Note: Descriptions are shown in the official language in which they were submitted.
WO 92/11038 PCr/US91J09463
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PoLyA~E ~RuG-R~lN CQ~PLEX~
TECHNICAL FIEL~
The present invention relates to oral pharmaceutical
preparations which comprise a pharmacologically-active polyamine
drug bound to a cation~exchange resin to provide a drug-resin
complex havlng a drug content greater than one equivalent of amine
per equivalent of cation-exchange capac1ty. The drug-resin complex
is optionally coated ~ith a water-permeable diffusion barrier
coat1ng that is insoluble in gastrointestinal fluids thereby
providing a controllable release of drug under conditions
encountered in the gastrointestinal tract.
BACKG~pUH~ OF T~E INVE~ U ON
Susta1ned or prolonged-release dosage forms provide a
controlled and constant supply of drug to an organism. The control
o~ cough, sleep, enuresls, and migraine headaches ire all benefits
obta1ned froR such ~ controlled release of a specific drug.
Add1t10nally, controlled release of antlm1croblals can be obtained
through such a dosage form. Such a controlled release of drugs
elimlnates the need to interrupt sleep to take medlcatlon, and can
also prevent missed doses. They also provlde the convenience of
dayt1~e doslng where the dosage form can be taken first thing in the
morning and prov1de therapéutic levels of thè drug throughout the
.., .. ~ . . . , . . -
. b controlled drug-release system delivers drug in a manner
that will ma1ntain therapeùtically effective plasma levels over a
~peri~d cf t1~e that i3 significantly longer than that~which is given
;by ~tjp1cal dug do~age form.
- Uncoated 10n-exchange res~n-drug complexes which delay release
of a drug 1n the gastro~ntestinal tract are described in U.S. Patent
No. ~,788,055 and 2,9gO,332. ~owever, such uncoated complexes
provide only a relatively short delay of drug release in comparlson
w~th the preparations of thls invention and provide poor control of
drug releasè be~ause the control is limited to variation ln particle
size and cruss-linkage of the sulfonic acid-type resln. used to
prepare the adsorption compounds.
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WO 92/11038 Pcl/US9lJog463
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Yar~ous coated resin-drug complexes have been reparted (e.g.
in U.S. Patent Yos. 3 138 525; 3 499 960; and ~ 594 470; Belgian
Patiqnt No. 729 827; German Patent Ho. 2 246 037; and ~orodkins et
al. ~ournal of Phanm~eutlç~l ~cience Yol. 60 pages 1523-1527
1971) but none are believed to employ the preparations of the
subject inventton or to provide the controllable release obtained
with the present preparations.
The present inventlon provides controlled-release
phar~cteut1cal co~positlons obtalned by complexlng greater than one
equiv~lent of a polyamine drug w~th a pharmaceutilcally acceptable
catlon-exchange resin and optlonally coat1ng such comp1exes with a
substance that will act as a barrler to control the dilffus10n of the
drug from 1ts core complex into the gistrolntestlnal fluids.
It ls kno~n that the pharmaceut1c~ acceptable reslns and
lS theilr drug conplexes can undergo s1gnlf1cant swell1ng (up to about a
6JX lncrease 1n volumei) when the dry non-hydrated form 1s placed in
contact i~lth gastrotntestlnal flulds.
~hen the coiated drug-resln complex ls suspended 1n an aqueous
dosage for~ or when lt contacts gastrolntestlnal flutds it expands
to its swollen state and in doing so ruptures the dlffusion
barrler coat~ng. The result is loss of 'control of the dlffusion of
released drug.
Controlled-release drugs for use in the gastrointestinal tract
are described in U.S.''P~tent Numbers 4 847 077 and 4 221 778 and
- ~ 25 Europ2an P~ent Applilcatton 254 8ll all to Raghunathan; and
European PatenS' Application' 254 822 to Chow et al. The method
descrtbed ther~1n for preparing'products'i'having controlled release
pro~rt1es involvod~'2'''three-step process: ~i) prëparation of a
drug-rei31n caaplQx; (ill)''treating` this complex with a suitable
~ tapr~gnatlng ~age`nt ' 'and ~(iilj"li'coa't`ing 'thé'`partlcles of treated
r T' ~' ~ 7 i l .' ?~
complex ~1th a water-pQrmeable d~ffusion barrter. 'European Patent
Appl1catton 249,9~9 to'''Sellai'sle et' al.~'descrtbes''three-component
' ' coated complexes conta1n~ng~a neutral polymeric btntder such 25
hyctroxyjropyicellulos~ 'A11 of thésie"'drug-res'in `complexes have the
d1sadvantage of requiring that the t~rug-resin complex be treated
. . . ;~ ~ , 3 5 i~ . .; ?; :~ t .~ f i ~ i
wlth an lmpregnattng agent or binder in"order'"to achieve the desired
J l ~ u (~ t~r~ j t~b,l 5` ~ t~
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control of release of drug when placed 1n contact wlth aqueous
flu~ds such as ~re found ln the gastrointestina7 tract.
Ccated drug-resin comple~es, which do not require any such
impregnat10n, and yet which do not undergo s~?elling sufficient to
rupture the diffusion barrier coating when placed in contact with an
aqueous veh1cle or with gastrointestinal fluids, are described in
European Patent Application Number 367,7~6, to Kelleher, W.J. et
al., published May 9, l990. This document ~s incorporated herein in
its entirety by reference.
