CA2098200A1 - Polyamine drug-resin complexes - Google Patents
Polyamine drug-resin complexesInfo
- Publication number
- CA2098200A1 CA2098200A1 CA002098200A CA2098200A CA2098200A1 CA 2098200 A1 CA2098200 A1 CA 2098200A1 CA 002098200 A CA002098200 A CA 002098200A CA 2098200 A CA2098200 A CA 2098200A CA 2098200 A1 CA2098200 A1 CA 2098200A1
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- drug
- pharmaceutical composition
- composition according
- cation
- exchange resin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Disclosed are oral pharmaceutical preparations which comprise a pharmacologically-active polyamine drug bound to a cation-exchange resin to provide a drug-resin complex having a drug content greater than one equivalent of amine per equivalent of cation-exchange capacity. The drug-resin complex is optionally coated with a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids thereby providing a controllable release of drug under conditions encountered in the gastrointestinal tract.
Description
WO 92/11038 PCr/US91J09463 f ~ 2 ~ ~9 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 ~ V ~
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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.
:
WO 92/11038 Pcl/US9lJog463 ~ V ~
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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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WO 92/11038 PCl/US91/09463 ~' ' ` 2~9~2~ , 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.
:. ' . . ' . , , ' ,. ' ,' ' ' " ~ " ' ' '. ' . ' ' ' WO 92~1 1038 PCI'/U!~91/09463 2~9~2~
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 :.
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W 0 92/1]038 P ~ /US91~09463 ..- , 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 æi~9~ao ~! ' 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 .
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 ' .
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WO 92/11038 PCl/US91/û9463 ~2~9~2~
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 : -,: - . .. .. ~
W O 92/11038 ~c~r/US9l/09463 2 0 ~
g 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.
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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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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 ~ ` `
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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.
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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~
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 6~ 68 ~S
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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 (~
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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' ~
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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 :':
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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 . `
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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.
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X Chlorpheniramin~ Released Time _L~in~tes~ ComD?ex (A) (0.1 N HCl) 6q 72 (pH 7.2 phosphate buffer) 1~ 120 103 .
~HAT IS CLAIMED IS: :
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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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WO 92/11038 PCl/US91/09463 ~' ' ` 2~9~2~ , 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 :.
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W 0 92/1]038 P ~ /US91~09463 ..- , 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 æi~9~ao ~! ' 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 .
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 ' .
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WO 92/11038 PCl/US91/û9463 ~2~9~2~
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 : -,: - . .. .. ~
W O 92/11038 ~c~r/US9l/09463 2 0 ~
g 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.
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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~
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 6~ 68 ~S
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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 (~
1~30 72 41 ....
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WO 92tl1038 PCI/US91J09463 ~g~
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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 . `
l20 63 38 28 18 180 62 41 29 2l -, .
~, - . .
.. .
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) 6q 72 (pH 7.2 phosphate buffer) 1~ 120 103 .
~HAT IS CLAIMED IS: :
. . :
.
. 25 .. ..
. .
' ' : ' ~ ~l5 .
~ . .'.
:
:
Claims (20)
1. An oral pharmaceutical composition in unit dosage form compris-ing cation-exchange resin particles ranging from about 10 to about 500 microns, said particles having a pharmacologi-cally-active polyamine drug bound thereto at a capacity greater than 1 equivalent of amine per equivalent of cation-exchange capacity, wherein said composition provides controlled release of said active drug.
2. A pharmaceutical composition according to Claim 1 wherein said particles range from about 35 microns to about 150 microns.
3. A pharmaceutical composition according to Claim 2 wherein said particles range from about 40 microns to about 80 microns.
4. A pharmaceutical composition according to Claim 3 wherein said drug-resin complex further comprises, from about 1.5% to about 25% by weight of the drug-resin complex, of a water-permeable diffusion barrier coating.
5. A pharmaceutical composition according to Claim 4 wherein said water-permeable diffusion barrier coating is selected from the group consisting of ethyl cellulose, methyl cellulose and mixtures thereof.
6. A pharmaceutical composition according to Claim 5 wherein said pharmacologically-active polyamine drug is selected from the group consisting of acetophenazine, amitriptyline, brompheniramine, carbinoxamine, chlorcyclizine, chlorpheniramine, chlorpromazine, clonidine, cyclizine, desipramine, dexbrompheniramine, dexchlorpheniramine, doxylamine, ergotamine, fluphenazine, hydroxychloroquine, hydroxyzine, imipramine, meclizine, mesoridazine, methdilazine, methysergide, pheniramine, pyrilamine, tripelennamine, triprolidine, promazine, and quinidine, and mixtures thereof.
