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~=~1 ~ he present lnve~tion rel~te~ to a time-released pharmaceutical ~or~ulation o~ both ~ o~lcium channel blocking agent and an ACE inhibitor ~or the tr~a~m~nt ~ hyperten~ion, conge~tive beart ailur~ ~nd rel~ted coronary ~il~e~ in mam~al~. The lnventi~n ~18Q rel~t~s to an i~prov~d ~ethod o~. tr~ating the afore~entioned coronary problem~.
Calcium channel block~ng a~ents ~re very o~ten the drug of choice in the treatment of ~ngina pectori~, supraventricular ~achycardia and hypertension. Thes~ agen~ ~re c~lcium-ion in~lux inhibitors ~low-channel bloc~ing ~gents). Alth~ugh their mechanlsm i6 not complet~ly understo~d, they are thought to inhibit calcium ion entry through ~elect voltage-~en~itive intracellular calcium concentration in cardiac ~nd va~cular smooth ~uscle cells, they dilate coronary arter~es and peripheral art~ri~s and ~rteriole~, ~nd ray re~uce heart rate, decrease ~yo~ardial contractility (negative inotropic ef~e~t), and 810w atr~oventricular ~AV) nodal conduction.
~ ypically, calciu~ channel blocker~ ~re incorpvrated into what i5 ~nown in the phArmaoeutic~l art ~ ~u~t~ined relea~e, 6ustained action, prolonged ~ction, controlled relea~e, ~xtended ~tion, timed rele~e, depot ~nd repository dosa~e ~orms. Tbese ~denti~y drug delivery sy6tems th~t ~re designed to achievc ~
prolonged therapeutlc e~ect by continuously relQasing ~edication over an extended p~riod o~ time aft~r ~dministration o~ a ~lngle ,' ' ~ : .
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~a~ s .. . .
dose~ Thus, a timed-relea~e ~ormulation oompriGing a ~alcium channel ~lo~ker i6 made to release sublst~n~ially all of the calcium ~ntagoni~t over a peri~d of time, u~su~lly over ~bout 24 hour~, rather than immediately a~ in a ~tAndard immediate-release formulation. ~ypi~lly, then, a r~imen o~ trea~ment with a calcium channel bl~ker w~uld c~mpr~e ~dmini~tration o~ ~ ~ingle ~ose o~ ~ time~-relQa~e for~ul~t~on ~noe daily over A peri~d extendlng up to several ~ont~s or ~ars.
Example~ o~ calc~um channel blocker~ include diltiaze~, nicardipine, nl~ed$plne, nimodipin~ and verapamil. These h~v~ b0e~
marketed under v~rious tradename~. Formulati~s c~nta~ning verapamil, for example, ~re descri~ed in U.S. Patent No.s 4,832,958, 4,B63,742 and 4,9~7,565.
Angiotensin-converting enzyme (ACE) inhibitor~ have ~l~o been pr~scribed ~or th~ treatment of hypertension and conge6tive heart ~ailure. The exact mechani~m o~ antihypertensive ~ction i~
unknown but may be rel~ted to competitive inhibition o~ ang~oten6in I-converting enzym~ (ACE) ~ctivity, re~ulting in a d~creas~d r~te of conver~ion of angiotenQin I to angiotensin II~ which 1~ ~ potent vasoconstrictor~ Decrea~ed ~ngioten~in II ooncentration~ re~ulk in a secondary increa~e in pla~m~ renln ~ctivity (PRA), ~hrough removal of tha negatlve ~eedb~ck 9~ renin release, and ~ direct reduction ln aldo6terone s~cretion.
Examples of ACE inh$bitor~ include captopril, enalapril, lisinopril and trand~laprll. Trandol~pril, for exa~ple, i8 described ~n U.S. Patent No. 4,933,361.