IO The pri~ary concern in the design of controlled-release drug
delivery systems has been wlth delaying the re1ease or dissolution
of the act1ve drug und'er the cond~t10ns wh1'ch ex1st in the
gastro1ntestlnal tract.- Early evaluatlon of candldate delivery
syste~s are most often performed with the use of simulated gastric
~5 and intes~lnal fluids. Se~, USY _ ~XI ~ Thi~ _ United States
eh3J;:.ZQIIi~, Pp. 1788-1789 (1990), wh~ch is incorporated by
reference here1n. Having achieved a des~red in vitro release rate,
the second concern 1s ~1th the extent or co~pleteness of release or
d1ssolut10n, ~ithln a t1me frame that ls reasonably conslstent with
the trans1t t1~æ through the ent~re ali~entary canal.
A certaln. cate~ory of drugs presents d1fflcultles ~n th1s
latter respect when used with 10n-exchange resin-based controlled
.. release syste~s:. these are basic drugs ,with more than one amine
functlonal group, i.e. polyamine drugs. A 'tenet of ion-exchange
" 25 technology ls that the strength of the binding is increased as 'the
- number of::b1ndlng sites.;on a molecule is increased. A negative
- cons~quence of th1s strengthened binding ~is that-~ drug molecules
-, , bound- by.;t~o or more.s~es ,might be ,released ..too slowly or
tnco~pl6t~1y, und~r condit~ons~encauntered.l ~n ~the~.gastrointestinal
~?,...;-,30 :; tract; ~An ,,lllustratlve, example is,i~provided by .Amsel ç~ al.,
?i!n~ .~n~ phar~a~eut1calJl~sl~lQllgyi~Apr~ g8~ pages 2B-48, th~s document
`I ` t: ~ ;i'.i ~,be~ng,i~ncorporated,,hereln.by t.reference,,jwherein,,jthe results of a
~ i7m"~' phanmi~cok1net1cestudy3~of~ a(~l iquid .suspensioni.contalning ~Q~
`' -! `I ii ~ .i~ codelne areslnatel.part1cles and. ~nsQ3~ chlorpheni,r,amine resirate.
~:.i; .. 35 ~opart1cles~nwere. reported.~ .Codeine ;is~ a, monoamine (M~ ~299 and
equivalen't:~w~ight ~299);~.its~;.releasei~into,."50.lN~ HCl from coated
res1nate part kles was ~escribed as ~ being adequate.
:. ' . . ' . , , ' ,. ' ,' ' ' " ~ " ' ' '. ' . ' ' '
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Chlorpheniramine is a diamine (M~ 275 and equivalent weight 137.5);
its r~le~se tnto O.lN HCl was not adequate despite the fact that its
restnate p~rt1cles had no coating. In order to match the release
profile glven ln O.lH HCl by the coated codelne res1nate, the
relat1vely severe and nonphysiologic release med1um consisting of
0.4M KCl had to be employed. The inadequacy of the loading dose of
chlarpheniramine i5 borne out by the increased t1me taken to reach
pe2k plasma concentrat10ns: 5.9 hours for the resinate ver~uS 3.6
hours for the drug ad~1nistered in solut10n.
The ~ost obv10us ~a~ of achieving a 103d1ng dose is to
1ncorporat~ unbound polyJ~1ne drug into the dos~ge form. A negative
consequenoe of having thls unbound material is that the formulat10n
would suffer fro~ the disadvantage of having an unpleasant taste,
since many polya~ine drugs have a bitter, unpalatable taste.
It is another tenet of ion-exchange technology that bind1ng is
on an equlvalent-to-equlvalent basls, just as is the case for
ac1d-base resctions. A negat1ve consequence of this is that for a
b2s1c drug ~ith an equiv~lent we1ght of only 120 (e.g.,
phenira~ine), even drug loads wh k h approach lOOX of the binding
capac1ty of the restn ~111 fatl to meet the minlmu~ load needed to
insure the 1ntegrity of the opt10nal coat1ng of the present
invent10n ~ith non-impregnated complexes.
: : The: polyam1ne drug resin complexes, of the..instant invention
: overcome these del1very and t~ste masking problems.... ~ithout being.
25 : lim1ted by theory,. 1t is bel~eved that by bindtng..... more than one
: e~uivalent of a polyamine drug to a cation-exchange resin (i.e. in a
`~ ratio:of greater than one equivalent of amine .per.equivalent of
: : ca~on exch~nge capactty) it would be possible.to provide drug-resin
co0pl~x~s~ wh1ch prov~de. both.-an immed~at~ release of the drug
- present it~ e~cess of:sone equ1valsnt; and ra slo~er or ;sustained
;`~~: `'~ c~ releas`~ of?ithe re~a1nlng:drug..~.:.In other...~ords,.~eachipolyamine drug
`'J ~I molecule ~ould b~bound l~o the restn.substant1~11y~by only one of
`,,,I,IrS~ lt5 am1ne groups and would therefore occupy only one.blndlng site on '!
iS" " ~:f~ the-!resln.a ~hen.~coupled wlth an opt10nal..water-1nsoluble barrier
~ 3~'h~ dlffusion coat~ng,~such~coated:polyamine ~drug-resin~complexes would `:
J~ .' Ti~i provide add~tionalacontrol~over.the release profile.;~7 :.
.~3;if::if~ f~ -~
:
. . . . . . . . . . . .