7. A pharmaceutical composition according to Claim 6 wherein said resin particles have an ion-exchange capacity of less than about 6 meq/gram.
8. A pharmaceutical composition according to Claim 7 wherein said pharmacologically-active polyamine drug is selected from chlorpheniramine, doxylamine, and pheniramine.
9. A pharmaceutical composition according to Claim 8 wherein said pharmacologically-active polyamine drug is chlorpheniramine.
10. A pharmaceutical composition according to Claim 9 wherein said resin has bound thereto between about 1.5 equivalents and about 1.7 equivalents of chlorpheniramine per equivalent of cation-exchange capacity.
11. An oral pharmaceutical composition according to Claim 1 wherein said cation-exchange resin further comprises irregularly shaped particles.
12. An oral pharmaceutical composition according to Claim 4 wherein said cation-exchange resin further comprises irregularly shaped particles.
13. An oral pharmaceutical composition according to Claim 6 wherein said cation-exchange resin further comprises irregularly shaped particles.
14. An oral pharmaceutical composition according to Claim 9 wherein said cation-exchange resin further comprises irregularly shaped particles.
15. An oral pharmaceutical composition according to Claim 10 wherein said cation-exchange resin further comprises irregularly shaped particles.
16. An oral pharmaceutical composition according to Claim 1 wherein said cation-exchange resin further comprises regularly shaped particles.
17. An oral pharmaceutical composition according to Claim 4 wherein said cation-exchange resin further comprises regularly shaped particles.
18. An oral pharmaceutical composition according to Claim 6 wherein said cation-exchange resin further comprises regularly shaped particles.
19. An oral pharmaceutical composition according to Claim 9 wherein said cation-exchange resin further comprises regularly shaped particles.
20. An oral pharmaceutical composition according to Claim 10 wherein said cation-exchange resin further comprises regularly shaped particles.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63229090A | 1990-12-21 | 1990-12-21 | |
| US632,290 | 1990-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2098200A1 true CA2098200A1 (en) | 1992-06-21 |
Family
ID=24534913
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002098200A Abandoned CA2098200A1 (en) | 1990-12-21 | 1991-12-16 | Polyamine drug-resin complexes |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0563294A1 (en) |
| JP (1) | JPH06504059A (en) |
| CN (1) | CN1063221A (en) |
| AU (1) | AU663695B2 (en) |
| BR (1) | BR9107173A (en) |
| CA (1) | CA2098200A1 (en) |
| CZ (1) | CZ119793A3 (en) |
| FI (1) | FI932842A0 (en) |
| HU (1) | HUT74642A (en) |
| IE (1) | IE914513A1 (en) |
| MX (1) | MX9102753A (en) |
| MY (1) | MY107811A (en) |
| NO (1) | NO932212L (en) |
| NZ (1) | NZ241097A (en) |
| PT (1) | PT99912A (en) |
| SK (1) | SK59493A3 (en) |
| WO (1) | WO1992011038A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995005161A1 (en) * | 1993-08-13 | 1995-02-23 | Vitaphore Corporation | Hydrogel-based microsphere drug delivery systems |
| JP4619457B2 (en) * | 1993-11-18 | 2011-01-26 | シルテックス、メディカル、リミテッド | Sustained release formulation |
| ES2097087B1 (en) * | 1994-08-01 | 1997-12-16 | Univ Sevilla | CONTROLLED RELEASE SYSTEM FOR MORPHINE AND OTHER PHARMACLES SOLUBLE IN WATER BY COMPLEXING WITH POLYMERIC SUBSTANCES. |
| CA2269679A1 (en) * | 1996-12-20 | 1998-07-02 | Warner-Lambert Company | Antitussive drugs delivered by partially coated ion exchange resins |
| UA73092C2 (en) * | 1998-07-17 | 2005-06-15 | Брістол-Майерс Сквібб Компані | Tablets with enteric coating and method for their manufacture |
