CA1220423A - Pharmaceutical combination composition and associated method - Google Patents

Abstract

/EP? TELECOPIER 495;24- 4-84; 4:13PM 2435630903:# 8 ABSTRACT

A novel combination pharmaceutical compostion is described, together with a method for making the same, wherein the pharmaceutically active ingredients are seperately milled and then formed into separate granules, and onlu thereafter blended together to form the combination composition. The method for achieving this novel combination composition is also described.
In particular, a novel combination composition of triamterene and hydrochlorothiazide having improved bioavialability and novel effectiveness to prevent or eliminate hypokalemic side effects is also described.

Description

PHARMACEUrICAL COM~INATION COMPOSITION
AND ASSOCIAq'E:D METHOD

Fi eld of the Invention This 1 nventLon relates to a novel p~armaceutical composition having ef~ctlve combined diuretic and an~ihypertenRlve propertie~ whlle also being capable o~ resiQtlng o~ rever3ing hypokalemla. More ~pecifically, thi-~ invention provlde~ a novel pharmaceutical composition containing hydrochlorothiazlde ~6-chloro 3,4-dihydro-2H-1,2,4-benzothladlazlde-7-sulfonamlde-1,1-dioxide) and trlamteren~
~2,4,7-triamlno-6-phenylpte~idine), and exhibitlng enhanc~d bloavailability of both ingredients. Also an lmprov~d nov~l m~thod ~o~ uslng and adminlstering a d~uretic and antlhyperten~lve combination medicatlon wlth preventlon or eliminat~on o~ hypokalemic side e~fects is providad. This lnvention further provide~ a novel method for generally maklng ~ phar~ ceutlcal composi~ions composed of two or more act~ve ingredients whlch differ slgnificantly from each other in their rela~lve hydrophoblc and/or hydrophilic characteristlcs and/or physiological fluld ~olubilities.
De~cription of the Prlor Art ~ he preparation of pharmaceutical compositions having two or more active ingredients has been and is a common requirement in med~cioe. Frequently, ingredients may be ~imp y comblned without difficulties pertaining. to stability or bloavailabillty. In other inst~nce~, the re~pectlve ~ctlve :

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~L22~ 3 lngredi~nts have the capablli~y of Interac~ng~.with each o~her, lntroducing ~tabi1ity problems e~en ln sol~d preparation~, which then require specla1 preparatory measures. In other instances, c~re must be taken to ensure th~t the b;oavai1abi1ity o~ the active ingredlents ln combination pharmaceutlcal preparations 15 not adverRe1y ~ffected by each other or by the various pharmaceutlcally acceptable but inert components whlch typ~cally must be inc1u~ed ln the compo~ltion when formulated in~o tab1et or cap~u1e ~orm.
~he pte8ent ~nvention 1~ concerned wl~h pharmdceut:lc~l preparatlon~ havlng at least two active lngredlent8, at 1ea~t one of wh~ch is sparingly soluble in aqueous physlological fluids, and which al50 slgnlficant1y dif~er from each other ln their respective hydro~hobicltles ~r hydrophi1icities.In such compositions, the actlve ingredient must typica11y be m~de available in very f inely ~ivided form to provlde maximum ~urface area in order to aid the dissolution thereof in the physiological fluids. However, when one of the ingredients has hydrophobic characterigtlcs, lt appears that the f ~ne particles of that ingredient wi11 tend to cover the surface of the finely divided particles of a second, re1ative1y hydrophilic ingredient, and thus significant1y dep~ess the ability of ~hè latter ingredient to enter into solution ln the body fluid.
Indeed, it is sometim~s the case that the relatively 25 hydrophobic ingredl~nt mus~ be used in a relatively greater we~ht ~mount than the relatlvely hydrophilic ingredient, and thus ~tatistic~lly the hydrophilic p~rticles will ve~y significant1y tend to be coated or covered by the greater number of flne hydrophobic partlcl~!;, in a k~nd o~ small aggll~nerate . ~

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XE~ TEiLE~I:O~ER 4g5;c4- 4-a~u 3:.~'5S~ '3~5t:~9~3;~ ~
0 ~ ~2 4 1 5 2 4 P 0 3 ~ 3 particlQ formed during tableting or granulatLon procedure~
employed for making up a ind~vidual dose for~ulat~on, particularly in elther tablet or capsule form. The r~ult i8 that the bioavailabil$ty of the hydrophllic ~aterlal 1~ sdv~rsely ~~ 5 affected, depressed, and the formulations exhlblt erratlc behavior in terms of the amount o~ ~edicatlon actually recelved ~y the patlent. This can cause grave diffic~ltles in the treatment o~ serious illnesses. At time~, also, the hydrophob~c materlal it~elf in such compositlon3 is also only erratlcally 10 bloav~ ble.
In any evcnt, ln ~uch composltionq the pharmncological goals ~re to make each of the ingredlents maximally b~oavallable, at the lowest adminlstered dose level posslble, and pr~ferably ln a ~lngle tablet or capsule (rather than multiple tabl~ts or cap~ule3). Further, the formulation should also be such that the bioavallabi~ity level of the ingredient~ should be deslrably uniform, i.e with a relatively low coefflcient of variatlon when ~ .
multlple patient responqes are ~tatistically analyzed.
A ca~e in point illustrating these problems and, relatng to one embodiment ~or the practice o~ this invention, $~
the antlhypertensive medication combination of h~drochlorothlazl~e and trlamterene.
Hydrochlorothiazide is a kno~n single entity pharmaceutical for administration to human patients in order to provide diuretic and antihypertensive medicatlon and treatment~
In addition to producing ~eneflcial effects on hypertension, ~he diuretic action ser~es to relieve edema caused by renal, cardla~, hepa~i~ ineffect~veness or o~her cauge~.

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2~:~1~3 ~ owever, one of the problems which arises when thus administerlng single-entity hydrochlorothiazide is that thi~
medicatlon also tends to cause a loss of potassium from the patient, which may be excessive, and which may thereby ~reate an S undesired hypokalem$c condition. Among the undesired result~ of hypokalem$a in the patlent are mu~cle weaknes , seneral fatlgue and an exaggeratlon of the cardiac responses to various drugs whlch may also ~e admin1stered to the patlent. While potasslum ~upplements ha~e been prescrlbed, this may cause further adverse 3l~0 e~qat~ such as gastro-intestlnal teact leslons, ~ormlng ~lto ~o~ po~31ble ulceratlon an~ possible per~oration, ~tc~
It has alao been known to adm$nister hyarochloroth1azlde ln comblnation with the admini tration of tr$amterene. The latter compound has the capability of resisting hypokalem~a by retarding the dlscharge of potassium from the patlent's body.
Description of such prior actlv$ties are found in U.S~ Patent

3,0~1,230; "Maintenance o~ Potassium Balance During Dluretlc Therapy~ by ~ohvakka et al. 205 ~cta Med Scand, ~ol. 2as, pages 319~324 ~1979) and "The Influence of Do~age ~orm on ~he Act~ vit~
20 of a Diueetic Agent~, by ~annenbaum et al., Clinical Pharmacology aTrd Therapeu'cics, Vollune 9, No. ~, pp. 598-604 ~1968) . Typ~ cally such prlor art unlt dosage forms hav~ been prepared with an lntmate mlxng together of all o the various, finely dlvided, components.
~owever, one o~ the problems whlch has continued to exist wlth such comblnations as previoasly provided in the art is that the combined compositions have been only erratica1ly ~nd incomplet~ly absorbed in pa~cients, and have provided only rela'cively low bioavailability of the components, which has in ~.

- 4 EFiJ~ T~-El-rJ~lEF~ 5~ 4-3~ P~ 135~q~ 5 ~; IJ4 /2 d 1 5 2 4 P ~ 5 ~L~20~:3 turn obscured or increa~d the apparent ~mount of triamterene required by a patient.
Another pro~lem wh~ch has been encountered has been th~
risk of loqs of effective control o hypertenslon or edema wh~n 4 patlent under treatment with an ~ptimally bioavailable singl~
entity hydrochlorothlazide i~ 3ubsequently transferred to a triamterene-hydrochlorothlazide combination to a~tempt ~o control hypokalemla. A prevlously acceptable and e~fective do3e l~vel of hydrochloroth~zlde may now be rel~tiv~ly inadequate due to dep~o~ed blo~v~ bllity~ Moreover, there has not been oxperi~nc~d e~ec~lv~ control or reveraal of hypokalemia~ Whlle it mlght be thought that such d~fficulties could be ~urmounted by administering liqyid suspenslons, or separat~ solid dose levels of the act~ve ingrediente in separate ta U ets or capsules, such approache5 ar~ ln general undesirea because, ~nter all~, of problemq of patient compliance in taking the proper prescribed medication level at all tim~s.
Thus, while the properties and medlcinal benefiSs of hydrochlorothiazid~ have long been known, as well as those o triamterene, a9 well as the expected benefits to arise ~rom aaministering a combination of the two ~ogether, there has remained a need for a pharma~eutical composition combinlng these two materials in such a manner that each ingredient is optimally bioavailable with enhanced safety and pharmaceutical ef~ect've-ness. Speaiflcally there has remained a need for a ~in~le,~olid-form dosage unit composition containing both hydrochloro~
thiazide and triam~erene, with~combined diuretic and antihyper-tensive propertiesr w~le also exhibiting a bioa~ailability of the active ingredient~ at leas~ about comparable to that o~ the . . .

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XEF~O ' TELE'-O~IER ~35; ~ 4-~34; S: C7P~ -4356~3Y~S, ~ 6 4~24 15: 2~ P06 2~

~ingle dosage hydroch1Oroth~ azlde and/or triamterene and whi~h w~11 al~o resist or rever~e hydroch1O~othia~lde-lnduc~d hypokalem~ a whl1e using the min~mum re1atYe amount s~f tri amter~ne.

- GE~RAL SUMMARY OF THE INVENTION
The present invention provide~J ln a presently preerred embodiment, a pharmaceutica1 comp~sition containing bo~h hydroah1Orothi~zide and triamterene, partlcularly ln so1id do~age form, with th~ characteri3tics and properties of optlmal 10 bloavaL1ablllty, with rnore uniform absorptlon of both ingredient~, which perm~ts optimal effective diuretic: and antihyp~rtensive a~'civity whi1e resLsting or reverslng hypokalemia at minimi~ed dose levels o~ triamterene.
It i~ ~herefore an object of the present lnvention ~o 15 provide a 8afe and efective pharmaceutical composition comblning hydrochlorothia~lde and triamterene and which is adapted ~o sèrve as an aneihypertensive and diuretic agent wh~le resi~t$ng vr reversing undesired hypokalemic side ef~ectsO
An additional object of th~s invention is to provide a 20 method for manuEacturing pharmaceutica1 compositions, and the result~ng compc>~itions, having at least ~cwo activ~ ingredients, at le~t one of which is spar~ngly soluble i n physlological f~uids, and of ~igniicantly different hydrophobic and,~or , hydrophi1ic characteristlcs, wherein the resul'c~ng composition 25 exhibits enhanced bloava~labi1lty Of the medicat~on and o~

increa~ed uni~ormity of behavior in physiolo~ica1 absorE~tion.
A further s~lfia object of the present inv~ntlon i~ 'co provide a me'chod of manu~actur~ng ~uch a ph~rm~ceuti~al ~,.
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composltlon, c3mpo~ed o~ hydrochlorQ~hiazide ~nd ~r~ter~n~, ~he r~ultant pharmaceut~calO and 1~ ~e~ho~3 of u~, belng such th~t the actlve lngredlent& of the composlt~on will be unlformly Absorbed ~nd provide h~gh bio~vall~blli~:y whch 1 comparabl~~~o s that provided by a single~en~ty hydrochlsro~hiaxide me~ic~tlon or ~lngle ~nti~y trlsmterene.
It i~ yet anothQr o~ ect o thi~ ~nv~ntlon to provide ~uch a compo3it~0n and ~s~ociated method which wlll permit ~ re~l~tance to or reversal o hydrochlorothlazide-~nduced hypokalemla whlle employing a mln~um amount of triamterene in combination th~r ewi th .
In ~eneral, the prime ~peci~lc objective of khe lnvention 13 to provide a compo~itlon employ$~g a minimum do3a~e of ~riamtere~e, wh~le proaucin~ effec~iv~ ~ioavalla~ility ana 15 avoidin~ or reducing or rever~ing hydroahlorothiazide-indu~ed hypokalemla. In general, hypskalemia may be considered ~o exi~
at a serun potasslwn level o~ about equal to or less than 3. 5 ~..
mEq~L.
~hese and other objects of ~he inven~io~ will become apparent ~rom the following de~ailed descriptlon.

DESCRIPTION OF THE PRE~ERRED ~MBODIMENTS
~ n d preerred embodiment of th~ present invention, hydrochlorothiazide ~6-chloro 3, 4 dlhydro~ 1, 2, 4-b~nzo~hiad~a~ine-7-~ulfonami~e 1, l-~ioxide~ is combined wlth tria~terene t2, 4, 7-trlamlno-6-phenylpteri~ine), and non-toxic phar~aceutically acceptable carrier~ or other materi~l~ to produce the ~eslre~ pharmaceutical actlon.

x~RO~ TE~ ECOFIER 495:Z4~ 84; .s:29F'1~ 24:35630~el3,~ B
~4. ~4~'24 15: 2~ PO~ *

A preferred embc~diment ~or the metho~ o~ m~nu:Eacturing the pharmaceutic~l cC3mpO8l tlon of the pr~ent invent~on lnvolv~
~he steps o~ ~rovldlng respective ~qu~n~ltl~ tri~nt~rene and hydro~hlorotl~la~ide at ~ we~ht ratio of tr~amterene t~

5 hydtochlorothlAzide of ~out 1.75 to 1.~5sl. ~h~se irigredl~nts ~re separately ~dmlxed wlth certaln ~dditional c~rrier mat~ri~ls whlch contr~bute to thelr enhanced bioavail~b~llty. ~he separ3te mixkures, ~ter granulation, are then c~mbined. The pharmaceut~cal composlt~on which results i5 preEerahly provlded 10 ln ~olld dosage form, particularly as ~ tablet~ or altern~tively as a C3p~ ul e.
$he quantity of triAmteren~, on a welght basls, ~hould be In the range of about 1.75 to 1.25 times the quantlty of hydrochlc)rothla~ide and advantageously and most prefer~bly about 15 1.5:~. As used he~einafter the expres~on wtriamterene weight ~ase" shalI re~r to the ra~io of the ~mount, on a weight basls, of ~nother cornponent to the amount o~ triamterene.
~ he ~riamterene lngredient itself, in finely al~rided mllled form, pre~erably such that at least about 953 pass thro~gh 20 a 200 mesh screenl may be made up in a f ~rst mixture contaln$ng about~ 25 to 75 per~ent (on a triamterene weight bas~ ~ o~ a wicking agent, such as powdered celluIos~ .F., ~C6HloO!j)n ~nd ::: ` ~ :
- pre~erably ~bou~ 3$ to 55 perc~nt. A suitable wickln~ ~gent 1B
that sold under the trade designat~on "REXC~L" by E. Mendell Co., :: ~s :~n~w n~ned ~OLK~-FLOC BW-100) or th~t sold under the 'crade de`slgnation "~X-CE~ by Sitco Chem~cal~ Such a wlcking agent should be effective to induct water to wlthin the ~ub~eguently ' .
forme~ g~anules ~see below) to swell and otherwi~e ~id in the f ragmentation of the ~une when exposed to aqueous phy~iological XERnx TELECI~PIER 4q5;C~l- 4-84: 3:3CPM ; i .~

~4. 04~24 1 5: 2~ P09 '~' fluia. It 1~ preferred that this material have a longltudl~
dimens~on greater than would pas3 through a l3creen of abou~ 2Q0 mesh, in order to enhance its w$ckin~ action ln the compo~it~on.
Al~o added to ~his ml xture ls a~ut 20 ~o 240 per~ent lon a triamteren~ welght ba~ percent and E:~re~erably ~bout 150 to l9û percent of a ~inely-divided binder~ di~integrant, ~uch a~
y microcryst~ ne cellulo~e, ~.F. (C6ElloO5)~. A sultabl~ binder di~ln~egrant i8 that ~old under the trade de~gnation ~Y:tOE~ P~-10~" by FMC Corporatlon. ~ suitabl~ wett~ng a~ent such A3 ~Od~
laur~l ~ulf~te ~dodecyl sodi~n sul~ate tCH~C}~2)10C~32~O3Na] may also be added ~n quantit~es sf about 2 to lû percent on ~
trl~mterene we~ght basi~ an~ p~eferably abou~ 4 t~ 7 p~rcent, A
su~ ta~le materlal 18 that sold under the trade de~lgnation "Maprof1x" ~Onyx Chemical Co. ~.
Other addltlonal non-toxic pharmaceutically-~ocep~able but inac~cive c~rrier material~ may also be present and al} of the~e components are admixed together to create a fir~t mixture.
Anong the addit~onal component~ which may b~ included in ~u~h f1rst ml xture as pharmaceutically inac~ive materlals, a~ 1 ln ~o finely-divlded form, nlay be a~ disintegrant 3uch as croscarmelIose sodiurn, N.F~ ~a cross linked sodiwn carboxymethyl cellulose material), in quantities of about 6 ~o 22 percent on a ~ ~ tr1anterene welght bas~s and pre~er~bly about 10 to 1~ parcent, :~ Suitabl~ materials are those sold under the trade desi~nations ;25 ~Ac~D1-Sol~ (FMC Corporatlon~ and "CLD" ~Buckeye Cellulose Corp,~
hlso added to thi~ ~itst mixture i5 a dosag~ lubricant, ; suoh a~ magnesium stearate~sodium lauryl sulfate, pre~parlsd by provid~ng ninety-four parts, on a we~ght ba~i~, of the former and xEF~LI>( TELE~l_OPiEFI -lq5:--4~ 4; ~.:31Prl ; ~ 24355~ 5:~:1EI
~,4 ~14,'24 15: 24 P10 *

8iX par'cs of the latt~r" p~eferably ~nitally we~ xed and then dr~ed and milled, in quantities of a~out 3 to 12 percent ~n ~
tri~mterene wel~ht basis and preFerably abDu~ 6 ~o lG percent.
~Thi~ m~xture may, ~or iLnstance, consis~ c~f 94 parts magnesium S stearate, N.F, ~Octadecanoic acid magnesi~n salt m~ ~C18 B35 2) 2 and 6 parts of ~odium laur3rl ~ulfate, N.F. Idode~yl sodi~R
~ulfate, 1 (CH3 (CH2)10~1~0S03Na~ . A s~litable lubrlc~nt o~ th~s type 18 that which h~ been marketed under th~ 'crade deslgna'clon "Stear~ W~t M"~ Addiltionally, a su~table flo~ enh~ncer~ I uch ~3 10 colloia31 sllicon diox~de, ~ .F., may be provided in ql~ant~t~ e~ o~
about 1 ~o 5 percent on a triamterene weight basi~ and preferably about 2,5 to 4 percent. Suita~la mater1als are those sold under the trade designation~ "Cab-O-SilU, tCabot Corporatlon~ and "Aero~iln, (Degussa, Inc. J.
P.Q now u~ed hereinaf ter the expression "hydrochlorothlazide weight bas1s" shall refer to the ratio of ~he amount on a weight basls of another 1ngredient to the amoun~
of hydrochlorothiazide.
A second mixture i5 made up by mixing finely divided 20 hydrochloro'chiaæide, preferably such that ~t least 95~ passes through a lOû mesh screen, with abou~ 120 'co 240 percent ~on hydrochlQrothiazide weight basis3 of a ~uitable binder-disintegrant such as the m~crocrystalline ~ellulose, N.F.
:: (described above) and preferably about 160 to 200 pera~ntt pll~s 25 about 4 ~o 16 percent on a hydrochlorothia~ide weight basis of a dis~ll'ce~rant, such ~s the croscarmellose sodium, N.~. ~described ab~ve) and preferably about 10 to 12 ~ercen~; plu flow enhancar, 8uch as collo1dal ~ilicon dioxide, N.F. (SiO2) in quantities of ~bout 0.5 ~o 4 percant on a hydrs:ch1orothiazide weight basis and ~,~
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XERrl~ TELE~-OPI~ 4~5;~ 4-84: 3: s~P~ 35~3~ 3;~11 84. 04.~2~ 15: ~4 Pl 1 ~

~2~3 preferably ~bout 1 to 3 perCQnt; plus a lubric:ant uch a~
magnÆsiwn stearateJsodium laucyl sulfate (94/6~ ln quantlti~s of about 0.5 to 4 percent on a hydrochloro~hlazlde weight ~s~s and prefera~ly about 1 to 3 percent. Suitable ~lvw enhancers lnclLJde 5 ~:hose sold under the trade designatlons "Cab-O-Sil~ ~C~bot eOrpor~tion~ and ~Aerosll~ eguss~).
Each of the~e two ~eparately prepar~d mixtures of ~he re8pect~ve ac~Ye ingredients an~ carr~ er m~ter~ als i~ thoroughly mixed and further mllled ~f desired to op~clmum partlcle ~$2e for 10 e~fectlve ph~rmacautlcal use.
Each of these two mixtures ls next separately compacted or compressed for the purp~se of making granule~ c~ each mixture. The separate compaction steps form compressed materiAl compo~ites oE the respec~clve mixtures, fo~ ~nstance in large disk lS or gheet form 8uch that the individual activa ingredient particl~s are now ln lntimate physical, ~ubstantlally homogeneous~ admixture wlth the above mentloned additlve ma'cerial .
part~ C18E~.
Next, the compacted materials are separately subjected 20 to a comminutln~ operat~on to divlde the same înto a granulated ~orm, whereby the respective granules of each mixture will be composed o~ the respective active ingredient and l:he above-~ mentioned various additives, The granules thus-formed f rom the : compactlvns shou~d have adequate structural lntegrity to cont,1nue 2S t:o exi~t a~ ~in~te entlties in the followlng operations.
In a preerred form o~ the practic~ of the present invention, in ~eparate proce~sing of each o~ the two mixture3 they are pre~erably pa~ed through a ~itzmill, No. 00 ~c~een, and ~f te~ they have been separately compaated, they are comminuted to ~.

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0~ rELECOPlER 4~5:c4- 4-8~ .3P~ 35~ 3~:~12 04,/24 1 5: ~4 P 1 2 form re~petive granule~ of th~ separate mixtures w~th the granulated materials being pa3~ea through ~ ~itzmill No. 2 ~c,eQn ~or capsule~ ol: a F~t2anill No. ZA for ~abl~t~ ~the~ equl~m~nt of comparable funct~on may of course be used for the~e purpo~es.
- 5 ~he thus formed gr~nules sho~lld have a ~ize range from not more than 5% ~eing larger than 2 mm to not more than 20&
~ing ~mall~r than 0. 075 mm, preferably with not more th~n 5S
having a dimension exc~ding l.S mml especially when a capsule ~$
~o be ~aade.
Thereaf ter the thu~-for~ed gr~nules of the f ~Ist and ~econd mixture~ are blended together ~o create a third, now comb~ned, mIxture. In a preferred form of the practice o~ th~s inventlont a further quantity o~ lubricant, 3uch as a mlxture ~preerably made up ~et, dried and ~illed~ of magne~
15 stearat~odium lauryl sulfate (e.g. 94~6 welght ratlo) ~
admixed ln khe third mixture~ ~h~ may be about 0. ~ to 1. û
percent of the ~otal blended we~ght of the two mixtùres and pref erably about 0,, 4 to 0. 7 percent. r1hen the comblned composition i~ ultimately formulated in capsules suitable 20 stabilizer~, suractants and antimicrobial agents may b~
pre~ent. If in~tead ~ tablet is to be made~ a coloring agent may be added, such as l~C yellow ~10 aluminum lake in suita~le colorlng amount, as de~ire~.
The comblned granulated and blended mixture composi~ion 25 then produced by the above-described method may now be formulated lnto unlt do age form, e. g. as a tablet or as a capsul~.
In a pre~erred form of the practice o~ the irlventlon, th~ ultlmat~ unit do~a~e form o~ tl~e comblned mixture may include hyd~ochlo~oth~zid~ in quantities o~ about 25 milllgram~ to 100 ~..,~, xE~O~ TELECOPIER ~5:24- 4-1~4; 3:_4PM : ~ ~4~5c~ 13 84. 04,~24 15: 24 Pl:~ *

æ204z~
mlll~grams and d~s}rably ~uch that the combln~d wei~ht o the actlve p~a~naceu~ical ingredlent~, l. e., hydrochlorothl~zide and triamte:rene, wlll be ~bou~ 62.5 mllllgram to 250 ralll~gram~
tot~l. For example, at a weight ra~io of 1. 5s 1, the unit do~age 5 breakdown of ~riamterene to hydrochlorothlazi~le might be 3?~5/~5 ~ng, 75J50 mg. or 150floo mg. It ha~ been found that ~ Yery effectit~ weight ra'c~o is 75/S0~ In general, lt w~
des~rabl~ to limi~ the amount o~ the total patien~ con~np~ion of trlamterene per day to no more than about lSO milligranl~ and of 10 hydrochlorothl~zide per day to no more than about 100 mllllgrams. ~As used he~ein, the term ~patient" shall refer to members o the anIm~l kingdom, IncludIng hunan b2~ ngs. ~
One o~ the key ~eatures of the pre~nt lnvention whIch contr~bute~ to the h~gh ~ioavailability cerlt~rs ~round the ability of ~aid re~ul~ing unit ~osage formx of thi3 com~ined compositlon to di~integrate rapidly in the presence of physiological ~luids into pre-formed separate granules, ~nd subsequen~ly the ability o~ the respective lndividual granule~ to break up rapidly in such~fluids into their much smaller p~rtlcul~te component~ Th~s is accomplished by specific control : o~ relative particle slzes, the blending of hydrophoblc and : hydrophllic materi~ls, only a~er they have been saparately granulated, and in a pref erred embodiment, the use of wicking - maeer~s, par~cularly with ~he hydrophobic component.
~: ~2~ In general, with two exceptions, in ~he pre~erred prac~ice o~ the inven~1On most of th~ ~tarting materials Incorporated lnto the f irst and second ~nixtures will have a par~icle ~e o about 95~ passing through a 200 mesh sor~en. In or~er to provde ef~ect~ve w~cking action ~to cause moi~ture to ~ ~.