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W 0 92/1]038 P ~ /US91~09463
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The polya~ine drug-resin complexes of the 4nstant invention,
when added to gastrolntestinal fluids will (i) rapidly release a
portlon of the polyamlne drug bound in excess of 1 equivlaent, ~ii)
release the remaining port10n of drug at a slower rate so as to
provide a sustalning dose, and (lii) release a total amount of drug
that is substantially in excess of the total ax unt released from a
resin complex which contains the same polyamine drug loaded at a
level of one equiYalent or less per equivalent of cat~on-e~change
capac1ty.
o It i5 therefore an object of the present 1nvent10n to provide a
polya~1ne drug-resin complex, containlng ~ polyamine drug load1ng
greater than one equivalent of am1ne per equivalent of
cat10n-exchange capacity, which provides a controllable release of
drug under conditlons encountered in the gastrointestinal tract.
It is a further ob~ect of the present invention to provide a
polya~lne drug-res1n complex, containing a polyamine drug loading
greater than one .equ~v~lent of a~lne per equivalent of
cat1Dn-exchange capactty, wh k h provides an immedlate release of the
poly~tne drug bound ln excess of one equivalent and a slower
release of the remaining po1yamine drug under conditlons encountered
in the gastrointestinal tract.
It ls another object of the present invention to provide a
polyamine drug-resin complex, containing a polyamine drug loading
greater~ :th~nn one~.equivalent of.! amine ~ per equlvalent of
cat10n-exchange capaclty and wh1ch.1s also optionally coated with a
' ' '; A' water-per~eable d1ffusion barrier coating that is insoluble in
. --. ; gastrointestin~l flu1ds, ~hioh provides a!controllable release of
drug ~nde~ cond~t~ons encountered in the gastrointes~inal tract.
: ; ~ It Isiyet~another object of-the present invention to provide a
polya~Sine drug-res1n complex which prov~des a taste-mask1ng benefit.
t~ 7 -~Thes~ and other objects of.this::invention.will become apparent
S c~.m..~n l~ght'-of-.the~follow~ng d~sclosure. ;.~ `n
'3i`~ JSUMMARY_OF THE IN~ENTI~N i~ r
,.~' ;''~ "n?"`.";i ,An oral pharmaceut1cal composition in unit dosage form compris-
3~5 ~ ;ing cat10n-excrange restn parti les ranging`"from.~about lO..to about
. 500 'mlcrons,~'said .part kles Jhaving .ia~phaS~macologicaily-active
polyam1ne~dru~ bound,thereto at~a capacity greater'~than I equivalent
,
WO 92/11038 PCI'/US91/09463
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of a~tne per e~ut~alent of catlon-exchange capacity, wherein said
co~po~lt1On prov1des controlled release of sa~d act1ve drug.
All percenta~es and ratios used herein are by welght and all
measure~Rnts are at 25C, unless otherwise ind1cated.
5: DESCRIPTIQ~LQF THE INVENI~Q~ -
As used herein, the term water-per~eible is used to ind~cate
that the fluids of the allmentary canal wlll per~eate or penetrate
the opt1Onal barrier coating film with or w1thout d1ssolvlng the
fil~ or parts of the film. Depending on the permeab~lity or
solub111ty of the chosen coat1ng (polyler or. polymer mlxture) a
llghter or heavier appl k at10n thereof ls requ1red so that the drug
does not le~ch out from the complex to an extent of m4re than 4% in
artlf~clal sal~va a~ 20-40C ln 2 minutes.
As used herein, the ter~ regul~rly shaped pArt1cles refe~ to
thosi~ part1cles whlch substant1ally confor~ to geo~etrlc shapes such
as spherlcal, elllpt1cal, cyl1ndrlcal and the llke. These shape~
are ordered accord1ng to establ1shed geo~etrtc pr1nc1pl s. For
exiaYple, regularly shaped.1On-exchange res1ns of th1s type are
exe~pl1f1ed by Dow XYS-40010.00 (supplled by Dow Chem1cal Company),
and to the drug-resln complexes fonmed by b1ndlng drugs to these
res1ns.
As used heretn,.the term irregularly shaped partlcles refers to
: .:those part1cles excluded from the above def1n1t1On,, such as those
partlcles!~1th ~0rphous shapes wlth increased surface areas due to
surface area channels or dlstort1Ons. For.. example, 1rregularly
. shaped 1On-exchange resins of thls type ars exempllfled by Amberlite
.~ ~ .IRP-69 (suppl1ed~by Roh~ and Haas),~- and to the drug-resin complexes
fon~ed by~b~nd1ng drugs to these resins. .
. ~nt~ J m AS- used ~ here~n, the.m tenm :?.meq 3.is an abbreviatlon for
. . ~.-~a7riu 3;0!;'i ' .mllllequ1.valent~s).
! mi !;U~.''.! i ~ The~drugs;th~t are su~able for use.;ln these preparations arebi~s1c, h~Y1ng ?t~rleast twoi.a~no or ~substttuted~-am1no moieties
ava11able for,~b1nd1ng. Examples of drugs useful ln the present
~ ;14~ 1nvent~onu ,~ncludc, ll bu~ are not .~ mtted l to, acetophena~ine,
.mii~Cri~i JJ3'~1 J a~1tr1ptyllnej-~n bromphen1ramine, ~ carb1noxa~1ne,!l1,chlor.cyclizlne,
it~ n^~; chlorph~ntramine,~chlorpro~azine, clonidinej~cycltzine, deslpramine,
; ~ .";t'ri j /'1~ { ~dexbrompheniramin~,:ædcxchl~rpheniram1ne~n~doxylamine, ergo~aDine,
.
. ,- ... . : . . . . .: : .
~`"O 92/11038 P~IUS91/09463
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7 ~ 2 ~ ~
fluph~n~zine, hydroxychloroqulne, hydroxy~ine, i~lpramine,
~ecl1z1ne, ~esoridazine, m2thd11azine, methysergide, pheniramine,
pyr11~1ne, tr1pelennamine, triprolidine, promazine, and quinidine,
and ~1xtures thereof.
5~he ion-exchange resins suitable for use in these preparations
are water-insolubte and consist of a pharmacologically inert organic
or inorganlc matrix containing covalently bound functional groups
that are ion~c or capable of being ionlzed under the appropriate
cond1t10ns of pH. The organic matrix may b~ synthetic (e.g.,
10poly~ers or copolymers of ~cryl1c actd, methacryltc acid, sulfonated
styrene, sulfonated divinylbenzene), or part1ally synthetlc (e.g.,
modif~ed cellulose and dextrans). The inorganic matrix can also be,
e.g., s11 ka gel mod1fied by the addit10n of lonic groups. The
covalently bound ionic groups may be strongly acidic (e.g., sulfonlc
15ac~d) or weakly acidic (e.g., carboxyllc ac1d). In general, those
types of cat10n-exchangers suitable for use in ion-exchangc
chro~tography and for such appl kat10ns as delon k ation of ~ater
are su1table for use iln these controlled release drug preparat1nns.
Such 10n-exchangers are described by H.F. ~alton ln ~Pr1nciples nf
20Ion Exchange~ (pp. 312-343) and ~Technlques and Applicatlons of lon-
Exchange Chro~atograph~a (pp. 344-361) 1n ChromatoqrilDhY, (E.
Heftmann, ediltor), Van Hostrand Reinhold Co~pany, New York (1975),
: v incorporated by reference herein. The cat10n-exchange resins useful
in the present 1nvent~on pre~erably have exchange capacities below
~a~out 6 meQ~gra~ and -more preferably below about 5.5 meq/gram.
- - Preferabl~, these c~t10n-exchange resins conta1n covalently bound
- ~ ~ lonlc groups ~h1ch are strongly-acidlc.
Th~ s~ze of the ion-exchange particles should preferably fall
wlthin thc rangs of about 40 microns~to 3bout 150 microns. Particle
~;s1z~s substantlally below the lower limit are d~fflcult to handle in
m~ all st~ps-o~ the processing. Par~icle sizes substantially above the
r~ ; upp~r llm1t;!~.9 " commerc1ally-available ion-exchanse resins having
~ `,a spher1cal shape and dla~eters~up to about 1000 microns, are gritty
"7j 1n;r,i~ ; in ~11qu~id,dosag~fon~s~and~haYeJa. gre~ter~ endency~to fracture ~hen
~ei7 subjected.to dry-ing-hydratiing cycles. 7 Mo~eover, dt.is believed that
i'` nJ the ~31ncreased,~distance ~that a d~splacing~liion must~travel in its
d~f~usion into these large particles, and the increased distance the
'
.
..
' : . . . ,.", ,, .,, j .,.. ,, .. ,.. ,,._, ,,_,,__,_~,, ! '
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WO 92/11038 PCl/US91/û9463
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displaced drug must travel in its diffusion out of these large
part1cles, cause a measurable but not readily controlled prolon-
gat1On of release even when the drug-resin complexes are uncoated.
Representative restns useful in this invention include
Amberlite IRP-69 (obtained from Rohm and Haas) and Dow XYS-40010.00
(obtained from The Dow Chemical Company). Both are sulfonated
polymers 'composed of 'polystyrene cross-linked with 8X of
divinylbenzene, with an ion-exchange capacity of about 4.5 to 5.5
meq/gra~ of dry resin (H+-form). Their essent1al difference is in
physical form. Amberlite IRP-69 consists of irregularly-shaped
part~cles with a size range of 47 microns to 149 microns, produced
by mill1ng the parent large-sized spheres of A~qberlite IRP-120. The
Dow XYS-40010.00 product consists of spherical particles wlth a size
range of 45 microns to 150 microns.
The bind1ng may be performed, for example, as a batch or
column process, as is known in the art. In most of the illustrative
examples described below, the drug-resin complexes are prepared by a
b~tch process. The drug-resin complex ehus formed is collected by
f~ltrat1On and ~ashed with ethanol and/or water to insure removal of
any un~ound drug. The complexes are usually air~dried in trays at
room temperature.
' Further control of the release of drugs from drug-resin
complexes has been achieved by the direct application of an optional
''' :"~''' diffus~on'barrier coating to -particles of~such complexes, provided
''' ' 25 that the drug content of the complexes is above a critical value.''''~ ~ '' -~Any coatlng procedure which provides a contiguous coating on each
partic1e of drug-resin complex without significant agglomeration of
particles ~a~ be 'used. In the illustratlve examples below, the
''coat1ng$ ~r~ appl~ed with a fluid-bed coatlng apparatus having the
~ i' 30 ''~urster conflgurat1On.~ 7; ~q,~
'' i'"'~ '~ `; ~The coating materials may' be any ofna~large number of natural
'f`~ or'synthetlc'film-~ormers used singly, in 'ad~txture'with each other~
and ln'adm1xture w'ithiplast~cizers, pigments and other substances to
` ''"? " ~2;altei the characterist~cs of,the coating. ~,ln general, the major
' ~ '''35`;- components~of,the~coat~ng should be`insoluble~in, and permeabie to.