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~, J t ~ lany t~me~ a caloium Gh~nnel bloGker i~ pre~crlb~d along with an AC~ ltDr. ~ormulati`on~s oon~ainlng ~ ~ombination o~
one ore more c~ cium channel blocking ~gent~ with ~ne or more ACE
lnhibitor~ have al~ er~ ~ormulat@d. Tho ~2ction of the~e drugs 6e~ms tc) com~lement onQ ~no~her ln ~ tr~atment o~ hypezten~lon ~nd c~ther coronary proble~o6. ~he~e for~ula~10ns are described, ~or exa~nple, ln U.S. Patent No.~ 4,931,430 ~nd 4,808,413, as well a~
European Patent Al?pllcatlorl M~. O,3ll,382.
In instance~ wher~ a calciura c:h~nnel blo~ker ~n~l ~n ACE
$nhibltor have been utiliz~d toqether ln one oomposltion or method o~E treatment, the calc~u~n channel blocker h~s been ~ormulated 80 a~
to be released ov0r ti~e, while the ACE inh$bitor ha~ been formulated to be released i~medi~ely to begin lowering ACE
activity. (~he term "immedia~e rele~se" ~s used herein mean~ that the dissolution and absorption rate~ are not delay~d by ~anipulation cf the physical ~nd/or ¢hemical or other parameter~ of the drug itsel or through modifioation o~ the drug release ~ta cbaracteristics of th~ dosage that ~f~ct bioava$1ability). In fact, the pr~vailing wisdom ha~ been that it i6 nece,ssary not to delay the releas~ of the ACE inhibitor. Moreover, there appears to have been a ~urther reluctance to ~mploy ~n ACE inhi~itor ln a time-released fo~mulation because it h~ been felt th~t the quantity of the drug ~ployed would have to b~ greatly inorea~ed in order ~o ~chieve ~ therapeutlc respon~e over time.
However, because hypertans~on ~nd it~ relat¢d ailment~
~re most typically c~ronic ln nature, ~nd becau e cQncomitant '` ' `' ' . , '~ ' 3q?~t~
therapy ~ al~o u~u~lly lon~-t~rm, whnt ~8 need~d 1 pharmaceutical compo~ition and ~treatm~nt r~gimen which will decrease ~CE ac~ivity to a comp~rabl~ leY~l over ~ period of t~e, ~or example with$n about 12 ~o 24 hour~ ~ter ~dmini~tration o2 the t dose, ~ compared with an i~di~t~-rele~e ~ ul~tion.
~hat i~, there ~hould be ~o~par~tlvely llttle or ~o di~rence ln ACE acti~i~y levols when measur~d ~rom a time period oP within approximat~ly 12 ~o ~ou~ 24 hour~, an~ b~yond ~or the dur~tion o~
the treat~ent.
Furthermore, what i8 ne~ded i8 ~ method o~ treatmen~ and composition utilizing both a c~lclum ehannal blocker ~nd an ACE
inhibitor in time-relea~ed form wh$ch will be ~t least as effective ~n trea~ing hypertension in ter~s of decrea~ing ACE ~ctivity over a prolonged period, as mea~ured by ~ time period 6tarting from abGut 1~ to 24 hour~ dfter beginn~ng treatment, ~ ~re ~urrently utili2ed treatment regim~ns which ~eek a marked reduc~ion in ACE
activity level immediately.
OBJE,",'rS 0~ T~IE; IILY~IQII
It i~ there~ore ~n ob~ect o~ the present invention to provide a pharmaceutic~l compositlon compri~lng both a calclum ehannel blocking a~nt and ~n ACE l~hibitor in time-rel~ed ~orm for the treatment o~ hypertension and congest~v~ heart ra~lure in ~ammals, especially ~umæn~.
Ano~her oh~ect o~ ~he invantion 18 to provide a therapeutically ef~ective gu~ntlty of a c~lcium channel blocker ~nd ::~ 4 , , .
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r~ 'lri : , I` I ) an ACE lnhib~tor in tim~-rel~ed ~EonD.
A fuxther ob~ect o9~ the inventlon i~ tc~ provide ~ time-released rormulation of ~ therapeutl.c~lly eiEfective quantity of verapamil and trandolaprll.
Still another ob~ec:t o~ the pre~e~t lnventl,on ~ tv provide a time-relea$~d l::ompo~ition o~ both ~ calcium c:hannel blocking agen~ ~nd ~n ~CE inhibitor ~lc~ effective in the long-ran~0 trea~m~nt sf hlgh blood pres~ure and rel~tQd ooronary Ail~ent~ ~ tho~e co~po~itions and r¢gl~en~ o~ treatment ~urrently available in which the action o~ ths ACE inhib~tor i~ ~ot delayed.
Another ob~ec~ o~ the invantion i~ to prov~de an improved method o~ treating hypertension and cor~nary problems in which an effective quantity of a time-released formulation o~ a calcium channel blocker ~nd ~n ACE inhibitor ~re admini~tered on ~ periodic basi6. .
~Ry~--QF . ~11~
The~e ~nd other object~ o~ the inventlon are a ~ ieved by providing a pharmaceutical c:omposition for the ~reatment of hypertensiont congest~ve hear1: *ailur~ and oth~ar c:oronary ailmant~
in mammal , e . ~ O human~, ape~, monXey~, ~arm animals, ~51~ and c:at, compri~lng a therap~uti~ally ef~ectlve quarJtlty o~ both one or ~nore c:~lcium channel blocXirl~ agent~ ~nd one or ~or~ ACE
inhibitors ln time-rleleased ~or~ in c:omblnation wlth a pharrnaceutically acoeptable c~rr~rO
Al60 provided as p~rt c~f the inventic~n is ~n ~mprov~d ..~
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method of treaklng hyperten~ion and r~lated coronary proble~s in ~ammal~ which oomprises ~dministering to a patient a therapeutically ~ffectiv~ qu~ntlty of a tlme-released ~ormulation o~ Dne or more ~21ciu~ ~han~el blocker~ ~nd one ox ~ore ACE
inhibitore ln ~ombination with ~ ph~aceutically ~cceptabl~
~ehicle.
T~58~R~P ~c:lN ~ Q~
Figure 1 i~ a graph o~ verap~mil ~nd norver~pamil concentration6 over time.
Figure 2 1~ ~ graph oP tr~ndolaprll and trandolaprllat concentrations over time.
~ igure 3 i8 a chart ~f ACE ~ctivity over time ~or the time~released ~ormulation of ver3pamil and trandolapril according to a preferred embodiment ~f the lnvention versus ACE activ$ty over time for an immediate release formulation of trandolapril.
DE~A:~ISRCRIP~IQN OF ~HE~ P~E~l~RRED ~SME~C~DIl!SB~F~
In the com~osition accord~n~ to the invention, one or more caloium chann~l blocking agent~ Are employed ~oge~her wtth one or more ACE inhibitor~ in ~ time-relea~ed formul~tion. The calci~m antag~ni~t may be any one ~elected ~rom ~ho~e known i~ the art ~nd can include ~or example diltiAzem, w~ich has the chemical n~me 3-(acetyloxy)-5-~2-~dimethylamino)ethyl-2,3-dihydro-2-~4-~ethoxyphenyl)-1,5-ben~othiaz~pin-4-(5~ ne.Dil~iaze~ ~s described in U.S. Patent No. 3,562,25~.4Phenyl-1,4-.,;
.
.' ~! ) dihydropyridine calciu~ antagoni~t~ ~ay ~l~o b8 employed, ~s well as nifedipine. Pr~sently pr~err~d i~ verapamil or 5-(3,4-di~ethoxyphenylethyl)~ethyl-Amino-;2-(3,4-dimethoxyphenyl)-~-$sopropyl ~aleronitril~, wbo~ 0~nt~he6i~ i~ de~cribed ln U~S.
Patent No. 3,2~1,859. Verapamil i¢ ~arketed by ~oll Pharmaceuticals o~ Whippany, Naw J~r~ey under ~he tradenam~ ISOPTIM
8R, Othex c~lciu~ ~n~gonis~ ~old under var~ous kr~den~mes ~y ~ther pharmaceutic~l co~paniQ~ ar~ e~ective $n the composition ~ccording ~o the invention, ~nd ~re ~herefore al60 within the ~cope of the invention.
; The calcium channel bl~cking agent i~ Also pre~era~ly present in the form o~ A phy~iologically ~ccept~ble salt. Examples o~ these include the 8~1t6 of such acids as hydrochlor~c acid, ~ulfuric acld, phosphoric ~cid, acetic acid, ~aloni~ ~cid, ~uccinic acid, fumaric acid, ~aleic acid, c~tr~c aoid, tartaric acid, lactic acid, ametosulfonic acid and oxalic ~cid. An especially desirable salt i hydrochloride. Thus, the mo~t preferred calclum channei blocking agen~ for use in the ti~e-rel~ased formulation ac~ord ng to the invention is yerap~mil ~Cl.
Th~ ACE inhibltor which i6 employed $n the compo~ition according to the inven~ion ~ay al~o be ~elected rrom thosa ~urrently available ln the art. For example, these may in~lude captopr~l, enalapril, ramipril, ell~zaprll and ll~lnoprll~ but presently preferred is trandolaprll ~N-lS-oarbethoxy-3-phenylpropyl) F-~lanyl-2S, 3a~, 7aS~octahydroindol-~-carboxylic acid, from U.S. Patent N~. 4,933,361~. Other ~CE lnhibi~or~ known J .. D
~, ! i in t~e art ~nd fiold under v~riou~ tr~dename~ are al~ w~thln the ~cope o~ the invention.
~ he ACE inhibltor may al~o be present ln the ~orm of a 6alt in the compo~tlon. ~ince tr~n~ol~prll has both ~n ~cidic and a ~aelc component, it ~an ~harefor~ ~orm ~alt6 with both ~he a~orementioned acld~, n~ well as with physiologlcally compa~ible bases, ~uch ~6 ~lkali hydroxide~ of ~llkalln~ e~rth hyaroxide~.
~ hè novel ti~e-rel~aæed compo~tion o~ a calcium channel blocker ~nd ~n ACE l~hibitor ~nay be proce~sed with pharmaceutically ~cceptAble vehicle and ~an include one or more ~d~uvants, bind~rs, fill~r~, pre~ervatives, ~ubricant~, tablet di6integrating agents, ~low or v16co~ity regulators, ~oftQners, wetting agent6, di~persing ~gent~, d~laying ~gents and axid1zing agent~. Examples oP visGosity regul~tore include ~icrocry~talline cellulose, ~odium alyinate and polyvi~ylpyrollidone. ~n ~xample o~
a suitable lubricant would be magne~ium ~tear~t~.
~ he calcium channel ~locklng agent(s), ACE inhibitor(sj and other ingr~dients are combined into ti~ed-relea~e ~ormulation. While parenteral a~ well a6 othe~ route~ of ~dministr~tlon may be contemplated by tho~e ~killed in the ~rt, it i~ preferred that ~ral dos~ge ~o~mul~tion~ be ut~lized.
Generally, there nre two types o~ ti~ed-rele~se do~ge form designs ~or oral admin~6trationO
One type involve~ the ~od$~ication ~f the physic~l and/or ~hemical properties of the p~rticul~r drug3 utilized. The other involves the modi~ication o~ tha dru~ release rate characteri~tics J
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. . . I ) of the dosage rOrm that a~2ct bioavallability. Those ~killed in the art ~ay find lt use~ul to aon~e$ve w~y~ to alter the physical ~nd/or chemical properties of the c~lclum ch~nnel clocXin~ agent~) and the ACE lnhibitor~6~ to achlev~ ~s:ope o~ ~he $n~ention. It 1~
preferred, however, that the approach to ~ustalned release o~ both the c~lcium an~agDnist ~nd th~ ACE i.nhibitor be based on dosage for~ ~od~flc~tion.
Formulations ~a~ed on ~od~$i~tiD~ o~ the physi~chemical propcrtie6 Or the do~ag~ for~ ~an q~erally be ola~d lnto ~our basic product typss: encapsulated 810w rel~a~e be~d~ (or ~ranule~), t~bletted ~low relea6e granulations, 610W r~lea~e oor~
tablets ("matrix" ~or ex~mple), ~nd osmotic relea~e tablets.
Numerous variations of the~e product typed exi~t in th~ ~rt, and the particular one cho~en will often depend on the ~pecific drug properties ~u~h a~ ~olubility, di~sociati~n con~ant, and stability, as well as on the ~anufacturing technology ~v~llable.
The composition according to the invention ~ay be incorporated into any one of the aforementioned dosage ~orm~, and may even be incorpor~ted under n liquid dosage ~or~. It is preferred, however, that the compoæitlon Accordl~g to the invention be incorpora~ed into a slow release core tnble~ compri~ing a core matrix of both calcium chann~l bloGk~r and ~CE inhibitors~ I~ this way, the ~anuacture o~ t~e tn~let~ ~llow~ for th~ d~rect incorporation o~ loading dose~, by preparat~on o~ either multilayered or press-coated ~able~s~ One layer of ~he ~uter ¢02t of the tablet is prepared ~rom a potentially rapid di~integrating ,~
granul~t~on, l~avlng ~he 1Q8~ qulokly disintegr~ting lay~r or core, which ~ontains the maint~nanoe do~.
~ he particulax time-r~l¢a~ oral ~ormulation utilized ~hould permi~ dis~oluti~n ~nd a~orpt~on o~ the ACE inhi~itor 50 that the ACE actiYlty will ~pprox.imRte that o~ a ~tand~rd immediate-rele~se formulation af~er ~ t perl~d o~ ti~e, 20r ex~mple a~ter ~bout 12 to 24 ~OUrfi 1~ pr~Perred- Those ~klll~d ln the art may contempl~te sDmewh~t lo~gor or ~horter periods~
Thu~, while ~he widely ~ocep~ed immediate-relea~e formulation will gener~lly h~ve a ~ore ~arked e~ect on ACE
activity a~er approximately 1 to 4 hour~, ln a lonqer time ~rame a~ ~et ~orth above, and ~specially a~ter ~everal days or even week~
or months of treatment, the A~E activity lsvel ~or the two fo~mulation~ xhould be approxi~ately the ~ame.
~ nother advantaqe of the composition accoxding to the invention lies $n lts relativ~ ea~Q ~nd s~mpliclty o~ manu~acture.
Both the ACE lnhibitor and calc~um channel bl~cker ar~ ~irectly mixed together into the slow-relea~e matrix, whioh helps ~o eliminate the chance of develop~ng de~ective lot~.
In a particularly preferred embodi~ent of the invention the timed-relea~e compo~ition will sompr~s~ the calcium channel blocker v~rapamil HCl and ~h~ inhlbltor trandol~pril ln about a 90 to 1 welght ratio. A partlcularly sultable dosa~e form w~ll comprise ~bout 180 ~g of ver~pamil ~Cl wit~ ~bout 2 ~g o~
trandolapxil in combination with a pharmaceutically ~ccep~able veh~cle to be ~rally administer~d oncs da$1y. The total weight of ~0 :
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~ aingle do~age rorm wlll ~e approxi~ately 540 to 545 ~., w~th binders ~nd v$6c08$ty agent~ ~tc. oomprl~ing the remainder o~ the dosage for~. This pre~erred dosage form wlll be ln the form of a 810w releas~ core tablet co~prl~ing ~ core ~atrix o~ vQrapamil and trandolapril.
Tho~e ~kllle~ $n the ~rt may ~ind ~ther w~ight rati~ o~
calcium channel block~r ~o ~CE ~nhlb~ors t~ b~ ective in a regimen o~ txea~ment con6i~t~n~ with the goal of ~nt~ining the ACE acti~ity level at a oert~in therapeutic l~vel for th~ duration of extended or long-r~nge tr~atment. ~actor~ to be consider~d may include, for exampl~, the l~vel of tr~atment ~nd r~sults de~ired, as well as the welght, age and condition~ of the patient and hi~ or her tolerance abillty. Thu~, hctual ratios ~ay of course vary outside the preferred range ~et forth herein.
,, ~ he followi~g ~xa~ples illu~trate the invention, and ~hould in no way be con~trued ~6 li~iting the 8cope tbereo~:
EXAMPLE ~
Thi~ ~xample illu~tra e~ a meth~d o~ preparing ~n e~pecially preferred embodi~t ~oc~rding t3 the ~nvention, wh~rein especially pre~erred ~inder6 ~nd vi~cosity agen~ etc. ~nd their quantitles are ~et forth.
1.~00 k~ o~ verapamll ~Cl, ~0 g of tra~dQlapr$~, 2.400 kg of 60dium alginate, 0.541 kg of ~$crocrystalllne cellulo~ and 0,~60 kg o~ polyvinylpyrollidone wer~ mixed in ~ ~mall P-~ blender .r " ' ' ' ' :. :
' ~or approxi~ately 35 ~lnut~ h~ :re~ultiny mixture W~5 ~hen tran6Serred ~o ~ ~obar~ ~ixer ~n~ 1.350 kg of puri~ied w~ter was added ~na mixed ~or ~bout 10 minut~. 150 g of ~lcohol (9.5%) was the~ ~dded and khe re~ulting mixtur~ blend~d ~or another 5 minute~.
The yield wa~ ~ppr~xl~tely 10,000 tablet~ o~ ~bout 542 mg~ each.
~ 16501ution rates of th~ ~03.emsntioned preferred do~age ~orm ~howed th~t the trandolapril ls rele~sed ~5 $oll~ws: ~bDUt 13% after approx. ~ hour, ~bout ~0% a~eter ~pprox, 2 hours, ~bout 41% after approx. 3.5 hour~, ~bout 63% a~ter approx. 5 hour6, and 95~ after approx. ~ hour~. These r~ults ~re ~as~d on the ~v~rage dis~olution/release r~te6 $or ~ix ~amples o~ tablets containing ~pproximat~ly lBo mg. of ga6tric/intestinal iluid in a Bath #6 equipped wl h ~ 50 r.p.m. paddle stirrer.
EXAMPL~_~
A single-dose clinlcal Ftudy wa~ undertaken ~o evaluate the pharmacokine~lc~ ~f *he preferred timed-rele~se verapamll/trandolapr~l co~bination ~ccord~ng to the invention. The A~giotensin ConYerting En2yme tACE) actlvity W~5 al~o evAluated-This w~ an open-label, ~ingle-dose pilot ~udy of 36 hours duration. The ~ingle dose ~ontained tr~nd~lapr~l t2 ~g.) and verapamil (ISOPTIN SR) ~180 ~g.) in ~ Eingle tablet. (~h~ 2 mg. of trandolapril was 1noo~por~ted into th~ ~low releas~ alglnate matrix ~f the slow release verap~mil tablet~.
A total of six bealthy wh~te adult ~ales were enr~lled in ~, .
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., ". . . ~ ) the study. ~ub~ct~ h~d ~ an age og 30.3 year~ ~nd ~ Dean wei~ht Df 157 . 5 lbs .
~ rhe ~tudy drug wa6 ~dmini~ter~d se~auent~all~ to 6u}~ect~
at five ~ninute lnt~ bQglnnin~ ~t B: 30 a.D~. All ~ ect~
reo~$vod a ~lngl~ do~ o~ the ~tudy drug lDIme~telY ~ollow~rlq a st~ndardized break~t.
~ o ~igniic~nt adv~r~ r~ct.lon~ wQre r~portad during the ~;tudy. No ~linically ~ignlf~e~ant z~nor3l~al v~tal ~gns, ECa ~r ol$nical labor~tory f1ndins~s war~ ræported t!l~lring ~e ~tudy.
Mean phArmaookln~tic paralDeters for trAndolapril, trandolaprllat ~l'che ~ctivt3 me~a~olite oP trandolApril), verapamll and norverapamil (the aotive ~etabolite o~ verapamil) were as follows: t~x(h~mr~ AUC0 lr~ pril~ /~ 5.2 1~a3.s p~
Ir~ndol~pril~t123~ 2 32~2.3 pa/~4~hr ~r~p~m~ .a~ n.s ~/~/br ~l~rv~r3pomil51 0 na~11.~ 1167.1 ~/01~hr A graph of the average ver~pa~ nd nvrverap~mil ~oncentratlons over time ~nd ~hown in Figur~ er~pamil and norverapamil concentrations begin ~o peak at about ~ hcur~ r~p~ o~ the average tr~ndol~pril ~nd trandol~pril~t conc~ntration~ over time are shown in Pigure 2. Con~entration6 ~ trandola~r$1 p~k ~t approxi~at21y 5 hour~ ~ter do~ing, whila the lev~l og trandolaprllat beglns to p~ak st a~out 10 hour~ ~n~ ~tays at approximately that l~vel for the durhtion o~ ~h~ ~tudy.
The ~ng$ot~nsin Converting Æn~y~ ~r ~CE ~tivity w~s ~lso evAluated during th~ study. ~an (+SD~ ~E actlv~ty was as ~ , ~.
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~ _ _ ~ . _ ~Icrl~ ngt 2.0 r.!i Act~v~ty Unl~ .
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O ~ ~ ~ ~_ _ e ThP resu t6 i dic t~ that A~E ct~ lty ~ ~lr s ts ~ ~1 belvw the normal range at somewher~ between ~botlt.~ to 6 bo~lr6 after do~lng.
Next~, a c omparison ln ~ c'clvity level~ was ~dQ
betwe~n ~he ext~ndea-rel~a~ ~Eo~ul~ti~n o~ verapamll ~Jld trandolapril nccordin5~ to th4 preferr~d embodi~aent ~ the inventl~n, ~nd an immediatQ rel~ e Pormulatio~- o~ trandolapr~l alone. The result~ are lndicated in 'che chart of ~igure 3. lV--1 represents the ACE actlv~ty K~ b~elin6~ ~ctivity ver~u6 time for tha immediate r~lease ~onnulatlc~ og trandol~pril, while TV-2 represents the ACE ~c~ ty versus ti~e for the extended release ~ornulation of 180 mg. I~f verapamll with 2 2llg. of trand~l~prilO
The ~omparison o~ ACE ~ctlvity for TV- 2 v~. ~rv 1 was such that ~fter ~pproximately 24 hour~, there were rel-ltively insignl~icant di~ference~ in ACE inhibition ~etween the timad-release compo ition o;~ ver~p~l and ~r~n~olnpril acc~ding ~o the preferred embodiment of the ~n~ention when ~ompared with the ~t~ndard immed$ats-rel~ase ~or~ulation.
Al60 provlded a~ pqrt v~ th~ invent~on is an lmproved method of tre~ting hyperten~$on o~ hlgh ~lo~d pres~ure, ~nd rel~ted eoronary problems which eompr~se~ ~mln~terlng to a p~ient a ther2peutically ~f~ect~ve guantity o~ ~ t~d-rele~6e ~or~ulat~on of both one ~r more c~lci~m ch~nnel blookers and one or ~ore ACE
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inhibitors ~n combination with ~ phanm~ceutioally ~cceptable çarr~er or veh~cle. It iB hi~hly de~lrablo ~hat the timad-relea~e formulatlon will eompri~e verapamil ~Cl and trandolapril according to the preferred ambodi~ent o~ thl~ inv~ntion, ~nd will be admin~stered to A pa~ien~ oral~y one daily. ~hus, ~mproved ~ethod of tre~ting hyperten~ion etc. w~ mpri~e administ~ring to a p~tient ~ timed-rele~se ~or~ul~tion o~pri~ing abouk 180 mg. o~
verapamil and 2 mg. of ~randolapr;Ll in oomb~nation wit~ a pbarmaceutically e~fect$ve c~rr~er.
Other treat~en~ regimens con~istent with the overAll goal of maintaining low ACE activlty lev~ls ~or the dur~tion o~
treatment are al80 wlthin the ~ope o~ the inventlon.
While the inventlon has been described in detail in lt~
various embodiment~ ~or the purpose o~ ~llustratio~, it i8 to ~e understo3d that ~uch descrlption ls 801~1y ~or that purpose and that variations may be ~ade therein by those ~killed in the art without department ~rom the ~pirit and ~cope of the invention ~et forth in the ~ollowing claims.
.
: 15