XEF~Ox TELE~-~PIER l~5;~4- 4-~14; 3:3~PM ; ~ 3~
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penetr~te ~o the dosaqe unit interiox), ~he wlcking agen~ ~hould have a lonsltudin~l dimen~ion greater than would pa~s through d 2~0 me~h screen~ The ~relatively hydrophilic ~ hydrochloroth~a-zide p~rticles should al~o pa~s g59~ throuqh a 200 mesh ~cre~n, but pa6slng ~bout ~5% through ~ lO0 me~h screen le al80 ~cceptable. The particle ~i~e of the lngredien~ ~nd carr.ler~ ln the sep~rately formed m~xtures should be sub3tantially ~maller t:han the ~1 z~ o~ th~ ~ubsequently formed granules by At le~t one or more or~er~ of magnitude.
Of the actlve ingredient9, hydrochlorothia2ide, i~
relat~vely hy~rophilic~, while triamterene i~ relatively hydrophobic. As described above, it is believed that one of the problem~ encountered with the prlor art m~teri~l~ and composltions has been the rather un~form presence o~ fine ~ 1~ particlQs o~ tr$amterene on the ~urface o the ~olid dosaa~ for~
~and ~l~o of agglcmerates therein~f thu~ creating a hydrophobic barrler to passage of moi~ture therethrough. This ph~nomen~n ~videntl~ occurred because of the blending together of ~he ~wo active ingredlents, and the other conventional tableting or 20 encapsullnq ~dditive6, all in finely dit~ided ~orm without preliminary separate compos~ tlon ~nd granulaton thereof .
Moisture thu6 Pails or ~s inhlbited from comlng in contact with the hydrochlo~oth~d~i~e. This has resulted in a failure of the dos~ge ~orm to dislntegrate rapidly and, as a result/ such : 25 ~ompo itions exhibit limited and erratic bloavailability.
By contrast, in the present invention, the separ~te ~nit~at granulation of the Actlve ingredients with other ma'cerlals prior to admixture and blend~ng of the actlve in~redients togethe~ ~erve~ to ~eparate the hy~drophobio and xEROx TELECOF:'IER 4S5:2~ -84; 3:37F`M ; ~ 24356309~13,#15 8~. 04/24 1 5: 24 P 1 ~ ~' hydrophillc particulate materlals rom ~ach oth~r thereby al~o ~vo~ding ~uch ~urf~ce ef~ect, and thus al~o facillt~ting dl~integratlon o ~he ~olld do~age form into preformed granule~
which are themselves ~5190 ~ble to disintegrat~ rap~dly ~co disper~e th~ f ~ne particl~ of the actiYe ~ngredi~nt~. Thi~
~ffect ls further enhanc~d by the increased exposeâ ~urfac~ ~rea o~ the re~p~ctive ground granul~ted partlcles, which ln turn lncreas~ the rate of ~olutionD
As shown below~ the di~solution and bioavailablllty of the triamterene ingredlent i~ also enhanced when presenl: in the granular orm of this invent~on.
It w~ll also be appreciated that this method form~
separate granules which are tl~emselves e~sentially homogenous, with each other, of the respectlva components, but that ln the final comp~ition, a heterogenelty 15 present in that the d~ff erent granul~ are now blended ~cog2ther . ~urther, di~erent formulating additives may be employed w~th the different active ingredient~, as deslred, to enhance the ultimate dissolution thereof while avoiding ~ncompabillty problem~.
By "~ranularly-heterogenous" 'chere ~ meant: herein ~he existenc~ of individualIy distinct granules, one set c~ such granule :containlng the triamterene c~nponent and the other ~et of granule~ Gontainin~ 'che hydrochlorothiazide. The term ls thus lnappo~ïte with respect to a co~position in whi~h the respec~ive 25~ granuLes we~e lnitially ~ormed containing ~oth the tri3mterene ana the hyarochlorothiaz~de. l`he term "granularly heterogenousl' cc~ntinues to be apposlte to the invention even when the lnltial Snd~ v~du~l g~anule~, after being l~lended togethert may be again .~ . .

XEROi~ TELEC~)PIEF~ 495:,_4- a-~4: ~ 313~ 4~ 3~
4,~4 1 5 : 2 ~ P 1 ~ ~

~ 3 compres~ed, ~ompacted, or ~lugged, together to for~ cOm~oBit~
larger granules for tableting, encapsulatlng, or the l~ke.
~ ~econd stage of lncre~sing bioavallabillty in~olves phy~lologic~l }r~gmenting the separa~e pre-ormed granul~ ~nto ~ 5 thelr 3tlll ~maller components. By using ~ wiok~ng ~g@nt, mola~ure ~ d~awn into, and swell~, the interior o~ such ~ranules. Al~o, the disintegr~nts and the sur~ac~ant ~ontribute to such ae~irea ~r~entation.
~t wlll be appreci~ted that one of the advantageou8 ~pects o~ this emb5dlment of the present lnventlon 1B ~he ability to achieve resistance to or even reversal of hydrochloro-thiazide-in~uced hypokalemla through the action o~ th~
~ri~mterene~ a~ ~ result:of the high bioavallab~l~ty level3 ~or this materlal being ~chieved by the use o~ P~nely-dlvi~ed particle slzes of the active ingredients ~ombined wlth indepen~ent mixing of each ~ctive ingredient with ~he above-de3cr~bed pharmaceutlcal carrler materials to create the ~epara~e granules. The hydrophobic triamterene granules are preferably provided wlth a wicking agent to assist with fragmentation o~
such granules. The hydrophllic hydcochloroth;azlde granules, whether in a tablet or capsule form of the presen~ ~nventlon also : : readily absorb ~ater or o~her ~ody fluids and facilitate prompt ~ragmentatlon o~ the solid dosage form into granulas~ The gra~ules preferably as~sted by disintegrants, a wetting agent and a w~cking agent in the triameterene granule~, are then broken up.
~he ~ollowing examples and data wlll ur~h~r illustrate the me~ho~ ~na a compo~ltion of the pr~sent inventlon, ~. ,.

>~ERO`, T_LEl_OPIER ~95:24-- 4--34; ~:4~PM ; ~ 2~3~D3~g~33 ~1~

Exampl e To prepare 50 kLlogr am~ of ~he ph~rmaceutlcal composltion of the present ~nvention, at a ratlo o~ tri~t~ren~
to hydroch}orGkhlaxide of 1.5:1 on ~ we~ght bas~s, the followlng 5 procedure 1~ employed~
The first m~xture ~ 5113de Up to contain ~bout 9.3~
kilQgrams of ~riamterene, U.~ 4.75 kllQgram of ~ wi~klng a~n~, 15.6 kilo3rams o4 ~ binder-dlsintegrant, 1025 kllog~ of a d~sintegrar~tl 500 gram~ o~ a wetting agent or surfaGtant Buah lD a~ 80dium lauryl sulf ate, 750 grams magnesi~n stearate~odlum lauryl ~ulfate ~94/6) and 250 grams o~ a flow enhancer.
The dis~nt~grant, magnesi~n ~tearate/sodium lauryl ~ul~ate (94/6) and flow enhancer com~n~nts are thoroughly pre-mix~d~ Thi pre-mix ~ then passed throu~h: a 30 m~h screen.
15 The triamtere~2, binder-dis~nt~grant and wicking agent component~
~r~ pa~ed through a ~creen. All of the ingredient~ are then pIacea in a flYe cublc ~oot V-blender and blended for aboùt t 5 minute5. Irhe mixed material is then passed through a Fit2m~11 No, 00 scr~en, high speed, impac~ forward, and the thus-mill~d 20 mixture i5 subsequently slugged or compacted to create granules o the;~r~t mixture. The ~lu~ging or compactlng may e~ther form :hard; alsas of about 1/2" d~neter o~ sheets o about 1~8"
thlckness, e'cc., achieved by using about 2 to 4 tons per square nch o pressure,. This cornpressed material l$ then pa~3ed ~5 through a Fitzmill NoO 2A screen, med~um speed, knives forward to orm oomminuted granu1es. In the event it i5 des~re~ tO make a capsule, a P'it~111 NO. 2 ~creen may be substituted in thia fina s'cep o~ pe~parirlg the granulated ~irst mixture.