| KR20020016069A (en) * | 2000-08-24 | 2002-03-04 | 민경윤 | An oral composition of a macrolide antibiotic and a process for preparing same |
| MXPA06002300A (en) | 2003-09-03 | 2006-05-19 | Mallinckrodt Inc | Granular sustained release preparation and production thereof. |
| CN100411629C (en) * | 2006-08-28 | 2008-08-20 | 浙江大学 | Slow-released type iron-complement agent, prepn. method and use thereof |
| CN100415297C (en) * | 2006-08-28 | 2008-09-03 | 浙江大学 | Zinc supplements based on cation exchange resin and its preparation method and use |
| EP2500016A1 (en) | 2011-03-18 | 2012-09-19 | Laboratorios Del. Dr. Esteve, S.A. | Doxylamine resinate complex |
| WO2015076821A1 (en) * | 2013-11-22 | 2015-05-28 | Tris Pharma, Inc. | Novel clonidine formulation |
| US11918689B1 (en) | 2020-07-28 | 2024-03-05 | Tris Pharma Inc | Liquid clonidine extended release composition |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4221778A (en) * | 1979-01-08 | 1980-09-09 | Pennwalt Corporation | Prolonged release pharmaceutical preparations |
| CA1236023A (en) * | 1984-07-18 | 1988-05-03 | Yegnaswami Raghunathan | Controlled release pharmaceutical preparations |
| US4894239A (en) * | 1987-06-02 | 1990-01-16 | Takeda Chemical Industries, Ltd. | Sustained-release preparation and production thereof |
| IL90245A (en) * | 1988-05-11 | 1994-04-12 | Glaxo Group Ltd | Resin adsorbate comprising ranitidine together with a synthetic cation exchange resin, its preparation and pharmaceutical compositions containing it |
| FR2634377B1 (en) * | 1988-06-30 | 1991-09-27 | Cortial | NOVEL EXTENDED RELEASE PHARMACEUTICAL FORM BASED ON AN ACTIVE RESIN-PRINCIPLE COMPLEX |
| US4996047A (en) * | 1988-11-02 | 1991-02-26 | Richardson-Vicks, Inc. | Sustained release drug-resin complexes |
-
1991
- 1991-12-16 CA CA002098200A patent/CA2098200A1/en not_active Abandoned
- 1991-12-16 WO PCT/US1991/009463 patent/WO1992011038A1/en not_active Application Discontinuation
- 1991-12-16 BR BR919107173A patent/BR9107173A/en not_active Application Discontinuation
- 1991-12-16 JP JP4503722A patent/JPH06504059A/en active Pending
- 1991-12-16 AU AU91687/91A patent/AU663695B2/en not_active Ceased
- 1991-12-16 HU HU9301819A patent/HUT74642A/en unknown
- 1991-12-16 SK SK594-93A patent/SK59493A3/en unknown
- 1991-12-16 CZ CS931197A patent/CZ119793A3/en unknown
- 1991-12-16 EP EP92903625A patent/EP0563294A1/en not_active Withdrawn
- 1991-12-20 NZ NZ241097A patent/NZ241097A/en unknown
- 1991-12-20 PT PT99912A patent/PT99912A/en not_active Application Discontinuation
- 1991-12-20 IE IE451391A patent/IE914513A1/en not_active Application Discontinuation
- 1991-12-20 MX MX9102753A patent/MX9102753A/en unknown
- 1991-12-20 MY MYPI91002365A patent/MY107811A/en unknown
- 1991-12-21 CN CN91109058A patent/CN1063221A/en active Pending
-
1993
- 1993-06-16 NO NO93932212A patent/NO932212L/en unknown
- 1993-06-18 FI FI932842A patent/FI932842A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU9168791A (en) | 1992-07-22 |
| AU663695B2 (en) | 1995-10-19 |
| BR9107173A (en) | 1993-11-16 |
| NO932212L (en) | 1993-08-20 |
| HUT74642A (en) | 1997-01-28 |
| JPH06504059A (en) | 1994-05-12 |
| MX9102753A (en) | 1992-06-30 |
| HU9301819D0 (en) | 1993-09-28 |
| NO932212D0 (en) | 1993-06-16 |
| EP0563294A1 (en) | 1993-10-06 |
| FI932842A (en) | 1993-06-18 |
| PT99912A (en) | 1993-01-29 |
| SK59493A3 (en) | 1993-11-10 |
| WO1992011038A1 (en) | 1992-07-09 |
| NZ241097A (en) | 1994-11-25 |
| FI932842A0 (en) | 1993-06-18 |
| CN1063221A (en) | 1992-08-05 |
| IE914513A1 (en) | 1992-07-01 |
| CZ119793A3 (en) | 1994-01-19 |
| MY107811A (en) | 1996-06-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |