurbipro~n, 1 5 fenb/u~en, fQp~a~one~ -~odium aurothiomalate, nay 0~
~O~ Oren, AlO~lr~ia, l~d~o~y~Lloroq~ine st~l~h~te, - az~ ~7qn~, ~ol~mtin~
cho}ine m~ ltF ~ l~m tr~ d~ l i aylate, diclofQnac~
adrenal steroi~ ~UCh as pre~ r~n~ or ~ qA~ one~
white willo~ax~ and itS extract~, other ~on ~LQro~ dal anti-in~lammatory ag~nt~ of plant origin ~vening primrOse oil gamma linole~a aci~
bor~ge oil ~l~x seed 21~1126 ~_ g Th~ compo~it~on~ of the present invention may be used in the treatm~nt of rheumato~d ar~hrit~s, ost~oarthriti~, arthriti~ a~sociated with Felty'~ syndrome, 5till~s di~Qase, ~ystemia lupu5 erythemato~u~, polyarter~tis nodosa, sclero~erma, gout, achalasia of ~he cardia, Crohn~
disQa~e, chronlc ~ruc~llo~is, ankylo~ng spondyliti~, ~arcoidosi~, psoria~is an~ gonorrhoea.
The preparatione are ~el~eved to be useful ~n the ~v~J,Lion o~ ths above arthr~tids~, betng effective in reducing ths freq~ncy, 6ever~ty and durstion of the ~X ~oms The preparations can ~lgo be u~ to treat the acut~ attack~ of th~ above arthritides r~At~a~ n~ th~r ~uration, ~ ity ana a~ t~d ~ymptom8.
It is alao bellevsd that th~ e~f icacy Of She 1~ compositiong o~ the y~ t in~ntion c~n be ~nh~n~QA by the ~ of gamma ~ c aa~. Thu~, the compasitions way compr~6e, in add~tion to a se~g~t~
lactons and a B-co~plsx ~itamin, gamma linol~c acid or a ~ur~ th~a~L. The l~n~ts;~ ac~ -~u~e m~y b~, for exa~p~e, evening pri~ross oll or Lor~y~ oil.
For th~ tr~atm~nt o4 ast~ma~ ~l ~L~L~ an~ in accordan~e wi~ th~ in~ntion ~ay be aaministersd orally, -or ~a~ erally and ~A~,~.i~ntly take-the form o~ a ~abl~t, ~p~tl~, in~ A~l~, liquid ~~ -a~on or ~irc~m~ -c~-- may ari8a where $t is ~e~t a~ni~tsred by Y~ 'o~;tory~ ~nh~l~tion~ 810w rel~ass implan~, ~low r~leass patch or other ~opical ~hicl~. Do6age and administrat$on-are a~ ind$catsd above.
A preparation in accor~anc~ ~ith ths invent$on may bs 30 co - a~ ter~d ~ith o~ addi~A 1 1 y lnclu~e oth~r ingr~i~nts ~uch as ~o--~hod~lator, antihistamine an~ anti-~nf~ctivs agent~, ~xample~ o~ which ag~nt~ are:
i~opr~ n~ sulphate, orcipr~n~l~ne, adr~n~l~r~, ter~u~aline ~-11rh~
- -- 2~112~
theophyllin~, brazil~an cocoa choline th~Qphyllina~Q, aminophyll~ne, ~rhQ~rin~ hydrochloride, papaverin~ hydr~chloride, ipratropium ~L~
atropinQ methonitratQ, b~cl ~ ~n~On~ dipropionate, fenot~rol ~r~L ~m~d~, be~ t~, ieoetharine me~ylate or hy~v~.lorid~, phenyl~phrin~ ~dhG~ de or bitartrate, thenyidia~ne hy~ ~id~, -~p~o~ol ~k ~hlQ~i~e, de ~ opin~ citrate, bu~etha~ate cl~rate, pify~ n~
diphenylpyraline L~3r~hlQr~e, ~ ~ cromoglycate, -etaE$phylllne camsylat~, in~ ~ r~ ~la~ine, etaredrine h~d~l.lorid~, bufylline, g~ el ~.,.. ; n, ~d~ a~amlnQ h~ de and o~her hi~
Hl~ ~. anta~oni~t6, dly~l.~ll5.ne, mcU.~X~ na~in~ 1,~l~o~l-loride, rimitQr~l hydrobro~ide, - hyo~n~ hydrobromid~, ~albut~ol ~ulphate, ketotifen hy~L~I fumarate, ~S~ ~rh9~rine hy~Lo~lloride, 3~ ne hy~rochlorid~, and antifungal, ant~bacterial and antiviral agents -Th~ comp~sition in accordana~3 with th~ pre~ent invention i~; ~elieved to be useful in the ~r~atmen~ of bronchial a~thma, 3~ronchocon~ ction a~sociate~l with chronic bronchiti~, and ~ymptom~; asso~iated ~ th hist~rl nQ
5 release in all~rgic hyper~snsiti~rity ph~nomena such a6 hay fever and anaphylaxis.
~ __ ition~3 in accordance with th~ invention will now bQ illus'crat~ in more d~tail with refeL~-~:e to the ~ollo~ing Exan~ple:
~XP~E 1 on o~ r~ 5 F~w~e ~ feverfew ~ and riboflavin are mixed in ths ~ollowing ~, ~.po~ Lions:
~ æt~nd~~ Qverfew lea~ rd~r tcon~ ; n~ at leaet ~.29~ LLcnol~de) 125 mg ribofla~in 400 mg ~he mixturs 1~ ~.c~ l atea into a ~o~t shell ca,~ e or ha~d ~hell ¢~p~-l~ or two pie¢e hard shell gelatin c~r~ . The c~ may be treat~d to r~tard ~ie~ntegratlon ar ab~orption by th~ u~e of ga~LLo r~_istant caatlnge, ~uch a~ dLo~m~thyl propy} c~ll~lo-^, or th~
- contsnt may ~ mixsd w~th polymer~c matr~x materials a~
those known to the pharmaeeutical indus~ry, to r~l~e~ the ac~ivQ ingr~ient6 ~t a ~l~r~lled rate. The soft shell or t~o piece har~ ~hell gelatin ~ -18 may be us8~ via the oral or re~t~l r~ute.
I~:~a2U?~;E Z
~?r~paration ~ tabl~ts:
~ f~ollowing ingre~ ent~ ar~ mixe.d in the ~iven r~lativ~ ,~r V~.J.L Lions:
st.;~nA~rdized f~verf~w leaf~ powd~r (r~ ch in ~squiterpen~ lactone~) 60 mg ribof~lavin 200 mg , !
milk ~ug~r (p~wder) 150 mg starch 4 4 m~
talc 40 mg stearic acid 1. 4 mg tartar~c acid as reguired All ingr~dient~ ar~ m~xed tho~ y. SUf f ici~nt tart3ric acid sho~ld ~e ussd in th~ mixtur~ to adju~t ths pH to L~_~n 2 and 6 5, prefer~bly to ~ 4.5. The mixture i~
compressQd ~nto ~lug~, which are ~ro~,d and Fcreened to 14-16 me6h gr~n~ , which ar~ then rscom~r~s~ed into tablsts.
The tabl~ts may bs ~nteric coated, sugar coatea, filmcoatsd or ~o~ as a laminatQd tablQt. Two tabl~te ars rQcommsn~ed for daily ing~tion.
~a~PLæ 3 :' 15 Preparat~on of in~ectable:
The ~ollowing ar~ mixed;
part~ 2500 ~g ribofla~in 2 g ~8P wat~r for in~ection lO ml The p~ ie ad~uste~ to ~ _an 2 and 6.s, u~ng HCl.
~he in~ ~tA~l ~ may be administered by intram~
~Pcu~o~d, or iuL~ n~ct$on. The ~.~.~Lion ~o~ be ~tored in ti~ht, light-resistant con~.~in~r~
-preferably L~ ~n 15-25 C.
E~ANPL~ ~
Preparation o~ capl~t~:
ThQ following ingr~ient~ ars ~Ye~ in the g~Ven rslative ~.~ion~
~t~n~-rdized feverfew lsaf pow~er (rich ~n ssSquit~rpen~ la~tone~) 60 g r~bo~lavin 750 g ~tarch gs g ~141126 lactose 4 2 g zein 4 5 g magne~ium ~tearate 8 g ThQ mixture of riboflavin, starch and lacto~e is granulated with z~in (10~ in ethyl alcohol, adding additi~nal alcohol if necessary to obtain good w~t granule~)~ The granulatsd mixture i~ wet ~creen~ through 8 ~tainle~s 6~el ~creen and ~ry at 110-120 F, and i~ then dry screened thr~u~l~ a ~0 ~tainle~6 eteel ~cre~n. F~V~rew lQaf pow~er i~ then added, which ha~ been 8~r~ ~ ~ ' u~ing a ~8 e~nl~ ~tee~
~creen. The ~ompoeition i~ then mixed thoroughly, lubricated and compL---~d into caplets. ~ach caplet should w~igh S00 mg.
Caplets may ~e enteric coated, ~ugar coa~ed, film coated or ~a~l a8 a lamin~tsd tabl~t.
~2~NP~ 5 ,eration of D~srQn~on:
ThQ ~ollowing are ~Y9~
~ethyl c~llulo~ 0.5 g ~ ~d fs~Qrfe~ leaf ~
~rich in ~esquit~L~- e lactone~ 2.0 g riboflavln 4,0 g purifi~ wat~r 100 ml bsnzoic acid (pre6ervative~ 0.1 g ~la~oring aqent (e.g.; v~ n) 0.1 ml ~he dry solids are tritur~te~ an~ ~he purifis~ ~ater i8 810wly a~ed wi~h ~rituration. The pH i8 a~u~ted to between 3 and 6.5 u8ing ~Cl as req~ired.
The s~l~rsn~on may be adminlstQred by ing~tion. ~he preparation ~houl~ be ~or~d i~ tight~ light-resletan~
conta~ner~, pr~rably b~tw~n lS-Z5 C
,
Claims (24)
1. A pharmaceutical composition useful for alleviating migraine and related headaches, arthritis and asthma comprising:
A) a sesquiterpene lactone an b) a B-complex vitamin.
A) a sesquiterpene lactone an b) a B-complex vitamin.
2. The composition of claim 1 wherein the sesquiterpene lactone is provided by a source selected from the group consisting of plant materials and plant extracts containing sesquiterpene lactone.
3. The composition of claim 1 wherein the sesquiterpene lactone is provided by a source selected from the group consisting of feverfew leaf powder and feverfew extract.
4. The composition of claim 1 wherein the sesquiterpene lactone is provided by a source selected from the group consisting of Asteracea leaf powder and Asteracea extract.
5. The composition of claim 1 wherein the sesquiterpene lactone is provided by a source selected from the group consisting of Magnoliacea leaf powder and Magnoliacea extract.
6. The composition of claim 1 wherein the sesquiterpene lactone is parthenolide.
7. The composition of claim 1 wherein B-complex vitamin is riboflavin.
8. The composition of claim 3 wherein the B-complex vitamin is riboflavin.
9. The pharmaceutical preparation of claim 1 which comprises feverfew leaf powder in combination with riboflavin.
10. The pharmaceutical preparation of claim 1 which comprises parthenolide in combination with riboflavin.
11. The pharmaceutical composition of claim 1 in the form of a tablet, capsule, caplet, lozenge, suspension, elixir, injectable, inhalant, suppository, slow-release implant, slow-release patch or other topical vehicle.
12. The pharmaceutical composition of claim 3 in the form of a tablet, capsule, caplet, lozenge, suspension, elixir, injectable, inhalant, suppository, slow-release implant, slow-release patch or other topical vehicle.
13. A method of treating a patient suffering from an illness selected from the group consisting of migraine, arthritis, and asthma by administering to said patient both a source of sesquiterpene lactone and a B-complex vitamin, in a therapeutically effective amount.
14. The method of claim 12 wherein the sesquiterpene lactone and the B-complex vitamin are administered by independent dosage forms.
15. The method of claim 12 wherein the sesquiterpene lactone and the B-complex vitamin are administered in the same dosage form.
16. A method of preventing or reducing the severity of an illness selected from the group consisting of migraine, arthritis, and asthma by administering to said patient both a source of sesquiterpene lactone and a B-complex vitamin, in a prophylactically effective amount.
17. The method of claim 15 wherein the sesquiterpene lactone and the B-complex vitamin are administered by independent dosage forms.
18. The method of claim 16 wherein the sesquiterpene lactone and the B-complex vitamin are administered in the same dosage form.
19. The composition of claim 1 also comprising gamma linoleic acid.
20. The composition of claim 19 wherein gamma lineoleic acid source is selected from the group consisting of evening primrose of borage oil.
21. The composition of claim 20 wherein the source of sesquiterpene lactone is feverfew and the B-complex vitamin is riboflavin.
22. The composition of claim 1 comprising feverfew, riboflavin, and a nonsteroidal anti-inflammatory drug.
23. The composition of claim 22 wherein the nonsteroidal anti-inflammatory drug is of plant origin.
24. The composition of claim 23 wherein the nonsteroidal anti-inflammatory drug is white willow bark or its extracts.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002141126A CA2141126A1 (en) | 1995-01-26 | 1995-01-26 | Combinational drug for treating migraine and other illnesses |
| JP8522519A JPH10512573A (en) | 1995-01-26 | 1996-01-25 | Combination agent for treating migraine and other diseases, comprising sesquiterpene lactone and vitamin B complex |
| KR1019970705116A KR19980701720A (en) | 1995-01-26 | 1996-01-25 | Combination medicine for the treatment of migraine and other diseases containing sesquiterpene lactones and vitamin B complex |
| EP96900799A EP0805680A2 (en) | 1995-01-26 | 1996-01-25 | Combinational drugs for treating migraine and other illnesses, comprising sesquiterpene lactones and b-complex vitamins |
| AU44780/96A AU4478096A (en) | 1995-01-26 | 1996-01-25 | Combinational drugs for treating migraine and other illnesses, comprising sesquiterpene lactones and b-complex vitamins |
| PCT/CA1996/000052 WO1996022774A2 (en) | 1995-01-26 | 1996-01-25 | Combinational drugs for treating migraine and other illnesses, comprising sesquiterpene lactones and b-complex vitamins |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002141126A CA2141126A1 (en) | 1995-01-26 | 1995-01-26 | Combinational drug for treating migraine and other illnesses |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2141126A1 true CA2141126A1 (en) | 1996-07-27 |
Family
ID=4155120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002141126A Abandoned CA2141126A1 (en) | 1995-01-26 | 1995-01-26 | Combinational drug for treating migraine and other illnesses |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0805680A2 (en) |
| JP (1) | JPH10512573A (en) |
| KR (1) | KR19980701720A (en) |
| AU (1) | AU4478096A (en) |
| CA (1) | CA2141126A1 (en) |
| WO (1) | WO1996022774A2 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2283122A1 (en) * | 1997-03-03 | 1998-09-11 | Laboratoires Remilea | Plant extract compositions, method of preparation, and pharmaceutical compositions containing them |
| US6365180B1 (en) * | 1998-01-20 | 2002-04-02 | Glenn A. Meyer | Oral liquid compositions |
| US6068999A (en) * | 1998-06-25 | 2000-05-30 | Hendrix; Curt | Dietary supplement for supporting cerebrovascular tone and treating migraine headaches |
| DE19844836A1 (en) * | 1998-09-30 | 2000-04-20 | Hexal Ag | Pharmaceutical, effective, herbal preparation for the treatment of migraines |
| ATE228779T1 (en) | 1999-01-20 | 2002-12-15 | Nutricia Nv | INFANT NUTRITIONAL PREPARATION |
| US6312736B1 (en) * | 1999-12-09 | 2001-11-06 | Biotech Corporation | Herbal composition to relieve pain |
| WO2001045699A1 (en) * | 1999-12-23 | 2001-06-28 | Advanced Research And Technology Institute, Inc. | Use of parthenolide to inhibit cancer |
| US6890946B2 (en) | 1999-12-23 | 2005-05-10 | Indiana University Research And Technology Corporation | Use of parthenolide to inhibit cancer |
| US7192614B2 (en) * | 2002-11-05 | 2007-03-20 | Gelstat Corporation | Compositions and methods of treatment to alleviate or prevent migrainous headaches and their associated symptoms |
| US20040247705A1 (en) * | 2003-06-06 | 2004-12-09 | Roberts Stephen C. | Transdermal compositions and methods of treatment to alleviate or prevent migrainous headaches and their associated symptoms |
| WO2008010335A1 (en) * | 2006-07-21 | 2008-01-24 | Mmt Co., Ltd. | Plant extract having arthritis-preventive effect |
| JPWO2008075466A1 (en) * | 2006-12-20 | 2010-04-08 | 株式会社エム・エム・ティー | Food and drink for promoting hair growth, quasi-drug, pharmaceutical composition and method for promoting hair growth |
| WO2008075649A1 (en) * | 2006-12-20 | 2008-06-26 | Mmt Co., Ltd. | Food or drink, quasi drug and medicinal composition for promoting hair growth and method of promoting hair growth |
| CN101278928B (en) | 2007-04-06 | 2011-09-07 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Medicament composition containing levocarnitine or its derivatives and use thereof |
| US20100284986A1 (en) * | 2009-05-06 | 2010-11-11 | Kelleher Kevin J | Compositions and methods for prevention and treatment of migraines |
| IT201700085185A1 (en) * | 2017-07-26 | 2019-01-26 | Cristalfarma S R L | Food supplement for use as an adjunct in the treatment and prophylaxis of migraine |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR4173M (en) * | 1965-02-01 | 1966-05-23 | ||
| CA1270843A (en) * | 1982-05-19 | 1990-06-26 | Edward Stewart Johnson | Sesquiterpene lactones |
| US4542026A (en) * | 1983-04-29 | 1985-09-17 | Jose Rios | Method of treating vasomotor disorders |
| JPS63303915A (en) * | 1987-06-05 | 1988-12-12 | Nikko Sogyo Kk | Hair tonic |
| DE3808141A1 (en) * | 1988-03-11 | 1989-09-21 | Mai Jutta | Composition for controlling migraine |
| JPH0713021B2 (en) * | 1991-08-01 | 1995-02-15 | 文夫 堂園 | Oral drug for treatment of digestive system diseases |
| JPH05306231A (en) * | 1992-04-24 | 1993-11-19 | Pola Chem Ind Inc | Skin external preparation |
| WO1994001899A1 (en) * | 1992-07-02 | 1994-01-20 | W. L. Gore & Associates, Inc. | Sealing frame and protective membrane for a radar dish or horn |
-
1995
- 1995-01-26 CA CA002141126A patent/CA2141126A1/en not_active Abandoned
-
1996
- 1996-01-25 WO PCT/CA1996/000052 patent/WO1996022774A2/en not_active Application Discontinuation
- 1996-01-25 JP JP8522519A patent/JPH10512573A/en active Pending
- 1996-01-25 EP EP96900799A patent/EP0805680A2/en not_active Withdrawn
- 1996-01-25 KR KR1019970705116A patent/KR19980701720A/en not_active Application Discontinuation
- 1996-01-25 AU AU44780/96A patent/AU4478096A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0805680A2 (en) | 1997-11-12 |
| WO1996022774A2 (en) | 1996-08-01 |
| WO1996022774A3 (en) | 1996-09-26 |
| KR19980701720A (en) | 1998-06-25 |
| AU4478096A (en) | 1996-08-14 |
| JPH10512573A (en) | 1998-12-02 |
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