CA2135767A1 - System for controlled release of antiarrhythmic agents - Google Patents

Abstract

A system for controlled release, site-specific delivery of therapeutic agents, particularly myocardial agents such as antiarrhythmic agents, comprises a biocompatible polymeric patch (30) with an incorporated therapeutic agent for direct placement at the epicardium of heart (31). The dosage form is fabricated so as to tailor the release characteristics as required by the nature of the physical condition desired to be treated. In a specific illustrative embodiment, ibutilide, a potent, but toxic, Class III
antiarrhythmic agent, is incorporated in polyurethane and solvent-cast to form a monolithic drug delivery device which can be co-implanted with an implantable cardiac defibrillator. Advantageously, very low doses of ibutilide administered directly to the epicardium in this manner produces a reduction in defibrillation threshold.

Description

. WO 94/212372 13 5 7 6 7 PCT/US94/02838 SYSTEM FO~ CONTROLLED RELEASE .
:` ` OF ANTI~W~EIYIIIM~C AGENTS ~;

Backgrounds of the Invention FIELD OF THE~INVENTION
~ ~ ;This invention~ relates to ~ con ro~led release dosage form for site-specific ~: ~ delivery of therapeutic agents and, more~specifically,~to a controlled release :~ ~ dosage~form for dir~t~trarsmyocardial delivery:of anstiarrhythmic agents either alone or in combination with cardiac rhythm controlling~devlFes and methodss:~f ` making and usmg same.~
10 ~ DESCRIrrION OF TllE~ PlUOR ART
Life-threatening~ ca diac ~rhythmias ~ a ~m~ic problem confron ing millions of persons ~daib. ~ Arrhythmias ~are the p incipal ~cause of death followlng myoc~dial inf~ction:in~hundr~s~of thou~ds~of o~er persons. Fu~ermore, cardiac arrhythmlas complicate one-thlrd to~one-h~f of ~e more tha th~
:15~ h:undred~ihousandopQheartsurgeriesrarried~out~annuallymtheUn~ted~States The te~ "cardiac ~rhythmià" 1 S: us~-:gener~ly: in the ~,~ and h~ein, to~cover conditions~of no~héart~rhythm,~ and s~cifi~ly includes ventricular arrhythmia, ~ven~ fibdllation, :and: supervent~c~ ~ythmias,l such ~s atrial~fibnllad~on, atri~ flutta,; su~entricul~ tachycardia, multifoc~atrial' ~;' `,r` ' j'` ~ ta~ch~da~ ~unc~` ~t h rdia, etc~
i ~s ing~ m~ y~m~
abn alities ~ d~g `th~p . ~E pl ~of~u~ ~p d:~
~ e~D~ e~ r~ir_e~

WO 94/21237 PCTfUS~4/02838 21357 67 ! ~
..

' Other antiarrhythmic agents, such as lidocaine or amiodarone are g;ven in~rave- ;
nously. Conventional drug therapy is often ineffec~ive in either preventing or i~
treating life-threatening ventricular arrhythmias due to inad~quate drug concentra-tions where and/or when needed and adverse side effects of the drugs. ~ ;
`:
S ~ In addition to drug therapy, many patients per year now receive intracar-diac electronic pacémalcers or implan~table countershock d~vices, such as ~;
automatlc~ defibrillator/cardioverter~ dèvlces, for severe cardiac rhythm distur- ;
bances. However, there are signific~nt pro~lems created with surgical implanta-don and subsequent mai;ntenance of electronic pacemakers and implantable ~10~ countershock devices. In particular, it would be desirable to enhance the function of such devices s~ that less~discharge current is required and the episodes of use are diminished. L:owering the~requirements of dischar~e current would advanta~
geously,increase the~lifetlme of the battery and could facilitate miniatun~ation.
In`~general, patient- with~lmplanttble countersho~k devlces are also tre ed ;;

15;~ with antialThythmic~agents to prevent arrhythmias. However, few of the drugs administered~systenucally in associatlon~with ~hese devices haYe been shown to be of real benefit ~or reducing ventricular defibrillation threshold. ;~
Recently, abl~tivé surgical and:cathetenzation techniques have~beeni~
de~veloped~to destroy~1rritable myocardiàl Ussue; ~but~this has not~been pardcularly;
0 ~ e~fecdve. Accordingly, drug~:lherapy~, ;pacemaker~implantation, ~d surgery~e~at best~only~pa ~Iy èff~t ve for preven~ng~d/or suppre ng~ ac ~yth~

` WO 94121237 PCT/US94/02838 `:, .!" ; ~ 1. 3 5 ~ 6 7 Sustained site-specific cardiac drug delivery systems have been de~eloped to prevent bacterial endocarditis, to prevent bioprosthetic heart valve calcification and to prevent fibrous tissue buildup. Thyroid and adrenal medulla myocardial :: autografts were investigated as "endocrinologic cardiac pacemakers." Drug :
: ~ :
S delivery of chronotropic agents has also been accomplished by myocardial implants of silastic reservoirs containing.a variety of compounds, including digoxin, isoproterenolj and thyroid hormone, all of which can effectively ~ :
accelerate cardiac rate when delivered directly into the myocardium.
While these methods~have been employed to stimulate and control~cardiac : . :
lO~ rate by transmyocardial drug administration, there have been no~ examples in the : :
. prior ~art of treatment of ventricular or atrial arrhythmias by transmyocardial~ : :
~5~ : administratlon of antia~hythmlc agents. Nor:has there b~n:àny disclosure in the pdor~art of lowering defibrillation threshold: in life-threatening fibrillation ~
sltuations or~of increasing res~i5tance to these episodes by trans~ny~dial delivery 5~ of antiarrhythmic agents.
Mor~ver, none~:of the:abové-described ~lymeric ~evices ~ be~
fabricated so as ta~ have:~a~particular dosage release charactenstic. There~are obvidus:advantagès:to'rapld release of;the antiarrhythmic agént imm~lately~post~implantation, ~followed~by~s!ower, sustiuned rolease, in the:treatment of certain ~
condit ons,~ such as~acute a hythmi~. ;: ~ t It is ~erefore ~ ~obj~t~of the inven~on~ to~provid8 biologic~ or ~
synthetic~polymeric materirls~whlcn~rre compatible with body ~tissues :and ~hich wo 94,2l235l ~ ~ 5 ~ 6 ~ PCT/US94/02838 g: ~; `` ` `.

:

- incorporate therapeutic agents, such as antiarrhythmic agents, for the treatn1ent of cardiac rh~thm disturbances.
lt is a further object of the`invention to provide a biocompatible polymenc matrix with incorporated antiarrhythmic agent which can be applied directly to the S heart muscle via the epicardium, endocardium, or pericardium.
It is an additional object of the invention to provide~a technique for fabricating~a biocompatible poiymeric matrix with incorporated antiarrhythmic agent wherein the release characteristics of the antiarrhythmic agent can be !
~; ~; selectably varied.
lo ~ It is yet a fur~her obiect~of th~s invention to provide a biocompatible polymeric matrix with incorporated antiarrhythmic agent~which can be applied ; dlre~tly to the heart:muscle~in~conjunction with a cardiac rhythm controlling -: : : : ~ ~ , , device to augment the ef~ectiveness of the rhythm controlling devices and/or suppress~onset of rhythm ~dlsturbances. : ~
s :~ `Summary of; the~:~I~`vention ~
The~foregoing~ d other~obj~ts a~e achieve by t is mvention~which provides an arrangement~for~ controlling the heart rhythm of a patient. In àccordànce with'the inventlon, the arrangement is ~provided with an electrode for condùcting an electrical~signal; to or from the h~art of the patient. AD implantable con~oll~rel se d e~r r ~ a the~u~ y ive a ount of anti~rhythmlc agent~to~the~h~ of the patient. ~

f 'WO 94/21237 21 3 S 7 6 7 PCT111594/0~838 ~, , `::
S !.
In one embodiment of the invention, a substrate formed of a biocompatible polymeric material has incorporated therein at least one antiarrhythmic agent. In ' `q preferred embodiments, the biocompatible polymenc material is a synthetic, ~ .
nonblodegradable polymer such as polyurethane, polydimethylsiloxane, ethylene vinyl acetate, polymethyl methacrylate,~ polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoro-ethylene, or cellulose aoetate. Of course, the polymenc matnx material may be a mixture of two or more biocornpatible polymersj or a copolymer.
.
In alternative embodiments, the biocompatible polymeric~material is a 0~ bi:oJegradable polymeric material such as collagen, polylactic-polyglycolic acid, ~ ~ ~ t, ` or polyanhydride. ~ ~ ~
~he incorporated antlarrhythmic agent may be~any therapeutic agent or cotnbination of agents which have an effect on;~cardlac rhythm disturbances. In some embodiments, the~ antiarrhythmic a~ent may be either a cardiac stimu}ant, 15~ ;` such as~ isoproterenol,~dopamine, or norepinephrine or~ a cardiac suppressant, such as lidocain~. In other~advantàgeous embodiments, t~ie antiarrhythmic agent may be a calciurn channel b!ocker, verapamil or diltiazem. In other advantageous embodiments, and~specifically in embodiments used m conjuncbon cardiac rhythml !` :
`controlllng;devices, ;the antiarrhythmic agent may be proloogers of acdon ~20 ~ potential duratlon,~such as amiodarone,~ ilide, ibutilide, sotal~l, or clofilillm.
In typlcal~embodiments,~tbe an~ùar~hythmic agent compdses betw~n about 5%
and 40% by weight of the substrate. ~

WO 94/21237 PCT/IJSg4/02838 ~

I
,~3$ 16 ~
.. i Dosage release characteristics may also be tailored in some embodiments ~y the acldition of a pharmacologlcally inert filler or co-cipient, illustratively polyethylene glycol, inulin, or dimethyl tartrate, which has a water solu~ility ;~ whlch varies from the water solubility of the antlarrhythmic agent. Advanta-geously, the anionic tartrate may form an anion-~cation pair with a cationic antiarrhythmic agent which serves to retard the release rate. The pharrnacologi-cally inert~filler is selected from;the group consistmg of inulm, polyethylene glycol, and dimethyl tartrate.
The substrate is adapted; for direct application to the heart of the patient ; ~for effecting transmyocardial delivery of the anbarrhythmic agent. The term "transmyocardîal delivery" refers to delivery to the~heart mùscle and specifically ; ~ also includes contacting the epicardium, endocardlum and peAcardium~ ~
.
The Implantable device may be in any form which may be attached to ehe h~
muscle~ in some manner such~ as a patch of film, coated electrode wires, anchor~
15~ able~ ~ratheter~tip, etc.~ ln some embodiments,theelect~ode is; prov~dedwith tissue engagemen:~means~for engagmg the heart tissue of the patient, such~as a ; conical ;tip.
In some jembodiments of the invenbon, the electrode IS further provided with a pacing;~electrode.~ln~still other emb~iments, the el~e is~provid~ with ;~a sensor on a~dis~ end there~f for sensing a predetermined condltion of ~the heart~
of d c ~padent. ~ ~The electrode~ may ~cont dn a plulal~y~ o( defibrillator/cardloverter ~ ,~ WO 94/21237 2 t 3 5 7 6 7 PCT/US94/02838 ~ i !
As stated above, ~the substrate may be configured in the form of a film, ~ `
which is some embodiments; is fixedly attached to the electrode. The film has a thickness on the order of 20 ~m to I cm, and preferably about 200 mm.` In the `
alternative, the film may be multilamellar. In other embodiments, the substrate is S in the form of a molded cardiac contacting component attached to the~ electrcde means. Certain drug release characteristics can be achieved by~ molding under compression, illustratively in the range of about 8-l0 tons per square inch.
A method of treating cardiæ rhythm disturbances in living beings comprises direct controlled release delivery of an antiarrhythmic agent to the ~ : :
0 epicardium or endocardium by application of an implantable device comprising a polymeric matrix incorporating the desired antiarrhythmic agent.
In accordance with a further aspece of the invention, a cardiac rhythm controlling device is provided with a cardiac contact for conducting an electrical ~ .
: :
~ ~ signal to the heart of a living being, and a controlled release dos~ge arrangement ~:
~:~15 ~ ~for producing a controlled reiease of an antiarrhythmic agent.
In accordance with a method aspect of the invention for treating cardiac rhythm disturbances in a living ;being have a heart, there is provided the step of ~ ;
placing a polymeric ma~ix incorporating a therapeutically effective amount of atleast one antiarrhythmic agent~ in direct contac~ with the eplcardium or endocar-20~ ; dium of the~heart of ~the living being in conJunction with a ~diac rhythm controlling devlcc.~

~:~
WO 94/21237 PCT/US94/0~838 ; ' 2~3S'1'6~1 '' .`, In accordance with this method aspect of the invention, the cardiæ ~hythm ; l;
controll;ng deYice is an implantable cardioverter-defibrillation device. In someembodiments, the cardiac rhythm controlllng device is~ an lmplantable pacemaker.In accordance with a further rnethod aspect of the invention, for treating or preventing ventricular or atrial~fibr;illation, or ventricular~:tachycardia, in a living being having a heart, thè~method is provided;wlth the step of placing;a ~:
polymenc matrix incorporating a therapeutic~lly effecdve amount o~ at least one antiarrhythmic agent of the type which is a prolonger of action potential duration :: in direct contact with the jepicardium of the heart of:the llving being in conjunc~
lO;~ tion with a cardiac rhythm controll1ng devlce.
Brief Description ~f the Drawing These and other~objècts, features and~advantages will be better appreci~ted from~consideration ~of the followlng ~detailed descnption read in conjunction w~th :
theaccom~anying~dra~wings,~wherein~
,';`~ ~15~ Fig.~ l is a:g~hl~ represent~on of ~he short te~ release~ch~cteristlcs of lidocaine-polyureth~e~matrices~fabricated m ~ccor~nce wi~h the invention and exprèssed as % cumulàtive release versus time in minutes;
Fig. 2 is a~graphical representadon~ of longer term DleaSe characteristlcs of lidoc~ne-polyure~th~ane~matnGes fabncated in accQr~ce with ~e in en ion ~d ~' ~ 29~ express~as % ~cùmulative~rel~se;versus tlme m ~ys;
Fig. 3 ls~a ~graphical representation o f long tenn~ rel~se characten~cs of lidoD~ olyurethal~e matrices~ nD~ accordance :with~ thc mvention and . ~WO 9~/21237 2 1 3 5 7 6 7 PCTfUS94/02838 ~ i~

hav;ng varying drug loading ratios (wt. lidocaine: wt. polymer precursor)~
expressed as % cumulative release versus time in days;
Fig. 4 is a graphical rèpresentation of short term release characteristics of a lidocaine-polyurethane matrix fabricated in accordance with an alternative embodiment of the invention wherein the matrix mixture was subjected to compression molding expressed as % cumulative release versus time in minutes;
Fig. 5 is a graphical representation of longer term release characteristics of a lidocaine-polyurethane matr~x fabricated in accordance with an alternative embodiment of the invention wherein the matrix rnixture was subJected to :: : : : :
compression molding expressed as % cumulative release versus time in days;
Fig. 6 is a graphical representation of long term re!ease characteristics of a lidocaine~polyurethane matrix fabncated in accordance~with an alternative embodiment of the inven:tion wherein the matrix mixture was solvent cast ~om a solution of dirnethylacet~mide expressed as % curnulative release versus time in ; . :
j . ~
i5 ~ 'days;, Fig. 7 is an illustrative,electrocardiogram of a canine subjected to ouabain-~; induced tachycardia followed by direct application of a lidocaine-polyurethane f ~ patch fabricat~d irl accordance with this invention`to the epi~dial lèft ventncular myocardium;
20 `~ ~ ~ Fig. 8 is a graphical representation of ~lood plasma level of lidocaine in a ~ ~ ~
canine subject with time for trrnsnnyocardial delivery v~a a lidocaine-polyurethane I' pa~ch;in accordance wi~h this invendon ~; ~

~ ~"~ ~
WO 94t21~37 PCTtlJS94/02838 `` I .
~1 ' , .

- 10 . ' .
Fig. 9 is a graphical representation of blood plasma level of lidc~aine in a canine subject with time for an intravenous bolus dose of lidocaine, comparable to ~
the transmyocardial dose administered and shown in Flg. 8; -Fig. 10 is a graphic representation of the difference in coronary venous blood levels of antiarrhythmic agent versus systemic biood levels for ~ransmyocar-dial delivery of lidocaine in a controlled release lidocaine-polyurethane matriees :
~28% wlw; 44 mg, 5 mm x 5 mm epicardial patches) of the present invention;
Fig. l l is a graphic representation of an ibutilide-polyurethane matrix exhibiting a burst effect releasing about 30% of the antiarrhythmic agent from a ` 10 po}yurethane matrix in the first 15 minutes, and at a reduced rate thereafter;
Fig. 12 is a graphic~representation of the in vitro release of the antiar-: ~ :
rhythmic agent from an ibuti}ide-polyureth~ne matrix containing an inert co-c~pient, dimethyl tartratc;
Pig. 13 is a graphic representation of is a graphical representation of ~ ~
S ~ ~ ~ VERP in ms as measured~ by an eplcardlal electrode and an endocardl~ electrode ~ ;
located proximal to an~ibutilide-containing matrix;
" ~ ~ Fig. 14 is a graphic representation of the~effect on acbvation time of ' ibbtiilde-polybrethàne lmatnces,~`in~milliseconds, the epicardial electr~de located ' proxlmal~ to the matrix locadon; ~
20 ~ ; Fig. ~15~ is a graphic~ representation of the probabili~y of ;successful defibrillàtion by an implantabIé cardiac~defibrillator ~or the application of a ~-2U
ms ~monophasic pulse of ener~y, measured in joules~

~135767 ~ .WO 94/;!1237 PCTIUS94102838 i "~ ' : ~` .` , I ! ~

11 ., Fig. 16 is a graphic representation of the defibrillation threshold for~a monophasic pulse bèfore and after administration of 0.025 mg/kg ibutilide; '~`
Fig. 17 is a graphic representation of the defibrillation threshold for a biphasic pulse before and after administration of 0.0025 mg/kg ibutilide;
Fig. 18 is a graphic representation of the % conversion of hbrillation relatlve to an applied biphasic pulse in joules for the epicardial application of ibutilide-polyurethane matrices having an~ inert co-cipient therein;
Fig. 19 is a graphic representation of a defibrillation for a clofilium-polyurethane patch UpQn application of a biphasic pulse from a cardiac defibnlla-` ~I0 tion;
Fig. 20 is a~graphic representation of the change in activation time, in milliseconds, as measured by electrodes placed at various distances from the epicardially placed matrix containing sotalol or ibutilide (0.025 mg/kg) as ~ :
~indicated on the drawin~g;
S ~ Pig. 21 is a schematic representation of atrial pacing electrode embodiment of the present~inwnhon~having a muldlamellar ibutilide-containmg polyurethane coa~ng;
. i ! i Fig. 22 is a graphical representation of the long terrn in Yitro release ;oharacterisdcs~ of a~ dip-coated wire fabricated;in accordance wlth the invention ~ 't., ;- 20~ expressed~as~% cumul~tive release~versus time in days;
Fig. 23 is~a~bar graph sh~wing the reduction~of atrial flutter induclbility by ibutilide-polyureth~ane~ coat~ atrial electrodes of the present invention; ~

WO 94/21237 PCT/US94/02838 t; '~
357 6 ~ ! ```. :

;, '~
,1~ . ' Fig. 24 is a schemabc representation of a paclng-transvenous defib~llator catheter having a molded annular conical tip ~abricated in accordant~e with the invention; "
Fig. 25 is a graphical representàtion of the in vi~ro release rate of a :::
~ molded annular conical tlp of the type shown In Flg. 24 expressed as %
t~umulative release versus time in dàys; and ~ ~ ~
Fig. 26 is a graphical~ representation of the probabllity of successful ~defibrillation by a pacing-transvenous defibrillator catheter made in accordance with the present invention.
o ~ ~ ~Detailed Description A novel controlléd release~dosage form~is described~ hereinbelow for the therapy ~of cardiac arrhythmia,~wherein a substrate compnsing a polyMenc ma~ix incorporating at least~ one therapeutic agent is directly pla~ed in contact with the~
ht muscle. The therapeutic agént;~then elutes,~or diffuses, directly into the~site~
~15 ~ wb re it~is needed resulting~in~a rapid conversion from tachycardia to normal sinus rhythms. Direct con~a~t of;the~dosage form with~the heart muscle, either~at~
t he epicardium or the endocard;um, or in some instances through the pericardium, is horeln termed "transmyoc~dial delivery." A SpeCiflC advan~ge of ~the novel do~ form Is that~smyoca di~ delive~r ts a lower do e o ~ i rhythmic æent to~be~ usèd~ for lo~ized, or~leglonal, treatment, ~ thereby~ nutigating~
the:usual adveFsé ~side effèc~ts of .uch drugs when admimstered~systemi~ly in doses ufficient~to b- efficacious.~

, WO 94/21237 2 1:~ 5 7 6 7 PCT/IJ594/02838 .''" ~ ' ' ~. '`'.

f The polymeric matrix materifal is illustratively synthetic, such as poly- I
urethane or dimethylpolysiloxane ~S;lastic). The synthetic polyme~ic matrix . `
materifal is preferably flexlble, elastomeric, and of great tensile strength so that the resulting controlled release ~osage form for transmyocardial delivery will be .
S ; able to withstand the intense m~hanical activity of the heart. In this regard, polyurethane and dimethylpolysiloxane are ideal. High molecul~r weight ..
polyurethane (e.g.,, 40,fOOO to 80,fOOO daltons),~for example,~has desirable surface properties, such as an overall negative surface charge. Advantageotlsly, ~f : ~
the negative surface chary,e binds the cationic antiarrhythmic agents well for ; ~sustained release (see, Fig. 2). In particular embodiments, where rapid release of f antiarrhythmic agent would be desirable, such as to convert life-threatening arrhythmias to normal sinus ~hythm as qulckly as possible,~ hydrophilic ~Iymers, :
such as polyurethane, are preferrerl.
Qther examples include,~without !imitation, any biocompatible polymer, whether hydrophilic or~hydrophobic, such~asf ~ethylene vinyl acetate, palymethyl methacrylate, polyamide~,~ polycarbonate, polyester, ~Iyethylene, polypropylen~
polystyrene, polyvinyl~chloride, polyte~afluor~thylene, or cellulose acef~ate. In ';I iain'falternativè: iil~st~ive embodiment, a blologicalIy: derivèd paiymèr, such as protein collagen, polylacf~ic-polyglycolic~acid, or polyanhydride, is a sulf~able `; ~ 2~Q` ~ ~lyme~c~ ma~ix~ mate . ~
For eertain ~sit`uàf~ions~ su~h as~sho~t te~ f~hythmias~s~iat~ with car~fiac surgeries, biologicalfy deeradable¦polymeric matnces ~e~advantageous~
since they~can~;be resorbed by~ the b(ldy ~ er a penod~ of ~ su.tair od drug delivery.

WO ~4/21237 PCT/US94/02838 æi3s76~

,.
14 ~ ' On the other hand, for chronic recurring arrhythmias, nondegraidable and/or potentially refillable or renewable, systems, such as a hollow polymeric reservoir, 1 might be more appropnate.
Specific examples of two therapeut:c agènts, or d~ugs, ~which are currently 5 ~ ~ ~ i n widespread usage~f~r cardiac rhythmic disturbances and~ which are well-suited for inclusion in the controlled~relèase` dosage form; of this mvenhon are lldoeaine and amiodarone. Lidocaine is;a highly effect~ve aintiarrhythmio agent whlch is t~pically administered mtravenously, and then only for a~limlted time due to the - ~;
adverse sidc effects produced by this agent. Amiodarone~ ean be given orally, but ~10 ~ ~ ~ causes severé side effects in over 70% of the~patients receiving it. Controlled ;
; ~lease dosa`ge forms: of the~prèsent invention~ have ~beèn formulated to incorporate `
andanhythmic ~agents ~from lhe four; generally~ recogni~ed~classes of antialrhythmic agonts~augh~-Williàms assifi a on). Somee ~les` regiven below in 1~,., WO 94/21~37 2 1 3 5 7 S 7 PCT/~JS94/02838 amiodarone ^
artilide bretylium clofilium ibutilide .
sotalol.

.:
~ Class IV - Calcium Channel Blockers ::
verapamil .
diltiazem nickel chloride . ~.
Lidocaine, for example~ is a cardiac depressant. Cardiac stimulants, such .
as isoproterenol, dopamine, and norepinephrine, c~n also be incorporated into ;, poiymeric matrices in accordance with the principles of this invention and, in:
~` ~ 15 ~ some instances, may be:used to treat.heart failure. An exemplary combination of more than one myocardial agent ls the digoxin/quinidine system used to treat .~ ~
atrial fibrillation.
It is to be understood, however, that any antiarrhythmic agent, or :
comb~nation s)f anbarrhythmic agents or other d~ug5 which are suitable for co~
ZO.~ administration~wihantiarrhythmicagents,is:withinthecontemplahon~ofthe ~
invention. Therefore, the ~term "antiarrhythmic agent" as::used herem means any àgent or combination of agents that can :bie used to treat, o'r con~ol, cardiac rThythmias ~whose mechanlsm of action ~conforms~ to~one or more of the four aughan-Williams~classifications or which;otherwise has a therapeutic effect:on:
zs~ cardiac arrhythn~-as. ~

WO ~/21237 PCT/US94/02838 213S7~

The antiarrhythmic agents are preferably provided in a water soluble form, ! . 2 such as the hydrochloride salt of lidocaine, to facilitate elution from the polymeric . . . i .
matrix material in the presence of body fluids.
The controlled release dosage forms may be place~ directly on the heart ~5 muscle ~during open heart surgery, by cardlac catheter with a detachable tip, or by pericardiocentesis. Three lllustrative substrate ;configurations for cardiac applic~tions Include an èpicardlal design for direct attachment to the~ surface of the heart which could be in the form of a polymeric filmlpatch (see Fig. 7~, polymer-coated wlres (see F~ig.~ 21), ~or ngid screw-threaded molded polymenc . ~ 10 ;~ structures. For intravascular placement via a cardiac catheter, a detachable screw-threaded catheter tip, or~an expandable;(umbrella) system with anchoring prongs (see F~g. 24) àrè~among~ the~many possible configuradons which can be devised by one of ordinary~ .kill in ~the art. Other, onfigurations can be devised ;for intramyocardial placement via~a~stab wouod with a~ sharp t~ochar. Tech~
` l5~ ;niqaes,~ such~as film~ casting and compression molding, ~are applicable for ca~ng thè s~fic ~s~ configu~on of the antiarrhythmic agen~lym~
enc matrix controlled~release dosage form.
The cor~figuia'don chosen would depend upon the type of arrhythmia conditionbeing~ ~dosage~rm~in~;~te~sh~o a`p~hmight~v~
geously be placed~ op~qfilly OI endocardially~durng ~pen-heart ~sureey to~avoid~
~t v ` ~ mi A~ :in:~
threaded~atheter~ p might~ p~ide~p~
;~hythmias:fQll ~ my di în e on.~ Mor~ ,~as~ose of ~11 In the~

j.`,.~`~,WO 94/21237 ~13 5 7 6 7 PCT/U594102838 17 1 ;
art are aware, certain antiarrhythmic agents are more suitable for chronic ~ , `
arrhythmias, for example, than acute arrhythmias, and therefore agents such as ç ~;
procainamide or sotalol would be a drug of choice for incorporation into à
controlled re}ease dosage form for application in a chronic arrhythmia situation.
The dosage form may be a m~nolithic drug/polymer matrix, such as a film or implantable device, from which diffusion-mediated release occurs. In an alternative embodiment, a reservo~r-type drug delivery system can be devised.
Illustratively, the polymenc matrix material would be configured to form a hollow core reservoir with an access for refilling (see Example 17).
~ Irrespective of form, the dosage forms of the present invention should preferably have a nonporous,` ne rly pinhole-free, smooth surfaee to prevent formation of thrombus and cellular ingrowth. In particular, fibrous or endothe-lial cellular ;ngrowth could interfere with efficient release~ and metabolism ofantiarrhy~hmic agen~. Incorporation of an anticoagulan~, such as heparin, into the ~ `poiymeric matdx could minimize thrombus ~ormation.
The novel dosage~ form would either replace or provide an importan~
` adjunct to existing oral or intravenous antiarrhythmic therapy. In addition, the dosage` form co~ld be used as part of procedures such as coronary ar~eriography, angioplæty, routine cardiaG:surgeries,:cathetedzation and clinical electrophysiol~
20 ~ ogy studies. ~Moreover,~mclusion of a dosage form such;as~descnbed herein ` ~ would provide :addidonal drug therapy;~ subsequent to pacemaJ~er~ implantadorl or could enhance~ the efficiency of an ;~mplanted automatic cardiac defibrilia~
tor/cardioverter.

WO 94121237 ~ ~ : PCT/USg4102838 ~`~` ~ ~

2~3~ 6 ; ` I ~

There are various techniques for incorporating~the therapeutic agent into the polymenc matenàl matrix of the controlled rel~e dosage~ form of the instant invention~ General IllustDtive techniques inclùdè ~he followln~
1;. The theràpeutic agent can be comblned with the` polymenc ;
; ~5~ precursors so that~the ag;en~t~ ls ~lncorporated as an ~elemènt of the polymenc mixtùre pnor to solid phase~;polymen~ation. Examples~ and`2 ~herein ~e i llustrativé of this techni~ue.
2.~ Polymenzed màtrix matenal is dissolved in an ~rganic solvent. ~he;
therapèutic agent should i so~be`solùble in~thè ~e org~ic solvent so that~the~
lp ~ therapeuhc agen~ can~ be addd directly ~to the dissolved polymer~matrix mate in~the desired~ wugh~ raho.~; lhe mixture~ is~ theA poured ~(solven~ cast) into a '"~:or ~t~as~a~film, a~id~thè `
d ~ for~example,~t~ of thls t ` hmque.

3;~ ~; Fully~ d matrix materlal can~be~milled,~or mixed,~with~
th~e~e en ;rate~ànd~
dù~ion ~be~ u ss~ . ~d v ~`~
~s ~e~ sion mol d ~ i~e i ~ ym c}r~-~dtse ~ her~illustrate~the e~ects~of some of `W094/7.17.37 PC~/U594102838 .` 2135767 ` `

: t 19 , these parameter variations. The results are graphically depicted in Figs. 1-6. In other emhodiments, the release~ rate is varied by the addition of a pharmacologi-cally inert co-cipient, such as described in Example 14, Formulation 14b, and shown graphically on Fig. 12. In sbll further embodiments, configuration, such the provision of multiple layers, can affect the drug release rate as shown graphically on Fig. 22.
Release characteristlcs of the drug-polymer combmation can also be rnade responsive to feedback signals. An electrically responsive acrylamide polymer orsilicone rubber containing a cation-exchange resin, for example, could be made to 10 ~ provide more drug when arrhythmia is detected and ~then to down-re~ulate when the abnormal rhythm has ceased. Such an electrically responsive embodiment would be particularly useful ~in conjunction with a cardiac rhythm controllmg dèvice. ~ ~
Given below are several specific illustratlve embodiments of biocompatible , IS ;~ ~ controlled release dosage forms~in accordance~with the invention and methods of making same. Also included~ ~are experimental results showing the efficacy and advantageous features of the dosage form under in vitro and in vivo condltions.
ilthough Examples 1-5 are primarily direct~ to the preparation of p~lymeric~
matrices incorporatlng the antialThythmic agent lidocaine, the~techniques 20~ described~hercin~e~applicable to~the~cre~'don of;~a wlde varie~y of other drug/polymer comblnations and devices formed theteof. Additional exasnples (Exampl~, 6 b ~17~ demonstra~e that controlled release dosage forms m accor~

,;!i~' ,~
WO 94/21237 PCTtllS94tO2838 ~ .~
2~ 35~ 6~ ~

dance with the princlples of the invention have been fabricated to incorporà~e antiarrhythmic agents from all four classes o~antiarrhythmic agents. .- ~'' ExamRle 1~
Lidocaine-polyurethane matrices were prepared by mlxing about one t o s four parts of lldocaine hydrochlonde (particle size 75-150 ~Lm) with ten parts~of Tecoflex 2-80A (a polyurethane~prepolymer made by Thermed~c~lnc., Woburn, MA) comprising 0.21 parts of dilsocyanate monomer and 0.79 parts of polyether monomer. ' ' In the ~lidocainetpolyurethane~ example, prepolymerized ~polyurethane 0`~ components will not react to form polymer m ~the presence ol~more than about;
20% by weight~of the~antiarrhythmic agent. However, a FeCl3 cat~1yst and slow cur~ng~ at low temperatures will result in the formahon of a stable polymer. In ; general, O.l ~M to ~l.O ~M FeCl3 pet g of polyether mono~mer is effective to provide a viable polymer~c structure with up to 40% w/w drug ioading.
U~ Advantàgeously,~ the;resul~arit antiarrhythmic agent-polyme~ matrix will release anti~hythmic~ agent with~ ~ accele~ted e~ly rate follow~ by a sust~n~, `~ slower~diffusion-controlle~ rate. T he accelerate~ early rate is particularly~
àdvantàg~us in'`the treatment of acute arrhythmlc~dlsturbances.
In~the~ specific illùst'rative~embodiment~f ~ample 1,~ 0.74 ~M FeCI3 pe~
20~ gran~ of polye~her monomer~was added~as a~catalyst. ~The mix~ture was then cast;~
as;a~llm of approximately 200~m thlc ness ~d cure f'or 48 hours a 55~C.
Of course, film thichesses can vary,~ as a practical mattor; such thlcl~iesses range~
rom about~ 20 ~m~to:1 cm. Temperature~and bme ranges for polymeri~ation can~

~.' WO 94/21237 2 I 3 5 7 6 7 PCT/US94102838 ~ .:

21 1. `.also range, respectlvely, from about 50 C to 60 and from about 24 hour~ to 3 days. ~.;
a) In Vitro Experiments:
Cumulative drug delivery in vilro of 28% w/w loaded lidocaine-poly-S urethane matrices, fabricated by the technique of Example 1, was monitored spectrophotometrically by absorbance at 2~0 nm. Samples of a perfect sink ~ ;
buffer solutlon were talcen over time and the data was expressed as the m~ns of duplicate measurements. The perfect sink buffer solut~on compnsed 0.54 ~ ~ `
aqueous K2PO4 at a pH of 7.4 and temperature of 37 C.
.
0 ; Pigs. 1 and 2 show the results of certain process variations to the method of Example 1 which affect the release of lidocaine. These process variations are(1) polymerization at 55 C as descAbed in Example 1; (2) an additional step of I, ~; ~ stirring the polymerizatlon mixture after about 2 hours (post-long chain polymer-ization~ nd pre-crosslinking) of reaction time; rnd (3) polymerization at room temperature. Referring specifically to Fig. 1, the short term release charactens~
:
tics are graphically sho-vn~ as a plot of % cumulative releàse versus time in minutes. Line 1 rèpresents the release characteristics of the` matrix formed in ccbrdance with the process described iD Example l (process variatiol (I)~ above); i lin`e 2 represents ~process :vanation (2) above; and line 3 represents pr~ s ~
~`20~ v~ation~3i~above. ~ 3s ?
Fig. 2 Is a; graphlcal ~representation of long; term~ release chalacteristics shown~as;~a plot~ of % cumulatlve rel~e~versus time~in days. ;~ I,ines 1 through 3 1:` ' `
WO 9~/21237 PCT/IJS94102838 ~3S~16~Z :

represent the release charactenstics~ of the matrices formed in accordance wl~h processes (1) through (3), respectively ~.. ; i.
The in vitro results show that variations In process parameters do affect the drug release characteristics of the drug/polymer matrix. :In the polyurethane ~ ;
system of Example 1, the use of a hlgher molecular~ weight polyol in the polymer segmcnts resulted in a more hydrophobic productj and hence a product capable of greater retention of the drug over time.
In other experiments, the effect of vanous drug ioading ratios was examined in vitro. Reference to Fig. 3 shows a graphical~representation of long ~ :
,~10 ~ term release charactenstics of :lldocaine/polyurethane matrices having varying weight~ ratios of lidocaiine to polyurethane. The data was obtained by spectropho-tometric absorbance measurements and is expressed as % cumulative release versus time in days. The particular ratios exarnined were 2:10, 3:10, and 4:10 which are r presented on Fig. 3 as lines l, 2, and 3, respec~ively. The release ~l5 ~ `rate profiles consisted ~of higher inihal rates than the~ longer term diffusion ;
controlled rates. Moreover, a. drug concentration was~lncreased, mitial rates increase~ while the diffusion-controlled rates remained about the same.

; ; A lidocadne polyurethane matrix combinaAioA ~was ;prepared ln accordallce with the~method of ~xample I. ~ However, after a period o~ about 2 hours, when ~ '~
long chain polymerization ~was essentially~completed, but pdor to crosslinhng, ; `
the reachon~ mlxture~ was stirred~ for ~a short period of bme, m~ this specific example,~ for~5 minutes. ~

~ .
s~O94121237 213576~ PCT/US94/0~838 I

This mixture was then compresslon molded under 8-10 tons per square inch. The lvng and short term release characteristics in vitro of the resultant 'i `
dosage form are shown in Figs. 4 and 5 as a funcdon of % cumulative release versus minutes and days, respectively. Compression moldmg markedly decreases S the release rate.
Exarnple ~
A lidocaine-polyurethane matri~ combination~was prepared by a solvent casting technique. F~ully polymerized polyurethane was dissolv~d in an organic solvent, such as~ to form a clear, liquid solution. ~ ~The desired amount of lidocaine~
lo ~ ; was added into this solution. The ~solutlon was then cast; as films 2-4 mm in thicl~n~ss.
Fi~. 6 is a graphlcal illustrahon of the long term release characteristics for he solvent cast ~dosage fo,rm :fabr~cated ;in accordance wlth thls Exarnple. This m:
vitro~expe 'me t w s c uGt~;at~ 7.4 In the~e m~ner'as desc ibe ~'~i5~ hereinabove with~resp t~ ~ le l.~Comp 'ng the re ults of Fig. 2 with Fig.~6,~it Is,obse~ that the;solvent casting technique~results in a greater ~ s prolongà~on of susta n ~relèà e~of the th~dc agent.
A ~Iymë c matnx ~of the t~ descnb~ hèreinabove ~was us~ to i~ s demon,trate~;the~effective~ttansmyocardlàl ~dministration~of lidocdne by~dr ect~2'0, '~ placement of~a'patch of~d~ma~x~on~the epi~i~ su~ace of a ~ine h~.
The follo ,wing ~experImènt~ de~ls~e inhibibon ~of ouab~n-indu~ vS~tricu~
tachycardia with:;epimyocardial~implanl of the~:controlled~release~lldoc~dne~
"lyurethane matrix~ sysiem, fabricated 1n accord~e~ wlth ~xample 1 WO 94/21237 PCT/IJ59410:Z838 l~3S~6~ ~

24 i `
b) In ~vo Ex~eriments: ¦ :
i. ~
Ventricular tachycardia was inducedi ~ith ouabain administration in accordanee with a method described in an artiele by Kniffen, et al., Cirçulation, Vol. 49, page 264, 1974. Ouabain is a cardiac glycoside which is used therapeu-tieally for its rapid digitali~ing effect. The expenment mvolved 14 male mongreldogs weighing from 12-14 kg each~. Ouabain obtalned from Sigma Inc., St.
Louis, MO, was administered at an initial dose of 40 micrograms/kg at a rate of . . .
40 mierograms/minute, and at subsequently halved dosages until sustained ventrieular tachyeardia was documented by electrocardiogram.
to ; Eaeh dog was subjected to a Ieft thoracotomy in order to induce ventricu-lar taehyeardia with administered ouabain. Referring to Fig. 7, a polymeric patch 30 having dimensions of 3 em x 3 em x 0.2 cm was applied to the epieardial lef~
. .
ventrieular myoeardium of he~t 31 about 1-2 em to the left of the anterior deseending. eoronary artery, about 1-2 em below the eircumflex coronary.
~lS ~ ~ Fig. ~7 is also i!lustrative of an eleetroeardiogram~ obtained as a result of this ~ experiment. Eleetroeardiographic eonfiguration was obtained with standard ~ i `~ ` surfaee limb leads, as well as atrial and ventrieular leads. Recordings from the lim~ leads are sh~wn at 11 ;and 12 and atrial and ventneular defleetions are 13 and 14, respeetlvely.~ Conversion of ventrieular~taehyeardia after placement of a ; 2(~ ;; ` lidocaine-polyurethane matrix to norma: smus rhythm is mdicated by arrow 10.
ln eaeh animal, the lidoeaine-polyurethane ~matnx patch `30 was left in plaee onthe lef~ ~ventrieular myoeardium~ for the time neededi to eonver~ the ventneular-taehyeardia to normal~smus ~rhythm. When normal sinus rhythm reappeared, ~O 94/21237 ~ 213 5 7 6 7 PCT/11S94/0283~ ~;
I ~ ` , .

patch 30 was removed after one minute had elapsed, and the experiment w'as continued in order to detect the return of the induced arrhythmia. Some dogs had ~`
' patches of polyurethane only as controls.
Ouabain-induced ventricular ~tachycardla in the dog was converted to normal sinus rhythm in all experimental animals studied~via~controlled release ,`
drug delivery of lidocaine from~a polymeric matnx attached directly to the ventricular myocardium as~shown in;Table I wherein dme is;given in terms of ; mean i standard error. ;, TABLE I
lo PolYmer A~plication Number or Animals In Time (min~
Ventricular TachYcardia Polyurethane ~ ~4/4 ~ 4/4 ~ ~ >60 Lidoca~ne/Polyurethanè 6/6 0/6 1.5 + 0.77 15 ~ Removal of Lidocaine/ ' ~ 0/6 : 3/6 lS.0 * 25.0 ;Polyurethane ~

The~ results glven in ~able' I for the ~ime rarrge for returr of ventricular ` :` '~dhYCard;a afterremov~ ofthe'lidocaine-polyure~lanem~ix~is for three animals. :~The remain,ng three~ animals ~continued~ in~norrnal sinus rhythm~ for` ~ grèater ~àn~60~minute`s.' In ~lm~s~ wi, the~ntrol~h s,~ven~ UIOE
tachyc~dia~continû~ for mor~th~ 60~;mlnutes without the~,resù~on:`of~
5inus rhythm~s.~ The' lidocrun*polyuretharle~patch convr,rtr,d tht ven~cular t~hyc~dia~to noFmal sinus rhythm~in 1.5~+ 0.77 minutes.~

WO 94/21237 PCT/IJS94/02838 ~` '~`` i~ ' ~ 3s7 6~ I ~

Dog studies analyzing blood plasma levels of lidocaine Indicated tha~
myocardial application of a lidocaine-polyurethane patch resulted in therapeuticeffects as rapidly as lldocaine administered intravenously by bolus dose, but with comparatively lower plasma levels as determined by high per~ormance liquid chromatography. Referring to Fig. 8, lidocaine plasma levels In the c~nine study ,`
~re shown as the means of duplicate~ measurements for plasma levels in six dogs and their time-dependent decay after epicardial lldocaine-polyureth~ne therapy. In comparison, Fig. 9 shows plasma levels for 2 dogs following intravenous ~;; administration of 24 mg/kg and 45 mg/kg doses of lidocaine. The intravenous ~0 dosage levels were chosen to correspond to approximately the same dosage level as epicardial administration achieved by the polymeric~patch as determined by ~ ~ sohxlet methanolic extraction of the residual drug remaining in the polymeric `; ~ ` matrices after in viv~ use, followed by subsequent high performance liquid , chromatography utilizing a Waters Model 60~0A system ~Waters? Inc., Bedford, 15 ~ MA) with a~prepacked C18 column (par~icle size 5 ,um), Altex ultrasphere-ODS, 25~ cm x 4.6 mm I.D. (Bec~nan lnc., San Ramon, CA) and an isocratic moblle phase of O. IM sodium phosphate buffer at pH 3.0 with 0.7% v/v triethylamine-ac~tonltrile (50 50). Absorbance was monitored at 210 nm.
Thè abwe-described experimental~ results demonstrate that transmyo~rdlal ', ~20~ site-specific; drug dellv~ s an~ effective ~route for the administration of antiar- t `~ rhythmic therapy. The direct~epicardial placement of hdocaine polyurethane controlled releàse~a~ces resulted in the prompt conversion of indueed arrhythmia to normal smus rhythm ~n~ all~expenmental animals st l,died in about S~l35767 ~WO 94/21237 ; PCT/IJS94/02838 1.5 minute, while controls had persistent ventricular tachycardia for more tha~i 60 minutes. Site specific therapy was as rapid as intravenous administration, yet resulted in lower plasma lidocaine levels for comparable dosages.
In a study conducted on the transmyocardial delivery of lidocaine-loaded polyurethane patches attached to the epicardia of dogs, net ~oses of between 19 : ~ :
, ~ mg/kg and 45 mg/kg of lidocaine vwere delivered. However, the plasma le~els of lido~aine ~were 8.75 to 25 ,ug/ml for the controlled relea~ dosage ~form of the present invention as compared to 36.7 to 101.2 ~Lg/ml following administration, o f a comparable dose intravenously. Thus, the direct myocardial placement of the , 0 ~ ~ ~ dosage form described ~herein would midgate adverse slde effects of lidocainej or any other antiarrhythm~c agent administered in~ that manner, Lidocaine has been inco~o~t~ into an ethylcell ose m ix by~a so ca~dne~techniqueusln~ varlous;--l~vent-, includin~ chloroform, melhylene i 5; ~ ; chloride, and ethylace~ate. The~lidocaine Ioading ra~io~was 2:10.

`~ Lidocaine in a~silastic mat~ix was madeby blending fully polymenæd ; ; '~ Silasti~ 382, a ~r~dema~c ot~Dow-Corning,~Midland, Ml, wlth lidocaine.~ln th~
instantcase, 5% lidocame~by~weightwas~addedto~theSilasdc. Thlsblendwas polymerized~by~the~addi~tion~of a .tannouscc~noa~cataly~

' Al~ isoproterenol-polydimethylsiloxarc~matrix dosage form has ~been~
fabrirated and~found~to pro ce efficaclous results. Pre-polymerizedpolydi~

S~ WO 9'1/21237 PCT/US94/02838 21357 6~ I
` .
28 1, rrlethylsiloxane (PDMS) was milled together with powdered isoproterenol (5-2~%
by weight relative to the weight of PDMS)~to ~rm a blend. The blend was then ' cataly~ed, either by heat or by addition of a chemical such as stannous octanoate or platinum oxide, and permitted to polymerize.
Controlled release matnces having antiarrhythmic agents from the four Vaughan-Wllliams classifications of antiarrhythmic agents have been formulated in various polymeric matrices. Specific illustrative examples are set forth hereinbelow. The~Class I sodium channel blockers, such as lidocaine, procain-amide, encainide, and flecanide, are represent:ed ~n~Examples~ 1-5 hereinabove.

A Class II (beta adrenergic blockers) antiarrhythmic agent, propranolol, ~ ~ ~ has been incorporated into vanous polymenc matrix materials, particularly `'! ~ polyurethanes, such as~ Mitralthane MPU-5 (a polyurethane available ~rom Symbion, Denver, CO) or biorner (a polyurethane available from Ethicon, s~ Somerville, NJ), in amounts of up to 30% wVwt. In accordance~ with tho method of Example 3.

; ~m~
` ~ Class III ~intiarrhythmics, which prolong the action potential duration, aIe ; represent~d~by amloda~one~(available ~rom Wyeth, Philadelphia, PA) in specific ;
o ~ illus~tive èmbodiments. ~
Aml~darone has~ boen inco~ rated m a polyurethane matrix by the method of ~Example 3. ~ M~re~ ~e~ifically, amiodarone was dissolved in dimethyl-ace~mide to form-a~soludon~havmg a~concentraùon of 10() mg/ml thera~eutic ~NO 94/21237 PCT/US94/02838 ~.

29 ~ l' agent. This solution was further dissolved in a 10% solution of polyurethane~
(Thyomer, Thermedics, Inc., Woburn, MA) with polyethyleneglycol (PEG 200, Dow, Midland? MI) as a 10% co-cipient. This solution was solvent cast into a ~ 0.2 mm filrn and used in the studies reported below in Table II. Polyethylene gly-~ col facilitates the release of the amiodarone from the polyurethane matrix.
In addition to amiodarone, ~artilide has been incoIporated into a poly-urethane matrix by the solvent casting technique of Example 3. Artilide ls a;
Class III antiarrhythmic agent that is structurally related to sotalol and ibutilide.
Artilide, like ibutilide, does not~block beta adrenergic receptors ànd prolongs~0 ~ ; ~ action potentiat duration and refractodness by asl ionic mechanisrn which differs from other Class III drugs, such as sotalol.
x~mpl~
;Another Class III anha;~rhythmic agentr d-sotalol ~(Br stol-Meyers Squibb, WaLllingford, CT) was lncoIporated into polyurethane (Mi~althane MPU-5) in 5 ~ accordance~withtheproc~ureof~Example3~and;usedmthec~ines~dy~
i',~ r~Q~rt~ her`einbelow~in Tabte~
i ~ In~yet another~ embodiment, d-sotalol was dispersed in leviga~ed silicone ~ J
;nubbe~ (Silastic `Q7~48J~O; ~ to form~a composite. In a specific ihustrative oxample, tAe composlte~was compressed~ in ;a stainless steel slab; mold at 2000 0 ~ ~unds~rsqùareinch~for;one`minute.~The~compress~com tew~cu 24~ hours ~Dt ~37 ' ~

WO 94/zl~l ~ 6'1 PCTIL594102838 ', _m~;
.

Class IV antiarrhythmic agents, or calcium channel blockers, including ~ -verapamil, diltia~em, and nickel chloride have~been incorporated into various ~ polymeric matrix materials, such as polyurethanes such as Mltralthane MPU-S, ~ and silastics such as Q7-4850 m accordance with a solvent càsting technique as ~3 ~ ` described in Example 3.
Example ll:
Antiarrhythmic agents have been incorporated into exemplary biodegrad-able~ matrices such as a high` molecular weight polyanhydride, polysebacic acid-~ carbox~rphenoxy propane (Nova, Baltimore, MD) and~punfied rat tail collagen.
' ` Films can be cast from the anhydride by dissolving it in methylene dichloride.
The collagen may be cast from a solubon in 0.1M~ acetic acid.
; ~ ;In a specific embodiment of a biodegradable matrix, sotalol was formu^
~ ; lated into a poly (dl-iactide-co-glycolide) (PLGA) matrix by an "in water" drying IS'~ ~ ~ techniqueasreportedbyOgawa,~tal.,J.Pharm Pha~col.~,Vol.41,pages ~;

4 39~444 (1989). In a~typicà ~ procedure, 800 rng sotalol and 100 mg gelatin were ` ~ dissolved` in 1 ml water m a 60 C water bath. The drug solution was emulsified ~ ~' unthi~ polym'er~solution~by sonificaoon (Model W-22'5R, Heat Systems~
;` ` ' ~ Ultrasonics, Tnc.~ Farmingdale, NY) at 3~ ~Hz for l5 minutes in an ice bath. I'he D ~ polymer~soludon~comprisei1.8~gPLGAdissolvedin20mlmethyl~echlo~de.
` ~ lhisemulsion~was~added~drop-wisewithconhnuouss~ing(Stir^pak, Cole ~, `Parmer~lnstrument~Co.,~ Chlcago,~ at 400~rpm;into 200 ml of 1% wh ` ~ polyvinyl alcohol (PVA) adjqs~ed to apH of 9.0 with sodium~phosphate dlbasic ~`~ 2 t 3 ~ W0 94/21237 S 7 6 7 PCT/IJS94/02838 ~
, . " ' '' ' : ....

: ~ .' ., and saturated with methylene chloride. After I hour of stlrring, the emulsiob was i.-added into 2 liters of aqueous 0.1% w/v PVA solution (pH = 9.0) and stlrred for j:
~: an additional 3 hours. The ~microspheres so~ formed were passed through a #IQ0 :mesh sieve. The fraction remainlng Qn: the #4~0 mesh sleve were reeovered by ~ ~:
;5.~ centrifugation,~washedfourtimeswithdlstilled:water,~lyophilizedfor4g:hours, and~ then dried under vilcuuln`:for 48 ~;hours.
~ In an illustrative example ~of~ use, the sotàlol-PLGA microspheres can be ~
:~; ~ . .suspended in a saline solutlon,~ for example, and injected into~a space prepared in t e;pericardium.`
Example 12 :,ln Viv(~ ~entnculàr~Pacing St~d~es ``~ : Vent cu18~t ch ià~w~ ind ce a d~ m i~n~ by ~id ven icula;
~ ~" `~ ~ing~;in an o n-ch s :~`~m~el u ing~m~ ~m ng do I ~ `.`sèt" of~bipol~epic rdia:elè trod s ` pl e ~at 2~cm:dis~ces from th le~
ventricular~apex~to~d~the~ba8e ol the ~h~art.~ A Gra.s Uodel 8 stimulator (Grass Instruments, Quin~ us~t ~s m ``sqùar~waveimpul i ~5 m cle~:~le ~hv a:sd ul sisol~n:~unit~
dom ~ Associate6, `~ing, PA) .;~ ~e stimulus isolation unit th~rèsholds. Af~tor inductian af ventricular:tachycar~
:dosage::~fo~ of:the ~ v ~ n in the::~d~ ic;~m~ w~ pla~:
~n~trodq ~ to convert~th~ ventricular tachycardia ~to ég~ bn~eco~ livcob~g~

WO 94/21237 PCT.'US94/02838 ~ i3 S r~ 6 ~

32 , for sustaining the induction of ventncul3r tachycardia. The results are repo~rted below in Table II. The effects of controlled release wore monitored for up to 4 hours after conversion to normal sinus rhythm. ~ `
The lidocaine-Tecoflex patch was manufactured in accordance with ~5 Example I hereinabove. AII other dosage forms were fabricated by dlssolving the therapeutic agent In dlniethylacetamide at a concentration of I~OG mg/ml therapeutic agent. This solution was further dissolved in a 10% solution of a Thyomer polyurethane and solvent cast into a 0~2 mm films. Amiodarone I `
matrices` were~cast~with~polyethyleneglycol a5~a 10% Gociplent as `described in ~10~ Example 8. Contro1s compnsed patches of each pdymer~c matrix matenal.
Table II
:: Transmyocardial Controlled-Releass Conversivn `; ~ of:Ventricular Tachycardia (Vl")s , ~ lnduced by:Rap;d Ventncular:Pacing~
` ~ : Pol~ymer ~ ' ` Drug :: Conversion : ~ Peak % Increase ;: Agent No. : IMatrix ` :: : L<~ading: (minute~) ` in VT Threshold Lidocaine ~ ~ 16: ~ Tecoflex ~ 28% ~ 0.86 + 0.68 367.7 ~183.1 . ` ~ Proca~nam;de: 7 : ,~Thyomer ~ 30% 4.05 + 3.15 ~ 206.7 ~ 172.6 . 20~ mi'odaro'ne~ ~:3: ~ Thyo'mer:~ : 30% ~ 5,90+5.45 36.1 + :12.7 ,~ NiCI2~ 4 ~ Thyomer~ 50.% ~ ~ 2.08 + 1.71 : ~ 122.6 + 101.3 Control : ::: ' S ~ Tecoflex;,~ 0,0 no effect : no effect 2 ~ ~` om r ~ : 0 0 ~ t : n e~t lOhpolye.hylene:g!ycol,~PEG;20C;Dsuasm,ean+standarderror.
Refen~sng:to~Table~lI, `the~site-sp~ific~aRlication permitted the lidocaine:
contaimng;:form :to :13e~ effective at na dQsag~s of only~ 0.~1 mg/kg. ' Moreover, ~ ~pher ~plà ma s of e~ ~ und le~d te ~ ~eness;~m '` 30~ converdng~hchycardia,to normal sinus rhythm. O~her studies revealed~that ~

l` `` WO ~4/21237 ~ X 1 3 5 7 6 7 PCT/US94/02838 t. ~ r .
,~ i ` ..

~ 33 lidocaine administered by this route created no other signlficant ef~ects on n~ormal cardiac function. ; `
Procainamide was~also effective in converting ventncular tachycardia In the ven~ricular pacing model.
~5 ~ Amiodarone is~a~highly~effective andarrhythmic agent~which~is ~requently ~ ;
l , ~
assoclated wlth severe side eff~cts. ;It efficacy~ when utilized in ` the controlled release dosage~form~of the~present lnventlon demonsuates that the transmyo~
cardial route of administration may be the safest and most effective manner of : ~ : :
delivenng this drug. ~
- 10 ~ Nickel ~chloride is~an~ example of a prototype drug~ system which would~be difficult~to~admlnister~systemicà}ly, but which has shown promise as an~ antiar~
;rhyth`mic.~ However, the results of ~Table II show that nickel chloride is effective to convert tachycardiato~ orrnal ~sinus rhy~hm~by direct eptcardial appllcation in the~controlled ~release~ dosagé ~form ~ of the presént invenUon.
~`15~ A pharmaco~netic~-st dy ~rf~`r ~ with cont~ll~ rel~e the lid~ne~
polyurethane~matrices~(~8%~v/w; 44~mg, 5~mm x~5~mm epic dial patches) ;`
i~ demons~t~the significance of~sitë- if c~appli~ton of t e cont oll~`r e e do~eoftheins~tmvëntion. ~Fig.~lOisa~grap~r ~sln of~l e ;ow blood lev-ls of wdarrhythrllic wl ~su5 ~ wffornl ~ tl4~ w o~ wpb;c _wy n ~n~plw~

W0 94nl237 PCT/U594102838 ~
213~ 6~

~ 34 obtained over a 4 hour period of epicardial matnx application. Referring to Flg.
I0, a total dose of 920 ~g/kg was delivered. Regional coronary venous plasma levels of lidocaine were in~ the range of 0.$-2.3 ,ug/ml whlle simu!taneously sampled peripheral biood levels were about 100-fold lower, or 5.4-20.3 ng/ml).
Ex~nple ~13~
In Vivo Ischemia-lnduce~ Ventricular~Tachycardia Studies Controlled release dosage forms of the present invention have been successful in preventing ischemia-induced ventricular tachycardia in a canine model. Ventricular occlusions of the leR antenor de:scending wronary artery of a dog were produced by exposlng and isolating the artery in a dog under anesthesia.
A~ snare with a sliding closure was placed around the artery. Ventricular tachycardia was produced;by closing the snare for 10 mmutes to shut off the blood supply to lefl ventricle. The snare was vpened; for an hour, and then the snare was closed, for 1~0 mlnutes~; Thls;procedure can be repeated up six times and ~simulates a heart attack. ~ Ventncular tachycardia (VT) was defined as the occurrence of ~ 3 0r more sequential; ventricular premature beats. The efficacy of various controlled release do~ge fonns of the present invention were documented by icoddnuous rec`ording of the electrophysiologic data' on a Hewlett Packard Physiologic~ecords,~ and an 8-channel analogue tape deck (~Iewlett Pac~d, Philadelphia, PA). The results~are showo m Table~

~`~ WO 94121237 213 5 7 6 7 PCT/IJ594102838 ``, I`

T~BLE m ~ ~
Antiarrhythm;c Controlled Reiease Therapy: Resul6 of Acute ~:Ischemia-Ventricular Tachycardia (VT) Studies iri Do~s Dru~ MechMism Polymer Load~ng Dose: N VT
S (~glltgl2hr~ ~cr/r~mutc) Lidocaine Na Channel Tecoflex 28% ~ ~0.~3 5 0.6+0.2 Blocker `Propranolol Beta Blocker MPU-5 30%: 0.14 ~ 6 1.22+.12 D-Sotalol~ Delayed Re- ~ MPU-S 30% 0.20 ~ 9.046+.11 :10 ~ ~ ~ polarization~
:
Verapamil Calcium Chan-: MPII-5 30% : ~ : 0.30 11 0.10+.03 nel Blocker ~ ~ ~
` ~ No Therapy - Control ~ -- 9 1,10~0.30 Referring to Table III, the total dose over a 2 hour pe~ mglkg/2hr) lS;'~ for~ the VanQus drug-loaded matrices was estimated from in vi~ro release data which has been~found to correLate well with in vlvo release~rates. ~he data ls express~ as the averagè for the numbe N of dogs ~r ~group. Epis~es of ~ ~
.~ werè~pac d~at one per~minutès.~ Table III shows the number~of ~ epls~e er minutè followmg~epicardial~ placement of the~ident fi~
20~ Clà s II Lcium~cha nei~blo ker,~ver pamll,; nd the ~lass nl agent, D-sot ol, were ~ the most ef~ Ye ,for arrhythmias due to acute myocarcdal~ lschemia.
In~e~reidngly,verapamills~contraindi~for~arrhythmias~when~gi~ensyst ' ::
caLly.~ ~ Howevèr, Table lll demonstrite. ~the effectLveness ol verapamil for t~smy~ardi~ deliy~

wos4nlu7 ~cTnJss4102s3s ,~
` ` !:
213~6~ . , , Example 14:
ln Vivo ElectroPhvsiolo~ic and Defibnlla~ion Threshold Studies In an advantageous application of the pnnciples of the invention, : : ~
antiarrhythmic agent-contaming controlled release dosage forms of the present ~ invention are used ln conjunction~ with a cardiac defibrillator. ~ Epicardial delivery of Vaughan-Williams Class ~III antiarrhythmic agents has been shown to decrease ~; defibrillation threshold in dog studies. ~ ~
ImpTantable cardiac defibrillators, such as the automatic cardiac defibrilla-tor marketed by Cardlac Pacemakers, Inc., M1nneapolis, MN, (5ee, for example, ~:
10 ~ U.S.~ Patent No5. 3,614,954 and 3,6l4,955~ are well known for the purpo5e of applying a direct current to the heart in life-threatening or chronic situatiolls.
Tmplantable;cardiac defibrillators comprtse a miniaturized power source, `~ two bipolar lead systems, and~;a computer chlp which is an electrocardiogram ; sensing~m~hanism~for~disch~ing; monophasic 0r biphasic el~tri~ pulses~
S~ through;~the electrode leàd5 for short du~ation5 ~u5ual1y 2-20 ms). 1n one ;
embodiment, a lead i5 placed~ transvenously via a~ catheter in the endocardium of ;
the~ dght ventricle and the;~second lead compri5es an array of :electr~des which are ' ~ ` plàc~d 5ubder~11y. A maximum of approximàtély 20~ to 25 joules is typically requlred~tore5torenormalheartrhy~hm.~In~;otha~embodiment5,both~declrode ~` ~ lead5~mày~be~placed~dir~ted on~the~epicardium~ or erldocardium of ~e ~ght ~d~
left ventricles~o~ the ;h~ ~during o~n h~ surge~. ln this~ emb~iment9 typically~5~1oules ol energy~ls r~u~red to restore normal he~ rhythm.

VO 94121237 ~ 1 3 5 7 6 7 PCT/U594102838 While the implantable cardiac defibrillators have been used successfuIly, it would be desirable to enhance their function so that less discharge current is re~uired and the episodes of use are diminished. Lowering the requirements of discharge current would advantageously increase the lifehme of the battery and could facilitate miniaturizabon.
The Class III drugs are prolongers of cardiac action potential duration.
Several newly developed potent Class~lII drugs are toxic when administered intravenously or by other known ~techniques. These agents include ibutilide, c lofiliumj and sotalol. Ibutilide, for example, has been shown to be effective ` -10 ~ against atrial and ventricular arrhythmia in dogs and atrial arrhythmia in humans.
Action~ potentlal duration (APD) studies in dogs has also ~shown that ibutilide ,~ ~
increases the action potential duration at very low doses and elevates the plateau .
height.
Studies were conducted to assess electrophy~iological~effects and~
~t5~ defibrillation threshdd when ~ the aforementioned Class lll :drugs wer ~e incorpo~
rated~ into the controlled release ~dellvery system of the present invention andappl;ed epicardially to~ dogs during defibrillation.` In the studies~reported herelnblelow, a monollthlc controlled release matrix was co-implanted with the implrntahle automadc ¢ardiac defibriDator.~ However, it ~is anticipated that the`2 o ~ drug-loaded ma~rix can be~int~grated di~ectly with an~automatic implantable cardiac defibrillator, such as by coating thè~ electrode l~ds with the drug-loaded polymeric mattix materirl (~ee r~g. 21~

WO 94/21237 PCTIUS94/02838 ~
`~ 3~jrj 6~
1. ' .

For the ~ollowing in YiVo studies, drug-loaded matrices were prepared as follows~
. ~ - ~
Formulation 14a:
Antiarrhythmic agent and Pellathane~' polyurethane ~a hlgh molecular ~ weight polyurethane sold by Dow~Chemical Company,~Midland, Ml) were dissolved ~in THF and solvent cast in a Teflon-coated mold to form films of 50 ~m thickness. A quantity of àntiarrhythmic agent sufficlent to result in 20%
wt./wt. drug-loading was usecl. `
In a specific illustratlve~embodlment, 100 mg ibutilide fuma~ateand 400 ~10 ~mg polyurethane were dissolved ~n 10 ml THF and stirred for 60-90 minutes in a closed vial. Following solvent casting, the cast films were pl~ced in a fume hood , ~ `so that~the solvent could evaporate~at room temperature~for about 4~hours.
Fo~nulation 14b~
The release kinetics of the resulting drug-matrix was varied by repIacing a;
I5~ cè~n~propo~ion of ~the~tia~hythmic agent with an inert, i.e.j non-pharmacc-logic~ly~a~tive, co-cipient~or filler with a~lower~water solubility, such as inu!in or dimethyl tartrate. ~ ln thè specific formulations used in the~present studies, 16%
wt./wt. dimethyl t~è;~and 4 % wt.iwt. ibutilide was incorporaited in ~'a Pellathane'' ~p plypre~h~ne matrix~ However~ to be understood th--the propo~on of antiarrhythmi~ agent to filler can be valied to achi~e a desired effect. Dimethyl t ` ate~,~ for~example,~h a so~org~l~ly soluble.
,In thi-~specifib~illustradveembodiment,~20 mgibut idefumarate,~80mg dlmeth~tar~ate~d 4~mg~polyureth~e~were dissolv i~in lO ml ~F a d ~ ;

,~`` WO 94/21237 2 1 3 5 7 6 7 PCTIUS94102B38 , 39 .
solvent case to yield matrices with welghts and dimensions similar to the matrices obtained in Formu]ation 14a.
~ .
In vitro release studies were conducted in phosphate buffered salinè ~pH
7.4) at 37 C under perfect sink conditions. The matnx specimens were placed in the buffered solution~ on a rotary shaker (110 rpm) and the drug levels were monitored spectrophotometrically at 2~7 nm. Matrices fabrica~ed in accordance with Forrnulation 14a have an initial burst effect releasing~about 30% of the antiarrhythmic agent in the first 15 minutes and at a decreased rate so that there is about 40% depletlon by 1~0 mi~nutes as shown in Flg. 11.~ In contrast, matrices lo fabricated in accordance with Formulation 14b release only about 9.6% of the antiarrhyîhmic agent during the first 15 minutes followed~ by an almost linearlyincreasing rate until about 17.1% depletion is achieved at 120 minutes as shown in Flg. 12. Thus, the dose administered over a given time period can be lowered ; by~ retarding the release rate~ in this ~manner.
~15~ Standard~14cm2)~defibrillation~1ectrodeswereplacedovertheleftand right ventricles~ of the~ heart of a dog. In order to cause fibrillation, an epicardial~
electrode (Bloom stimulator, Bloom Associates, Reading, PA) was sewn înto the ` leftlventricle to deliverlan electrical impulse (T =~ 10 ms~. A pair of recording ~ ~
electrodes were placed in the nght ventncle to measure aectrophysological ~ t ~20~ changes. T est shocks were delivered;in a random sequence~to detennine baseline defibrillation threshold ~I3FT). ~ The drug-loaded matrix (1.5 cm x 1.5 cm patchw`èi~hing about 25-28 mg) was plac~d in the anterior left ven~îcle and DFI
studies~;were conducted for a 2~ hour period post-implantation.

WO 94l~1237 2 1~ 5 7 ~ 7 PCT/l~S94/02838 ,~

Epicardially placed ibutilide-polyurethane matrices S~ormula~ion 14a) had a significant effect on electrophysiological parameters. The ventncular effective refractory period (VERP) changed from a baseline, in milliseconds ~ms~, of 124.9i 3.3 - 136.a * 1.71 to 151.7 i 3.4 - 154.6 3.5 at an epicardial electrode located proximal to the matrix location. At an endocardial electrode located proxlmal to the matrix location, the baseline changed from 129.1 ~ 2.2 - 137.3 i 2.1 to l48.0 ~ 1.7 - 152.0 4.7. See Fig. 13 wh-ch is a graphlcal representation of VERP in ms as measured by an epicardial electrode and an endocardial electrode located proximal to the ibutilide-containing matrix. Similar ~lo ~ changes were recorded for VERP at an endocardial electrode placed distal to the ` ~ matrtx location.
The same ibutilide-polyurethane~ matrices~ (Formulation 14a) had a ` ~ ~ ~ significant effect on activation time (AT). Referring to Fig. 14, AT, in ~ ;
`;~ milliseconds,changedfromaba5elineof27.1 :!: 1.4-27.1 + 1.7msto65.1 i is ~ 6.2~- 71.`8 ~ 6.9 ms at; tho~èpicardial electrode located proximal to the matrix `~ lo~tion. ~ At tho~endocardi~ electrodo lo~t~ proxim~ to the ma~ix l~ation, ~e ` ~ bàseline changed from 27.1 i 1.4 - 27.1 1.7 to 50.2 i 7.2 - 54.2 ~ 7.1.
` Changes In AT of the same magmtude w, re~recorded at an endocardial electrto~e~ placed dist~l t,o the matrix~iocation.; ~
2~ The defibnllathn threshold (Dl:'l') was ~slgnifi~tly ;~decreased ~fter `~ application of the ibublide~ matrices (Formulation 14a)~.~ Fig. 1~5 is a graphic~
representadon o~ the probablllty~of success~ul defibrillation by arl Implantable ~ -defibriilator for the applica~ion ~of~a~;2-20 ms ~onophasiç pulse of energy, ;.` ' ~YO 94/21;!37 ~ 1 3 5 7 6 7 PCT/IJ594102838 ~': `'' .
"',' measured in joules. Referring to Fig. lS, the control data represents defibrilfa-tion prior to the admlnistration of ibutilide. Following epicardial attachment of an ibutilide-polyurethane matrix in accordance with Formulation 14a, the ènergy associated with an 80% probability of successful defibrillauon (DFT 80) S decreased from 15 ~oules at baseline to 3.9 joules after epicardial~ administration of the ibutilide ~matrix. DFT 90 d~ecreased from about greater than 20 joùles to4.9 joules. No changes in heart rate or artenal pressure were observed. The ibutilide-polyurethane matrix dispensed a 0.025 mg/kg dose over the expenmental ~; period (p~ 0.001, paired t-tests).
:. :
O The estimated dose of ibutilide released ~rom the matrix over the 2 ~hour experimental period was 0.025 mg/kg. This small dose, when applied to the epicardium, produced a 4-fold decrease in DFT. Dose response studies were conducted and it was noted that ibutilide is e~fective to reduce DFT at a Jose as ~ low as 0.0025~ mg/kg.
lS ~ For comparative purposes, defibrillation threshold was measur~d following ; ~ intravenous a~ministration of ibutilide at equlvalent doses (0.25 mg/kg and :
` 0.0025 mg/kg). The results are shown on Figs. 16 and 17 which are graphlcalrepresen~ons of the probàbility of successfùl defibrillation for an application of ~ ~ a 2-20 ms pulse of energy in joules. Fig 16 shows the ~DFT for a ~monophasic r ~0;~ pulse before and after administration of O.025 mg/kg ibutilide. ~ FIg. 17 shows the DFI for a blphasic pulse~ before and after admmistrahon of 0.0~25 ~mg/kg ibuhlide.

`
WO 94121237 2t35~ 67 PCT/IJS94/02838 1"

Ibutilide-polyurethane matrices in accordance with Formulation 14b were ~ , .
appliecl to the epicardium of dogs in conJuncbon witb standard implantable ;`
cardiac defîbrillator electrode. Fig. 18 is a graphical representation of the %
conversion of fibriilation relative to an appliëd biphasic pulse in joules.
~ In another embodiment, clofilium-containing polyurethane matrices were made in accordance with the procedure set forth in Formulabon ~14a. This : ~ resulted in a 2 mg/kg dose of clofilium released over the~expenmental 2 hour : ~ ~
: period. Referring to Fig~ 19, a decrease in DFT 80 from:~about 18.5 joules to~. ` ..
: ; ~ 14.7 joules is observed when a clofiiium-polyurethane patch is co-implanted with ~0~ an implantable cardiac defibrillator electrode and a biphasic~impulse is used to : defibrillate induced fibrilladon.
:
In a still further~ embodiment, 20% wt./wt. sotalol was incorporated into a .~ polyurethane matrix in~accordance with the procedure set~forth In Formulaoon `.

`` ~ : 14a.~ ThisresultedinanO~8mg/kg :doseof sotalolovertheexperimental2hour 15~ period. ~ Fig. 20 shows; the ch~nge in activation time, ;In milliseconds, as !` ~ : m~sured by electrodes ~placed~:at ~varlous distances from the epicardially placed matrix containing sotalol or ibutili`de 10.025 mg/kg) as indicat~d~on the drawing.
i In` conclusion, ibutilide-polymer matrices as well as other formulations i : ~
: (specifically~including~formulations:containing:~clofillum and/or sotalt)l) were successfully:fabdcated ànd;.demonstrated to have~Class llI el~ophyslologic . ~ eff~ts (i.e., prolong~tion~:~of refractoriness ~d:conduc~on vel~ity), which will be beneficial for; pr~venting ventricular arrhythmirs.~Thù~ controlled Dlease .` `~ epicardial~ Implants`of:~the~present~invention have~been demonstrated~to be:supenor ;

~"` `WQ 94/21237 ~13 5 7 6 7 PCT/(JS94/02838 43 ~`
to intravenous administration of the drugs both in terrns of potency and sustained electrophysiologic effe¢ts.
The ibutilide-polyurethane matrices used as cardiac implants also produced the unusual effect of lowering de~lbrillation energy threshold requirements.
Therefore, use of an ibutilide-polyurethane drug delivery system in combination with an implantable defibrillator could significantly enhance the function of the implantable defibrillator. In contrast, intravenously administered ibutilide, used at the sarne dosages as the cardiac implants, did not have a significant effect in reducing the defibrillation energy threshold. Including an lbutilide-containing controlled release drug delivery system as a component part of implantable defibrillator electrodes, or as an adjunct thereto, would lower the electrical energy requirements to defibrillate the heart. In addition, since ibutilide is a Class m antiarrhythmic agent as well, episodes of ventricular arrhythmias which might lead to ventricular fibrillation would be redu~ed. Thus, the overall design of an ~IS implantable defibrillator wlth an ibutilide controlled release drug delivery system ;~ could be greatly improved over compedng systems, since~the electric~l~apparatus would be of a lesser scale, and there would~be fewer episodes requiring its active use for defibrillation.
The following examples are additional embodiments which employ the ~,~
20; ~ antiarrhythmic agent-containing controlled~ r~lease dosage fonns of the present ~ ~ t invention in conJunction with cardiac rhythm controlllng devices. As used hereinil ~ the term "cardiæ arrhythmia" covers condihons of ~abnormal heart rhythm, and specifically includes ventricular arrhythmia, ventricular fibrillation, and su~en-WO 94/21237 2 1 3 5 7 6 ~ PCTlU594/02338 '~
.

44 l -tricular arrhythmias, such as atrial fibnlladon, atrial f utter, superventricular tachycardia, multifocal atrial tachycardia, juncuona~ tachycardia, e~c. Therefore, the term "cardiac rhythm controlling devices" mea~is any device which functions to control heart rhythm by delivering an electrical pulse to the heart, and 3 s includes, but is not limited to, implantable cardioverter-defibn]lator, countershock and anti-tachycardia pacemakers, overdrive~pacemakers, etc.
In these embodiments, however, the anti3rrhythmic agent may be any agent that functions to control defibrillation and/or tachycardia provided that it ~ does not produce an effect whlch is otherwise detrimental to the effect~ of the cardiac rhythm conkolling de~ice. The selection of an ~appropnate antiarrhythmic agent i9 within the skill of a person of ordinary skil1 in the art. Polymers loaded ~ ~ :
with Class III antiarrh~thmic agents, specifically ibutilide, sotalol, and artilide, have~ been ubserved to significantly lower defibnliation threshold in ventricular ~ arrhythmias, to lower risks of atrial flutter, and to prolong refractoriness and 15~ conduction times of ventricularextrastimuli.

: In another specific embodiment of the invendon, an atrial pacing elect~ode is coated with an ibutiIide-polyurethane as shown in Flg. 21, which IS a schematic ' ~ ..
representa ion ~of ~atnal pacing electrode 20.~ At~ial pacmg electrode 20 has an~0 ~ budlide-polyDrethrne~mDltilamellar coating;2~l ~on end 22 Of an e1ectrode~body ;~
` ~ 23.~ ~ In praetice, atrial pacing ~electrode ~20 ls implanted ~in the atrial epl~diDm ~ ¦
dunng open heart surge~. ~ ~ For acute a~ ~hy~mias, the dis~ end 24 of the ;
pacing electrode ls ~oupled~to a~lead (noi shown) which~ls threaded through~the `.VO 94/21237 213 5 7 6 7 PCTIIlS94/02838 .~`
.

chest wall by needle puncture. The lead(s) is electrically coupled to means for ~, ~.
applying an electrical current to the heart of the patient. When acute atrial r arrhythmia is no longer a risk, typically lO days after surgery, the pacing electrode can be removed by a slmple pull-thro gh maneuver. Of course, atrial , pacing electrode 20 can be permanently installed for chronic atrial arrhythmias.In a preferre~ embodiment, the following technique Is~used t~ form multilamellar coating 21, which ~is shown in cross-section on the inset to Fig. 21, surrounding electrode body 23:
PormulatiQn !~a:
, : .
10 ~ ~ ~ Ibutilide and Pellathane~ polyurethane ~Dow Chemical Company, Midland, MI) wer~ dissolved in l'H~ to form a coating solution. A quanhty of ibutilide sufficient to result in 10% wt./wt. drug-loading was~used. ~ -In thls~specific;~embodimcnt,;an atnais pacing electr~de wire lead;(--1 m ln diameter) was dipped in the above-described coabng solution eighteen ~`15 ~ times to form a well-adhered coating approximately 85 ~m thiclc. T he coated wire was ~ 270 ~m~ in diameter. Of course, the number of layers wl be adjusted ;
~` to produce ~a coating of ary desired thickness. Advantageously, the dip-coating ~ ~~ ` r tec~nique results~in ~etter adhesion of the polymenc coating to the wire. i ~
~ . ~ : , ;
Mor~ver, the~multilamellar g~mèt~ retards the~release ~te of ibutil~de from 20~ the polymer m~x.;~ Fig. 22 ~is a graphlcal ~represen~tion of the long te~ in ~rr~`release characteristtcs of~a dip-coated wire fabricated in accordance with ;~ula~ion~lSa~expressed as % cumulative release versus dme in days.

~ WO 94/21237 213 ~ 7 6 7 : ; PCTIUS94/02838 ~. ~ .

: ~ The antiarrhythmic and electrophysiologic effects of ~the ibutilide-polyurethane coated atria} pacing electrode of the present inven;tion were studied in a canine model of atrial flutter.~ ~Atrial flutter was Induced~ in dogs following : ~ the creation of an intercaval Y-shaped incision on the~ right; atrium in accordance `. . S~ with a modification `of the:~method of Buchana~i,j;el al.. ~J. Cardiovascular .~:

Phr~rm~c~lo~Y~ vol~ 33~ ~No~ ~ lo-l41 l993; F~amel et a~ ~ col. 58 pages:~495-51:1~(1986);~Wu, et~a/.,~Cardioyasc. Res.~, Vol.:23,:pages~400-409 ~
; ~ ~ I (1991). The Y-shaped incision creàtes an:~area of circuitous conduction. Bipolàr ~ ~ :
` ~ platinum~pacing~and~ recordin~ electrodes ~wéte sutured 2 mm apart to the right~
~10 ` ;~ a~m`for:~a~al pacing ànd~measurement; of:~ effec~ve refracto~ ~n~
(A~).~ The~ele :1 ads~we e~con ` t ~m udng e ulpment. ~
A~al~bi~l~signr~swéreamplified~with a~differential~AC:eoupled ;amplifier ~d dls~l~`;on ~ oscillosco~...
~orded: ~by ~a~lygraph ~Gràss~ Mo e1 79-D, :~Quincy, M~
trial~pacmg~for detenn~nadon of ~refractonness~and~the abiLity to ~ce~ flu ter~ w~ as ~ using à Bl~m~;~el~ D~ :1 10 ~s~mulator (Bloom Associates,~Reading,~ and WPI Model A 385 constant current on unit, wi~pacing t thnce~thrèshold cu t th .0 2l3s767 ~; ~,VO 94/21237 ^ PCT/US94/02838 . i . I`

induced by pacing for 2 to 3 second intervals at cycle lengths start~ng at 150 ms and decremented by 10 ms to a minimum cycle length of 50 ms. Dogs were considered to have inducible atrial flutter if the arrhythmia~persisted for a minimum of S minutes. If the arrhythmia could not be initiated in two repetitions

5: of the protocol, the atnal flutter was considered to be non-mducible. The cycle length of atrial flutter was ~determined by averaging the inter:Yal between several atrial electrograms. Atrial flutter was consldered to be sustain~d if it did not .. :
terminate spontaneously during measurement and recording of the arrhythmia (about 2 mlns.) Sustained atrial flutter was terminated by overdlive pacing at ~lO rapid cycIe lengths between 50 and 150 ms. ~
Fig. 23 is a bar graph showing the reduction of atrial flutter inducibility by the ibutilidè-polyurethane coated atnal electrodes. During a two hour study per~od,; acute atriat arrhythmias ~were induced as described above. Following implantation~ of rn ibutilide-polyurethane~ coated ~atrirll electrode, the inducibility ~o~
15~ at~ flutterwas signific~tly~educed~p~< 0.00l;paire~T-test). Theestimated dosc~of~ibutilide dur~ng thc~two~ hour study period was~about 1 ~Lg/kg. No adversc effects from the d~ug administration were observed.
Exampl`e `1 6 Referring ~tD~ Fis 24, a schema~dc representation of ~yet rnother spec~fic embodimentof~theinvention~is`shown. Fig. 24~shows a pacing-transvenous defiibrillator catheter 4Q having~almular conical~dp 41 comprising a~silicone ~bbèr~ m~x con~ning:~3~% ~ibu~1ide-fum~té by weight made ln a m~ner ,, ~
~ analogous to Examp~es 5 and 6.~ Coni tip 41 and anchoring tines 43 are WO 94/21237 PCTfU594/02838 .~`.`.'`. ~
~2~3~i~ 6~
`

configured to engage in the endocardium of the heart of the patient. Fig. 25 ls a , graphieal representation of the release rate of: ibutilide from the: molded conical tip of Fig. 24. About one year's worth Oe drùg is deliverable from the conicr~
tip. ~:
Pacing-transvenous defibrillator catheter 40 comprises two defibr;llator electrodes 42 and 43 disposed on :opposite ends of catheter wire 44. Conical tip 41 surrounds a pacing electrode 45 which is disposed:on the:c~rdlac-contacting I

: end of pacing-transvenous defibrillator catheter 40 which ;may be a commercially ~ available model, such as the~Endotak Catheter (Cardlac Pacemakers 1nc., I0 `~ Minneapolis,~MN). In~use, the pacing-transvenous defibrillator catheter 40 is installed~by catdiac ca~heterization so lhat conical~ hp 41 is in cmtact with ~he endocardium and electrodes 42 ~and 43;lie~in a :ventricle.
. : ~ A pacing-transvenous~dèfibrillator catheter~of the type shown in Fig. 24 ~ was~ ~nst~l~ In the ante~or ~lëft ventricle in ~ a dog. In order to c use fibnllation, iU"~ ~ epicardial electrode (Bl~om ~tlmulator, Bloom Associates,~Reading, PA) was~
sewn into the~left ven~cle to~deliver ~electric~ lmpuis ~ ~= 10~ ms). A p ir~
"~ of ~r~ording èl~odes wére`plàc~ ~in the ~ght ventricle to m~sure electro- : `~
.` ;~ physiologlc~ ch~ges.'` Test shocks were dellve~ i'n a ~dom: s~uen' to detennine baseline defibrillation threshold ~).~ ~ D~ studies~were conducted :for ~a 2 hour pe~Q ~ ~pl~ on. ~
The defib~ threshold was slgniQcantly~decr~ed by use~oi t pacing-transv`enous dé~1b~llat~r catheter~of the~prese t 'n e ~. ~g. 26 Is~a~
"~ hiCil ~e~LIllon~lheproba~ v~ ~s_s ~d r~blllbhon~by~e .WO 94/21237 21 3 5 7 6 7 PCT/US94/02838 . ! : 1 t 49 .
pacing-transvenous defibrillator catheter for the application of a 2-~0 ms ~ ' monophasic pulse of energy, measured in joules. Referling to Fig. 26, th~- i control data represents deflbrillation of animals in which a control catheterj i.e., no drug-loaded tip, was used. The energy required ~or 90% success decreased S from 10 or more joules predrug to between 3 and 5 joules following implantation 3 of pacing-transvenous defibrillator catheter 40. Similarly,~; 80~/o success post-implantation could be achieved with the application of 3 Joules or less whereas 10 joules or more were required predrug. No changes in heart rate or arterial pressure were observed. The~ibutilide-polyurethane~matrix dispensed a 3 ~glkg lo ~ ~ dose over the experimentaI period (p< 0.001, paired t-tests)~. Fig. ~5 demon-strates~that the pacing-transvonous defibnllator catheter of ~the present invention ~ successfully reduces the energy~level required for ventricular defibrillation.

`~ In another embodiment of the invention, an ~ontophoretic device for ;~
i5 ~ epicardial delivery of antiarrhythmic agents in response to electncal signals. In a .~ specifio embodimen~ a rate-limiting permselecbve heterogeneous~cabon;exchange member for use in a hollow reservoir iontophoretic ~devlce was formulated from a dry conditione~ polyst~yrene cation exchange resin (Dowex~'50W, ~2X, I~H+ form, ;
2 00~400 mesh,~ Sigma,~St.; L:ouis, MO) and a medical~grade silicone rubber~
specifi'callySilastic~Q7-4840~(partsA&B~mal~ o)~ ;Thepolystyrenec~tion~
;~ exchange resin compnsed~42% wt /wt. The resulting disp~rsion was placed in a moId and subjected to~ a vacuum for 20 ~mmut~s; to remoYe air bubbles. Then the mold~was~compressed at~about 1~ pounds of forGe.

WO 94/21237 ~ ~ PCT/IJS94/02838 ,' ` `
2~s~ 6~ ! !
, ;; ` ;
Although the invenbon has been describf~ in terms of specific embo~
;~ ~ ments and applications, persons skilled in the art, in light of this~ teaching,~ can generate numerous and varied embodiments with these pr~nciples wlthout depart:ng ~from the spint and scope of the claimed invent~on. ~For example, non-~ ~ pharmacologically active co-cipients are~ well known In~ the art, and a person of ordlnary skill in the~art~can select~one or~;more~ co-clplents for use in the prachce of the present~ inve~ltion. ¦~Accordlngly, it IS~tO be understood that the descriptions in this disclosf,lre are proffered- to facllltate comprehension of the invention and should not be consu~ ~to limit~ the scopè t'hereof.

I :~

Claims (35)

What is claimed is:

1. An arrangement for controlling the heart rhythm of a patient, the arrangement comprising:
electrode means for conducting an electrical signal to or from the heart of the patient; and:
implantable controlled release means for releasing a therapeutically effective amount of an antiarrhythmic agent to the heart of the patient

2. The arrangement of claim 1 wherein said implantable controlled release means comprises a substrate formed of a biocompatible polymeric material incorporating said antiarrhythmic agent therein, said substrate being adapted for direct application to the heart of the patient for effecting transmyocardial delivery of said antiarrhythmic agent.

3. The arrangement of claim 2 wherein said therapeutically effective amount of said antiarrhythmic agent is between about 5 % and 40% by weight of said substrate.

4. The arrangement of claim 2 wherein said substrate comprises at least one pharmacologically inert filler having a water solubility characteristic which differs from that of said antiarrhythmic agent.

5. The arrangement of claim 4 wherein the pharmacologically inert filler is selected from the group consisting of inulin polyethylene glycol, and dimethyl tartrate.

6. The arrangement of claim 2 wherein said biocompatible polymeric material is nonbiodegradable and selected from the group consisting of poly-urethane, polydimethylsiloxane, ethylene vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, and cellulose acetate.

7. The arrangement of claim 1 wherein said electrode means comprises tissue engagement means for engaging the heart tissue of the patient.

8. The arrangement of claim 7 wherein said engagement means is configured as an annular conical tip arranged on a distal end of said electrode means.

9. The arrangement of claim 1 wherein said electrode means further comprises a pacing electrode arranged on said electrode means.

10. The arrangement of claim 1 wherein said electrode means comprises sensing means disposed on a distal end thereof for sensing a predeter-mined condition of the heart of the patient.

11. The arrangement of claim 1 wherein said electrode means comprises a plurality of defibrillator/cardioverter electrodes.

12. The arrangement of claim 2 wherein said biocompatible polymeric material is biodegradable and selected from the group consisting of collagen, polylactic-polyglycolic acid, and polyanhydride.

13. The arrangement of claim 1 wherein said antiarrhythmic agent is a prolonger of action potential duration and is selected from the group consisting of artilide, clofilium, ibutilide, and sotalol.

AMENDED CLAIMS
[received by the International Bureau on 15 July 1994 (15.07.94);
original claims 14-35 amended; claims 36-38 cancelled;
remaining claims unchanged (3 pages]

14. The arrangement of claim 1 wherein said substrate is in the form of a film.

15. The arrangement of claim 14 wherein the film is multilamellar.

16. The arrangement of claim 1 wherein said substrate is in the form of a molded cardiac contacting component attached to said electrode means.

17. A cardiac rhythm controlling device comprising:
cardiac contact means for conducting an electrical signal to the heart of a living being; and controlled release dosage means for producing a controlled release of an antiarrhythmic agent.

18. The cardiac rhythm controlling device of claim 17 wherein said controlled release dosage means comprises a substrate of a biocompatible polymeric material which has incorporated therein a therapeutically effective amount of an antiarrhythmic agent.

19. The cardiac rhythm controlling device of claim 17 incorporating a pharmacologically inert filler having a water solubility different from that of said antiarrhythmic agent.

20. The cardiac rhythm controlling device of claim 19 wherein said pharmacologically inert filler is selected from the group consisting of inulin, polyethylene glycol, and dimethyl tartrate.

21. The cardiac rhythm controlling device of claim 17 wherein said biocompatible polymeric material is nonbiodegradable.

22. The cardiac rhythm controlling device of claim 21 wherein said nonbiodegradable biocompatible polymeric material is selected from the group consisting of polyurethane, polydimethylsiloxane, ethylene vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, and cellulose acetate.

23. The cardiac rhythm controlling device of claim 17 wherein said antiarrhythmic agent is a prolonger of action potential duration.

24. The cardiac rhythm controlling device of claim 17 wherein said antiarrhythmic agent is selected from the group consisting of artilide, clofilium, ibutilide, sotalol.

25. The cardiac rhythm controlling device of claim 17 wherein said antiarrhythmic agent is ibutilide.

26. The cardiac rhythm controlling device of claim 17 wherein said antiarrhythmic agent is artilide.

27. The cardiac rhythm controlling device of claim 17 wherein said antiarrhythmic agent is sotalol.

28. The cardiac rhythm controlling device of claim 18 wherein said substrate is in the form of a film adhered to said cardiac rhythm controlling device.

29. The cardiac rhythm controlling device of claim 28 wherein said film is multilammelar.

30. The cardiac rhythm controlling device of claim 28 wherein said film has a thickness on the order of 20 µm to 1 cm.

31. The cardiac rhythm controlling device of claim 18 wherein said substrate is in the form of a molded cardiac contacting component attached to the cardiac rhythm controlling device.

32. A method of treating cardiac rhythm disturbances in a living being have a heart, said method comprising:
placing a polymeric matrix incorporating a therapeutically effective amount of at least one antiarrhythmic agent in direct contact with the epicardium of the heart of the living being in conjunction with a cardiac rhythm controlling device.

33. The method of claim 32 wherein the cardiac rhythm controlling device is an implantable cardioverter-defibrillation device.

34. The method of claim 32 wherein the cardiac rhythm controlling device is an implantable pacemaker.

35. A method of treating g or preventing ventricular or atrial fibrillation in a living being having a heart, the method comprising step of placing a polymeric matrix incorporating a therapeutically effective amount of at least one antiarrhythmic agent of the type which is a prolonger of action potential duration in direct contact with the epicardium of the hear of the living being in conjunc-tion with a cardiac rhythm controlling device.