Note: Descriptions are shown in the official language in which they were submitted.
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
:
- 1 -
,
'`' ' ' :
~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
. ~
.
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, $~
the antlhypertensive medication combination of
h~drochlorothlazl~e and trlamterene.
Hydrochlorothiazide is a kno~n single entity
pharmaceutical for administration to human patients in order to
provide diuretic and antihypertensive medicatlon and treatment~
In addition to producing ~eneflcial effects on hypertension, ~he
diuretic action ser~es to relieve edema caused by renal, cardla~,
hepa~i~ ineffect~veness or o~her cauge~.
~ . .
~ 3
:
~ERQ T~l E~ OPIE~ 495;~ 4-84: 3:c~P~ 435~3QS~;# ~
~/2~ 15: 24 P04
2~:~1~3
~ owever, one of the problems which arises when thus
administerlng single-entity hydrochlorothiazide is that thi~
medicatlon also tends to cause a loss of potassium from the
patient, which may be excessive, and which may thereby ~reate an
S undesired hypokalem$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
~.
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~; 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
. . .
_ 5 _
.
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$ng vr
reversing undesired hypokalemic side ef~ectsO
An additional object of th~s invention is to provide a
20 method for manuEacturing pharmaceutica1 compositions, and the
result~ng compc>~itions, having at least ~cwo activ~ ingredients,
at le~t one of which is spar~ngly soluble i n physlological
f~uids, and of ~igniicantly different hydrophobic and,~or
,
hydrophi1ic characteristlcs, wherein the resul'c~ng composition
25 exhibits enhanced bloava~labi1lty Of the medicat~on and o~
increa~ed uni~ormity of behavior in physiolo~ica1 absorE~tion.
A further s~lfia object of the present inv~ntlon i~ 'co
provide a me'chod of manu~actur~ng ~uch a ph~rm~ceuti~al
~,.
:
- 6-
composltlon, c3mpo~ed o~ hydrochlorQ~hiazide ~nd ~r~ter~n~, ~he
r~ultant pharmaceut~calO and 1~ ~e~ho~3 of u~, belng such th~t
the actlve lngredlent& of the composlt~on will be unlformly
Absorbed ~nd provide h~gh bio~vall~blli~:y whch 1 comparabl~~~o
s that provided by a single~en~ty hydrochlsro~hiaxide me~ic~tlon
or ~lngle ~nti~y trlsmterene.
It i~ yet anothQr o~ ect o thi~ ~nv~ntlon to provide
~uch a compo3it~0n and ~s~ociated method which wlll permit
~ re~l~tance to or reversal o hydrochlorothlazide-~nduced
hypokalemla whlle employing a mln~um amount of triamterene in
combination th~r ewi th .
In ~eneral, the prime ~peci~lc objective of khe
lnvention 13 to provide a compo~itlon employ$~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~ *
4Z3
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 '~'
Z3
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 ~$2e for
10 e~fectlve ph~rmacautlcal use.
Each of these two mixtures ls next separately compacted
or compressed for the purp~se of making granule~ c~ each
mixture. The separate compaction steps form compressed materiAl
compo~ites oE the respec~clve mixtures, fo~ ~nstance in large disk
lS or gheet form 8uch that the individual activa ingredient
particl~s are now ln lntimate physical, ~ubstantlally
homogeneous~ admixture wlth the above mentloned additlve ma'cerial
.
part~ C18E~.
Next, the compacted materials are separately subjected
20 to a comminutln~ operat~on to divlde the same înto a granulated
~orm, whereby the respective granules of each mixture will be
composed o~ the respective active ingredient and l:he above-
~ mentioned various additives, The granules thus-formed f rom the
: compactlvns shou~d have adequate structural lntegrity to cont,1nue
2S t:o exi~t a~ ~in~te entlties in the followlng operations.
In a preerred form o~ the practic~ of the present
invention, in ~eparate proce~sing of each o~ the two mixture3
they are pre~erably pa~ed through a ~itzmill, No. 00 ~c~een, and
~f te~ they have been separately compaated, they are comminuted to
~.
:
0~ rELECOPlER 4~5:c4- 4-8~ .3P~ 35~ 3~:~12
04,/24 1 5: ~4 P 1 2
form re~petive granule~ of th~ separate mixtures w~th the
granulated materials being pa3~ea through ~ ~itzmill No. 2 ~c,eQn
~or capsule~ ol: a F~t2anill No. ZA for ~abl~t~ ~the~ equl~m~nt
of comparable funct~on may of course be used for the~e purpo~es.
- 5 ~he thus formed gr~nules sho~lld have a ~ize range from
not more than 5% ~eing larger than 2 mm to not more than 20&
~ing ~mall~r than 0. 075 mm, preferably with not more th~n 5S
having a dimension exc~ding l.S mml especially when a capsule ~$
~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
~..,~,
- 12-
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
~ ~.
- 13 -
XEF~Ox TELE~-~PIER l~5;~4- 4-~14; 3:3~PM ; ~ 3~
84. 04/24 1~: 24 P14 ~
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
- 14 -
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,
~. ,.
- 16 -
>~ERO`, T_LEl_OPIER ~95:24-- 4--34; ~:4~PM ; ~ 2~3~D3~g~33 ~1~
23
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,
~,.
- 18 -
)~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~
~"
- 19 -
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` ,
,:
- 20-
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
1220423
.
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
- 22
:
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).
- 24 -
;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
26 -
:
.
~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).
- 27 -
~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.
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~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 30 3 76
100 3.15 3.78
100 3 s3 i 03
3 577 ~ 03
3.47 ~.17
3 53 3 48
3 58 4 28
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
3 15 3 566
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.
- 29 -
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)
- 30 -
;
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.
,
:
; ~
:::
'~
0423
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
- 32 -
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.
- 33 -