ater.~ However,.e;it:i m~9ht~`be~;desirable!r~to~ ncorporate a
''~'water-soluble~ substance, 7such~-as imethyli^cellulose'. to alter the
: -
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W O 92/11038 ~c~r/US9l/09463
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per~eabtllty of the coat1ng, or to incorporate an acid-insoluble,
base-soluble substance to act as an enterlc coatlng. The coating
matnr1als may be applied as a suspenslon in an aque~ous fluid or as a
solutlon ln organlc solvents. Sultable examples of such coating
mater~ls are described by R.C. Rowe in Materials used in
Pharma~rçut1cal Formul~tion, (A.T. Florence, editor), Blackwell
Scient1fic Publications, Oxford, 1-36 ~l98~), incorporated by
reference here1n. Preferably the water-permeable d1ffusion barrier
is selected fro~ the group conststing of ethyl cetlulcse, methyl
1~ cellulose, and mixtures thereof.
The coated drug-restn ~art~cles prepared according to the
teachtngs of th1s 1nventton are suitable for suspe~nding in an
essentlally aqueous veh1cle with the only restricttons on its
co~pos1t10n be1ng (1) an absence of, or very low levels of ionic
15 ingredients, and (11) a li~itat10n o~ the concentrations of
~ater-~tsc1ble organ1c solvents, such as alcohol, to those levels
wh k h do not cause d1ssolution of the d1ffus10n barr1er coating.
These coated drug-resln part1cles are also su1table for placing into
c~psules as ~ solld dosage form.
~L~Y;D~2Q
Motsture deter~1nat10ns were perfor~ed ~1th a Mettler LPl6
lnfrared he~ter on a PEl60 balance. Because of the variat10n tn
; . .mo1sture content over re?at1vely short. t1~e per10ds, moisture
. deter~1nat10ns ~ere always perforred tmmed1ately prlor to the use of
.any res1n or drug-resin complex, and correct10ns were made in
..quant1t~es taken sc that all values are expressed on a dry weight
bas1s.
.. I~ned1ately after preparation, all drug-resin complexes were
. ~. - . ; .; ~.. . w~sh~- w~th an .~approprlate solvent to ~tnsure removal of unbound
30. . drug, ~hon the salt; forms of drugs were used in the binding
, .m1xtur~, ~ater was.used~to wash tne complex. ~hen the free base
.. . . forms of the drugs werFf ~ us~ed ln the blndlng m~xture, ethanol was
used to wash the complex. W?shtng ~as contlnued 1n a batch or
percolat10n mod~ unt11 the ~ashings were shown by spectrophotometric
,35 neasurements to be essen~tally free of drug.
All complexes were .analyzed for drug content by adding ~n
accurately wetghed sample tabout 500 mg~ to a 200 mL volu~etric
,
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WO 92/11038 PCr/US91/09~
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flack contalnlng 100 mL of 0.5 H sodium acetate in 90X ethanol and
he~t1ng the ~lxture at reflux for one hour. The mix~ure was allowed
to c wl to roo~ temperature and ~as diluted to 200 mL with ethanol.
An al1quot was removed fro~ the clear supernatant after settl1ng or
centr~fugat1On. After approprlate dllutlon, the drug content of the
susernatant w~s determined spectrophotometrlcally. Drug content of
the complex was expressed as weight percentage based on the free
base for~ of the drug, unless other~1se ind k ated.
Deter~1nat~ons of release of drug fro~ drug-resin cDmplexes
were perfQr~ed w1th equ1pment that confor~s to the USP D~ssolution
Apparatus 2. In all instances, a two-bladed paddle rotatlng at 50
rp~ was used. The rele~se mæd~um was either 900 mL of 0.1 N HCl or
0.1 H HCl converted in ~ to 0.07 M sodlu~ phosphate buffer (pH
~.2), by adtlng 2q.8 9 of trisodiu~ phosphate dodecahydnate to 900
mL of O.l N HCl. Release medl~ ~ere ma1nta1ned at 37C. Sufflcient
drug-restn complexes were added to proY1de the following doses
(expressed as the commonly ad~1ntstered forms): doxylaminq
succ1nate, 15 mg; chlorphenira~1ne maleate, 16 mg; and pheniramine
maleate, 25 ~9. The drug-resin complexes were added to the release
med1~ ~s dry powders. At appropriate tlme lntervals, samples of
- approxl~ately lO mL were removed from the dlssolutlan beaker and
lmmed1ately f11tered through a syr1nge-mounted fllter. Exactly 5.0
mL of the f11trate was reserved for analysis. The remainder of the
flltr~te was returned to the d~ssolutlon beaker. Partlcles of drug-
resin ''co0plex adher1ng to the f11ter were rinsed into the
d~s'solutton beaker ~1th exactly 5.~ mL of fresh release medium. The
absorbances of the flltered samples were measured 'at the wavelength
of the pe~k 1n the ultraviolet spectrum w~th a Perkin-Elmer model
' 552 oP 'Lu~bd~'3B UV/VIS spectrophotometer. The absorbance values
'' 30 wero convèrted to' percentiges of added'drug that''were released.