~.

- 17 ~

XE~:O, TEI_ECCIPIER 495:~'4- 4~ ; 3:41P~ 2~35BBa~a3:~1a _ ~ 0_~4~ ~1 5: ~ ~ P 1 8 ~;

~ 3 The second mlxture l5 made by mlxi~ ogether at7Out 6. 2$
kllograms o~ ~nely-divlded hydrochlorothiaz~d~l U.S.P., 10.00 kll~ratns of a ~lnder-dl~lntegrant; 62S gram3 of ~ in~egrant, 125 gr~ms of a flow enhancer and 125 grams o~ ~na~neslum arAte/~odlum lauryl ~ulfate ~94/6~. If a Sablet ls to be ~ade, about 125 grams of a colorlng agent may be ~dd~d. Th~
aisin'cegrarltO magnesi~ ~l:earate~odi~n lauryl ~ul~te ~n~ ~low ~nhan~r ~ong wi~h any coloring agen~ u~d) may be pre-~lxea and 1r~t pa~sed through a 30 ~aesh ~creen. ~he hydrochlor~
10 Shia%i~e nd binder-di3lntegrant may previously be pas~ed throu~h an 18 or 30 meRh screen to r~move any l~mps. The 3ubse~uent mlxi~g, m111ing, granulat1ng procedure employed may be identlcal to that employed with the f~st mlxture"
The co~ nuted granulated mixtures thus made 3eparately 15 by the ~ove-de~crLbed paraïlel granulat10n of each ~arate ~n~xture may be next separately milled to an approxitna~e gr~nular size range o~ from about not more~ than about 5~ b~ing greater than 2mm ln length ~the maximum dimen610n) to not more than about ~o% belng 3maller than 0. 075 mm ln length.
~ext, magnesium stearate~sodium lauryl sulfate, ln a quantity o~ 250 grams, and mixed at a ratio of 94.6 on a ~eight b~is, is pass~d through a 30 mesh screen. The two g~oup~ of : irs~ and second granules composed of the separate ~lr~t and second mixturss are next admixed and blended togethet w1th the ~ 25 :magnes1um stearate/~odium lauryl sulate in a five cubic f~ot V-: ~ ~ blenaer or a~uS 15 m1nuteR.
When ~ tablet is desirea, this final bl~nd may then be compres~d on ~ conven'cional tablet press, ~,.

)~ERQ~ TELECOPIEF~ 495;~4- 4`-8~; 3:43F'~1 ; ~ 2435~30gÇ)3,#19 S 04 '24 1 5: 24 P l '3 ~

~22~ 3 In produc:iny a capsul~ solid-dosage form, t~3e mixed ~nd ~lended materlal may be ~ntroduced lnto e~ch cap~ule ~y appropr~te, ~utoma~ed e~i~ment~ If a c:apsul~ i~ to be produced the coloring agent may be elimlna~ed and th~ upper limlt of ~
S granul~ e, may be ~uch that no~ ~ore than 5~ exceed~ 1. 5 s~m in length.
I:~eslrably, a unit-dc~sa~e form may be a 0. 4 gram t:~blet, 1~19 ma~e by the ~ove ~netho~. Thi~ ~able'c would conta~n rom the ~r3t mixture about 7$ mill~grams of triam~erene, U.S.P.~ 38 10 mlll~grAms o~ wlcking agent, l25 milligrams of ~ binder-dislntegranS, lo mllllgrams o~ a disint~grant, 4 mllligrams of wett~ng agent o~ surfactant such as sodi~ lauryl sulfate, U~S.P., 6 milligrams of magnesi~ ~aratef~odi~n lauryl sulate (94/6) and 2 mllllgrams of a flow enhancer; ~nd will further 15 contaln, fran th~ ~econd mixture, S0 mllligrams of hydrochls~rothiaæide, U.S.P., 80 milllgrams of a binder-di~ntegrant, S mlll~grams of a disintegrant, 1 mill~g~am o~
flow enhancer, 1 m~lligram o~ magnesi~n stearate/sGdium lauryl sulfate ~4f6) and 1 milligram of a colo~ing agent. In addi'cion, 20 2 m~ rams o~ magnesium st~arate~sodium lauryl sulfate ~94/6) will be present, as introduced in the f inal blending operation.
:: :

A preferred tablet formulation, oonsist$ng of 50 mg hydrochlorothiaz~de and 75 rng triamterene $n the tablet, made up ~ccordIng to the foregoing proceduYe, uses th~ ollowing .
25 ~ mat~rials ln the ~ndicated amounts~

~"

XERCI;~ TELECCIPIEF~ 4-84;3:~4F'M ; ~ ~35!:>3~!3;#-0 4,~24 1 5: ~4 ~2iJ

Flrst Mixt~re ___ Arnount Tr1amt~rene g. 3~ Rg ~5 Av~ ~el, PH-102 15. 6 ~9 125 Rex~el 4,?5 Rg 3~
Ac-D1-Sol 1. 25 ~9 10 M~gne3~ um Ste~rate/Sod~ usn ~auryl Sulfate (94f6) 750 g 50dium ~auryl ~ulfat~, N.~ . 500 g 4 C~ $11, M-5 250 g 2 Amoun t ~ydrochloro~h~azide ~.25 ~tg 50 Av~cel~ PH-102 10. 0 Kg gO
~c-D i-Sol S2 5 g 5 ~Sagne~ 1 ~n S tear ate~Sodi um ~auryl Sulfate (g4~6) 125 9 Cab-0-Sil, M-5 125 9 ~ & C Yellow ~10 r.ake MT (17-20~) 125 g Af ter the ~eparate granules were prepared, 250 g of ma~nesium ~tearate/~odi~n lauryl sulfate ~94/6) were added and : the fi~nal mixture thoroughly blended and then formed into tablet~
25 (or capsul~s) by customary m~thods.
; r` , ,:

XEFO~' TELE~ F'IER ~:~;-4- 4-8'~; 3:45P~ 4~5~3~
04~4 15: 24 P.l ~t~
2~

~econd ~ablet ~ormulatlon, c~nt~ining 50 mg hydro-~hlorothlaz~de an~ 100 mg triamter~ne ln the tablet, wa~ made up ~ccording to the forego~ng procedure, using the ~oll~wlng S mater~al~ ln the lndicated amoun~s, ~E~
A~unt Trlamter~ns 10~0 X~ 100 Av~c~l, PN 102 18.5 1!~9 1~5 Rexo~l 5.80 E~g S0 A~-Dl-3O1 1. 6~ K~ 16 Magne~ium Steara~efSodiwn ~auryl $ulfat~ (94/6) 800 9 a So~iurn Lauryl 8ulate, M.F . 500 9 Cab-O-Sil, M-5 400 q 4 . ~

Can~E!nent Amount ~ydrochlorothiazide 5.00 gg 50 P~vicelr PH-102 10,. û Rg lO0 : : ~o~ Sol ~ : ~ 9 Uagn~s i ~n s tear at~sodi ~n uryl Xulfate t94/6) 100 g ~ : :
: : Cab-O-~il, M-5 lO0 g 2:5 : ~ 6 C Yellow #lû
ake HT ~17-~0%) lQ0 9 ~::
~:

- 21 ~
~ ' : :::

XERO;` TELECOPIER 495;~4-- 4-8~ qt:~PM : j 7435t~3~3:~7~
~14~24 l~: 24 P~2 .

A~ter the ffeparate granules were prepa~ed, 330 9 o~
magne~wn 3~e~rate~0dium lauryl ~ulfate (94~6) were added an~
the ~ame blended and then foraned ~nto tablets or capsul~
above.
. .

~G
A capsule ~ormul~tlon, con~aining 25 mg hy~ro-chlorothiazl~e and 50 mg trlamter~ne ln ~he cap~ule, was r~a~e up ~ccor~ng to the ~orego~ng prc)cedure, u3ing the ~ollowlng materlals ln the lndicated amounts.

10 ~3~
Amount _~ per CaPsul2 ~!rlamteren~ 10.0 Kg 50 ~ex~el 4.ûO Xg 20 A~ic~l, Ph-102 2. 40 Rg 12 ~c~I)i~501 ~oo 9 3 Sodlum Lauryl SulfaSe~
~.F . 60~ g 3 Magnes~um StearatefSodium l.auryl Sul~ats ~9~/6) 300 g 1.5 .
~ Cab~O-Sil, ~-5 lOû ~ o.s ç~, AmoUn t NYdrOCh1OrOthiaZide 5.00 ~t9 25 V1Ce1, PH-102 B. OO K9 40 ~: 2~ AC-D1-SO1 600 9 3 Cab~0 $11, M-~ ~ 9 ~-5 M~gne~Um SL~9arate/SOdiUm LaUrY1 SU1~Ate (94/6~ 100 g ~ 0,5 :

xEROx lELECOPlER 495:2~ 4-8~; 3:47PM ~ 435~3eU~ 3,~S3 04/24 15: 24 P23 ~Z2~ 3 After the separate gr~nules were prepared, 200 g of ma~ne~ tearate/fioalum l~uryl ~ulfate ~94,~6) were ~dded to the ~ame ~nd ~lended, and then formed ~nto No. ~ capsules ~y conventional methods.

5 --- xam~le 2 In ord~r to determine th~ bioav~ bility of the compos~t1On c~f the present inventlon ~s canpared with ~ prior, currently-markQted, ~mpo~ltion formed o~ an lnt~mate adm~xture of hydrochloroth~zlde and triamterene, and with ~ 5~5~pen310n l0 whlch latter serves as an optlmally bioavalla~le ref er~nce standard, the following test~ were performed.
An ~ eou 3uspension containing l00 mg o~ triamter~ne ~nd ~0 ~ng of hydrochl~rothiazide was admlnis~ered to ~ix healthy volunteer~. At a different time these part~cipants were giv~n a 15 ~lngle: t~blet Iconta~nin~ 75 m~ of triamteren~ and 50 mg o~
hydroch1Oro'chiazide~ formed according ~o this invent~on. Oth~r particl pant~ were giv~n two prior art presently-mar ~eted capsules (containing a con~bined total of l00 mg triamterene/50 mg hydro-chloroth1azide~ the only previously FDA-approveà
20 tri~Qter~nefhydrochlorothiazide combinat~on ~ormulation), Following each dosing, urine was collected and the amounts of : drug ~ecovered were quantified. A ~mary of the tri~t~rene urin~ry recovery re~ults ~in mg recovered in urine during a f2 ~¦ hout perlod after ~oslng) Is presented in Tabll3 I.

~:
.

- ~3~

~2~ 3 Table I - T~IA~TE~E~E BIo~v~IL~BILITx*

SUSPENSION** PRIOR ART** PR~SENT I~VENTION***
(100/50)(50/25 CAPS~LE) ~/50 TABLET) PARTICIPANT
1 61~2 28~3 45~5 2 S0.6 28.5 49.4 3 42.~ 18.6 39 5 4 55.9 20~8 36

6~.5 21.5 36.9 6 49.9 23.2 3q.7 Mean 54.1 23.5 40.4 Std. Dev. 8.2 4.1 5.8 C.V. 15.1 17.0 14.0 15Mean ~ Dose54.1 23.5 53~9 * ~epresents total triamterene plus hydroxy triamterene sulfate ester. (The conjugate res~lts from triamterene being metabolized in the liver~
** Total Dose = 100 mg triamterene; 50 mg hydrochloro-thiazide.
~0 *** Total Dose - 75 mg triamterene; 50 mg hydrochloro-thiazide.
These tests resulted in a mean triam~erene bioavailabil-ity of 53.9% of the dose administered for the compound of this invention, comparable to the value of 54.1~ for the suspension, as contrasted with a mean o~ only 23~5% for the prior art capsule.
Later a second test was performedj again with ~he first group of 8iX healthy volunteer participants, using the prior art capsules and capsules formulated according to the present invention (E~ample l-B). T~e resulting data, similarly measured is;presented in Table I~ (along with certain data from Table I
for~convenient comparison).

;23 T~ilE -- Tra~æ BIQ~I~BlLIr~
PA~IC:Il?ANT SUSPE~SION*PRIOR ARTPP~:2NT l~TION PRESENr INV~:E'ION
(100/50)(50~P.SULE) *~7~* (75~50 TP~i~*
61 . 2 16 . 3 45 . 5 45. 5 2 50. 6 26 . 8 4~ . 9 49. 4 3 42.2 20.1 34 4 3g~5 4 5~i. 9 45~ 9 33. 1- 36. 2 64.5 20.4 31.~; 36.9 6 49.9 23~4 40.1 34.7 Mean 54.1 25.5 3R.3 40.4 Std Dev8.2 10.6 6.1 5.8 C.~. 15.1 41.0 16.0 1~.0 Mean ~ Dose 54 . 1 25. 5 38. 3 53. 9 * Dose Administered~ 100 mg Triamterene/5 ~ Hydrochlorothiazide *~Dose Administered: 75mg Triamterene/5~ Hydrochlorothiazide A similar summary of the hydrochlorothiazide urinary 20 recovery results (in mg recovered in urine during a 72 hour period after dosing~ corresponding respectively to Tables I and I-A, is presented in Tables II and II-A.

: Z5 :: :

: 30:

~: 35 : - 25 -TAB LE I I - HYDROCHLOROTHIAZIDE BIOAVAILABILITY
PRESENT
PRIOR ART~ INVENTION
SUSPENSION*( 50/25 ( 75f 50 PARTICIPANT (100/50) C~PSULE) TABL~T)**
_ 1 31.5 2~.2 29.5 2 29.7 15.8 26.9 3 24.6 25.~ 31.7 4 26.4 21.6 24.9 3 3 ~ 3 31 n 1 6 32~8 15.~3 38~4 Mea~ 29.7 19.1 30.4 Std DeY 3.5 5~6 4.7 C,V 11.8 29.0 15.0 Mean ~ Dose 59. 4 38. 0 60. 8 * Total Dose = 100 mg Triamterene; 5Q mg Hydrochlorothiazide.
lS ** Total Dose = 75 mg Triamterene; 50 mg Hyrdrochlorothiazide TABLE II-A
HYDRQ~lLOROTHIAzIDE BIOAY~ILABILITY
PRESE~T PRESE~T
PRIOR ART* INVENTION* INVE~TIO~*
PARTICI-SUSPE~-t5o/25 (50/25 (75¦50 PAN T _ 5IO~* _ CAPSULE)__ CAPSULE~ TABLET) ` 1 321 7 10 3 ~28 6 29 5 : 25 3 ~4.6 14.3 24.5 31.7 4 26~4 23.3 16.3 24.9 ~ G 32.~ 17 ~ 34 4 31 1 ; ~:Mean 29.7 15.4 25.8 30.4 CtV~ 11 8 31 0 22 0 15 0 ~ Dose 59.4 30.8 sl.a 60.8 * Dose Administered: 100 mg Triamterene/50 mg Hydrochlorothia~ide.
: ** Dose Administered: 75 mg Triamterene/50 mg ~ ~ Hyrdrochlorothia~ide :

.

~2~23 ThU5 a significantly higher percentage of both active ingredients was availahle from ~he composi~ion made according to this invention than from the prior art product.
In still another test the same ~irs~ set of six volunteer participants (see Example ~ above) were treated with a tablet made using the technique according to this invention (Example l-A, above) but containing 100 mg triamterene and 50 mg hydrochlorothiazide. The results, measured in the same manner as in Tables I, IA, II and II-A, are shown in Table III.

TABLE III
TRIAMTERENE PLUS HY~ROCHLOROTHIAZIDE TABLETS
100mg 50mg PARTICIPANT #TRIAMTF,RENEHYDROCHLOROTHIAZIDE
1 53.~ 30.2 2 65~5 36.6 3 42.5 31.2 4 32.3 31.7 53-5 ~6.g 6 40.8 ~0.1 Mean 48.0 31.1 Std. Dev 11.8 3.2 C.V. 24.6 10.3 ~ Dose 48.0 62.2 These results indicate a mean level of bioavailability and absorption for triamterene for this tablet (48 mg from 100 mg) exceeding by some 25% what has been thought to be the limit in absorptive capacity of the gastrointestinal tract of about a mean of 39% from an administration of 100 mg, as reported in independent tests with differently formulated compositions: see Tannenbaum et al, Clinical Pharmacology and Therapeutic~, Vol. 5, ~o.
9, pp. 5g8-604 (1968).

~2~

Further this example illustrates the efectiveness of the present invention in a tablet with a ratio of triamterene: hydrochlorothiazide of 2:1 ~as also with the capsules in Tables I-A and II-Aj; however, for clinical reasons a ratio in the range of 1.75 to 1025:1 is more advantageously used.
It will al50 ~e seen from the oregoing tables that compositions formulated according to the present invention exhibit a high level of uniformity of response as evidenced by this relative low coefficient o~ variation (C.V~) figures (comparable ~o those shown by administering the same ingredients in suspension form~ Moreover, an adequate triamterene ~and hydrochlorothiazide) level is made available by administering a sin~le (e.g. 75/50) tablet, without need to resort to a multiple tablet prescription, and with the total admini~tered relative amount of triamterene being less than has been employed in the past.
Example 3 Other tests were performed to determine the triamterene do e response characteristics in hypertensive individuals who had become hypoXalemic (serum K+ 2.9-3.6 mEq/L) under treatment with hydrochlorothiazide, 50 mg/day. In an effort to determine the minimum amount of triamteren~ needed to reverse the hypokalemia precipitated by hydrochlorothiazide, each subject was continued on hydrochlorothiazide, S0 mg/day administered in a separate tablet, and was also given one of the following daily ;~ dosages of triamte~ene, admînistered in suspension form throughout the testing period: 0 mg, 25 mg, 50 mg, 75 mg, and 100 mg. The average serum potasgium reading in mEq/L
are chown in ~able IV, with each grouping of readings representing a given dosage level.

~2~3 Table IV
-Mean Serum K~ Mean Serum ~C~
De (m~ before~ ~ ~9**
100 3.58 3. sa lOû 3~22 3.77 100 3.15 3.78 100 3 s3 i 03 3 577 ~ 03 3.47 ~.17 lS 75 33.20 33 75 3.10 3.73 3.15 3.26 3.13 3.27 3.63 3.67 3.50 4.43 3.48 3 89 3.5~ 4.15 3.63 3.8 3 36 3.73 33'556 3 71 3.25 3.15 25: 3 50 ~ 3 51 3.60 3.71 0~(placebo) 3 67 3 75 J5 ~ 0 ~ 3.32 3-32 * Represents an average of 6 b~seline mea~urements taken : : over two weeks.
** Represents an average of 6 measurements taken over two weeks.

These data conflrm the effectiveness of optimally bioavailable triamterene for reversing hydrochlorothiazide-induced hypokalemia. The effectiveness waq particularly large in the upper ranges of the doses tegted. At a dosage level of about 75 mg triamterene (with S0 mg hydsochlorothi~zide), a near maximal response i5 seen.
By comparison of t~ese results with the data shown in Table I and I-A, it will be seen that the presently-marketed prior art composition fails to provide an adequate bioavailability of triamterene for the correction or reversal of a hypokalemic condition, in contrast to the levels provided by the compositions of the present invention.
Example 4 1'o further confirm the enhanced, optimal, bioavailability of the re~pective active ingredients of the compositions provided by this invention, tablets were formulated according to this invention containiny 75 ~g of triamterene and 50 mg of hydrochlorothiazide. Dissolution rate studies were then performed on these tablets using USP Paddle Method in 900 ml. of artificial gastric fluid without enzymes, pH 1~2, at 37C and at 50 RPM. This test is described under Dissolution, Method II o~ the 4th Supplement, United States Pharmacopeia XIXI National Formulary XIV, page 194, releasad January 31, 1978; such dissolution results have been utilized by the Food and Druy Administration for triamterene-hydrochlorothiazide combination products ~V.P. Shah, F.K. Prasad, J. Lin, G.
Knapp, and B. E. Cabana, Biophar~aceutics Laboratory, in a recent paper delivered at the ~ational Meeting of the American Pharmaceutical Association, Academy of Pharmaceutical Sciences Division, Nov. 14-18, 1982). The xesults of this test after 30 mlnute~ and 60 minutes are reported in Table V. For comparison, dissolution results obtained with the prior art presently marketed (50/25) ;

Z0~2;~
Capsule are also included in Table V. It will be noted that both the triamterene dissolution and the hydrochlorothiazide dissolution rates are very high for the product made by the present invention.

TABLE V ~ DISSOLUTION DATA* (%) Present Invention Prior Art ~Tablet) (Capsule) 30 min Hydrochlo- l'riam- Hydrochlo- Triam-rothia~ terene rothiazide terene 83.1 80.182.7 89.0 6.9 7.1 5.5 5;6 8~.3 79.187.0 79.7 3.9 7.2 3.9 5~4 100.7 ~g.990.9 89.5 4.1 9.0 ~.0 8.2 98.1 91 788.9 86.4 4.1 8.1 4.1 6.5 lQ0.6 78 893.1 87.7 3.7 ~.7 4.2 6.0 99.2 88,390.5 88.2 4.2 7.6 3.7 5.7 Mean89.5 87.8 6.1 5.3 Std. Dev. 8.5 3~6 2.0 1.2 : C.V.9.5 4.1 32.8 25.0 60 min 86.0 87.186.9 96.315.3 14.012.0 10.3 g0.7 87.392.1 87.313.0 14.810.1 10.:9 :~ 103.9 ~7. b94. 9 9~ . 912.7 17.310.5 11.8 : : 100.5 96.4 : 92.~91.3 L3.416.0 I2.~ 16.0 105 7 85 6:98.6 96.314.1 14.913.1 12.3 ~ :~ 100 4 91 6~1.4 92.7 13~.315.1 12.5 10~2 Mean94. 3 93.0 :14. 5 ll. 8 StdDev. 7.:2 3.6 1~3 1.7 C.V7.6 3.9 9.0 14.4 : * USP XX-Method II 50 rmp 900 ml:pH 1.2 Gastric Flui~ (0.1~ HCl) Without Enzymes ` ~ ~30 ; Thus, even though the~problem of fo~mulating hydrochlorothia~ide;and triamterene together in a solid ;:unit dosage form of enhanced bio-effectiveness has been recognized and is of longstanding,: the advance and `cont~ri~ution provided by the present invention has escaped dlscovery~y~skilled~workers in the field prior to the present invention.

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It will be appreciated, therefore, that the present invention provides a uni~ue method for manufacturing a non-toxic pharmaceutical combination composition which proviaes effective diuretic and antihypertensive properties while resisting or reversing undesired hydrochlorothiazide-induced hypokalemic action and minimizing the amount of triamterene which must be employed. A11 of thi~ i5 accomplished while producing bioavailability substantially equal to or even better than single entity dosage of hydrochlorothiazide, or of triamterene.
In administering such an embodi~ent of the present invention, a patient will typically be given the composition in daily dosages such that the total triamterene consumed per day need not be greater than the desired ceiling of about 150 milligrams per day. Daily dosages of triamterene will generally be about 37 to 150 milligrams.
While the foregoing examples have illustrated the practice of the invention with the preferred hydrochlorothiazide and triamterene ingredients, it will be understood that the same procedures may be followed with alternative ingredients. Thus, in place of triamterene, there may be used 2,4,7-~riamino-6-p-fluorophenylpteridine, 2,4,7 -triamino-6-p-trifluoromethyl-phenylpteridine, 2,4,7 -triamino-6-p-ethoxyphenylpteridine, 7 - dimethylamino -2,4-bismethyla~ino-6-phenylpteridine, 2,4,7 - triamino -6~thienylp~eridine, 2,4,7- triamino-6-o-methylphenylpteridine, 4,7-diamino-2-dimethylamino-6 a-phenylpteridine, 2,4,7-triamino-6-m-methoxy-phenylpteridine, 2,4,7-triamino-6-o-methylphenylpteridine. Metabolic products of triamterene and such other pteridine may also be employed, such as the hydroxy triamterne sulfuric acid ester. It will be understood th~t as used herein the phrase "a 4;;~

triamterene-active pteridine ingredient" refers to one or more of such components.
Further, in place of hydrochlorothiazide, there may instead be used chlorothiazide, benzydrc~flumethia~ide, trichloromethiazide, hydroflumethiazide, flumethiazide, methyclothiazide, chlorthalidone, or ~en~thiazide. It will be underRtood that as used herein the phrase "hydrochlorothiazide-active benzothiadiazide ingredient"
refers to one or more of these compounds~
More broadly, this invention also provides a general technique for the formulation of solid medicinal compositions containing at least two pharmaceutically active ingredients, at least one of which is relatively hydrophobic with respect to the other( 8 ), wherein the bioavailability of each of the active ingredients, when in the combination, is enhanced. That is, combinations of active ingredients other than as specifically mentioned above may also be employed, utilizing the same basic pEocedures, this invention having particular utility where one of such ingredients i8 relatively hydrophobic with respect to the other, but where a high level of bioavailability is desired for both. In general, in such compositions, the appropriate weight ratio of such pharmaceutically active ingredients will be chosen for maximal effectiveness of the respective active ingredients by straightforward clinical and laboratory tests, e.g. as described above, or other appropriate tests as will be selected by those skilled in the art.
Whereas particular embodiments of the invention have been described above for purposes of illustration, it will accordingly be evident to thoPe skilled in the art that numero~s variations of the details may be made without departing from the invention as defined in the following claims.

Claims (32)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method for enhancing the bioavailability of pharmaceutical combination compositions in solid unit dosage form and composed of at least two solid pharmaceutically-active ingredients of respectively different hydrophilic characteris-tics, at least one of which is sparingly soluble in physiological fluids, which method consists essentially in (1) separately providing each of said active ingre-dients in finely divided particulate solid form;
(2) separately mixing each of said finely divided active ingredients with respective non-toxic pharmaceutically-acceptable bioavailability-enhancing inert carrier materials, in finely divided particulate form, of the class including wicking agents, surfactants, lubricants, disintegrants, and at least one agent functionally capable of aiding in compacting operations (3) separately compacting said respective active ingredients with said respective carrier materials to form separate compactions thereof (4) thereafter separately comminuting said separate compactions to form respectively separate granules of said respective active ingredients each of such respective granules being composed of a large number of said respective individual finely divided active ingredient particles admixed with said finely divided particulate carrier materials (5) thereafter mechanically blending said respective granules together in desired optimum pharmaceuti-cally effective proportions to form a granularly heterogeneous blended combination and whereby said respective active ingredients particles are substantially retained within said respective granules whereafter said thus-blended composition is formulated into unit dosage entities.

2. A method according to claim 1 wherein said unit dosage entities are in capsule form containing said thus-blended composition.

3. A method according to claim 1 wherein said unit dosage entity is a solid tablet, containing in addition to said thus-blended composition a lubricant ingredient blended therewith to aid in the processing of the granules.

4. A method according to claim 3 wherein said tablet further contains a coloring additive.

5. A method according to claim 1 wherein said finely divided active ingredients will be such that at least 95% thereof will pass through a 100 mesh screen.

6. A method according to claim 1 wherein said granules have a size range from not more than 5% larger than 2 mm to not more than 20% being smaller than 0.075 mm.

7. A pharmaceutical combination composition having at least first and second pharmaceutically-active ingredients, at least one of which ingredients is sparingly soluble in an aqueous physiological fluid, and which ingredients are of respectively different hydrophobic or hydrophilic characteristics, and composed of a granularly heterogenous but substantially homogeneous blend of said ingredients said respective first and second ingredients being present in finely divided particulate form and having been first separately compacted and then separately comminuted into respectively separate granules, whereby one set of said respective granules contains substantially only said first active ingredient in admixture with a first set of non-toxic pharmac-eutically-acceptable bioavailability-enhancing inert carrier materials of the class including wicking agents, disintegrants, surfactants, lubricants and compacting aids, and a second set of said respective granules contains said second active ingredient in separate admixture with a second set of non-toxic pharmaceutically-acceptable inert carrier materials of the class including wicking agents, disintegrants, surfactants, lubricants and compacting aids, said respective first and second sets of carrier materials being respectively compatible with said first and second active ingredients and functionally capable of aiding disintegration of said respective granules and dissolution of said respective ingredient particles upon exposure of said granules to said physiological fluid, whereby said composition exhibits enhanced bioavailability of at least one of said ingredients, relative to the bioavailability thereof in a combination of homogenous granules containing both of said respective finely divided ingredient particles in intimate admixture with each other.

8. A composition according to claim 7 formulated in a capsule unit dosage.

9. A composition according to claim 7 formulated as a tablet, and containing a lubricant blended with said respective first and second sets of granules in said tablet.

10. A composition according to claim 7 wherein said finely-divided particulate form has a size range such that at least 95% will pass through a 100 mesh screen.

11. A composition according to claim 7 wherein said granules have a size range such that not more than 5% is larger than 2 mm, to not more than 20% being larger than 0.075 mm.

12. A solid antihypertensive diuretic medication composed of at least one hydrochlorothiazide-active thiazide ingredient and at least one triamterene-active pterdine ingredient which effectively inhibits and/or reverses benzothiadiazine-induced hypokalemia, and which consists essentially in a solid unit dose composition composed of, as active ingredients, finely-divided particles of said benzothiadiazine in-gredient which has been first separately admixed with at least one finely-divided pharmaceutically acceptable ingredient, and finely-divided particles of said pteridine ingredient, which had been first separately admixed with at least one finely-divided pharmaceutically-acceptable bioavailability-enhancing ingredient including a non-toxic pharmaceutically acceptable inert carrier materials of the class including wicking agents, surfactants, disintegrants, lubricants and compacting aids with said relatively hydrophobic pteridine ingredient particles being substantially isolated from direct content with said benzothiadiazide ingredient particles in said composition, and said composition exhibiting a sufficiently enhanced bioavailability of said pteridine ingredient, with respect to the bioavailability thereof in a solid composition having said finely divided active ingredients present in intimate admixture with each other, such that benzothiadiazide-induced hypokalemia is effectively resisted or reversed at dose levels of said benzothiadiazide ingredient effective for anti-hypertensive and diuretic control, said composition being in a form suitable for oral administra-tion to a patient.

13. A composition according to claim 12 wherein said unit dose composition is formulated as a capsule.

14. A composition according to claim 12 wherein said unit dose composition is formulated as a tablet, said tablet containing an additional lubricant blended in with said active ingredients in the formulation of said tablet.

15. A composition according to claim 12 wherein said respective finely-divided particles of each of said respective active ingredients is first separately blended together with said inert carrier materials, and separately compacted, after which they are respectively separately comminuted to form respective granules which are thereafter blended to form the combination composition.

16. A composition according to claim 12 wherein said benzothiadiazide ingredient is hydrochlorothiazide and said pteridine ingredient is triamterene at a weight ratio of triamterene to hydrochlorothiazide of from 1.25 to 1.75:1.

17. A composition according to claim 16 wherein said weight ratio is 1.5:1.

18. A method for forming a granularly-heterogenous composition having combined pharmaceutically-effective diuretic anti-hypokalemic and antihypertensive activity comprising the steps of mixing finely-divided particles of a triamterene active pteridine ingredient with at least one finely-divided pharmaceutically-acceptable inert ingredient to form a first mixture, and granulating said first mixture to form first granules composed of a homogeneous blend of the particles of said first mixture;

separately mixing finely-divided particles of a hydrochlorothiazide-active benzothiadiazide ingredient with at least one finely-divided pharmaceutically-acceptable bioavailability-enhancing inert ingredient to form a second mixture, and separately granulating said second mixture to form second granules composed of a homogeneous blend of the particles of said second mixture;
thereafter physically blending together said thus-formed first and second granules while substantially retaining the respective identities of said first and second granules, in respective amounts such that in the resulting blended composition the weight ratio of said pteridine ingredient to said benzothiadiazide ingredient provides an effective bioavailable amount of said pteridine to control the hypokalemic condition induced by the dosage amount of said benzothiadiazide.

19. A method according to claim 18 wherein said pteridine ingredient is triamterene and said benzothiadiazine ingredient is hydrochlorothiazide.

20. A method according to claim 19 wherein the triamterene:hydrochlorothiazide weight ratio is from 1.25 to 1.75:1.

21. A method according to claim 20 wherein said weight ratio is about 1.5:1.

22. A method according to claim 19 wherein said finely-divided triamterene particles have a size range such that at least 95% pass through a 200 mesh screen, and said finely divided hydrochlorothiazide particles have a size range such that at least 95% pass through a 100 mesh screen.

23. A method according to claim 22 wherein said granules have a size range from not more than 5% being larger than 2 mm to not more than 20% being smaller than 0.075 mm.

24. A method according to claim 23 wherein said granules have a size range such that not more than 5% have a dimension exceeding 1.5 mm.

25. A method according to claim 22 wherein said pharmaceutically-acceptable inert ingredients are of the class including wicking agents, disintergrants, surfactants, lubricants and compacting aids.

26. A method according to claim 25 wherein said wicking agent has a longitudinal dimension greater than would pass through a screen of about 200 mesh.

27. A granularly-heterogenous composition having combined pharmaceutically-effective antihypertensive, diuretic and antihypokalemic properties composed of (a) discrete, separately formed first granules contain-ing finely-divided particles of a triamterene active pteridine ingredient admixed with at least one finely-divided pharmaceutically-acceptable bioavailab-ility-enhancing inert ingredient, and (b) discrete, separately formed second granules con-taining finely-divided particles of a hydrochloro-thiazide active benzothiadiazine ingredient ad-mixed with at least one finely-divided pharmaceuti-cally-acceptable inert ingredient, with said first and second granules being admixed and blended together in amounts such that the resulting blended composition has a weight ratio of said pteridine ingredient to said benzothiadiazine ingredient provides an effective bioavailability of said pteridine to control the hypokalemic condition induced by the dosage amount of said benzothiadiazide.

28. A composition according to claim 27 wherein said finely-divided pharmaceutically inactive inert ingredients are of the class including wicking agents, disintegrants, surfactants, lubricants and compacting aids.

29. A composition according to claim 28 wherein said pteridine ingredient is triamterene and said benzothiadiazide ingredient is hydrochlorothiazide.

30. A composition according to claim 29 wherein said weight ratio is about 1.5:1.

31. A composition according to claim 27 formulated as a unit dosage capsule.

32. A composition according to claim 27 formulated as a unit dosage tablet, which includes at least one lubricant blended with said first and second granules.