'' Alternat1vciy,' the saimpies ~ere analyzed by HPLC on a reverse phase
' phznyl column uslng methànol:water:acet1c ?c1d (60:40:2 by volume,
' wlth 5 mM sod1um'hexane' sulfonate) 'with 'a ~aters'model 6000A pump
` ' 'in'd à mod~i 450 vartabie ~velength detector set at the ~avelength
- 35 of peak ab'ssrpt1On for the'~'~drug. l Peak'areas w'ere converted to
' ''' '' pë~rcentage'of drug released. J 0 `' ` i ~ ` `
. ~
WO 92/11038 P~/US91/09463
2~2~
D1~fusion barrier coatings were applied with a Glatt CPCG-5
urstor-type fluid-bed coater. The following T~ere the conditions
used 1n a typlcal coatlng procedure: inlet a1r temperilture, 70C;
ato~TIzat1on a1r pressure, 60 psi; spray rate, 20-25 g/~in; outlet
air temperature, 40-50C. M1croscopic examination of the coated
part1cles was performed with a trans~ission and stereo light
microseope.
The level of coat1ny contained on the coated drug-resin complex
~as determined by stripp~ng the coat1ng ~1th an appropriate solvent,
evaporat1ng the solvent, and wetghTng the dried residue. An
accurately weighed sample of coated drug-resin complex of about 2.0
g was placed in a 30-mL glass centr1fuge tube. Twenty mL of ethanol
was added and the mixture ~rTas st1rred ocoas1o?nally over a perlod of
a~out 30 minutes. The mixture was centrifuged and the supernatant
lS was decanted into 3 round botto~ flask. The extraction,
centrlfugat10n and deeantlng were repeated three more times. The
comblned ethanollc extracts ~tere concentr~ted to dryness in a rotary
vacuu~ evaporator. The flask cont~1n1ng the dr1ed resldue was
r1nsed ~our tTmes~ each wlth several mL of methylene
chlortde/acetone (9:l v/v). The rlnslngs were transferred to a
tared alu~1nu~ pan and allowe?d to evapori~te 1n a hood. The pan was
heate?d at 55C for 30 m1nutes, allo~ed to cool, and weighed. The
increase over the tare weight.was attributed to the ethylcellulose
~ coat1ng. The values obtained agr~ed very well ~Tith the amount of
coat1ng appl1ed 1n the fluid-bed co~ter.
The follo~ing examples illustrate embod1ments of the subject
- invent~on where1n both essential, and opt10nal ingredients are
-~cG~b~ned.
~ ' ' ' ''; ' ' ' . . ' .
~ ;,5 t;~i~ ?ift ~ o,~? ~
, . . . ~
.. .,. - . .. . . . . ~ . . - . . .
Wo 92/11038 PCr/US91/094~
2~9~2~
-12-
~L~
This example illustrates a drug resin complex comprising
doxyla~1ne bound to an Amberlite IRP-69 resin. This drug-resin
complex contains 1.92 equivalents of doxy1amine per equivalent of
cation-exchange capacity. The release profile for this drug-resin
complex in simulated gastric fluid is compared to that for a
doxylamine complex containing less than 1 equivalent of drug per
equivalent of cation-exchange capacity.
(A). Preparation of a doxylamine-Amberllte IRP-69 complex
having 1.92 e~uivalents of doxylamine per equivalent or
cation-exchange capacity.
Amberlite IRP-69 (~-form~ 3.556 g
Doxylamine (Free Base) 5.000 9
The resin ls added to a round bottom flask which is fltted
with a condenser and which contains 50 mL of ~ater pre-warmed to
100C. The doxylam1ne (free base) is added and the mixture is hPld
at 100C with ~1xing~for 2 hours. rhe mixture is suctisn filtered
and the retained drug-resin cake is ~ashed wlth ethanol until the
wash1ngs have a negllgible absorbance at 261 nm. The drug-resin
comp~ex wh1ch has now been washed free of unbound drug ~s dried at
rnom temper~ture. Analysis shows that the complex contains 57.0% by
weight of doxylamine.
'(B). 'Preparation of a doxylamine-Amberlite IRP-69 complex
' havin'g' '0.976' eauivalents 'of'i doxylamine' per equiYalent oF
'25 cation-exehange cap~city.'
~ ATberlite IRP-69 (H+-form) 2.500 g
'' -~::- ''' '''''''-':;` Dox~lamine succinate -2.4~6 9
The res1n 1s added to a round bottom flask con~aining 20 mL of
wat~r pre-~nK~d to 60C. The doxylamine succinate is added and
thQ 1xture is held ~t 60C with mixing for 2 hours. The mixture is
suctton f11ter2d and the retained drug-resin cake is washed with
wat~r until the w~shings have a negligible absorbance at 261 nm.
The drug-resin compl~x which has now been washed free of unbound
drug is dried at room temperature. Analysis shows that the complex
contains 40.2%'by weight of doxylamine.
(C). The complexes from (A) and (~) of this example are found
to give the follow1ng release prof;les for doxylamine when placed in
,
.. . .. .. .. . . . . . .
~) 92/11038 PCI'/US91/094ti3
2~9~2~
-13-
0.1 H HCl (s1mulilted gastric f1uid). The release of doxylamine from
co~pl~x (A) ts substantially greater than from complex (B).
% Doxylamine Released in 0.1 H HCl
T~me (min~tesl Com~lex (A) ComDlex (81
68 41
69 43
6~ 68 ~S
120 68 48
180 68 49
1 5 : :
,' ' .
: ;` .
: . . i ; - ,.
~.,. . . . ", i . :~
: i: 30 ~ ; 3i3 ~ ~ ;i i ` ^i
: ,
.
WO 92/11038 PCI/US91/09463
2~932`~ -14-
EX~MPLE II
Th1s exa~pl~ illustrates a drug-resin complex comprising
phen1ra~ine bound to an Amberl~te IRP-69 resin. Thls drug-resin
complex contains 1.93 equivalents of pheniramine per equivalent of
cation-exchange capacity. The release profile for th1s drug-resin
complex in simulated gastric fluid is compared to that for a
pheniramine complex containing less than 1 equivalent of drug per
equivalent of cation-exchange capacity.
(A). Preparat~on of a phen1ra~ine-~mberl1te IRP-69 c~mplex
having I.93 equ1valents of phen1ra~1ne per equivalent of
catton-exchange capacity.
Amberl1te I~P-69 (H~-form) 0.500 9
Pheniramine (Free Base) 0.632 9
The resin ~s added to a round bottom flask, whlch is fitted
w~th ~ condenser, and which contains 25 mL of water, pre-warmed ta
100C. The pheniram1ne (free base) is added and the mixture is held
at 100C with mix1ng for 3 hours. The m~xture 1s suct10n flltered
and the rEta~ned drug-res1n cake is washed with ethanol until the
wash~ngs have a negl~gible absorbance at 260 nm. The drug-resin
complex, wh1ch has now been washed free of unbound drug, is dried at
room temperature. Analysis shows that the complex contains 54.2% by
weight of phenira~lne.
(B). Prep~rat1On of a pheniramine-Amberl1te IRP-69 complex
having 0.91 equlvalents of pheniramine per equivalent of
cat1On-exchange eapacity.
Amberlt~e IRP-69 (H+-form) I.000 9
Phen1ramine ~aleate 0.927 9
~he res1n ls ~dded to a round bottom flask con~ain1ng I0 mL of
wator, pre-war~ed to 60C. The pheniramlne maleate is added and the
mixture ~s held at 60C with mixing for 3 hours. The mixture is
suctlon ~11tered and the retained drug-res1n cake is washed with
w~ter unt11 tho w~sh1ngs h~ve a negl191ble absorbance at 260 nm.
The drug-res1n complex, which has now been washed free of unbound
drug, is dr~ed at room temperature. Anatysis shows that ~he complex
conta1ns 35.g% by weight of phenirl~ine,
.: . ., , .
~'~ 92/11038 PC~r/US~1/09463
("-1 2~9~2~
- 1 5 - ~ '
(C). The complexes from ~A) and (B) of th1s example are found
to give the following release profiles for pheniramine when placed
in O.l H HC1 (simulated gastric fluid). The release of pheniramine
fro~ eo~plex (A) is substantially greater than from complex ~B).
% Pheniramine Released in 0.1 N HCl
Time (minutes! ComQLex iA~ ComDlex (~
69 35
- 30 69 37
39
120 70 41
1~30 72 41
....
: 25
;, . `- .:.. : . . - .
.. , ,: . .. . . . ... ..
' ! , ' . 30 '
' ' r~
' .::
:........ .. :.
. . : , , , ,, . ' :'' ' ' :'~'', .' ' ' ,: . . ' , . : .
WO 92tl1038 PCI/US91J09463
~g~
-16- . . .
EXAMPL~lI I , '
This examp1e illustrates a drug-resin complex comprising
chlorpheniramine bound to an Amberlite IRP-69 resin and the effect
of subsequent1y coating the resin ~ith a diffuslon barrier coating.
These drug-resin complexes (both uncoated and coated) contain 1.72
equivalents of chlorpheniramine per equivalent of cation-exchange
capacity. The release profiles for these drug-resin complexes in
simulated gastric fluid are compared to those for chlorpheniramine
complexes (both uncoated and coated) containing less than
equi~alent of drug per equiv~lent of cat1On-exchange capacity.
(A)~ Preparat1On of a chlorphenira~ine-Amberlite IRP-69
complex having 1.72 equivalents of chlorphen~ramine per equivalent
of cation-exchange capacity.
Amberlite IRP-69 Resin (H+-form) 1250 9
Chlorphenlramine (Free Base) 1759 9
The resin is added to a 70 L round bottom flask containing 15 L
of water pre-~armed to 70C. The chlorpheniramine (free base) is
added and the temp~rature is increased to 85C and the mixture is
stirred for one hour. The contents of the flask are transferred to
a 20 L polyethylene bucket and allowed to stand at room temperature
u~til most of the complex has settled. The supernatant liquid
containing suspended fine particles is decanted and discarded. The
sedimented complex is slurried with 2.5 L of ethanol, and the slurry
is suction filtered. The drug-resin cake retained on the filter is
washed with 5 L of ethanol. The washed drug-resin cake is slurriea
with 3 L of ethanol, and the slurry is suction filtered. The
drug-resin cake retained on the filter is washed with 4.5 L of
etha~ol. The f~nal ~ash~ng is found to have a negligible absorbance
at 264 n~. The washed drug-resin cake ls spread out to dry at room
S~mper~ture. Analysls shows that the complex contains 54.7% by
weight of chlorphenlramine.
(B). Coat~ng of the chlorpheniramine Amberlite IRP-69
com~lex from (A) above.
: ; Chlorpheniramine-Amberl~te IRP 69 Complex 1000 9
Ethyl Cellulosej N-10 100 9
Ethyl Acetate 1900 9
- -
: ~ . : .. . .. .. ... : :
WO 92/11038 P~/US91/09463
f' ~
I j -17- ~9~2~Q
The ethyl cellulose is dissolved in the ethyl acetate with
st1rrlng. The resin complex is placed in a pre-warmed fluid-bed
coat1ng apparatus and fluidized with 70C intake air. The coating
solution is applied at a rate of 20-25 g/minute until 2000 9 has
been applied. Fluidization is continued with the heated air for 2
minutes after the termination of the appli at1On of the coating
solution.
(C). Preparation of a chlorpheniramine-Amberlite IRP-69
complex having 0.92 equivalents of chlorpheniramine per equivalent
I0 of cation-exchange capactty.
Amberlite IRP-69 Resin (H~-form) 1500 9
Chlorpheniramine Maleate I495 9
The resin is added to a 70 L round botto~ flask containing I5 L
o~ water pre-wanmed to 60C. The chlorpheniramine maleate is added
and the mixture is st1rred for one hour at 60C. The contents of
the flask are transferred eO a 20 L polyethylene bucket and allowed
to stand at room temperature until most of the complex has settled.
The supernatant liqùid containing suspended fine particles is
decanted and d1scirded. The sedtmented complex is slurrted with 3.0
L of water, and the slurry is suction f~ltered. The drug-resin cake
retained on the ftlter ls washed with water (3 X I L). The washed
drug-resin cake is further washed with 5 L of ethanol. The final
wash1ng is found to have a negligible absorbance at 264 nm. The
washed drug-res1n cake ls spread out to dry at room temperature.
Analys1s shows that the complex contains 3g.2% by weight of
chlorpheniram1ne.
~ D). Coating R the chlorpheniramine-Amberlite IRP-69
oompl~x fro~ (C) above.
Chlorpheniramine-Amberl1te IRP-63 Complex I000 9
Ethyl Cellulose, N-10 - I00 9
Ethyl Acetate I900 9
The ethyl cellulose is dissolved in the ethyl acetate with
stlrrlng. The restn complex is placed tn a pre-warmed flu~d-bed
coat1ng apparatus and flutdtzed with 70C intake air. The coating
solution ~s arplted at a rate of 20-25 g/minute until 2000 9 has
been applted. Fluidlzat~on is continued with the heated air for 2
:':
.,
-'.:,'
.
..... . . . ~ , .. ..
~ . , . , . ,. ., , -, , , , . ~ .: , :
WO 92/1~038 PCIIUS91/09463
(,....
2 ~ ?
minutes after the ter~?inat~on of the appl1cation of the coating
solut1on.
(E~. The complexes from (A), (B), (C), and (D~ of this
exa3y?1e are found to give the following release prof11es for
chlorphen~?ram~ne when placed in O.l N HCl (s1mulated gastric fluid).
The release of chlorphenira~ine from uncoated complex (A) is
substantially greater than from uncoated complex (C). Moreover, the
uncoated complex from (A~ can be successfully coated with a
diffusion barrier coattng to provide a sustatned release of drug as
exemp~1f1ed by the coated complex from (B).
%Chlorpheniramine Released in O.l N HCl
Complex (A~ Complex (B) Complex (C) Complex (D)
T~m~ (min.L(Uncoi~ed! !~odt~dl ~Unc~at~?~ (CQ~t~)
58 15 19 5 . `
61 23 24 9
63 32 26 14
l20 63 38 28 18
180 62 41 29 2l
240 62 43 30 23
360 63 46 31 25
2 5
-
, .
~, - . .
.. .
i ;. ~ - , ~ ' . . .. .
, ..
,.,;, .,,., . , ; f . , .
; 35 ,; ., jj ,7j ~
,, ~,_ . ' ' '' ;
'
,'
'
" . "
'
. ': . .
WO 92/11038 PCI~/US91/09463
` 2~2~
-19- . ...
FXAMPLE IY
Th',s example illustrates the preparation of a
chlorpheniramine-Dow XYS Resin complex and the determ,nation of its
seauent1al release of chlorpheniramine into simulated gastric fluid
and pH 7.2 buffer.
A. Preparation of a chlorpheniramine-Dow XYS Resin
complex having 1.56 equivalents of chlorpheniramine per equivalent
of cation-exchange capacity.
DOW XYS 400l0.00 Resin (H~-forr) 5.000 9
Chlorpheniramine (Free Base) 7.227 9
The resin is added to a round botto~ flask, which is fitted
with a condenser, and which contains 50 mL of water pre-warr,ed to
100C. The chlorpheniramine (free base) is added and the mixture is
held at l00C with mixing for 2 hours. The mixture is suction
filtered and the retained drug-resin cake is washed with ethanol
unt',l the washings have a negligible absorbance at 264 nm. The
drug-res1n complex, whlch has now been washed free af unbound ,-,rug,
is dried at room temperature. Analysis shows that the complex
contains 53.0X by we',ght of chlorpheniramine.
(B). The complex from (A) is found to giYe the following release
profile for chlorpheniramine. The release is deter~,ined in O.l N
HCl (simulated gastr;,c fluid) for 60 minutes and then in pH 7.2
phosphate buffer for an additional 60 minutes. The release .Ot
chlorpheniramine into the simulated gastric fluid during the first
60 minutes is similar to the release observed for the drug resi~
complexes descrlbed in Examples I (A), II (A), and IlI (A). The
cha,nge to the pH 7.2 buffer gives a total release of the remaining
bou~d chlorphen~ramine.
3~
.
, ,.
.
-
W O 92/11038 PC~r/US91/09463
2~$2~ -20- ~ ;
X Chlorpheniramin~ Released
Time _L~in~tes~ ComD?ex (A)
(0.1 N HCl)
68
6q 72
(pH 7.2 phosphate buffer)
98
1~ 120 103
.
~HAT IS CLAIMED IS: :
1 5
. . :
.
. 25
.. ..
. .
' ' : '
~ ~l5
.
~ . .'.
:
:
